CN108456165B - Sulfonylurea compound and preparation method and application thereof - Google Patents
Sulfonylurea compound and preparation method and application thereof Download PDFInfo
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- CN108456165B CN108456165B CN201810543898.5A CN201810543898A CN108456165B CN 108456165 B CN108456165 B CN 108456165B CN 201810543898 A CN201810543898 A CN 201810543898A CN 108456165 B CN108456165 B CN 108456165B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen 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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- 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
- C07D401/14—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 three or more hetero rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention discloses a sulfonylurea compound, a geometric isomer thereof, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof and a preparation method thereof. The sulfonylurea compound, and pharmaceutically acceptable salts, hydrates or solvates thereof are used as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepared into clinically acceptable dosage forms. The compound disclosed by the invention is applied to preparation of medicines for treating and/or preventing proliferative diseases, medicines for treating and/or preventing cancers and medicines for treating and/or preventing prostate cancer, lung cancer and breast cancer.
Description
Technical Field
The invention relates to a drug for treating tumor, in particular to a sulfonylurea compound and a preparation method and application thereof.
Background
Tumor generally refers to a substance produced by abnormal growth of local tissue cells of the body under the action of various tumorigenic factors. Tumors are generally classified as benign or malignant according to their growth characteristics and the extent of damage to the body. Cancer, broadly malignant tumors, seriously harms health, and the control of cancer has become a key point of global health strategy. According to the World Health Organization (WHO) '2014 world cancer report', the annual incidence of 20 years in the future is predicted to rise to 2200 ten thousand, the death cases rise to 1300 ten thousand, and most of new cases in asia are in China.
The PI3K-Akt-mTOR signaling pathway is widely distributed in body tissue cells, is a complex intracellular pathway regulating cell proliferation, apoptosis, cell cycle, metabolism and angiogenesis, and activation of the pathway results in accelerated growth of tumor cells, and is considered as one of the most attractive targets for development of anticancer agents, so that intensive research on the specific mechanism by which the pathway is activated is crucial for tumor treatment. In recent years, the research on PI3K-Akt-mTOR signaling pathway drugs is increasing.
A series of quinoline PI3K/mTOR pathway inhibitors developed by Novartis corporation are the latest type of structure, and also have significant antitumor effects, such as NVP-BEZ-235(Serra, V., Markman, B., Scaltrti, M., et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, preservation PI3K signaling and inhibiting the growth of cancer cells with activating PI3 Kmutients [ J]Cancer Research,2008,68(19):8023-]Radiation Oncology,2012,7(1):48.) showed good inhibitory effect on PI3K/mTOR and IC50All values are at the nanomolar level. Wherein NVP-BEZ235 has good anti-cell proliferation activity and activity for treating xenograft tumor, and IC for PI3K/mTOR50The values are 4-76/6 nM respectively, currently in phase II clinical studies. A series of PI3K/mTOR dual inhibitors of pyridine sulfonamides currently developed by Kurarian Stecke show significant antitumor activity, such as GSK2126458(Knight S D, Adams N D, Bu) in clinical stage Irgess J L,et al.Discovery of GSK2126458,a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin.[J]Acs Medicinal Chemistry Letters,2010,1(1):39.) have Ki values of 19-130/180 pM for PI3K/mTOR respectively, and are the PI3K/mTOR dual inhibitors with best activity reported in the literature at present. Whitman developed a series of highly potent PI3K/mTOR dual inhibitors with a diarylurea structure as the target core, containing one or two morpholine rings, such as PKI-402(C.M. Dehnhardt, A.M. Venkatesan, E.D. Santos, et al.J.Med.Chem.53(2010) 798-.
The structures of NVP-BEZ-235, NVP-BGT226, GSK2126458, PKI-402 and PKI-587 are as follows:
the compound reported by the invention is subjected to structure optimization on the basis of the above, and a series of sulfonylurea compounds are screened, and the sulfonylurea compounds have strong selectivity on MCF-7 breast cancer cells and are superior to the lead compounds.
Disclosure of Invention
The invention aims to provide a sulfonylurea compound and a preparation method and application thereof.
The invention provides a sulfonylurea compound shown as a general formula I, a geometric isomer thereof, and pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein the general formula I is as follows:
wherein:
x ═ methoxy or bromo
Y-hydrogen or methyl
A. The B ring is selected from aromatic rings or heterocyclic rings containing 1-3 same or different R substitutions;
r is selected from 1-3 same or different hydrogen, halogen, methyl, trifluoromethyl, trifluoromethoxy, sulfydryl, cyano, carboxyl, trimethyl acetonitrile, amino, nitro, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkoxymethyl, C1-C4 alkylacyl, C1-C4 alkylthio and allyl.
Preferably, the A, B heterocycle is selected from:
r is selected from 1 to 3 same or different hydrogen, halogen, methoxy, trifluoromethyl, cyano, nitro, hydroxyl, trifluoromethoxy, amino, cyano, carboxyl, sulfydryl, methyl, ethyl, isopropyl, n-butyl, cyclopropyl, ethoxy, methylthio, acetyl and propionyl.
The compound of formula I may be any one of the following compounds:
n- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-chlorobenzenesulfonamide
N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
N- ((6-bromo-4- ((4-methoxyphenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
N- ((6-bromo-4- ((4-bromophenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
N- ((6-bromo-4- ((3-chloro-4-fluorophenyl) amino) quinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
N- ((4- ((4- (2-cyanopropan-2-yl) phenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
4-chloro-N- ((6-methoxy-4- ((4-methoxyphenyl) amino) -2-methylquinolin-3-yl) carbamoyl) benzenesulfonamide
N- ((4- ((4-bromophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
N- ((4- ((3-chloro-4-fluorophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
N- ((4- ((4-bromo-2-fluorophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
4-cyano-N- ((6-methoxy-4- ((3- (trifluoromethyl) phenyl) amino) quinolin-3-yl) carbamoyl) benzenesulfonamide
N- ((6-bromo-4- ((3-ethylphenyl) amino) -2-methylquinolin-3-yl) carbamoyl) -4-mercaptobenzenesulfonamide
N- ((4- ((4-cyclopropylphenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-ethoxybenzenesulfonamide
N- (4- ((6-methoxy-2-methyl-3- (3- ((3-vinylphenyl) sulfonyl) ureido) quinolin-4-yl) amino) phenyl) propanamide
N- (3- (N- ((6-bromo-4- ((3- (ethylthio) phenyl) amino) quinolin-3-yl) carbamoyl) sulfamoyl) phenyl) acetamide
N- ((6-bromo-4- ((3-cyanophenyl) amino) quinolin-3-yl) carbamoyl) -3-nitrobenzenesulfonamide
3-cyclopropyl-N- ((4- ((3-fluoro-4-methylphenyl) amino) -2, 6-dimethylquinolin-3-yl) carbamoyl) benzenesulfonamide
3-butyl-N- ((4- ((3, 4-difluorophenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) benzenesulfonamide
N- ((4- ((4-isopropylpyridin-2-yl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-methylfuran-2-sulfonamide
N- ((6-bromo-4- ((6-ethoxypyrimidin-4-yl) amino) -2-methylquinolin-3-yl) carbamoyl) -6-chloropyridine-3-sulfonamide
N- ((6-bromo-2-methyl-4- (thiophen-2-ylamino) quinolin-3-yl) carbamoyl) pyrimidine-4-sulfonamide
N- ((4- ((3, 4-dimethylfuran-2-yl) amino) -6-methoxyquinolin-3-yl) carbamoyl) thiophene-2-sulfonamide
The invention also provides a medicinal composition which comprises the sulfonylurea compound with the general formula I, the geometrical isomer thereof or the pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as an active ingredient and a pharmaceutically acceptable excipient.
The following synthetic schemes describe the preparation of the sulfonylureas of the general formula I of the present invention, all starting materials are prepared by the means described in these synthetic schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All final derivatives of the 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 the synthetic route are as defined below or in the claims.
Taking N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide as an example, the synthesis method is shown below, and all starting materials are commercially available and analytically pure.
Taking N- ((4- ((4- (2-cyanopropan-2-yl) phenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide as an example, the synthesis method is shown below, and all starting materials are commercially available and analytically pure.
The sulfonylurea compound of the above general formula I of the present invention may form a pharmaceutically acceptable salt with an acid according to some conventional methods in the art to which the present invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are those of formula I above which may themselves be less active or even inactive, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl.
The invention can contain the sulfonylurea compound with the general formula I, and pharmaceutically acceptable salt, hydrate or solvate thereof as active ingredients, and the sulfonylurea compound is mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier 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 sulfonylurea compound of the above general formula I of the present invention for patients can be determined according to: the therapeutic efficacy and bioavailability of the active ingredients in vivo, their metabolic and excretory rates and the age, sex, disease stage of the patient are suitably adjusted, although the daily dose for an adult should generally be 10 to 500mg, preferably 50 to 300 mg. Therefore, when the pharmaceutical composition of the present invention is formulated into a unit dosage form, each unit dosage form should contain 10 to 500mg, preferably 50 to 300mg, of the sulfonylurea compound of the above general formula I in consideration 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 active compounds of the present invention or their pharmaceutically acceptable salts and solvates thereof may be used alone as the sole anti-proliferative agent or may be used in combination with anti-proliferative agents which are currently on the market.
The compound of the invention has the activity of inhibiting the growth of tumor cells in vitro, so the compound can be used for preparing medicaments for treating and/or preventing cancers, such as breast, lung, prostate cytoma and the like.
Through in vitro inhibition activity tests of lung cancer cells A549, human prostate cancer cells PC-3 and breast cancer MCF-7, the compound has a remarkable inhibition effect on lung cancer cells, prostate cancer cells and breast cancer, and is particularly used for preparing medicines for treating and/or preventing prostate cancer, lung cancer and breast cancer.
The compounds of the invention are found to have obvious inhibition on the activity of PI3K kinase by PI3K/mTOR kinase activity test.
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.
Detailed Description
In order to better explain the invention, the following detailed description of the invention is given in conjunction with specific examples, which are not intended to limit the invention.
The examples are intended to illustrate, but not to limit, the scope of the invention. NMR of the derivatives was measured by Bruker ARX-400 and Mass Spectroscopy by Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
Sulfonylurea compounds of the general formula I:
the structural formulas of the embodiments 1 to 24 of the present invention are shown in the following table 1.
TABLE 1 structural formulae of examples 1 to 24
Example 1N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
Step A Synthesis of 5- (ethoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (1a)
The compound 2, 2-dimethyl-1, 3-dioxane-4, 6-dione (65.5g, 0.45mol) and triethyl orthoformate (231.0g, 2.73mol) were added to a three-necked flask, dissolved by stirring, heated to 105 ℃ and reacted with the open air for 2 hours. TLC [ developing agent: methylene chloride methanol (15: 1)]Shows complete reaction, is cooled to room temperature, is poured into ice petroleum ether (500ml) to be stirred for 30min,suction filtration and drying of the filter cake gave compound 1a as a yellow solid (71.6g, 80%). m.p.: 68.2-69.0 ℃; ESI-MS M/z [ M + H ]]+:201.1。
Step B Synthesis of 5- [ [ (4-bromophenyl) amino ] methylene ] -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (2a)
Compound 1a (71.0g,0.005mol) and 300mL of absolute ethanol were added to a three-necked flask and reacted under reflux for 0.5 h. Para-bromoaniline (67.2g,0.006mol) was added and reacted for 2 h. TLC assay [ V (dichloromethane): V (methanol) ═ 15:1]After the reaction, the reaction mixture is cooled to 50 ℃, filtered, and the filter cake is rinsed by 50mL of absolute ethyl alcohol to obtain 108.5g of white crystalline solid, wherein the yield is as follows: 93.9%, m.p.: 195.2-197.3 ℃, and the total yield of the two steps is 79.8%. ESI-MS M/z [ M-H ]]+:327.2.
Step C4-hydroxy-6-bromoquinoline (3a) Synthesis
Diphenyl ether (519.9g,3.064mol) was charged into a 1000mL three-necked flask, preheated to 190 deg.C, and Compound 2a (50.1g,0.153mol) was added slowly and reacted for 15 min. TLC assay [ V (dichloromethane): V (methanol) ═ 15:1]After the reaction is finished, cooling, pouring the reaction liquid into 600mL of petroleum ether, stirring, separating out a solid, performing suction filtration, and drying to obtain 29.9g of a gray yellow solid, wherein the yield is as follows: 85.2 percent. m.p.: 207.3-209.1 ℃; ESI-MS M/z [ M-H ]]+:224.1；1HNMR(400MHZ,DMSO)δ8.15(d,J＝2.4Hz,1H),7.95(m,1H),7.78(m,1H),7.51(d,J＝9.2Hz，1H),6.0(d,J＝7.2Hz，1H).
Step D Synthesis of 3-nitro-4-hydroxy-6-bromoquinoline (4a)
Adding the compound 3a (29.0g,0.130mol) into a three-neck flask containing 500mL, heating and stirring until the compound is dissolved, slowly dropwise adding a mixed solution of nitric acid (40.95g,0.650mol) and propionic acid (10mL) into the reaction flask, reacting for 2h after dropwise adding, and detecting by TLC (detection of [ V (dichloromethane): V (methanol): 15:1)]After the reaction is finished, cooling and filtering are carried out, filter residue is added into ice saturated sodium bicarbonate solution to be stirred and filtered, and the filter residue is dried to obtain 26.0g of yellow solid compound with the yield of 64.5%. m.p.: 226.1-227.2 ℃; ESI-MS [ M + H ]]+:269.1；1HNMR(400MHz,DMSO)δ9.20(s,1H),8.29(d,J＝2.3Hz,1H),7.91(dd,J＝8.8、2.3Hz,1H),7.66(d,J＝8.8Hz,1H).
Step E Synthesis of 3-Nitro-4-chloro-6-bromoquinoline (5a)
Compound 4a (19.5g, 0.072mol) was added to a three-necked flask containing phosphorus oxychloride (212ml, 2.174mol), 6 drops of DMF were added dropwise, the temperature was raised to 110 ℃ and stirred, and reflux was carried out for 0.2-3 h. TLC detection [ V (petroleum ether): (V ethyl acetate) ═ 1: 1%]After the reaction was completed, the reaction mixture was distilled under reduced pressure to give a brown viscous substance, ice-saturated sodium bicarbonate solution (500mL) was added, stirred for 1 hour, filtered, the residue was washed with water (20mL), extracted with ethyl acetate (30 mL. times.3) three times, and the extract was concentrated to dryness to give 19.0g of a beige solid, yield 91.1%. m.p. 130.1-132.2 ℃; ESI-MS M/z [ M + H ]]+:289.1；1H NMR(400MHz,DMSO)δ9.21(d,J＝3.2Hz,1H),8.30(d,J＝2.3Hz,1H),7.95(dd,J＝8.8、2.3Hz,1H),7.72(d,J＝8.8Hz,1H).
Step F Synthesis of 2- [4- [ (6-bromo-3-nitroquinolin-4-yl) amino ] phenyl ] -2-methylpropanenitrile (6a)
Compound 5a (19.0g,0.066mol) was added to 250mL of acetic acid, stirred for half an hour, and then compound 2- (4-aminobenzene) -2-methylpropanenitrile (13.8g,0.072mol) was added, and reacted at room temperature for 1 h. TLC detection [ V (petroleum ether): V (ethyl acetate): 3:1]After the reaction is finished, slowly adding the reaction solution into ice saturated sodium bicarbonate solution (250mL) until the solid is completely separated out, filtering, washing the filter residue twice with water (100mL), and drying the filter residue to obtain 13.6g of yellow solid with the yield of 50.1%. m.p. 205.2-209 ℃; ESI-MS M/z [ M + H ]]+:411.0；1H NMR(400MHz,DMSO)δ9.05(s,1H),8.69(s,1H),7.96(s,1H),7.90(d,J＝8.7Hz,1H),7.77(d,J＝8.3Hz,1H),7.43(d,J＝8.3Hz,2H),7.07(d,J＝8.2Hz,2H),1.68(s,6H).
Step G Synthesis of 2- {4- [ (3-amino-6-bromoquinolin-4-yl) amino ] phenyl } -2-methylpropanenitrile (7)
Compound 6a (13.5g,0.033mol) and 200mL of absolute ethanol were put in a 500mL three-necked flask, dissolved by stirring, and FeCl with crystal water was added thereto3(1.8g,0.007mol) and 14.1g of activated carbon, and the mixture is heated to 80 ℃ and stirred and refluxed. 80% hydrazine hydrate (11mL,0.33mol) was added dropwise and reacted for 2.5 h. TLC detection [ V (petroleum ether): V (ethyl acetate): 1]After the reaction, filtering, distilling the filtrate under reduced pressure, evaporating to dryness to obtain solid, adding water and dichloromethane for extractionAnd carrying out vacuum distillation and evaporation on the organic phase to obtain 11.1g of light yellow solid, wherein the yield is as follows: 89.0 percent. m.p. 209.2-212.1 ℃; ESI-MS M/z [ M + H ]]+:381.1；1HNMR(400MHz,DMSO)δ8.63(s,1H),7.92(s,1H),7.85(s,1H),7.78(d,J＝8.8Hz,1H),7.46(d,J＝8.7Hz,1H),7.27(d,J＝8.3Hz,2H),6.55(d,J＝8.3Hz,2H),5.46(s,2H),1.61(s,6H).
Synthesis of step H N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide (example 1)
With 2- [4- [ (6-bromo-3-aminoquinolin-4-yl) amino group]Phenyl radical]Starting from (0.2g,0.5mmol) of (7) 2-methylpropanenitrile and (8) propyl ((4-fluorophenyl) sulfonyl) carbamate (0.196g,0.75mmol), a white solid was obtained in 52% yield according to preparative method III. m.p.: 315.2-316.4 ℃; ESI-MS M/z [ M + H ]]+:582.1；1H NMR(400MHz,DMSO)δ12.01(s,1H),8.95(s,1H),8.08(d,J＝9.0Hz,1H),8.05–7.94(m,4H),7.82(dd,J＝16.8,8.6Hz,3H),7.59–7.50(m,3H),7.11(s,1H),1.95(s,6H).
The compounds of examples 2 to 7 were obtained by similar reactions according to the procedure for the synthesis of example 1.
Example 2N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-chlorobenzenesulfonamide
White solid was obtained according to the general procedure for preparation with a yield of 50%. m.p.: 279.2-280.1 ℃; ESI-MS M/z [ M + H ]]+:598.1；1H NMR(400MHz,DMSO)δ11.87(s,1H),8.81(s,1H),8.23(d,J＝9.8Hz,2H),7.94(d,J＝9.0Hz,1H),7.89(s,1H),7.88(d,J＝3.1Hz,1H),7.85(s,1H),7.83(s,1H),7.70(d,J＝8.2Hz,2H),7.66(d,J＝9.1Hz,1H),7.45–7.38(m,3H),6.97(s,1H),1.81(s,6H).
Example 3N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
White solid was obtained according to the general procedure for preparation with a yield of 50%. m.p.: 289.2-290.4 ℃; ESI-MS M/z [ M + H ]]+:578.1；1H NMR(400MHz,DMSO)δ12.01(s,1H),8.95(s,1H),8.25(d,J＝9.5Hz),8.08(d,J＝9.0Hz,1H),7.98(d,J＝8.4Hz,3H),7.84(d,J＝8.2Hz,2H),7.80(d,J＝9.1Hz,1H),7.59–7.51(m,3H),7.11(s,1H),6.23(s,1H),2.30(s,3H)1.95(s,6H).
Example 4N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
A white solid was obtained according to the general procedure for preparation with a yield of 45%. m.p.: 287.2-288.4 ℃; ESI-MS M/z [ M + H ]]+:620.1；1H NMR(400MHz,DMSO)δ12.06(s,1H),9.00(s,1H),8.23(s,1H),8.13(d,J＝9.0Hz,1H),8.03(d,J＝8.4Hz,4H),7.89(d,J＝8.2Hz,2H),7.85(d,J＝9.1Hz,1H),7.65–7.57(m,3H),7.16(s,1H),2.00(s,1H),1.63(s,9H).
Example 5N- ((6-bromo-4- ((4-methoxyphenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
A white solid was obtained according to the general procedure for preparation, with a yield of 47%. m.p.: 289.1-290.2 ℃; ESI-MS M/z [ M + H ]]+:545.1；1H NMR(400MHz,DMSO)δ11.93(s,1H),8.93(s,1H),8.08(d,J＝9.0Hz,1H),7.86(d,J＝8.0Hz,2H),7.82–7.77(d,J＝8.6Hz,1H),7.68(d,J＝8.7Hz,2H),7.52(d,J＝8.0Hz,2H),7.43(s,2H),7.37(d,J＝8.7Hz,2H),7.28(s,1H),4.05(s,3H).
Example 6N- ((6-bromo-4- ((4-bromophenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
A white solid was obtained according to the general procedure for preparation with a yield of 45%. m.p.: 278.7-279.5 ℃; ESI-MS M/z [ M + H ]]+:545.1；1H NMR(400MHz,DMSO)δ12.04(s,1H),8.95(s,1H),8.84(s,2H),8.76(s,1H),8.34(d,J＝12.0Hz,4H),8.19(s,1H),7.76(d,J＝8.5Hz,2H),7.42(d,J＝8.5Hz,2H),6.60(s,1H).
Example 7N- ((6-bromo-4- ((3-chloro-4-fluorophenyl) amino) quinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
A white solid was obtained according to the general procedure for preparation with a yield of 38%. m.p.: 290.1 to 291.6 ℃; ESI-MS M/z [ M + H ]]+:605.1；1H NMR(400MHz,DMSO)δ11.83(s,1H),10.40(s,1H),7.90(d,J＝7.3Hz,3H),7.75(d,J＝8.0Hz,3H),7.67(d,J＝7.5Hz,2H),7.52(d,J＝7.7Hz,1H),7.45(d,J＝7.9Hz,1H),6.66(s,1H),2.65(s,3H),1.86(s,9H).
Example 8
N- ((4- ((4- (2-cyanopropan-2-yl) phenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
Step A Synthesis of 2-methyl-4-hydroxy-6-methoxyquinoline (1b)
P-anisidine (30g,0.244mol), ethyl acetoacetate (317g,2.44mol) and polyphosphoric acid (PPA) (82g,0.244mol) were added to a 1000mL three-necked flask, heated to 190 ℃ and stirred to react for 5-6 h. TLC (dichloromethane: methanol 15:1) detection reaction is finished, cooling to 70 ℃ (PPA temperature is too low and coagulates into a soft paste to be unfavorable for post-treatment), adding 1000mL saturated sodium carbonate solution, stirring, separating out solid, filtering, drying filter cake to obtain gray solid 2-methyl-4-hydroxy-6-methoxyquinoline (1b)32g, yield is 70%. m.p. 210.2-211.1 ℃; ESI-MS M/z [ M-H ]]-:188.1；1H NMR(400MHz,DMSO)δ9.61(s,1H),7.95(d,J＝9.3Hz,1H),7.86(d,J＝9.5Hz,1H),7.52(d,J＝5.4Hz,1H),7.02(s,1H),3.88(s,3H),2.42(s,3H).
Step B Synthesis of 2-methyl-3-nitro-4-hydroxy-6-methoxyquinoline (2B)
Compound 1b (30g,0.158mol) was added to a 1000mL three-necked flask containing 500mL of propionic acid, the temperature was raised to 120 ℃, and the mixture was stirred for 1 hour, and then a mixture of nitric acid (50g,0.794mol) and 20mL of propionic acid was added dropwise to the flask, followed by reaction for 2 hours. TLC (dichloromethane: methanol 15:1) detection, cooling, filtering, adding a filter cake into ice saturated sodium bicarbonate solution (500mL), stirring for 1h, filtering, and drying the filter cake to obtain 18.6g of yellow solid 2-methyl-3-nitro-4-hydroxy-6-methoxyquinoline (2b) with the yield of 50%. m.p. 221.3-222.4 ℃; ESI-MS M/z [ M-H ]]-:233.1；1H NMR(400MHz,DMSO)δ9.51(s,1H),7.84(d,J＝9.1Hz,1H),7.63(d,J＝8.5Hz,1H),7.32(d,J＝7.4Hz,1H),3.65(s,3H),2.32(s,3H).
Step C Synthesis of 2-methyl-3-nitro-4-chloro-6-methoxyquinoline (3b)
Compound 2b (18g,0.077mol) and phosphorus oxychloride (154mL) were added to a 500mL three-necked flask, the temperature was raised to 110 ℃ and 6d DMF was added dropwise and the reaction was allowed to proceed for 2 h. TLC (petroleum ether: ethyl acetate 3:1) detection, cooling, concentrating to remove most phosphorus oxychloride, and addingAdding into a proper amount of ice saturated sodium bicarbonate solution, stirring to separate out a solid, extracting with ethyl acetate for three times, and concentrating the extract to dryness to obtain light yellow solid 2-methyl-3-nitro-4-chloro-6-methoxyquinoline (3b)15.6g with the yield of 80%. m.p. 141.2-142.8 ℃; ESI-MS M/z [ M-H ]]-:252.1；1H NMR(400MHz,DMSO)δ8.05(d,J＝9.2Hz,1H),7.66(dd,J＝9.2,2.5Hz,1H),7.48(d,J＝2.4Hz,1H),3.99(s,3H),2.64(s,3H).
Step D preparation of 2- (4 ((3-amino-6-methoxy-2-methylquinolin-4-yl) amino) phenyl) -2-methylpropanenitrile (4b)
Starting from 2-methyl-3-nitro-4-chloro-6-methoxy-quinoline (3b) (20g,0.079mol) and 2- (4-aminobenzene) -2-methylpropionitrile (18.1g,0.095mol), 9.6g of 2- (4- ((3-amino-6-methoxy-2-methylquinolin-4-yl) amino) phenyl) -2-methylpropionitrile (4b) were obtained as a yellow solid in 3.5.1.2, giving a yield of 70%. 258.2-259.1 ℃ in m.p.; ESI-MS M/z [ M-H ]]-:346.1；1H NMR(400MHz,DMSO)δ8.20(d,J＝8.5Hz,1H),7.75(s,1H),7.01(d,J＝10.3Hz,2H),6.57(d,J＝8.4Hz,2H),6.23(d,J＝8.3Hz,2H),5.12(s,2H),3.71(s,3H),2.62(s,3H),168(s,6H).
Step E Synthesis of 2- (4- ((3-amino-6-methoxyquinolin-4-yl) amino) phenyl) -2-methylpropanenitrile (5b)
Compound 4b (13.5g,0.033mol) and 200mL of absolute ethanol were added to a 500mL three-necked flask, and dissolved by stirring, and FeCl with crystal water was added thereto3(1.8g,0.007mol) and 14.1g of activated carbon, and the mixture is heated to 80 ℃ and stirred and refluxed. 80% hydrazine hydrate (11mL,0.33mol) was added dropwise and reacted for 2.5 h. TLC detection [ V (petroleum ether): V (ethyl acetate): 1]After the reaction is finished, performing suction filtration, distilling the filtrate under reduced pressure, evaporating to dryness to obtain a solid, adding water and dichloromethane for extraction, distilling the organic phase under reduced pressure, evaporating to dryness to obtain a light yellow solid 11.1g, wherein the yield is as follows: 89.0 percent. m.p. 201.2-202.1 deg.C; ESI-MS M/z [ M + H ]]+:333.1；
Synthesis of step F N- ((4- ((4- (2-cyanopropan-2-yl) phenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide (example 8)
With 2- (4- ((3-amino-6-methoxy-2-methylquinolin-4-yl) amino) phenyl) -2-methylpropanenitrile (5b) (0.2g,0.58 m)mol) and propyl ((4-methylphenyl) sulfonyl) carbamate (6b) (0.223g,0.87mmol) as starting materials, a white solid was prepared according to the general method of preparation in 40% yield. 266.7 to 267.4 ℃ in m.p.; ESI-MS M/z [ M + H ]]+:543.1；1H NMR(400MHz,DMSO)δ11.81(s,1H),7.88(d,J＝8.5Hz,1H),7.64(s,3H),7.60(d,J＝8.3Hz,2H),7.46(s,1H),7.37(d,J＝8.2Hz,3H),7.14(dd,J＝9.2,2.5Hz,1H),6.13(d,J＝2.4Hz,1H),3.96(s,3H),2.68(s,3H),2.30(s,3H),1.78(s,6H).
The compounds of examples 9-20 were prepared by analogous reactions according to the methods of synthetic example 1 and example 8.
Example 94-chloro-N- ((6-methoxy-4- ((4-methoxyphenyl) amino) -2-methylquinolin-3-yl) carbamoyl) benzenesulfonamide
A white solid was obtained according to the general procedure for preparation, with a yield of 42%. m.p.: 290.8-291.2 ℃; ESI-MS M/z [ M + H ]]+:526.1；1H NMR(400MHz,DMSO)δ11.86(s,1H),8.31(d,J＝10.8Hz,2H),8.25(s,1H),7.98(d,J＝9.2Hz,1H),7.78(d,J＝8.5Hz,1H),7.67(d,J＝8.8Hz,2H),7.55(d,J＝8.4Hz,1H),7.35(t,J＝10.7Hz,2H),7.33–7.16(m,2H),6.44(s,1H),4.04(s,3H),3.58(s,3H),2.83(s,3H).
Example 10N- ((4- ((4-bromophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
A white solid was obtained according to the general procedure for preparation, with a yield of 42%. m.p.: 342.1-343.5 ℃; ESI-MS M/z [ M + H ]]+:597.1；1H NMR(400MHz,DMSO)δ11.93(s,1H),8.02(d,J＝7.5Hz,4H),7.97(t,J＝10.2Hz,1H),7.90(d,J＝8.4Hz,2H),7.86(d,J＝9.0Hz,1H),7.31(dd,J＝9.2,2.7Hz,2H),7.17(dd,J＝9.0,2.5Hz,1H),7.09(d,J＝2.4Hz,1H),6.39(d,J＝2.5Hz,1H),3.85(s,3H),2.68(d,J＝5.3Hz,3H),1.45(s,9H).
Example 11N- ((4- ((3-chloro-4-fluorophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
A white solid was obtained according to the general procedure for preparation, with a yield of 39%. m.p.: 285.3-286.1 ℃; ESI-MS M/z [ M + H ]]+:532.1；1H NMR(400MHz,DMSO)δ11.87(s,1H),8.34(s,1H),7.81(d,J＝5.8Hz,1H),7.77–7.59(m,2H),7.50(d,J＝8.5Hz,2H),7.40(s,1H)7.18(q,J＝9.1Hz,2H),7.01(dd,J＝18.2,8.8Hz,1H),6.96–6.88(m,1H),6.04(d,J＝2.2Hz,1H),3.23(s,3H),2.26(s,3H).
Example 12N- ((4- ((4-bromo-2-fluorophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
White solid was obtained according to the general procedure for preparation with a yield of 41%. m.p.: 279.2-280.5 ℃; ESI-MS M/z [ M + H ]]+:573.1；1H NMR(400MHz,DMSO)δ11.75(s,1H),10.32(s,1H),7.67(d,J＝8.0Hz,3H),7.59(d,J＝7.5Hz,2H),7.52(d,J＝8.3Hz,1H),7.44(d,J＝7.7Hz,2H),7.37(d,J＝7.9Hz,2H),6.12(s,1H),3.85(s,3H),2.66(s,3H),2.57(s,3H).
Example 134-cyano-N- ((6-methoxy-4- ((3- (trifluoromethyl) phenyl) amino) quinolin-3-yl) carbamoyl) benzenesulfonamide
ESI-MS m/z:[M+H]-:542.1
Example 14N- ((6-bromo-4- ((3-ethylphenyl) amino) -2-methylquinolin-3-yl) carbamoyl) -4-mercaptobenzenesulfonamide
ESI-MS m/z:[M+H]-:571.1
Example 15N- ((4- ((4-cyclopropylphenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-ethoxybenzenesulfonamide
ESI-MS m/z:[M+H]-:533.1
Example 16N- (4- ((6-methoxy-2-methyl-3- (3- ((3-vinylphenyl) sulfonyl) ureido) quinolin-4-yl) amino) phenyl) propionamide
ESI-MS m/z:[M+H]-:560.2
Example 17N- (3- (N- ((6-bromo-4- ((3- (ethylthio) phenyl) amino) quinolin-3-yl) carbamoyl) sulfamoyl) phenyl) acetamide
ESI-MS m/z:[M+H]-:514.1
Example 18N- ((6-bromo-4- ((3-cyanophenyl) amino) quinolin-3-yl) carbamoyl) -3-nitrobenzenesulfonamide
ESI-MS m/z:[M+H]-:568.1
Example 193-cyclopropyl-N- ((4- ((3-fluoro-4-methylphenyl) amino) -2, 6-dimethylquinolin-3-yl) carbamoyl) benzenesulfonamide
ESI-MS m/z:[M+H]-:583.1
Example 203-butyl-N- ((4- ((3, 4-difluorophenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) benzenesulfonamide
ESI-MS m/z:[M+H]-:541.1
Example 21N- ((4- ((4-isopropylpyridin-2-yl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-methylfuran-2-sulfonamide
ESI-MS m/z:[M+H]-:496.1
Example 22N- ((6-bromo-4- ((6-ethoxypyrimidin-4-yl) amino) -2-methylquinolin-3-yl) carbamoyl) -6-chloropyridine-3-sulfonamide
ESI-MS m/z:[M+H]-:592.1
Example 23N- ((6-bromo-2-methyl-4- (thien-2-ylamino) quinolin-3-yl) carbamoyl) pyrimidine-4-sulfonamide
ESI-MS m/z:[M+H]-:519.0
Example 24N- ((4- ((3, 4-dimethylfuran-2-yl) amino) -6-methoxyquinolin-3-yl) carbamoyl) thiophene-2-sulfonamide
ESI-MS m/z:[M+H]-:473.1
Pharmacological study of the products of the invention
In vitro cytotoxic Activity
The sulfonylurea compound derivative of the formula I is subjected to in vitro activity screening for inhibiting breast cancer cells MCF-7, lung cancer cells A549 and prostate cancer PC-3, and a reference product GDC-0941 is prepared according to a method described in the literature (J.Med.chem.,2008,51(18), pp 5522-5532).
1) After the cells were revived and passaged for 2-3 times for stabilization, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into cell counting plate, counting, and adjusting cell concentration to 104Per well. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture solution was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20,4,0.8,0.16, 0.032. mu.g/mL in a 24-well plate.
3 wells were added for each concentration, two columns of cells surrounding each, which were greatly affected by the environment, and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
3) The drug-containing culture solution in the 96-well plate is discarded, the cells are washed twice by using Phosphate Buffer Solution (PBS), 100 mu L of MTT (tetrazole) (0.5mg/mL) is added into each well and put into an incubator for 4h, the MTT solution is discarded, and 100 mu L of dimethyl sulfoxide is added. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the activity of the compound on breast cancer cells MCF-7, lung cancer cells A549 and prostate cancer PC-3 are shown in Table 2.
PI3K alpha enzyme Activity assay
1. Solution preparation
1) The test compound was added to 1mL of DMSO to prepare a 10mM stock solution. The stock solution concentration of the positive compound GDC-0941 is 10mM (dissolved in DMSO), and the stock solution concentration of the positive compound cisplatin is 2mM (dissolved in DMSO).
2) Compound stock solutions were diluted in DMSO to make 2mM solutions (100X).
3) mu.L of 2mM solution was taken and 18. mu.L of reaction solution was added to dilute the compound to 200. mu.M (10X) solution.
4) mu.L of the above solution and 18. mu.L of the reaction solution were added to the plate to prepare a 10 Xsolution.
5) Take 1. mu.L of the solution in the above plate to the detection plate.
6) mu.L of the kinase reaction solution was added to the wells of the total inhibition control and the zero inhibition control of the assay plate so that the concentration of DMSO was 10%.
2. Experimental procedure
1) Layout of orifice plates
The 384 well plates were arranged according to experimental requirements, wherein:
a) HPE (total inhibition control): no kinase and compound were added, ATP, substrate and 1% DMSO were added.
b) ZPE (zero inhibition control): no compound was added, kinase, ATP, substrate and 1% DMSO were added.
c) Positive control compound wells: kinase, ATP, substrate and various concentrations of positive compounds were added.
d) Test compound wells: adding kinase, ATP, substrate and test compound.
2) Preparation of the used reagent
4 XATP: ATP was diluted to 4X with the reaction.
4X substrate solution: the substrate was diluted to 4X with the reaction.
2.5 Xkinase solution: the kinase was diluted to 2.5X with the reaction solution.
3) Kinase reaction
a) mu.L of 10X compound (test compound or positive control for each kinase) solution was added to each well, and 1. mu.L of reaction solution was added to both full and zero inhibition control wells, as arranged.
b) Per well 4 μ L2.5X kinase solution was added according to the arrangement. mu.L of the reaction was added to the total inhibition control wells.
c) Centrifuge the assay plate at 1000rpm to mix well.
d) The 4XATP solution was mixed with the 4X substrate solution in equal volumes to give a 2 XATP-substrate solution.
e) Add 5. mu.L of the above 2 XATP-substrate solution per well as arranged.
f) Centrifuge the assay plate at 1000rpm to mix well.
g) The test plate was left to react at 30 ℃ for 1 hour.
h) mu.L of Kinase Glo plus or ADP-Glo reaction reagent was added to each well and left at 27 ℃ for 20 minutes.
i) mu.L of Kinase Detection reagent was added to each well and left at 27 ℃ for 30 minutes.
j) Envision reads the fluorescence values.
Note that Kinase Glo plus, ADP-Glo and Kinase Detection reagents are preset at room temperature for half an hour prior to use.
4) Raw data analysis
Prism5.0 analyzes the raw data.
IC of the compound was calculated according to Bliss method50
Inhibition Ratio (%) (Ratio665/620 control wells-Ratio 665/620 dosing wells)/Ratio 665/620 control wells × 100%
The results of the experiment are shown in table 2. IC in Table 150>80% by weight, indicated as "+++", 80%>IC50>60% by weight, 60% by "+ +", and>IC50>40%, denoted "+", IC50<40%, indicated by "-", "NA" indicates no activity, and "ND" indicates not tested. Table 3 shows the results of anti-EGFR kinase Activity of some of the target Compounds
TABLE 2 antitumor Activity and enzyme Activity of the target Compounds in vitro
aNA active IC50>50μM
bND activity not tested
From the above test results, it is clear that the compound of formula I to be protected by the present invention has good in vitro anti-tumor activity and strong selectivity to MCF-7.
The compounds of general formula I of the present invention can be administered alone, but usually are administered in admixture with a pharmaceutically acceptable carrier selected according to the desired route of administration and standard pharmaceutical practice, and their novel use is illustrated below in the context of methods for the preparation of various pharmaceutical dosage forms, e.g., tablets, capsules, injections, aerosols, suppositories, films, dripping pills, liniments for external use and ointments, respectively, of such compounds.
Application example 1: tablet formulation
10g of the compound of example 2 is added with 20g of auxiliary materials according to a general tabletting method in pharmacy, and the mixture is pressed into 100 tablets, wherein each tablet weighs 300 mg.
Application example 2: capsule preparation
10g of the compound of example 4 is mixed with 20g of auxiliary materials according to the requirement of a pharmaceutical capsule, and then the mixture is filled into hollow capsules, wherein each capsule weighs 300 mg.
Application example 3: injection preparation
10g of the compound obtained in example 7 was adsorbed by activated carbon in accordance with a conventional pharmaceutical procedure, filtered through a 0.65 μm microporous membrane, and then filled in nitrogen gas bottles to prepare 2mL of each of water-injection preparations, each of which was filled in 100 bottles.
Application example 4: aerosol formulation
Dissolving 10g of the compound in example 10 in a proper amount of propylene glycol, adding distilled water and other auxiliary materials, and preparing 500mL of clear solution.
Application example 5: suppository
10g of the compound of example 13 was ground into fine powder and added with an appropriate amount of glycerin, after being ground uniformly, the mixture was added with melted glycerin gelatin, ground uniformly and poured into a mold coated with a lubricant to prepare 50 suppositories.
Application example 6: film agent
10g of the compound obtained in example 15 was dissolved by heating after swelling with stirring polyvinyl alcohol, medicinal glycerin, water, etc., and filtered through a 80-mesh screen, and the compound obtained in example 15 was dissolved by stirring in the filtrate, and 100 films were formed on a film coating machine.
Application example 7: drop pills
15g of the compound in example 16 and 50g of a matrix such as gelatin are heated, melted and mixed uniformly, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.
Application example 8: external liniment
10g of the compound of example 19 was mixed with 2.5g of an emulsifier and other adjuvants according to a conventional pharmaceutical method, and the mixture was ground, and then distilled water was added thereto to make 200 mL.
Application example 9: ointment formulation
Prepared by grinding 10g of the compound of example 22, and then uniformly grinding the ground compound with 500g of oil-based substances such as vaseline.
While the invention has been described with reference to specific embodiments, modifications and equivalent arrangements will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (6)
1. A sulfonylurea compound is characterized in that the structure is shown as the following general formula I:
wherein:
x ═ methoxy or bromo
Y-hydrogen or methyl
A. The B ring is selected from heterocyclic rings containing 1-3 same or different R substitutions;
the heterocycle is selected from:
r is selected from 1 to 3 same or different hydrogen, halogen, methoxy, trifluoromethyl, cyano, nitro, trifluoromethoxy, amino, carboxyl, sulfydryl, methyl, ethyl, isopropyl, n-butyl, cyclopropyl, ethoxy, methylthio, acetyl and propionyl.
2. A sulfonylurea compound characterized by: any one selected from the following compounds:
n- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-chlorobenzenesulfonamide
N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
N- ((6-bromo-4- ((4- (2-cyanopropan-2-yl) phenyl) amino) quinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
N- ((6-bromo-4- ((4-methoxyphenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
N- ((6-bromo-4- ((4-bromophenyl) amino) quinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
N- ((6-bromo-4- ((3-chloro-4-fluorophenyl) amino) quinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
N- ((4- ((4- (2-cyanopropan-2-yl) phenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
4-chloro-N- ((6-methoxy-4- ((4-methoxyphenyl) amino) -2-methylquinolin-3-yl) carbamoyl) benzenesulfonamide
N- ((4- ((4-bromophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4- (tert-butyl) benzenesulfonamide
N- ((4- ((3-chloro-4-fluorophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4-fluorobenzenesulfonamide
N- ((4- ((4-bromo-2-fluorophenyl) amino) -6-methoxy-2-methylquinolin-3-yl) carbamoyl) -4-methylbenzenesulfonamide
4-cyano-N- ((6-methoxy-4- ((3- (trifluoromethyl) phenyl) amino) quinolin-3-yl) carbamoyl) benzenesulfonamide
N- ((6-bromo-4- ((3-ethylphenyl) amino) -2-methylquinolin-3-yl) carbamoyl) -4-mercaptobenzenesulfonamide
N- ((4- ((4-cyclopropylphenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-ethoxybenzenesulfonamide
N- ((6-bromo-4- ((3-cyanophenyl) amino) quinolin-3-yl) carbamoyl) -3-nitrobenzenesulfonamide
3-cyclopropyl-N- ((4- ((3-fluoro-4-methylphenyl) amino) -2, 6-dimethylquinolin-3-yl) carbamoyl) benzenesulfonamide
3-butyl-N- ((4- ((3, 4-difluorophenyl) amino) -6-methoxyquinolin-3-yl) carbamoyl) benzenesulfonamide
N- ((4- ((4-isopropylpyridin-2-yl) amino) -6-methoxyquinolin-3-yl) carbamoyl) -4-methylfuran-2-sulfonamide
N- ((6-bromo-4- ((6-ethoxypyrimidin-4-yl) amino) -2-methylquinolin-3-yl) carbamoyl) -6-chloropyridine-3-sulfonamide
N- ((6-bromo-2-methyl-4- (thiophen-2-ylamino) quinolin-3-yl) carbamoyl) pyrimidine-4-sulfonamide
N- ((4- ((3, 4-dimethylfuran-2-yl) amino) -6-methoxyquinolin-3-yl) carbamoyl) thiophene-2-sulfonamide.
3. A pharmaceutical composition comprising a sulfonylurea compound according to any one of claims 1 or 2, characterized in that: the sulfonylurea compound is used as an active ingredient and is mixed with a pharmaceutically acceptable carrier or excipient to prepare the medicinal composition.
4. Use of the sulfonylurea compound according to claim 1 for the preparation of a medicament for the treatment and/or prevention of proliferative diseases.
5. Use of the sulfonylurea compound according to claim 1 for the preparation of a medicament for the treatment and/or prevention of cancer.
6. Use of the sulfonylurea compound according to claim 1 for the preparation of a medicament for the treatment and/or prevention of lung cancer, prostate cancer, breast cancer.
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