CN111333614A - Quinolinone compounds and use thereof - Google Patents
Quinolinone compounds and use thereof Download PDFInfo
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- CN111333614A CN111333614A CN202010291824.4A CN202010291824A CN111333614A CN 111333614 A CN111333614 A CN 111333614A CN 202010291824 A CN202010291824 A CN 202010291824A CN 111333614 A CN111333614 A CN 111333614A
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- thiohydantoin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The application discloses quinolinone compounds containing rhodanine and similar fragments thereof and pharmaceutically acceptable salts thereof, which are shown in a general formula I in the technical field of organic chemistry. Wherein, the substituent R1、X、R2Have the meanings given in the description. The invention also relates to the application of the compound of the general formula I and the pharmaceutically acceptable salt thereof in the preparation of medicines for treating diseases caused by abnormal expression of IDO, in particular to the application in the preparation of medicines for treating and/or preventing cancers.
Description
Technical Field
The invention relates to the technical field of organic chemistry, and relates to quinolinone compounds and application thereof, in particular to quinolinone skeleton compounds containing rhodanine and similar fragments thereof, pharmaceutically acceptable salts thereof, preparation methods thereof and pharmaceutical compositions containing the compounds; also relates to the application of the compounds and the compositions in the preparation of drugs for treating and/or preventing tumors or cancers and the application of the drugs for treating diseases caused by abnormal high expression of IDO.
Background
Cancer (cancer) refers to malignant tumor originated from epithelial tissue, accounts for 1/4 of all causes of death in China, has the first mortality rate, and is one of diseases seriously affecting the health of residents. The incidence of cancer has been on the rise worldwide over the last decade, with cancer incidence in china approaching and slightly above the average world level. For the treatment of cancer, different targeted therapeutic techniques can be used in addition to conventional surgery, radiotherapy, chemotherapy and biological therapy. Molecular targeted therapy, also known as "biological missiles", is a highly selective, low-toxicity and long-term applicable method for tumor molecular level, and is one of the popular approaches of specific anti-tumor research at present.
Normal body can specifically eliminate abnormal cancer cells through immune monitoring mechanism, and inhibit tumor generation and metastasis. Cells involved in immune monitoring include T cells, NK cells, B cells, and the like. Based on an immune escape mechanism, the immune microenvironment can be improved by regulating inhibitory molecules, and the research idea becomes a new strategy for treating cancer cells. Indoleamine- (2,3) -dioxygenase, an immunoregulatory enzyme, has immunosuppressive functions and can significantly inhibit the functional exertion and proliferation of regulatory T cells, thereby protecting cancer cells from the surveillance of the autoimmune system and producing immune tolerance, and therefore, inhibiting the expression of IDO can effectively promote the curative effects of immunization and chemotherapy. At present, a plurality of clinical studies prove that the IDO inhibitor has good curative effect in cooperation with the PD-1/PD-L1 inhibitor, although the Epacadostat and Keytruda combined study is terminated by the declaration of the Incyte and the Elsaton shadong in 2018, the Epacadostat clinical project is up to 47, and malignant melanoma ECHO-301 may not be the best test object of the immunotherapy, so that the IDO combined drug still has research value.
IDO is overexpressed in tumor cells. IDO-mediated tumor immune escape is mainly through three aspects: depletion of tryptophan, toxic metabolites of tryptophan and induction of proliferation and differentiation of regulatory T lymphocytes. Tryptophan metabolism rate-limiting enzymes include IDO1, IDO2, and IDO isozyme Tryptophan Dioxygenase (TDO). IDO is a heme-containing monomeric protease, IDO1 has homology at the amino acid level with IDO2, and the protein spatial structure is similar. TDO is heme-containing polymer dioxygenase, and the structure of the dioxygenase is greatly different from that of IDO. IDO1 has a broader distribution range than IDO2 and TDO, and is the major rate-limiting enzyme, and therefore IDO1 inhibitors are the major research direction for tumor immunotherapy. The IDO1 is used as oxidoreductase containing heme, and contains 403 amino acids, the substrate/product in and out is controlled by a flexible ring formed by 360-380 residues on a large structural domain, heme is located in the two domains, and IDO1 is inactivated when ferrous ions are oxidized. Over-expression of IDO1 will inhibit proliferation of T lymphocytes, promote apoptosis thereof, and promote transformation of macrophages into alternatively activated macrophages (M2). M2 can promote tumor angiogenesis and inhibit body's autoimmune function. Second, the normal function of NK cells will be inhibited, aiding tumor escape. Therefore, inhibition of IDO1 activity would be effective in restoring the body's immune response to cancer cells.
Indoleamine-2, 3-dioxygenase 1(IDO1), as a natural immunomodulatory enzyme in the body, can form an immunosuppressive state within the microenvironment. At present, IDO inhibitors have no medicines on the market, and provide abundant possibility for compound design due to large spatial structure change. It is believed that in the near future, treatment of IDO will be an important research direction for immunotherapy, especially in combination with PD-1 inhibitors, with broad application prospects.
Disclosure of Invention
The inventor designs and synthesizes 18 quinoline ketone derivatives containing rhodanine and analogues thereof which are not reported in documents by taking an IDO inhibitor PF-0694003 as a lead compound, and finds that the 18 compounds have the potential effect of remarkably inhibiting the IDO activity, and the result shows that the compounds have the potential effect of treating cancers.
The invention mainly aims to provide quinolinone compounds containing rhodanine and similar fragments thereof and pharmaceutically acceptable salts thereof, which are shown in the general formula I,
wherein the content of the first and second substances,
R1is C1-C6Alkyl or C3-C5A cycloalkyl group;
x is N or S;
R2is hydrogen, C1-C6Alkyl or
n is an integer between 1 and 6;
ar is C6-C10Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is 1-3 identical or different R3A substituent group;
R3is 1-4 selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, C optionally substituted by hydroxy, amino or halo1-C6Alkyl or C1-C6Alkoxy radical, by 1-2C1-C6Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkanoyl, carbamoyl, substituted by 1-2C1-C6Alkyl-substituted carbamoyl, C1-C3Alkylenedioxy or allyl.
The invention preferably relates to compounds of the general formula I and pharmaceutically acceptable salts thereof, wherein R1Is hydrogen or methyl;
R2is hydrogen, methyl or
n is an integer between 1 and 3.
Ar is C6-C10Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is 1-3 identical or different R3A substituent group;
R3is 1-4 selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl, aryl, heteroaryl, and heteroaryl,C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, C optionally substituted by hydroxy, amino or halo1-C6Alkyl or C1-C6Alkoxy radical, by 1-2C1-C6Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkanoyl, carbamoyl, substituted by 1-2C1-C6Alkyl-substituted carbamoyl, C1-C3Alkylenedioxy or allyl.
The invention preferably relates to compounds of the general formula I and pharmaceutically acceptable salts thereof, wherein R1Is hydrogen or methyl;
R2is hydrogen, methyl or
n is an integer between 1 and 3;
ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl, thienyl, pyrrolyl or pyrimidinyl, and Ar is 1-3 identical or different R3A substituent group;
R3is 1-4 selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, C optionally substituted by hydroxy, amino or halo1-C6Alkyl or C1-C6Alkoxy radical, by 1-2C1-C6Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl radical, C1-C6Alkoxy radicalBase, C1-C6Alkyl radical, C1-C6Alkanoyl, carbamoyl, substituted by 1-2C1-C6Alkyl-substituted carbamoyl, C1-C3Alkylenedioxy or allyl.
The invention preferably relates to compounds of the general formula I and pharmaceutically acceptable salts thereof, wherein R1Is hydrogen or methyl;
R2is hydrogen, methyl,
n is an integer between 1 and 3;
ar is phenyl, furyl or thienyl, and Ar is 1-3 identical or different R3A substituent group;
and R is3Is hydrogen, halogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, methoxy, methylthio, tert-butyl or methylsulfonyl.
The compounds of the general formula I according to the invention and their pharmaceutically acceptable salts are particularly preferably the following compounds, but these are not intended to limit the invention in any way:
3- ((1- (m-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
3- ((1- (3-chloro-4-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
3- ((1- (p-methoxybenzyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
3- ((1- (p-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
3- ((2-thiohydantoin-4-yl) methine) -4-quinolinone;
1-methyl-3- ((1- (m-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
1-methyl-3- ((1- (p-methoxybenzyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
1-methyl-3- ((1- (p-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
1-methyl-3- ((1-methyl-2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
(Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-methylbenzene-2-thioxo-4-thiazolidinone;
(Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-thienylethyl-2-thioxo-4-thiazolidinone;
(Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-fluorophenyl-2-thioxo-4-thiazolidinone;
(Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-methyl-2-thioxo-4-thiazolidinone;
(Z)5- ((1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methine) -2-thioxo-4-thiazolidinone.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
The term "halo" as used herein, unless otherwise indicated, refers to fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "alkenyl" means straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl groups; "aryl" refers to an organic group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as phenyl, naphthyl; 5-to 10-membered heteroaryl includes those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, the ring system is aromatic, and contains a total of 5 to 10 atoms, and examples thereof include imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, (1,2,3) -and (1,2,4) -triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl, benzothiazolyl, indolyl, quinolyl and the like; 5-10 membered heterocyclic groups include those containing one or more heteroatoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic but is non-aromatic, the ring system containing a total of 5 to 10 atoms and may optionally include 1 or 2 carbon-carbon double or triple bonds, and there may be mentioned, for example, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, thiazolinyl and the like. The invention can contain the quinolinone compounds containing rhodanine and similar fragments thereof in the formula I, and pharmaceutically acceptable salts and solvates thereof as active ingredients, and the quinolinone compounds and the pharmaceutically acceptable salts and solvates thereof are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The clinical dosage of the quinolinone compounds containing rhodanine and analogous fragments thereof of formula I above for a patient may be based on: the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolism and excretion rates and the age, sex, disease stage of the patient are suitably adjusted, although the daily dose for an adult should generally be 10-500mg, preferably 50-300 mg. Thus, when the pharmaceutical composition of the present invention is formulated into a unit dosage form, each unit preparation should contain 10 to 500mg of the pyrimido-azaheterocyclic compound of the above formula I, preferably 50 to 300mg, in view of the above effective dose. These formulations may be administered in several doses (preferably one to six times) at regular intervals, according to the guidance of a doctor or pharmacist.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The compound of the present invention is found to have certain antitumor activity by an in vitro enzyme activity test method, so the compound of the present invention can be used for preparing medicines for treating and/or preventing various cancers, such as breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissues, head and neck, thyroid, esophagus, leukemia, neuroblastoma, etc.
In addition, the compound can be used for preparing medicaments for treating and/or preventing diseases caused by abnormally high expression of IDO.
The active compound or the medicinal salt and the solvate thereof can be used alone as a unique antitumor medicament or can be used together with the antitumor medicaments (such as platinum medicament cisplatin, camptothecin medicament irinotecan, vinca base medicament novinova, deoxycytidine medicament gemcitabine, etoposide, taxol and the like) on the market at present. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The following synthetic schemes describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the methods described in these synthetic schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these synthetic routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these synthetic routes are as defined below or in the claims.
According to the general formula I derivative, o-aminoacetophenone is used as a starting material, a Vilsmeier-Haack reaction is carried out, hydrolysis is carried out to obtain 4-quinolinone-3-aldehyde group (an intermediate A3), and methylation is carried out to obtain N-methyl-4-quinolinone-3-aldehyde group (an intermediate A4). Different substituted amines are taken as starting materials, 3-substituted hydantoin or 3-substituted rhodanine is obtained through addition and cyclization, and the target compounds T-1 to T-14 are obtained through the reaction of the intermediates A3 and A4 with 3-substituted-2-thiohydantoin or 3-substituted rhodanine through Knoevenagel. As shown in the synthetic route:
Detailed Description
The nuclear magnetic resonance hydrogen spectrum of the compound is measured by a BrukeraRX-400 type nuclear magnetic resonance analyzer (DMSO-d6) as a solvent, and TMS as an internal standard; the mass spectrum is measured by Agilent 1100 LC/MS; the melting point is measured by a WRS-1A digital melting point instrument, and the temperature is not corrected; the reagents used in the experiment are all analytically pure or chemically pure.
EXAMPLE 1 preparation of intermediate 4-chloro-3-quinolinecarboxaldehyde (A2)
At 0 ℃, 22mL (241.6mmol) of phosphorus oxychloride is slowly added into 50mL of N, N-dimethylformamide, and after the reaction is carried out for 15min at room temperature, 5mL (40.3mmol) of 2-aminoacetophenone is slowly dropped, and after the addition, the temperature is raised to 70 ℃ for reaction for 3 h. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was slowly poured into ice water (300mL), the pH of the solution was neutralized to 7 with sodium acetate, the existing solid was precipitated, filtered, the filter cake was washed with a small amount of water, and the filter cake was dried to obtain 4.5g of a yellow solid with a yield of 70%.
EXAMPLE 2 preparation of intermediate 4-hydroxyquinoline-3-carbaldehyde (A3)
A50 mL three-necked flask was charged with 20mL of 90% ethanol, 0.2mL of concentrated hydrochloric acid, and 2.7g (48.0mmol) of iron powder, and heated to 60 ℃ to activate for 10 min. 2.0g (8.0mmol) of A-3 was added and the temperature was raised to reflux. After 1.5h, after the reaction is finished, 0.01g of activated carbon is added, the mixture is refluxed for 0.5h, filtered by diatomite, naturally cooled to room temperature, concentrated to 1/3 of the original product, the filtrate is poured into 10mL of 10% NaOH aqueous solution, crystallized for 1h at room temperature, and the pH value is measured again to be 11. Suction filtration and drying are carried out to obtain 1.6g of gray solid with the yield of 90.5 percent.
EXAMPLE 3 preparation of N-methyl-4-hydroxyquinoline-3-carbaldehyde (A4)
2g (11.6mmol) of A3, 3.2g (23.2mmol) of potassium carbonate are added to 20mL of N, N-dimethylformamide, stirred at room temperature for 30min, then 0.47g (17.4mmol) of potassium iodide is slowly added dropwise, the reaction is carried out at room temperature for 1h, after completion of the reaction, 40mL of water is added to the reaction solution and extracted with 3 × 50mL of ethyl acetate, the organic phases are combined, the organic solvent is evaporated off, 1.2g of a dry white solid is obtained, the yield is 56%.
ESI-MS m/z:210.2[M+Na]+,1H NMR(400MHz,DMSO-d6)δ(ppm):12.68(s,1H,NH),10.20(s,1H,CHO),8.49(s,J＝5.9,1H,-NH-CH＝),8.22(d,J＝9.0,1H,Ar-H),7.77(t,1H,J＝8.0,Ar-H),7.67(d,J＝8.0,1H,Ar-H),7.48(t,J＝8.0,1H,Ar-H).
EXAMPLE 4 preparation of intermediate substituted Thiocyanates (B1) (general procedure I for the preparation of intermediate 3-substituted-2-Thiohydantoin of the B2 series)
Dissolving 5mmol of substituted amine in 40mL of ethyl acetate water (2:1), sequentially adding 50mmol of carbon disulfide and 10mmol of triethylamine, reacting at room temperature for 1h, adding 0.25mmol of copper sulfate pentahydrate into the reaction solution, reacting at room temperature for 1h, filtering with diatomite, washing a small amount of filter cake with water, extracting the filtrate with 3 × 20mL of ethyl acetate, combining organic phases, evaporating to remove the organic solvent, and carrying out column chromatography to obtain substituted thioisocyanate.
EXAMPLE 5 preparation of intermediate 3-substituted-2-thiohydantoin (B2)
Dissolving 5mmol substituted thioisocyanate in 40mL N, N-dimethyl formamide water (4:1), sequentially adding 5mmol glycine and 5.5mmol triethylamine, reacting at room temperature for 1h, cooling to room temperature, extracting the reaction liquid with 3 × 20mL ethyl acetate, combining organic phases, evaporating to remove the solvent, and drying to obtain substituted thiohydantoin.
Example 63 preparation of m-fluorophenyl-2-thiohydantoin
M-fluoroaniline was used as a starting material, and 0.18g of a yellow solid was obtained in a total yield of 24.1% according to preparative general method I.
Example 73 preparation of- (3-chloro-4-fluorophenyl) -2-thiohydantoin
3-chloro-4-fluorophenyl aniline as a raw material was prepared into 0.21g of a yellow solid according to preparation method I, and the total yield was 22.3%.
Example 83 preparation of- (4-methoxybenzyl) -2-thiohydantoin
By using 4-methoxybenzylamine as a raw material, 0.23g of yellow solid is prepared according to the general preparation method I, and the total yield is 25.5%.
Example 93 preparation of p-fluorophenyl-2-thiohydantoin
P-fluorophenyl aniline as a raw material is prepared into 0.19g of yellow solid according to the general preparation method I, and the total yield is 25.3%.
EXAMPLE 103 preparation of (3, 4-methylenedioxyphenethylamino) -2-thiocarbaine
3, 4-methylenedioxyphenethylamine is used as a raw material, and 0.26g of yellow solid is prepared according to the general preparation method I, and the total yield is 26.8%.
EXAMPLE 11 preparation of N-methyl-2-thiohydantoin
With methylamine water solution as raw material, 0.36g of yellow solid is prepared according to the general preparation method I, and the total yield is 66.1%.
EXAMPLE 12B 3 preparation of 3-substituted rhodanines series intermediate general method II
5mmol of substituted thioisocyanate was dissolved in 40mL of dichloromethane, and 5mmol of ethyl thioglycolate and 5.5mmol of triethylamine were sequentially added and reacted at room temperature for 2 hours. And (5) finishing the reaction. After the solvent is removed by evaporation, 10mL of methanol is added and stirred for 10min, and then the 3-substituted rhodanine is obtained after suction filtration and drying.
EXAMPLE 13 preparation of Rhodanine-3-acetic acid
Dissolving 2g (26.6mmol) of glycine in 40mL of water, sequentially adding 4g (100mmol) of sodium hydroxide and 2g (26.3mmol) of carbon disulfide, reacting at room temperature for 5h, adding 2.52g (21.6mmol) of sodium chloroacetate, reacting at room temperature for 3h, adjusting the pH of the reaction solution to 4 by using 6N hydrochloric acid, heating to 100 ℃, reacting for 4h, cooling to room temperature, extracting the reaction solution by using 3 × 50mL of ethyl acetate, combining organic phases, evaporating the solvent, and drying to obtain 1.8g of light yellow solid, wherein the yield is 36.1%.
EXAMPLE 143 preparation of p-Methylphenylrhodanine
Using p-toluidine as a starting material, 0.17g of a yellow solid was obtained in 23.3% overall yield according to preparative general method II.
EXAMPLE 153 preparation of (2-thienylethylamino) rhodanine
2-thiophene ethylamine was used as a raw material, and a yellow solid (0.20 g) was obtained according to general preparation II, with a total yield of 24.4%.
EXAMPLE 163 preparation of p-fluorophenyl rhodanine
Para-fluoroaniline was used as a starting material, and 0.19g of a yellow solid was obtained in a total yield of 24.4% according to preparative general method II.
Example 173 preparation of (3, 4-methylenedioxyphenethylamine) rhodanine
Using 3, 4-methylenedioxyphenethylamine as a raw material, 0.36g of yellow solid was prepared according to preparation method II, with a total yield of 27.6%.
Example 183 preparation of- ((1- (m-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-1)
Starting from intermediate a3, 3-M-fluorophenyl-2-thiohydantoin, 0.12g of a yellow solid was prepared according to general preparation iii in a total yield of 57.6% ((Z: E ═ 3:1) M.p. >300 ℃; ESI-MS M/Z:364.1[ M-H ] -,1H-NMR (400MHz, DMSO-d6) δ (ppm) 13.15(s,0.67 × 2H,2 × NH),12.49(s,0.21 × 2H,2 × NH),9.67(s,0.23H, -NH-CH ═ 8.73(s,0.76H, -NH-CH ═ H)), 8.25(d, J ═ 7.9, (0.75+0.25) × 1H), Ar-H),7.76(t, J ═ 7.7, (0.76+0.24) H), 1H-3H, 3- × 1, Ar-H3H, Ar-H3, 3H 3969, Ar-H, Ar-3H, r-3H, 2H, 9H, and Ar-H.
Example 193 preparation of- ((1- (3-chloro-4-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-2)
Starting from intermediate a3, 3- (3-chloro-4-fluorophenyl) -2-thiohydantoin, 0.14g of a yellow solid was obtained according to preparative general method iii in 60.8% yield (Z: E ═ 6:1) M.p ℃ >300 ℃; ESI-MS M/Z:398.3[ M-H ] -,1H NMR (400MHz, DMSO-d6) δ (ppm):13.10(brs,2H, NH),9.67(s,0.13H, -NH-CH ═ 8.74(s,0.83H, -NH-CH ═ 8.25(d, J ═ 7.7, (0.8+0.13) × 1H, Ar-H),7.83-7.33(M,6H, Ar-H),6.69(s,1H, -CH ═ 6).
Example 203 preparation of- ((1- (p-methoxybenzyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-3)
Starting from intermediate A3, 3- (4-methoxybenzyl) -2-thiohydantoin, 0.1g of a yellow solid was prepared according to preparative general method III in 45% yield. (Z: E ═ 5.5: 1). M.p. >300 ℃; ESI-MS M/z 390.4[ M-H ] -,1H NMR (400MHz, DMSO-d6) δ (ppm):13.12(s,2H, NH),9.74(s,0.15H, -NH-CH ═ 8.67(s,0.82H, -NH-CH ═ 8.28(d, J ═ 7.6,0.81H, Ar-H),8.17(d, J ═ 7.3,0.15H, Ar-H),7.80-7.62(M,2H, Ar-H),7.48(t, J ═ 7.4,0.87H, Ar-H),7.41(t, J ═ 7.0,0.19H, Ar-H),7.32(d, J ═ 7.9,2H, ph-H),6.89(d, 8.8, J ═ 7.3, H ═ 7, 3, CH-H, CH-3, CH-H ═ 3, CH-H2, CH3, CH-H, 3693).
Example 213 preparation of- ((1- (p-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-4)
0.15g of a yellow solid was obtained in 42.9% yield according to preparation III starting from intermediate A3, 3-p-fluorophenyl-2-thiohydantoin. (Z: E ═ 9: 1). M.p. >300 ℃; ESI-MS M/z 364.4[ M-H ] -,1H NMR (400MHz, DMSO-d6) δ (ppm):13.39(s,2H, NH),13.18(s,1H, NH), 9.68(s,0.11H, -NH-CH ═ 8.72(s,0.92H, -NH-CH ═ 8.31(d, J ═ 8.0,1H,0.92H, Ar-H),8.19(d, J ═ 8.3,0.13H, Ar-H),7.83-7.63(M,2H, Ar-H),7.53-7.33(M,5H, Ar-H),6.69(s,1H, -CH) —, respectively.
Example 223 preparation of- ((2-Thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-5)
0.11g of a yellow solid was obtained in 73.3% yield according to preparation III starting from intermediate A3, 2-thiohydantoin. (Z: E ═ 4.8: 1). M.p. >300 ℃; ESI-MS M/z 270.2[ M-H ] -,1H NMR (400MHz, DMSO-d6) δ (ppm) 12.94(s,1H, NH),12.56(s,0.72H, NH),12.39(s,0.23H, NH),12.16(s,0.74H, NH),11.99(s,0.16H, NH),9.72(s,0.16H, -NH-CH), 8.63(s,0.77H, -NH-CH), 8.28(d, J-7.6, 0.92H, Ar-H),8.18(d, J-7.9, 0.19H, Ar-H),7.77(t, J-7.6, 0.91H, Ar-H),7.71(t, J-7.1, 0.15H, 7.6, Ar-H),7.5 (t, J-H, Ar-H), 8.8.8, 8.6, Ar-H, 8.8.6, J-H, Ar-H, 7.5 (d, J-H, Ar-H, 8.8, 8, J-H, 8.8, J-H, 8.6, 8.5, 8.8.8.6, 8.6, 7.6, 7, 8, j ═ 7.5,0.19H, Ar-H),7.19(s,0.18H, -CH ═),6.47(s,0.79H, -CH ═ CH).
Example preparation of 231-methyl-3- ((1- (m-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-6)
Starting from intermediate a4, 3-M-fluorophenyl-2-thiohydantoin, 0.12g of a yellow solid was prepared according to general preparation iii in 60% yield (Z: E ═ 2.3: 1. > M.p. >300 ℃; ESI-MS M/Z:378.2[ M-H ] -,1H NMR (400MHz, DMSO-d6) δ (ppm):13.05(s,0.67h.nh),12.57(s,0.27h.nh),9.75(s,0.31H, -NCH 3-CH) ═ 8.80(s,0.69H, -387h 2-CH ═ 8.38(d, J ═ 7.2,0.65H, Ar-H),8.27(d, J ═ 7.1,0.25H, Ar-H),7.92-7.73(M,2H, 7.62H, 7.47H, 3-H, 18H, 3.3H, 3H, 18H, 3H 3, 39H, 3H 3, 26, 3H 3, 26 ═ 26, 3H, 3H.
Example 241 preparation of methyl-3- ((1- (p-methoxybenzyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-7)
0.1g of a yellow solid was prepared in 45.5% yield according to general preparation III starting from intermediate A4, 3- (4-methoxybenzyl) -2-thiohydantoin. (Z: E ═ 1.2: 1). M.p. >300 ℃; ESI-MS M/z 404.3[ M-H ] -,1H NMR (400MHz, DMSO-d6) δ (ppm) 12.84(s,0.58H, NH),12.44(s,0.43H, NH),9.80(s,0.43H, -NH-CH), 8.82(s,0.53H, -NH-CH), 8.37(d, J-7.2, 0.53H, Ar-H),8.26(d, J-7.8, 0.42H, Ar-H),7.85(M,2H, Ar-H),7.57(t, J-7.3, 0.5H, Ar-H),7.50(t, J-7.2, 0.49H, Ar-H),7.31(d, J-9.2, ph 2H, ph 6.89H, CH-6H, CH-4, CH-H, CH-4, CH-H, 7.4, H, 7.7.7.7.7.7.6, 1.66H, -OCH3),3.92(s,1.33H, -OCH3),3.72(s,3H, CH3).
Example 251 preparation of methyl-3- ((1- (p-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-8)
0.14g of a yellow solid was obtained in 70% yield according to preparation III starting from intermediate A4, 3-p-fluorophenyl-2-thiohydantoin. (Z: E ═ 3: 1). M.p. >300 ℃; ESI-MS M/z 378,4[ M-H ] -,1H NMR (400MHz, DMSO-d6) δ (ppm):9.78(s,0.25H, -NH-CH ═ 9.26(s,0.74H, -NH-CH ═),8.33(d, J ═ 8.7,0.74H, Ar-H),8.27(d, J ═ 8.0,0.25H, Ar-H),7.80(M,2H, Ar-H),7.39(M,5H, Ar-H),6.61(s,1H, -CH ═),3.96(s,2.22H, CH3),3.89(s,0.75H, CH3).
Example 261 preparation of methyl-3- ((1-methyl-2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone (T-9)
0.11g of a yellow solid was obtained in 68.7% yield according to preparation III starting from intermediate A4, N-methyl-2-thiohydantoin. (Z: E ═ 1: 2.3). M.p. >300 ℃; ESI-MS M/z 298.3[ M-H ] -,300.4[ M + H ] +,1HNMR (400MHz, DMSO-d6) delta (ppm):8.78(s,0.72H, -NH-CH ═ 8.51(s,0.72H, -CH ═),7.92(s,0.34H, -NH-CH ═ 7.92(s,0.35H, -CH ═ 7.34, 7.22(M,2.58H, Ar-H),6.89(brs,0.75H, Ar-H),6.89(brs,0.72H, Ar-H),3.73(s,3H, CH3),3.02(s,3H, CH3).
Example 27 preparation of (Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-methylbenzene-2-thioxo-4-thiazolidinone (T-10)
Starting from intermediate A3, 3-p-methylphenylrhodanine, 0.13g of a yellow solid was obtained according to general preparation iii in 65% yield M.p (> 300 ℃; ESI-MS M/z 377.3[ M-H ] -,1H-NMR (400MHz, DMSO-d6) δ (ppm) 12.63(brs,1H, NH),8.63(s,1H, -NH-CH ═ 8.20(d, J ═ 8.0,1H, Ar-H),7.75(t, J ═ 7.6,1H, Ar-H),7.68(s,1H, -CH ═ 7.62(d, J ═ 8.2,1H, Ar-H),7.46(t, J ═ 7.5,1H, Ar-H),7.34(d, J ═ 8.1, ph 2H, ph 7.17, ph 2, ph 8.17, ph 2, ph 3.32, ph 0, ph 3, ph 0, 15, 7.5, 7H-460, 7.7, 7H-7, 7H-460).
Example 28 preparation of (Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-thienylethyl-2-thioxo-4-thiazolidinone (T-11)
0.1g of yellow solid was prepared according to general preparation III from intermediate A3, 3- (2-thienylmethylamino) rhodanine in 45.4% yield. M.p. >300 ℃; ESI-MS M/z 397.4[ M-H ] -,421.4[ M + Na ] +.1H NMR (400MHz, DMSO-d6) δ (ppm):12.86(s,1H, NH),8.62(s,1H, -NH-CH ═ 8.1,0.9,1H, Ar-H),7.78-7.72(M,1H, Ar-H),7.64(s,1H, -CH ═ 7.61(d, J ═ 8.2,1H, Ar-H),7.46(t, J ═ 7.5,1H, Ar-ddh), 7.37 (t, J ═ 5.1,1.0,1H, Ar-H),6.95(t, J ═ 3.5,1H, Ar-91.2, J ═ 8, J ═ 5, J ═ 7.3, H, J ═ 7.3, J ═ 7, J ═ 7.8, H, J ═ 7, H, 8, CH ═ 7, 8, 7, 3.19(t, J ═ 7.5,1.9H, -CH2-),3.09(d, J ═ 7.6,0.1H, -CH2-).
Example 29 preparation of (Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-fluorophenyl-2-thioxo-4-thiazolidinone (T-12)
Intermediate A3, 3-p-fluorophenyl rhodanine was used as a starting material to prepare 0.1g of a yellow solid in 50% yield according to preparation III. M.p. >300 ℃; ESI-MS M/z 383.4[ M + H ] +,1H NMR (400MHz, DMSO-d6 δ (ppm):12.76(brs,1H, NH),8.65(s,0.95H, -NH-CH), 8.48(s,0.05H, -NH-CH), 8.20(d, J-7.4, 1H, Ar-H),7.75(t, J-7.6, 1H, Ar-H),7.69(s,1H, -CH), 7.62(d, J-8.2, 1H, Ar-H),7.50-7.35(M,5H, Ar-H).
Example 30 preparation of (Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-methyl-2-thioxo-4-thiazolidinone (T-13)
Intermediate A3, rhodanine, was used as the starting material to make 0.07g of a yellow solid in 43.8% yield according to preparative general procedure III. M.p. >300 ℃; ESI-MS M/z 287.3[ M-H ] -, H NMR (400MHz, DMSO-d6) δ (ppm):12.96(brs,2H,2NH),8.51(s,1H, -NH-CH) ═ 8.0 (d, J ═ 8.0,1H, Ar-H),7.75(t, J ═ 8.2,1H, Ar-H),7.61(d, J ═ 8.2,1H, Ar-H),7.53(s,1H, -CH) ═ 7.45(t, J ═ 7.5,1H, Ar-H).
Example 31 preparation of (Z)5- ((1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methine) -2-thioxo-4-thiazolidinone (T-14)
Intermediate A4, rhodanine, was used as the starting material to make 0.07g of a yellow solid in 42.4% yield according to general procedure III. M.p. >300 ℃; ESI-MS M/z 301.1[ M-H ] -, H NMR (400MHz, DMSO-d6) δ (ppm):13.34(s,1H, NH),8.58(s,1H, -NH-CH ═ 8.25(d, J ═ 7.8,1H, Ar-H),7.84(t, J ═ 7.3,1H, Ar-H),7.77(d, J ═ 8.5,1H, Ar-H),7.53(t, J ═ 7.4,1H, Ar-H),7.41(s,1H, -CH ═),3.93(s,3H, CH3).
The data relating to the target compounds are shown in Table 1
TABLE 1
The in vitro antitumor cell activity of the product of the invention is verified as follows:
compound activity assay in vitro enzymatic activity assays were performed using the kinase hID kinase available from Mediclon. The specific method comprises the following steps: 20nM hIDO was prepared, the compound was concentrated in 100. mu.l buffer, the hIDO and buffer were pre-warmed to 37 ℃ and incubated at 37 ℃ for 30 min. After that, the cells were quenched with 50. mu.l of 30% trichloroacetic acid and incubated at 52 ℃ for 30 min. Centrifuging at room temperature, mixing 100 μ l of supernatant with 100 μ l of Ehrlich's reagent, reading at 480nm, and calculating inhibition rate according to the value, activity data shown in Table 2
TABLE 2
From the above experimental results, it is clear that the compound of formula I to be protected by the present invention has a certain in vitro anti-tumor activity.
It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the structure of the invention, and it is intended to cover all modifications and equivalents included within the spirit and scope of the invention.
Claims (8)
1. The quinoline ketone compound containing rhodanine and similar fragments thereof and pharmaceutically acceptable salts thereof are characterized in that the general formula I is shown as follows,
wherein the content of the first and second substances,
R1is C1-C6Alkyl or C3-C5A cycloalkyl group;
x is N or S;
R2is hydrogen, C1-C6Alkyl or
n is an integer between 1 and 6;
ar is C6-C10Aryl or 5-10 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O or S, and Ar is 1-3 identical or different R3A substituent group;
R3is 1-4 selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy, C optionally substituted by hydroxy, amino or halo1-C6Alkyl or C1-C6Alkoxy radical, by 1-2C1-C6Alkyl-substituted amino, C1-C6Alkylamido, free, salified, esterified and amidated carboxyl, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkanoyl, carbamoyl, substituted by 1-2C1-C6Alkyl-substituted carbamoyl, C1-C3Alkylenedioxy or allyl.
2. The compound of formula I and pharmaceutically acceptable salts thereof as claimed in claim 1 wherein R is1Is hydrogen or methyl;
R2is hydrogen, methyl or
n is an integer between 1 and 3.
3. The compound of formula I according to claim 2 and pharmaceutically acceptable salts thereof, characterized in that Ar is phenyl, naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl, thienyl, pyrrolyl or pyrimidinyl and Ar is 1-3 identical or different R3And (4) a substituent.
4. The compound of formula I and pharmaceutically acceptable salts thereof as claimed in claim 3 characterized in that Ar is phenyl, furyl or thienyl and Ar is 1-3 identical or different R3A substituent group;
and R is3Is hydrogen, halogen, hydroxyl, nitro, cyano, trifluoromethyl, trifluoromethoxyMethoxy, methylthio, tert-butyl or methylsulfonyl.
5. The compounds of formula I and their pharmaceutically acceptable salts according to claim 4, characterized by comprising the following compounds:
3- ((1- (m-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
3- ((1- (3-chloro-4-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
3- ((1- (p-methoxybenzyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
3- ((1- (p-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
3- ((2-thiohydantoin-4-yl) methine) -4-quinolinone;
1-methyl-3- ((1- (m-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
1-methyl-3- ((1- (p-methoxybenzyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
1-methyl-3- ((1- (p-fluorophenyl) -2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
1-methyl-3- ((1-methyl-2-thiohydantoin-4-yl) methine) -4-hydroxyquinolinone;
(Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-methylbenzene-2-thioxo-4-thiazolidinone;
(Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-thienylethyl-2-thioxo-4-thiazolidinone;
(Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-fluorophenyl-2-thioxo-4-thiazolidinone;
(Z)5- ((4-oxo-1, 4-dihydroquinolin-3-yl) methine) -3-p-methyl-2-thioxo-4-thiazolidinone;
(Z)5- ((1-methyl-4-oxo-1, 4-dihydroquinolin-3-yl) methine) -2-thioxo-4-thiazolidinone.
6. A pharmaceutical composition comprising a compound of any one of claims 1 to 5 and a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable excipient.
7. The use of a compound according to any one of claims 1 to 5, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
8. The use of a compound according to any one of claims 1 to 5, and pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment and/or prevention of diseases caused by abnormal expression of IDO.
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| WO2004028535A1 (en) * | 2002-09-26 | 2004-04-08 | Pintex Pharmaceuticals, Inc. | Pin1-modulating compounds and methods of use thereof |
| WO2004093803A2 (en) * | 2003-04-16 | 2004-11-04 | Pintex Pharmaceuticals, Inc. | Photochemotherapeutic compounds for use in treatment of pin1-associated states |
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| WO2004028535A1 (en) * | 2002-09-26 | 2004-04-08 | Pintex Pharmaceuticals, Inc. | Pin1-modulating compounds and methods of use thereof |
| WO2004093803A2 (en) * | 2003-04-16 | 2004-11-04 | Pintex Pharmaceuticals, Inc. | Photochemotherapeutic compounds for use in treatment of pin1-associated states |
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Inventor after: Gong Guowei Inventor after: Xu Jingyu Inventor after: Xie Rui Inventor before: Gong Guowei |