Quinazolines compound, preparation method therefor and application thereof
11504371 · 2022-11-22
Assignee
Inventors
Cpc classification
A61K9/0019
HUMAN NECESSITIES
A61K31/519
HUMAN NECESSITIES
A61K9/0053
HUMAN NECESSITIES
A61K35/00
HUMAN NECESSITIES
A61K31/44
HUMAN NECESSITIES
International classification
A61K31/519
HUMAN NECESSITIES
A61K9/00
HUMAN NECESSITIES
A61K31/44
HUMAN NECESSITIES
A61K35/00
HUMAN NECESSITIES
Abstract
The present invention discloses a compound of anilino polyethylene glycol ether cycloquinazoline substituted with a substituted arylmethyl heteroatomic group having the structure of formula (I) below, or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutical composition comprising the same. The compound and pharmaceutical composition disclosed herein can be used in tumor targeted therapy and in the regulation of tumors and related diseases. ##STR00001##
Claims
1. A compound of anilino polyethylene glycol ether cycloquinazoline substituted with a substituted arylmethyl heteroatomic group represented by formula (I), or a pharmaceutically acceptable salt, ester or solvate thereof, ##STR00027## wherein, n is 0, 1, 2, 3, 4, 5 or 6; X represents —O—, —S—, —NH—, —SO—, —SO.sub.2— or —CO—; R represents H—, F—, Cl—, Br—, I—, —CN, —CH.sub.3, —CF.sub.3 or —CCl.sub.3; Ar represents a monosubstituted, disubstituted or unsubstituted benzene, naphthalene, pyridine, furan, thiophene, indole, pyrimidine, benzopyrimidine, imidazole, thiazole, oxazole, benzoxazole or benzothiazole; when Ar is monosubstituted, a monosubstituent R.sub.1 group on Ar represents —NO.sub.2, —CF.sub.3, —Cl.sub.3, —CBr.sub.3, —CH.sub.2CF.sub.3, —H, F—, Cl—, Br—, —CH.sub.3, —CH.sub.2CHCH.sub.2, —CN, —CHO, —COOH, —COOCH.sub.3, —COOCH.sub.2CH.sub.3, —CONH.sub.2, —CON(CH.sub.3).sub.2, —N(CH.sub.3).sub.2, —N(CH.sub.2CH.sub.3).sub.2, —OCH.sub.3 or —OCH.sub.2CH.sub.3; and when Ar is disubstituted, disubstituents R.sub.2 and R.sub.3 on Ar each independently represent F—, Cl—, Br—, —CH.sub.3, CH.sub.3O—, —CF.sub.3, —CN, —CHO, —COOH, —COOCH.sub.3, —COOCH.sub.2CH.sub.3, —CONH.sub.2, —CON(CH.sub.3).sub.2, —OCH.sub.3, —N(CH.sub.3).sub.2 or —N(CH.sub.2CH.sub.3).sub.2.
2. The compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 1, wherein n is 0, 1, 2 or 3, X represents —O—, —S— or —NH—; R represents H—, F—, Cl— or —CF.sub.3; and Ar is ##STR00028## wherein R.sub.1 represents —NO.sub.2, —CF.sub.3, —CCl.sub.3, H—, Cl—, F—, —CH.sub.3, —CN, —CHO, —COOH, —COOCH.sub.3, —N(CH.sub.3).sub.2 or —OCH.sub.3; and R.sub.2 and R.sub.3 independently represent —F, —Cl, —CH.sub.3, CH.sub.3O—, —CF.sub.3, —CN, —CHO, —COOH or —N(CH.sub.3).sub.2.
3. The compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 1, wherein the pharmaceutically acceptable salt comprises: (1) a salt formed with an inorganic acid or inorganic base; (2) a salt formed with an organic acid or organic base; and (3) a pharmaceutically acceptable cation.
4. A pharmaceutical composition comprising the compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 1.
5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is formulated as a solid or liquid oral preparation, or an injection.
6. A method for preparing the compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 1, comprising: (1) reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (IV), and reacting the compound of formula (IV) with Y—CH.sub.2Ar in an organic solvent to obtain the compound of formula (I); ##STR00029## or (2) reacting a compound of formula (III) with Y—CH.sub.2Ar to obtain a compound of formula (V), and reacting the compound of formula (V) with a compound of formula (II) to obtain the compound of formula (I); ##STR00030## Y represents F, Cl, Br, I or a sulfonate group.
7. A method of treating a tumor in a subject comprising administering a therapeutically effective amount of an antitumor therapeutic drug comprising the compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof, or a pharmaceutical composition comprising the compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 1 to a subject in need thereof, wherein the tumor is lung cancer, prostate cancer, liver cancer, stomach cancer, neuroblastoma, breast cancer, gynecologic cancer, esophageal cancer, or colon cancer.
8. The method according to claim 7, further comprising administering a second therapeutic agent having an antitumor effect.
9. The compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 1, wherein the compound is selected from the group consisting of: N-(2-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (1), N-(3-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(4-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(2-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(3-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(4-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(2-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(3-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(4-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(3-((4-cyanophenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(4-((4-cyanophenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(2-((4-pyridyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(2-((3-chloro,4-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(3-((3-chloro,4-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(4-((3-chloro,4-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, N-(3-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(4-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(2-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(3-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(4-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(3-((phenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(2-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(3-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(4-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, N-(3-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(4-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(2-((phenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(3-((phenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(4-((phenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(2-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(3-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(4-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(2-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(3-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, N-(4-((4-trifluoromethylphenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, 2-(3-Fluoro-benzyloxy)-5-(7,8,10,11-tetrahydro-6,9,12-trioxa-1,3-diaza-cyclonona[b]naphthalen-4-ylamino)-benzonitrile (36), 3-(3-Fluoro-benzyloxy)-5-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalen-4-ylamino)-benzonitrile, 4-(3-Fluoro-benzyloxy)-5-(2,5,8,11,14-pentaoxa-18,20-diaza-tricyclo[13.8.0.0.sup.17,22]tricosa-16,18,20,22-tetraen-21-ylamino)-benzonitrile.
10. The compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 3, wherein the salt formed with an inorganic acid or inorganic base is a hydrochloride salt, a sulfate salt or a phosphate salt.
11. The compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 3, wherein the salt formed with an organic acid or organic base is a citrate salt, a p-toluenesulfonate salt, a stearate salt, a succinate salt, a lactate salt, a maleate salt, a tartrate salt, a palmitate salt, a salicylate salt, a dimethylamine salt, a piperidine salt or a morpholine salt.
12. The compound of formula (I), or the pharmaceutically acceptable salt, ester or solvate thereof according to claim 3, wherein the pharmaceutically acceptable cation is formed by the compound of formula (I) with potassium, sodium, calcium, magnesium, aluminum, lithium, zinc or ammonium ions.
13. The pharmaceutical composition according to claim 4, further comprising a pharmaceutically acceptable carrier or excipient.
14. The pharmaceutical composition according to claim 13, wherein the carrier or excipient is selected from the group consisting of water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gum, alcohol, petrolatum and combinations thereof.
15. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition further comprises a second therapeutic agent selected from regorafenib and sorafenib.
16. The method according to claim 8, wherein the second therapeutic agent is at least one selected from the group consisting of regorafenib, sorafenib, paclitaxel and docetaxel.
Description
DESCRIPTION OF THE DRAWINGS
(1) In order to illustrate the technical solutions of the embodiments of the present invention and the prior art more clearly, the drawings used in the embodiments and the prior art are briefly introduced in the following. Obviously, the drawings described below represent only some embodiments of the present invention. Those skilled in the art can obtain other drawings according to the drawings without any creative work.
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DETAILED DESCRIPTION OF THE INVENTION
(12) The following are embodiments of the invention. The embodiments described are used to describe the present invention, such that it can be more clearly understood and implemented by those skilled in the art. The described embodiments are only a part of the embodiments of the invention rather than all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without any creative work are within the scope of the present invention.
Example 1
(13) Synthesis of N-(2-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine Structural formula of N-(2-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine is as follows:
(14) ##STR00007##
(15) The intermediate compound (II) was firstly synthesized in steps 1.1 to 1.6. The last intermediate compound (IV) and the final product N-(2-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were obtained in sequence.
(16) 1.1 Synthesis of diethylene glycol di-p-toluenesulfonate 10 mL (0.105 mol) of diethylene glycol, 300 mL of dichloromethane, and 40 g (0.21 mol) of p-toluenesulfonyl chloride were added in a 500 mL round bottom flask, and 47 g of potassium hydroxide (0.84 mol) was slowly added in the presence of an ice bath. The reaction was substantially completed over 1.5 h. The reaction liquid was washed with water (3×100 mL) for three times. The obtained organic phase was collected and dried with anhydrous Na.sub.2SO.sub.4. After filtration and evaporation of solvent, the crude product was obtained and recrystallized from ethanol to afford 40 g of white solid, in a yield 95%. The resulting spectra are consistent with those reported in literatures.
(17) ##STR00008##
1.2 Synthesis of ethyl 3,4-(benzo-9-crown-3) Benzoate
(18) In a 250 mL round bottom flask, 6.68 g (48.31 mmol) of potassium carbonate and 50 mL of DMF were added and heated to 120° C. for 30 min. 9.12 g (21.96 mmol) of diethylene glycol di-p-toluenesulfonate was dissolved in 60 mL of DMF, and 4 g (21.96 mmol) of ethyl 3,4-dihydroxybenzoate was dissolved in 30 mL of DMF. Both of the DMF solutions were mixed uniformly and then slowly added dropwise to the flask. The reaction was monitored by TLC, and completed over about 2 hours. The reaction liquid was cooled, filtered. The filtrate was evaporated to remove DMF. Then the reaction was added with 100 mL of dichloromethane, filtered, and the filtrate was dried by rotary evaporation to give brown oil, which was subjected to column chromatography (petroleum ether:ethyl acetate=6:1) to give 2.9 g of product as colorless oil, in a yield of 50%.
(19) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.63-7.59 (m, 2H, ArH), 6.90 (d, J=8.4 Hz, 1H, ArH), 4.50-4.48 (m, 2H, —OCH.sub.2), 4.26 (q, J=7.2 Hz, 2H, —COOCH.sub.2), 4.22-4.20 (m, 2H, —OCH.sub.2), 3.87-3.81 (m, 4H, —OCH.sub.2), 1.38 (t, J=7.2 Hz, 3H, —CH.sub.3). .sup.13C NMR (100 MHz, CDCl.sub.3)δ 160.55, 157.20, 150.17, 145.17, 120.69, 120.03, 116.55, 68.70, 67.35, 67.22, 66.57, 55.49, 9.03 MS (ESI.sup.+) m/z: 253.1 [M+H.sup.+].
(20) ##STR00009##
1.3 Synthesis of ethyl 6-nitro-3,4-(benzo-9-crown-3)benzoate
(21) ##STR00010##
(22) In the presence of an ice bath, 2.6 g (10.4 mmol) of ethyl 3,4-(benzo-9-crown-3) benzoate and 5 mL of glacial acetic acid were added into a round bottom flask. Under stirring, 6 mL (187.2 mmol) of concentrated nitric acid was slowly added dropwise. 30 min after the addition was completed, the system was warmed to room temperature and the reaction was performed for another 24 h. Then, the reaction liquid was poured into 200 mL of ice water, then extracted with dichloromethane (3×100 mL), washed with saturated sodium bicarbonate (2×100 mL) followed by water (2×100 mL) and saturated NaCl (2×100 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered and rotary evaporated to dryness. 2 g of product was obtained as yellow oil, in a yield of 70%, which was directly used for the next reaction.
1.4 Synthesis of ethyl 6-amino-3,4-(benzo-9-crown-3)benzoate
(23) ##STR00011##
(24) 2 g (6.72 mmol) of ethyl 6-amino-3,4-(benzo-9-crown-3)benzoate was dissolved in 30 mL of methanol, and added with 0.6 g of palladium carbon (10%). Hydrogen gas was introduced. The reaction was completed after 13 h and filtrated over celite to remove the palladium carbon. The solvent was rotary evaporated to give 1.5 g of product as brown oil in a yield of 70%, which was put into the next reaction immediately.
1.5 Synthesis of 6,7-(benzo-9-crown-3)quinazolin-4-one
(25) ##STR00012##
(26) 1.5 g (5.61 mmol) of ethyl 6-amino-3,4-(benzo-9-crown-3)benzoate was dissolved in 10 mL of formamide, and added with 0.975 g (15.09 mmol) of ammonium formate. The mixture was slowly heated to 165° C. to perform the reaction for 4 h. After the reaction was cooled to room temperature, solid was precipitated and filtrated to give 0.7 g of white powdery solid, in a yield of 50%.
(27) .sup.1H NMR (400 MHz, DMSO-d6). δ 12.06 (s, 1H, ArH), 7.96 (s, 1H, ArH), 7.64 (s, 1H, ArH) 7.18 (s, 1H, ArH), 4.57-4.55 (m, 2H, —OCH.sub.2), 4.32-4.30 (m, 2H, —OCH.sub.2), 3.84-3.83 (m, 4H, —OCH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6) δ 162.82, 159.76, 157.12, 151.09, 145.91, 144.52, 118.63, 117.96, 74.75, 72.39, 71.80, 71.24. MS (ESI m/z: 249.2 [M+H.sup.+].
1.6 Synthesis of 4-chloro-6,7-(benzo-9-crown-3)quinazoline
(28) ##STR00013##
(29) 0.3 g (1.2 mmol) of 6,7-(benzo-9-crown-3) quinazolin-4-one and 1.5 mL (20.78 mmol) of phosphorus oxychloride were sequentially added to a single-neck flask under electromagnetic stirring, and heated to 110° C. to reflux for 4 h. After the completion of the reaction, phosphorus oxychloride was removed by rotary evaporation. 30 ml of saturated NaHCO.sub.3 was added, and the mixture was extracted with dichloromethane (3×20 mL). The organic phase was combined, washed with water (2×20 mL) followed by saturated NaCl (2×20 mL) and dried over anhydrous Na.sub.2SO.sub.4. The solvent was rotary evaporated to give yellow oil. 0.21 g of a white solid was obtained by column chromatography (petroleum ether:ethyl acetate=3:1), in a yield of 65%.
(30) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.88 (s, 1H, ArH), 7.80 (s, 1H, ArH), 7.59 (s, 1H, ArH), 7.26 (s, 1H, ArH), 4.68-4.66 (m, 2H, —OCH.sub.2), 4.51-4.49 (m, 2H, —OCH.sub.2), 3.98-3.95 (m, 4H, —OCH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6) δ 158.59, 1:57.44, 151.82, 146.56, 139.89, 119.64, 116.73, 114.38, 75.10, 71.90, 71.80, 70.83. MS (ESI.sup.+) m/z: 267.1 [M+H.sup.+].
1.7 Synthesis of N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(31) ##STR00014##
(32) 190 mg (0.7 mmol) of 4-chloro-6,7-(benzo-9-crown-3)quinazoline was dissolved in 12 mL of isopropanol, and added with 126 mg of o-aminophenol (1.15 mmol). The mixture was heated to reflux. After reacting for about 2 h, yellow solid appeared. The completion of the reaction was monitored by TLC. The reaction was placed stationarily to cool and suction filtered to give 168 mg of pale yellow solid (yield: 70.7%, m.p. 237° C.).
(33) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ11.12 (s, 1H, —NH), 9.90 (s, 1H, —OH), 8.71 (s, 1H, ArH), 8.55 (s, 1H, ArH), 7.41 (s, 1H, ArH), 7.31 (d, J=7.8 Hz, 1H, ArH), 7.220, J=7.4 Hz, 1H, ArH), 7.03 (d, J=8.1 Hz, 114, ArH), 6.90 (t, J=7.8 Hz, 1M, ArH), 4.78 (brs, 2H, —CH.sub.2), 4.43 (brs, 2H, —CH.sub.2), 3.89 (brs, 4H, —CH.sub.2).
1.8 Synthesis of N-(2-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(34) ##STR00015##
(35) 100 mg of N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (0.3 mmol), 250 mg (1.8 mmol) potassium carbonate, 16 mg (0.06 mmol) of 18-crown-6, 5 mg (0.03 mmol) KI was sequentially added to 2.5 mL of acetone, stirred at 35° C. for 0.5 h, then added with 45 μL of p-nitrobenzyl chloride (0.4 mmol), and stirred for another 6 h. The completion of the reaction was monitored by TLC. After the reaction was cooled to room temperature, it was poured into ice water and suction filtered to give bright yellow solid. The bright yellow solid was added to 5 mL of methanol, stirred for 0.5 h in the presence of an ice bath, and suction filtered, to give a pale yellow solid, in a yield of 40%, m.p. 192-193° C.
(36) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1H, —NH), 8.35 (s, 1H, ArH), 8.14 (s, 1H, ArH), 8.11 (d, J=5.2 Hz, 2H, ArH), 7.61 (d, J=8.5 Hz, 2H, ArH), 7.57 (d, J=7.8 Hz, 1H, ArH), 7.27 (s, 1H, ArH), 7.22 (t, J=7.3 Hz, 1H, ArH), 7.11 (d, J=8.0 Hz, 1H, ArH), 7.04 (1, J=7.5 Hz, 1H, ArH), 5.32 (s, 2H, —CH.sub.2), 4.56 (brs, 2H, —CH.sub.2), 4.39 (brs, 3.87 (brs, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6): δ157.78, 156.86, 154.06, 152.20, 151.46, 147.34, 146.77, 146.77, 145.17, 127.89, 127.56, 127.56, 126.48, 123.27, 123.27, 120.94, 117.75, 115.02, 113.39, 110.94, 74.88, 72.85, 71.86, 71.37, 68.45, MS (ESI.sup.+) m/z: 475.2[M−H].sup.+
Example 2
Synthesis of N-(3-((p-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(37) N-(3-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 2.1-2.7. Steps 2.1-2.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol as starting material was replaced with 3-aminophenol.
2.8 Synthesis of N-(3-((p-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(38) 100 mg (0.3 mmol) of N-(3-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, 250 mg (1.8 mmol) of potassium carbonate, 16 mg (0.06 mmol) of 18-crown-6, 5 mg (0.03 mmol) of KI was sequentially added to 2.5 mL of acetone, stirred at 35° C. for 0.5 h, then added with 45 μL (0.4 mmol) of p-nitrobenzyl chloride, and stirred for another 6 h. The completion of the reaction was monitored by TLC. After the reaction was cooled to room temperature, the reaction liquid was poured into ice water and suction filtered to give bright yellow solid. The bright yellow solid was added to 5 mL of methanol, stirred for 0.5 h in the presence of an ice bath, and suction filtered to give off-white solid, in a yield of 42%, m.p. 197-198° C.
(39) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 1H, —NH), 8.48 (s, 1H, ArH), 8.29 (s, 1H, ArH), 8.27 (s, 1H, ArH), 8.24 (s, 1H, ArH), 7.76 (s, 1H, ArH), 7.74 (s, 2H, ArH), 7.47 (d, J=7.8 Hz, 1H, ArH), 7.29 (s, 1H, ArH), 6.78 (dd, J=8.0 Hz, 1H, ArH), 5.31 (s, 2H, —CH.sub.2), 4.57 (s, 2H, —CH.sub.2), 4.42 (s, 2H, —CH.sub.2), 3.87 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6): δ 157.96, 156.93, 156.52, 153.57, 151.50, 147.47, 146.94, 145.08, 140.70, 129.19, 128.12, 128.12, 123.53, 123.53, 117.82, 115.16, 114.56, 111.12, 109.37, 108.60, 74.92, 72.82, 71.78, 71.37, 68.05. MS (ESI+) m/z: 475.4[M−H].sup.+
Example 3
Synthesis of N-(4-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(40) N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 3.1-3.7. Steps 3.1-3.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol was replaced with 4-aminophenol as starting material.
3.8 Synthesis of N-(4-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(41) The synthesis procedure was similar to that in Step 1.8 of Example 2 except that the reaction starting material N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine; the product was obtained as off-white solid, yield 36%, m.p. 192-193° C.
(42) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H, —NH), 8.39 (s, 1H, ArH), 8.28 (d, J=8.6 Hz, 2H, ArH), 8.19 (s, 1H, ArH), 7.74 (d, J=8.6 Hz, 2H, ArH), 7.71 (d, J=8.9 Hz, 2H, ArH), 7.26 (s, 1H, ArH), 7.06 (d, J=8.9 Hz, 2H, ArH), 5.30 (s, 2H, —CH.sub.2), 4.56 (brs, 2H, —CH.sub.2), 4.40 (brs, 2H, —CH.sub.2), 3.86 (brs, 4H, —CH.sub.2). .sup.13CNMR (100 MHz, DMSO-d6). δ 156.78, 156.71, 154.14, 153.82, 151.35, 147.35, 146.94, 145.18, 132.73, 128.15, 128.15, 123.88, 123.88, 123.54, 123.54, 117.75, 115.16, 114.67, 114.67, 110.96, 74.91, 72.82, 71.81, 71.39, 68.20. MS (ESI+) m/z: 475.1[M−H].sup.+
Example 4
Synthesis of N-(2-((4-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(43) Steps 4.1-4.7 were completely consistent with steps 1.1-1.7 in Example 1. N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazoline was firstly synthesized in steps 4.1-4.7.
4.8 Synthesis of N-(2-((4-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(44) The synthesis procedure was similar to that in Step 1.8 in Example 1, except that p-nitrobenzyl chloride was replaced with 4-fluorobenzyl chloride as starting material; and white solid was obtained (yield: 41%, m.p. 140-141° C.).
(45) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H, —NH), 8.33 (s, 1H, ArH), 8.10 (s, 1H, ArH), 8.06 (d, J=1.1 Hz, 2H, ArH), 7.60 (d, J=8.5 Hz, 2H, ArH), 7.51 (d, 1H, ArH), 7.30 (s, 1H, ArH), 7.24 (t, J=7.3 Hz, 1H, ArH), 7.20 (d, J=8.0 Hz, 1H, ArH), 7.06 (s, 1H, ArH), 7.03 (t, J=6.7 Hz, 1H, ArH), 5.18 (s, 2H, —CH.sub.2), 4.57 (brs, 2H, —CH.sub.2), 4.37 (brs, 2H, —CH.sub.2), 3.89 (brs, 4H, —CH.sub.2). .sup.13CNMR (100 MHz, DMSO-d6): δ 157.69, 156.83, 154.05, 152.19, 151.44, 147.33, 146.55, 146.55, 144.39, 128.01, 127.54, 127.54, 126.51, 123.35, 123.28, 120.67, 117.74, 114.99, 113.38, 110.95, 74.90, 72.84, 71.87, 71.37, 68.57. MS (ESI+) m/z: 448.1[M−H].sup.+
Example 5
Synthesis of N-(3-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(46) N-(3-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 5.1-5.7. Steps 5.1-5.7 were similar to steps 1.1-1.7 in Example 1, except that o-aminophenol was replaced with 3-aminophenol as starting material.
5.8 Synthesis of N-(3-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(47) The synthesis procedure was similar to that in step 1.8 of Example 1, except that p-nitrobenzyl chloride and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with 4-fluorobenzyl chloride and N-(3-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, respectively, as starting materials. The product was obtained as pale yellow solid in a yield of 43%, m.p. 215-216° C.
(48) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H, —NH), 8.48 (s, 1H, ArH), 8.28 (s, 1H, ArH), 8.25 (s, ArH), 8.22 (s, 1H, ArH), 7.74 (s, 1H, ArH), 7.69 (s, 2H, ArH), 7.42 (d, J=7.8 Hz, 1H, ArH), 7.23 (s, 1H, ArH), 7.10 (s, 1H, ArH), 6.77 (dd, J=8.0 Hz, 1H, ArH), 5.16 (s, 2H, —CH.sub.2), 4.60 (brs, 2H, —CH.sub.2), 4.48 (brs, 2H, —CH.sub.2), 3.89 (brs, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6). δ 158.22, 156.57, 156.23, 153.45, 151.32, 147.31, 140.50, 137.00, 129.02, 128.18, 128.20, 127.72, 127.61, 127.61, 117.77, 115.03, 114.22, 111.10, 109.21, 108.44, 74.69, 72.45, 71.79, 71.36, 69.21. MS (ESI+) 448.1[M−H].sup.+
Example 6
(49) Synthesis of N-(4-((4-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamineN-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 6.1-6.7. Steps 6.1-6.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol was replaced with 4-aminophenol as starting material.
(50) 6.8 The synthesis of N-(4-((4-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was similar to that of Step 1.8 in Example 1, except that p-nitrobenzyl chloride and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with 4-fluorobenzyl chloride and N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, respectively, as starting material. The product was obtained as off-white solid in a yield of 40%, m.p. 222-223° C.
(51) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H, —NH), 8.39 (s, 1H, ArH), 8.28 (d, J=8.6 Hz, 2H, ArH), 8.19 (s, 1H, ArH), 7.74 (d, J=8.6 Hz, 2H, ArH), 7.71 (d, J=8.9 Hz, 2H, ArH), 7.26 (s, 1H, ArH), 7.06 (d, J=8.9 Hz, 2H, ArH), 5.26 (s, 2H, —CH.sub.2). 4.51 (brs, 2H, —CH.sub.2), 4.33 (brs, 2H, —CH.sub.2), 3.81 (brs, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6): δ 156.68, 156.66, 154.12, 153.81, 151.35, 147.33, 142.12, 133.04, 128.26, 128.12, 128.02, 125.36, 125.28, 125.21, 125.09, 123.69, 122.92, 118.01, 115.36, 114.62, 111.05, 75.12, 72.72, 71.83, 71.34, 68.53. MS (ESI+) m/z: 448.2 [M−H].sup.+
Example 7
Synthesis of N-(2-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(52) Steps 7.1-7.7 were completely consistent with steps 1.1-1.7 in Example 1. N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazoline was firstly synthesized in steps 7.1-7.7.
7.8 Synthesis of N-(2-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(53) The synthetic route is as follows:
(54) ##STR00016##
(55) 100 mg of N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (0.3 mmol), 250 mg (1.8 mmol) of potassium carbonate, 16 mg (0.06 mmol) of 18-crown-6, and 5 mg (0.03 mmol) of KI was sequentially added to 2.5 mL of DMF, stirred at 35° C. for 0.5 h, then added with 96 mg (0.4 mmol) of 4-(trifluoromethyl)benzyl bromide, and stirred for 6 h. The completion of the reaction was monitored by TLC. After the reaction was cooled to room temperature, the reaction liquid was poured into ice water, extracted with CH.sub.2Cl.sub.2, and the organic phase was collected and washed with saturated sodium bicarbonate, water and saturated sodium chloride sequentially and dried over anhydrous sodium sulfate. After the solvent was rotary evaporated, 23 mg of pale yellow solid was obtained by column chromatography (petroleum ether:ethyl acetate=1:1) in a yield of 15%, m.p. 115-116° C.
(56) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.24 (s, 1H, —NH), 8.35 (s, 1H, ArH), 8.10 (s, 1H, ArH), 7.64 (m, 2H, ArH), 7.58 (m, 3H, ArH), 7.27 (s, 1H, ArH), 7.22 (m, 1H, ArH), 7.12 (m, 1H, ArH), 7.03 (m, 1H, ArH), 5.27 (s, 2H, —CH.sub.2), 4.56 (brs, 2H, —CH.sub.2), 4.38 (brs, 2H, CH.sub.2), 3.87 (brs, —CH.sub.2). .sup.33CNMR (100 MHz, DMSO-d.sub.6): δ 157.76, 15684, 154.06, 152.25, 151.45, 147.33, 142.11, 127.82, 127.36, 127.30, 127.30, 127.30, 126.42, 125.04, 125.00, 120.78, 117.73, 115.02, 113.27, 110.93, 74.86, 74.86, 72.82, 71.87, 71.34, 68.60. MS (ESI+) m/z: 498.36 [M−H].sup.+
Example 8
Synthesis of N-(3-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(57) N-(3-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 8.1-8.7. Steps 8.1-8.7 were the similar as steps 1.1-1.7 in Example 1, except that o-aminophenol was replaced with 3-aminophenol as starting material.
8.8 Synthesis of N-(3-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(58) The synthesis procedure was similar to that in step 7.8 of Example 7, except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(3-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine as starting material. The product was obtained as white solid in a yield of 16%, m.p. 206-207° C.
(59) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H, —NH), 8.47 (s, 1H, ArH), 8.30 (s, 1H, ArH), 7.74 (m, 6H, ArH), 7.49 (d, J=7.40 Hz, 1H, ArH), 7.29 (s, 2H, ArH), 6.77 (d, J=7.48 Hz, 1H, ArH), 5.26 (s, 2H, 4.58 (s, 2H, —CH.sub.2), 4.42 (s, 2H, —CH.sub.2), 3.87 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6): δ 158.05, 156.85, 156.58, 153.57, 151.52, 147.45, 142.05, 140.72, 129.11, 128.39, 127.94, 125.55, 125.28, 125.24, 122.84, 117.66, 115.46, 114.51, 111.14, 109.36, 108.61, 74.98, 72.68, 71.87, 71.31, 68.30. MS (ESI+) m/z: 498.1 [M−H].sup.+
Example 9
Synthesis of N-(4-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(60) N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 9.1-9.7. Steps 9.1-9.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol was replaced with 4-aminophenol as starting material.
9.8 Synthesis of N-(4-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(61) The synthesis procedure was similar to that in step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine as starting material. The product was obtained as white solid, yield 12%, m.p. 214° C.
(62) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H, —NH), 8.36 (s, 1H, ArH), 8.17 (s, 1H, ArH), 7.75 (m, 2H, ArH), 7.67 (m, 4H, ArH), 7.23 (s, 1H, ArH), 7.03 (d, J=9.08 Hz, 2H, ArH), 5.22 (s, 2H, —CH.sub.2), 4.54 (brs, 2H, —CH.sub.2), 4.38 (brs, 2H, —CH.sub.2), 3.84 (brs, 4H, —CH.sub.2). .sup.13C NMR (100 MHz. DMSO-d6): δ 156.75, 156.71, 154.26, 153.84, 151.36, 147.32, 142.12, 132.59, 128.36, 128.04, 127.92, 125.55, 125.30, 125.26, 125.22, 123.89, 122.85, 117.68, 115.23, 114.60, 110.94, 74.92, 72.74, 71.84, 71.36, 68.42. MS (ESI+) m/z: 498.40 [M−H].sup.+
Example 10
Synthesis of N-(4-((3-chloro-4-fluorophenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(63) N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 10.1-10.7. Steps 10.1-10.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol was replaced with 4-aminophenol as starting material.
10.8 Synthesis of N-(4-((3-chloro-4-fluorophenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(64) The synthesis procedure was similar to that in step 7.8 of Example 7 except that 4-(trifluoromethyl)benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with 3-chloro-4-fluorobenzyl chloride and N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, respectively, as starting materials. The product was obtained as pale yellow solid in a yield of 36%, m.p. 221-222° C.
(65) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H, —NH), 8.46 (s, 1H, ArH), 8.10 (d, J=4.9 Hz, 2H, ArH), 7.80 (s, 1H, ArH), 7.43 (t, J=9.1 Hz, 1H, ArH), 7.50 (d, J=6.9 Hz, 2H, ArH), 7.20 (s, 1H, ArH), 7.04 (d, J=6.8 Hz, 2H, ArH), 5.16 (s, 2H, —CH2), 4.60 (s, 2H, —CH2), 4.40 (s, 2H, —CH2), 3.87 (s, 4H, —CH2). .sup.13C NMR (100 MHz, DMSO-d6): δ 156.02, 154.350 (d, J=4.5 Hz, 2H), 153.89, 151.22, 151.90, 147.68, 147.39, 137.20, 1369.69, 132.19, 128.37, 127.60, 127.60, 123.89, 123.89, 117.76, 115.20, 114.61, 114.61, 111.00, 75.21, 73.01, 71.92, 71.51, 69.58. MS (ESI+) m/z: 494.76 [M−H].sup.+
Example 11
Synthesis of N-(2-((4-pyridyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(66) Steps 11.1-11.7 were completely consistent with steps 1.1-1.7 in Example 1. N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazoline was firstly synthesized in steps 11.1-11.7.
11.8 Synthesis of N-(2-((4-pyridyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(67) The synthesis procedure was similar to that in step 7.8 in Example 7, except that 4-(trifluoromethyl)benzyl bromide was replaced with 4-pyridylmethyl chloride as starting material. Pale yellow solid was obtained (yield: 33%, m.p. 231-232° C.).
(68) .sup.1HNMR (400 MHz, DMSO-d 6): δ 9.29 (s, 1H, —NH), 8.39 (s, 1H, ArH), 8.16 (s, 1H, ArH), 8.14 (d, J=5.8 Hz, 2H, ArH), 7.82 (d, J=7.0 Hz, 2H, ArH), 7.58 (d, J=7.5 Hz, 1H, ArH), 7.30 (s, 1H, ArH), 7.24 (brs, 1H, ArH), 7.12 (d, J=8.1 Hz, 1H, ArH), 7.10 (d, J=7.5 Hz, 1H, ArH), 5.32 (s, 2H, —CH.sub.2), 4.60 (brs, 2H, —CH.sub.2), 4.39 (brs, 2H, —CH.sub.2), 3.91 (brs, 4H, —CH.sub.2) NMR (100 MHz, DMSO-d 6): δ 157.60, 156.81, 154.00, 152.16, 151.39, 147.31, 145.32, 135.63, 128.09, 127.86, 127.59, 126.76, 126.22, 120.05, 117.75, 114.91, 11.2.35, 74.88, 72.85, 71.86, 71.37, 68.45. MS (ESI+) m/z: 431.36 [M−H].sup.+
Example 12
Synthesis of N-(3-((phenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(69) N-(3-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 12.1-12.7. Steps 12.1-12.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol was replaced with 3-aminophenol as starting material.
12.8 Synthesis of N-(3-((phenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(70) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that 4-(trifluoromethyl)benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with benzyl chloride and N-(3-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, respectively, as starting materials. The synthesis method was similar as in Example 7. The product was obtained as 50.4 mg of pale yellow solid in a yield of 39%, m.p. 223-214° C.
(71) .sup.1H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H, —NH), 8.48 (s, 1H, ArH), 8.25 (s, 1H, ArH), 7.71 (s, 1H, ArH), 7.47 (t, J=7.2 Hz, 3H, ArH), 7.41 (t, J=7.2 Hz, 2H, ArH), 7.35 (d, J=7.2 Hz, 1H, ArH), 7.28 (t, J=5.5 Hz, 2H, ArH), 6.77 (dd, J=8.1 Hz, 1H, ArH), 5.13 (s, 2H, —CH.sub.2), 4.57 (brs, 2H, —CH.sub.2). 4.42 (brs, 2H, —CH.sub.2), 3.87 (brs, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6): δ 158.42, 156.92, 156.54, 153.62, 151.50, 147.48, 140.60, 137.10, 129, 10, 128.38, 128.38, 127.76, 127.64, 127.64, 117.82, 115.18, 114.24, 111.12, 109.42, 108.57, 74.92, 72.83, 71.79, 71.38, 69.22. MS (ESI+) m/z: 430.1 [M−H].sup.+
Example 13
Synthesis of N-(4-((phenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(72) N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was firstly synthesized in steps 13.1-13.7. Steps 13.1-13.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol was replaced with 4-aminophenol as starting material.
13.8 Synthesis of N-(4-((phenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(73) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that 4-(trifluoromethyl)benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with benzyl chloride and N-(4-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine, respectively, as starting materials. The product was obtained as pale yellow solid in a yield of 39%, m.p. 229-230° C.
(74) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.44 (s, 1H, —NH), 8.39 (s, 1H, ArH), 8.19 (s, 1H, ArH), 7.69 (d, J=6.9 Hz, 2H, ArH), 7.46 (s, 2H, ArH), 7.41 (s, 2H, ArH), 7.35 (s, 1H, ArH), 7.26 (s, 1H, ArH), 7.04 (d, J=6.8 Hz, 2H, ArH), 5.12 (s, 2H, —CH.sub.2), 4.56 (s, 2H, —CH.sub.2), 4.40 (s, 2H, —CH.sub.2), 3.87 (s, 4H, —CH.sub.2). .sup.13CNMR (100 MHz, DMSO-d.sub.6): δ 156.76, 154.65, 153.87, 151.34, 147.37, 147.37, 137.19, 132.19, 128.37, 128.37, 127.73, 127.60, 127.60, 123.89, 123.89, 117.76, 115.20, 114.61, 114.61, 111.00, 74.93, 72.82, 71.83, 71.40, 69.38. MS (ESI+) m/z: 430.0 [M−H].sup.30
Example 14
Synthesis of N-(2-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(75) N-(2-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized in steps 14.1-14.7. Steps 14.1-14.7 were similar as steps 1.1-1.7 in Example 1, except that 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline was replaced with 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline as starting material.
14.8 Synthesis of N-(2-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(76) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(2-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine as starting material. The product was obtained as off-white solid in a yield of 30%, m.p. 197-198° C.
(77) .sup.1H NMR (400 MHz, DMSO-d 6): δ 9.20 (s, 1H, —NH), 8.37 (s, 1H, ArH), 8.12 (d, J=8.5 Hz, 2H, ArH), 8.03 (s, 1H, ArH), 7.62 (d, J=7.9 Hz, 2H, ArH), 7.60 (s, 1H, ArH), 7.28 (s, 1H, ArH), 7.22 (t, J=7.4 Hz, 1H, ArH), 7.12 (d, J=8.0 Hz, 1H, ArH), 7.0511, J=7.5 Hz, 1H, ArH). 5.32 (s, 2H, —CH.sub.2), 4.28 (brs, 4H, —CH.sub.2), 3.79 (brs, 4H, —CH.sub.2), 3.63 (s, brs, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d 6): δ157.89, 155.96, 153.85, 152.38, 149.79, 147.30, 146.91, 145.34, 128.02, 127.75, 127.75, 127.67, 126.68, 123.45, 123.45, 121.14, 113.52, 111.81, 109.99, 109.66, 72.80, 70.60, 70.51, 70.12, 68.86, 68.53, 48.73. MS (ESI+) m/z: 519.4 [M+H].sup.+
Example 15
Synthesis of N-(3-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(78) N-(3-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized in steps 15.1-15.7. Steps 15.1-15.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 3-aminophenol and 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline, respectively, as starting materials.
15.8 Synthesis of N-(3-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(79) The synthesis procedure was similar to that in step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(3-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine as starting material. The product was obtained as pale yellow solid in a yield of 23%, m.p. 153-154° C.
(80) .sup.1H NMR (400 MHz, DMSO-d 6): δ 9.46 (s, 1H, —NH), 8.48 (s, 1H, ArH), 8.28 (d, J=8.64 Hz, 2H, ArH), 8.17 (s, 1H, ArH), 7.76 (d, J=8.56 Hz, 2H, ArH), 7.72 (s, 1H, ArH), 7.46 (d, J=8.04 Hz, 1H, ArH), 7.29 (s, 2H, ArH), 6.78 (d, J=8.04 Hz, 1H, ArH), 5.31 (s, 2H, —CH.sub.2), 4.29 (brs, 4H, —CH.sub.2), 3.80 (brs, 2H, —CH.sub.2), 3.75 (brs, 2H, —CH.sub.2), 3.64 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d 6): δ 158.11, 156:66, 156.07, 153.44, 149.81, 147.69, 147.12, 145.30, 140.94, 129.36, 128.36, 128.36, 123.74, 123.74, 114.87, 111.70, 110.53, 109.89, 109.48, 108.90, 73.09, 70.55, 70.42, 70.06, 68.89, 68.48, 68.20. MS(ESI+) m/z: 519.1 [M+H].sup.+
Example 16
Synthesis of N-(4-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(81) N-(4-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized in steps 16.1-16.7. Steps 16.1-16.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 4-aminophenol and 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline, respectively, as starting materials.
16.8 Synthesis of N-(4-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(82) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(4-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine as starting material; the product was obtained as white solid, yield 36%, m.p. 192° C.
(83) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.45 (s, 1H, —NH), 8.39 (s, 1H, ArH), 8.28 (d, J=8.6 Hz, 2H, ArH), 8.19 (s, 1H, ArH), 7.74 (d, J=8.6 Hz, 2H, ArH), 7.71 (d, J=8.9 Hz, 2H, ArH), 7.26 (s, 1H, ArH), 7.06 (d, J=8.9 Hz, 2H, ArH), 5.30 (s, 2H, 4.56 (brs, 2H, —CH.sub.2), 4.40 (brs, 2H, —CH.sub.2), 3.86 (brs, 4H, —CH.sub.2). .sup.13CNMR (100 MHz, DMSO-d.sub.6): δ 156.78, 156.71, 154.14, 153.82, 151.35, 147.35, 146.94, 145.18, 132.73, 128.15, 128.15, 123.88, 123.88, 123.54, 123.54, 117.75, 115.16, 114.67, 114.67, 110.96, 74.91, 72.82, 71.81, 71.39, 68.20. MS (ESI+) m/z 475.1 [M−H].sup.+
Example 17
Synthesis of N-(2-((phenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(84) N-(4-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized in steps 17.1-17.7. Steps 17.1-17.7 were similar as steps 1.1-1.7 in Example 1, except that 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline was replaced with 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline as starting material.
17.8 Synthesis of N-(2-((phenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(85) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that 4-(trifluoromethyl) benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with benzyl chloride and N-(2-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, respectively, as starting materials; the product was obtained as off-white solid in a yield of 35%, m.p. 150-151° C.
(86) .sup.1HNMR (400 MHz, DMSO-d6): δ 9.09 (s, 1H, —NH), 8.36 (s, 1H, ArH), 7.97 (s, 1H, ArH), 7.66 (d, J=6.8 Hz, 1H, ArH), 7.35 (s, 2H, ArH), 7.26 (d, J=5.8 Hz, 4H, ArH), 7.21 (s, 1H, ArH), 7.18 (s, 1H, ArH), 7.02 (s, 1H, ArH), 5.15 (s, 2H, —CH.sub.2), 4.28 (s, 2H, —CH.sub.2), 4.22 (s, 2H, —CH.sub.2), 3.78 (s, 2H, —CH.sub.2), 3.74 (s, 2H, —CH.sub.2), 3.63 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d6): δ 157.53, 155.71, 153.70, 152.26, 149.57, 147.30, 137.10, 128.17, 128.17, 127.94, 127.54, 126.98, 126.98, 126.83, 126.08, 120.58, 113.25, 111.84, 109.64, 109.58, 72.64, 70.48, 70.40, 70.02, 69.58, 68.69, 68.41. MS (ESI+) m/z: 474.2 [M+H].sup.+
Example 18
Synthesis of N-(3-((phenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(87) N-(3-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized in steps 18.1-18.7; steps 18.1-18.7 were similar as 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 3-aminophenol and 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline, respectively, as starting materials.
18.8 Synthesis of N-(3-((phenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(88) The synthesis procedure was similar to that in step 7.8 of Example 7 except that 4-(trifluoromethyl) benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with benzyl chloride and N-(3-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, respectively, as starting materials; the product was obtained as pale yellow solid in a yield of 19%, m.p. 137-138° C.
(89) .sup.1H NMR (400 MHz, DMSO-d 6). δ 9.42 (s, 1H, —NH), 8.47 (s, 1H, ArH), 8.14 (s, 1H, ArH), 7.66 (brs, 1H, ArH), 7.47-7.24 (m, 8H, ArH), 6.75 (d, J=7.88 Hz. 1H, ArH), 5.10 (s, 2H, —CH.sub.2), 4.27 (brs, 4H, —CH.sub.2), 3.77 (brs, 2H, —CH.sub.2), 3.72 (brs, 2H, —CH.sub.2), 3.61 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d 6): δ58.41, 156.48, 155.87, 153.32, 149.59, 147.59, 140.69, 137.10, 129.08, 128.38, 128.38, 127.76, 127.64, 127.64, 114.33, 111.53, 110.37, 109.72, 109.26, 108.66, 72.92, 70.40, 70.18, 69.87, 69.19, 68.75, 68.31 MS (ESI+) m/z: 474.7 [M+H].sup.+
Example 19
Synthesis of N-(4-((phenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(90) N-(4-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized in steps 19.1-19.7; steps 19.1-19.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 4-aminophenol and 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline, respectively, as starting materials.
19.8 Synthesis of N-(4-((phenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(91) The synthesis procedure was similar to that in step 7.8 of Example 7 except that 4-(trifluoromethyl) benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with benzyl chloride and N-(4-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine, respectively, as starting materials; the product was obtained as off-white solid in a yield of 32%, m.p. 174-175° C.
(92) .sup.1H NMR (400 MHz, DMSO-d 6): δ 9.38 (s, 1H, —NH), 8.40 (s, 1H, ArH), 8.10 (s, 1H, ArH), 7.66 (d, J=8.5 Hz, 2H, ArH), 7.47 (d, J=7.1 Hz, 2H, ArH), 7.41 (t, J=7.1 Hz, 2H, ArH), 7.34 (d, J=6.8 Hz, 1H, ArH), 7.26 (s, 1H, ArH), 7.04 (d, J=8.5 Hz, 2H, ArH), 5.12 (s, 2H, —CH.sub.2), 4.28 (s, 4H, —CH.sub.2), 3.77 (d, J=16.8 Hz, 2H, —CH.sub.2), 3.64 (s, 4H, CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d 6): δ 156.74, 155.72, 154.64, 153.56, 149.47, 147.42, 137.19, 132.42, 128.37, 128.37, 127.73, 127.61, 127.61, 124.03, 124.03, 114.61, 114.61, 111.62, 110.24, 109.53, 72.86, 70.44, 70.25, 69.94, 69.38, 68.77, 68.38. MS (ESI+) m/z: 474.25 [M+H]+
Example 20
Synthesis of N-(2-((phenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(93) N-(4-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine firstly was synthesized in steps 20.1-20.7; steps 20.1-20.7 were similar as steps 1.1-1.7 in Example 1, except that 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline was replaced with 4-chloro-6,7-(benzo-15-crown-5)-4-quinazoline as starting material.
20.8 Synthesis of N-(2-((phenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(94) The synthesis procedure was similar to that of step 7.8 in Example 7, except that 4-(trifluoromethyl)benzyl bromide was replaced with benzyl chloride as starting material; light brown solid was obtained (yield: 18%, m.p. 128-129° C.).
(95) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.08 (s, 1H, —NH), 8.36 (s, 1H, ArH), 7.70 (m, 2H, ArH), 7.35 (m, 2H, ArH), 7.26 (m, 3H, ArH), 7.19 (m, 2H, ArH), 7.05 (s, 1H, ArH), 7.03 (m, 1H, ArH), 5.14 (s, 2H, —CH.sub.2), 4.21 (brs, 2H, —CH.sub.2), 4.12 (brs, 2H, —CH.sub.2), 3.84 (brs, 4H, —CH.sub.2), 3.66 (s, 4H, —CH.sub.2), 3.65 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d.sub.6): δ 157.38, 153.79, 153:32, 152.30, 148.28, 146.86, 137.24, 128.34, 128.34, 128.22, 127.74, 127.22, 127.22, 126.78, 126.08, 120.76, 113.31, 108.88, 107.96, 102.81, 70.82, 70.82, 69.73, 69.73, 69.74, 69.74, 68.69, 68.69, 68.32 MS (ESI+) m/z: 518.2 [M+H].sup.+
Example 21
Synthesis of N-(3-((phenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(96) N-(3-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine was firstly synthesized in steps 21.1-21.7; steps 21.1-21.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 3-aminophenol and 4-chloro-6,7-(benzo-15-crown-5)-4-quinazoline, respectively, as starting materials.
21.8 Synthesis of N-(3-((phenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(97) The synthesis procedure was similar to that in step 7.8 of Example 7 except that 4-(trifluoromethyl) benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with benzyl chloride and N-(3-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, respectively, as starting materials; the product was obtained as pale yellow solid in a yield of 19%, m.p. 137-138° C.
(98) .sup.1H NMR (400 MHz, DMSO-d 6): δ 9.39 (s, 1H, —NH) 8.40 (s, 1H, ArH), 7.98 (s, 1H, ArH), 7.61 (brs, 1H, ArH), 7.46-7.14 (m, 8H, ArH), 6.95 (d, J=7.88 Hz, 1H, ArH), 5.11 (s, 2H, —CH.sub.2), 4.21 (brs 4H, —CH.sub.2), 3.85 (brs, 2H, —CH.sub.2), 3.83 (brs, 2H, —CH.sub.2). 3.89 (s, 4H, —CH.sub.2), 3.68 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d 6): δ157.91, 155.66, 154.23, 153.69, 150.22, 147.46, 140.88, 137.02, 128.94, 128.55, 127.89, 127.56, 127.22, 127.12, 114.75, 111.21, 110.18, 109.32, 109.26, 108.35, 71.02, 70.43, 69.98, 69.58, 69.02, 69.00, 68.66, 68.27, 68.05, MS (ESI+) m/z: 518.86 [M+H].sup.+
Example 22
Synthesis of N-(2-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(99) N-(2-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized in steps 22.1-22.7. Steps 22.1-22.7 were similar as steps 1.1-1.7 in Example 1, except that 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline was replaced with 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline as starting material.
22.8 Synthesis of N-(2-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(100) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(2-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine as starting material; the product was obtained as pale yellow solid in a yield of 15%, m.p. 181-182° C.
(101) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.18 (s, 1H, —NH), 8.37 (s, 1H, ArH), 8.02 (s, 1H, ArH), 7.61 (m, 5H, ArH), 7.28 (s, 1H, ArH), 7.22 (m, 1H, ArH), 7.13 (m, 1H, ArH), 7.03 (m, 1H, ArH), 5.27 (s, 2H, —CH.sub.2), 4.29 (brs, 2H, —CH.sub.2), 4.25 (brs, 2H, —CH.sub.2), 3.78 (brs, 2H, —CH.sub.2), 3.74 (brs, 2H, —CH.sub.2), 3.63 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d.sub.6): δ 158.15, 156.22, 154.19, 152.69, 150.06, 147.73, 142.57, 128.94, 128.66, 128.3, 128.34, 127.80, 126.84, 125.51, 125.47, 123.27, 121.29, 113.71, 112.22, 110.27, 110.01, 73.08, 70.90, 70.80, 70.43, 69.15, 69.07, 68.84. MS (ESI+) m/z: 542.41 [M+H].sup.+
Example 23
Synthesis of N-(3-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(102) Structural formula of N-(3-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine is as follows:
(103) ##STR00017##
(104) N-(3-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized in steps 23.1-23.7. Steps 23.1-23.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 3-aminophenol and 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline, respectively, as starting materials.
23.8 Synthesis of N-(3-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(105) The synthesis procedure was similar to that in step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(3-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine as starting material; the product was obtained as pale yellow solid in a yield of 17%, m.p. 167-168° C.
(106) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.48 (s, 1H, —NH), 8.45 (s, 1H, ArH), 8.18 (s, 1H, ArH) 7.76 (m, 2H, ArH), 7.68 (m, 3H, ArH), 7.44 (d, J=8.08 Hz, 1H, ArH), 7.26 (m, 2H, ArH), 6.75 (d, J=8.16 Hz, 1H, ArH), 5.23 (s, 2H, —CH.sub.2), 4.27 (brs, 4H, —CH.sub.2), 3.77 (brs, 2H, —CH.sub.2), 3.72 (brs, 2H, —CH.sub.2), 3.61 (s, 4H, —CH.sub.2) .sup.13C NMR (100 MHz, DMSO-d.sub.6): δ 158.07, 156.50, 155.84, 153.25, 149.60, 147.56, 142.08, 140.83, 129.10, 128.07, 127.94, 127.94, 125.56, 125.29, 125.25, 114.58, 111.59, 110.43, 109.79, 109.25, 108.71, 72.89, 70.37, 70.26, 69.90, 68.72, 68.30, 68.30. MS (ESI+) m/z: 542.38 [M+H].sup.+
Example 24
Synthesis of N-(4-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(107) N-(4-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine was firstly synthesized by steps 24.1-24.7; steps 24.1-24.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 4-aminophenol and 4-chloro-6,7-(benzo-12-crown-4)-4-quinazoline, respectively, as starting materials.
24.8 Synthesis of N-(4-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(108) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(4-hydroxyphenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine as starting material; the product was obtained as white solid in a yield of 17%, m.p. 185-186° C.
(109) .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.40 (s, 1H, —NH), 8.40 (s, 1H, ArH), 8.11 (s, 1H, ArH), 7.78 (m, 2H, ArH), 7.69 (m, 3H, ArH), 7.26 (s, 1H, ArH), 7.06 (d, J=9.04 Hz, 2H, ArH), 5.25 (s, 2H, —CH.sub.2), 4.28 (brs, 4H, —CH.sub.2), 3.79 (brs, 2H, —CH.sub.2), 3.75 (brs, 2H, —CH.sub.2), 3.64 (s, 4H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d.sub.6): δ 156.90, 155.9, 154.45, 153.70, 149.66, 149.66, 147.57, 142.32, 132.85, 128.10, 128.10, 125.47, 125.44, 124.21, 124.21, 114.81, 114.81, 111.78, 110.44, 109.72, 73.03, 70.60, 70.44, 70.11, 68.93, 68.65, 68.54, 48.73. MS (ESI+) m/z: 542.9 [M+H].sup.+
Example 25
Synthesis of N-(3-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(110) Structural formula of N-(3-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine is as follows:
(111) ##STR00018##
(112) N-(3-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine was firstly synthesized in steps 25.1-25.7. Steps 25.1-25.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 3-aminophenol and 4-chloro-6,7-(benzo-15-crown-5)-4-quinazoline, respectively, as starting materials.
25.8 Synthesis of N-(3-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(113) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that 4-(trifluoromethyl)benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with 4-nitrobenzyl chloride and N-(3-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, respectively, as starting materials; the product was obtained as a yellow solid, yield 21%, m.p. 136-137° C.
(114) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.51 (s, 1H, —NH), 8.46 (s, 1H, ArH), 8.28 (d, J=8.60 Hz 2H, ArH), 7.95 (s, 1H, ArH), 7.76 (d, J=8.56 Hz, 2H, ArH), 7.72 (s, 1H, ArH), 7.46 (d, J=8.36 Hz, 1H, ArH), 7.30 (t, J=8.16 Hz, 1H, ArH), 7.17 (s, 1H, ArH), 6.78 (d, J=8.12 Hz, 1H, ArH), 5.31 (s, 2H, —CH.sub.2), 4.26 (brs, 2H, —CH.sub.2), 4.22 (brs, 2H, —CH.sub.2). 3.87 (brs, 2H, —CH.sub.2), 3.84 (brs, 2H, —CH.sub.2), 3.66 (s, 8H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d.sub.6): δ 157.87, 156.26, 153.54, 152.71, 148.03, 146.94, 146.87, 145.10, 140.95, 129.04, 128.11, 128.11, 123.49, 123.49, 114.80, 109.07, 109.07, 108.84, 107.78, 103.57, 70.25, 69.20, 69.13, 68.78, 68.27, 68.12, 68.04, 68.00, 67.87. MS (ESI+) m/z: 563.5 [M+H].sup.+
Example 26
Synthesis of N-(4-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(115) N-(4-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine was firstly synthesized in steps 26.1-26.7; steps 26.1-26.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline was replaced with 4-aminophenol and 4-chloro-6,7-(benzo-15-crown-5)-4-quinazoline, respectively, as starting material.
26.8 Synthesis of N-(4-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(116) The synthesis procedure was similar to that in step 7.8 of Example 7 except that 4-(trifluoromethyl)benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with 4-nitrobenzyl chloride and N-(4-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, respectively, as starting materials; the product was obtained as white solid in a yield of 16%, m.p. 209-210° C.
(117) .sup.1H NMR (400 MHz, DMSO-d 6): δ 9.42 (s, 1H, —NH), 8.38 (s, 1H, ArH), 8.28 (d, J=8.60 Hz, 2H, ArH), 7.87 (s, 1H, ArH), 7.75 (d, J=8.56 Hz, 2H, ArH), 7.67 (d, J=8.88 Hz, 2H, ArH), 7.14 (s, 1H, ArH), 7.07 (d, J=8.92 Hz, 2H, ArH), 5.30 (s, 2H, —CH.sub.2), 4.21 (brs, 4H, —CH.sub.2), 3.87 (brs, 2H, —CH.sub.2), 3.84 (brs, 2H, —CH.sub.2), 3.65 (brs, 8H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d 6): δ 156.49, 154.07, 153.54, 152.96, 148.04, 146.91, 146.76, 145.20, 132.85, 128.15, 128.15, 124.15, 124.15, 123.54, 123.54, 114.61, 114.61, 108.73, 107.79, 103.25, 70.53, 69.44, 69.35, 68.74, 68.44, 68.37, 68.31, 68.17, 68.02. MS (ESI+) m/z: 563.7 [M+H].sup.+
Example 27
Synthesis of N-(4-((phenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(118) N-(4-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine was firstly synthesized in steps 27.1-27.7; steps 27.1-27.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 4-aminophenol and 4-chloro-6,7-(benzo-15-crown-5)-4-quinazoline, respectively, as starting materials.
27.8 Synthesis of N-(4-((phenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(119) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that 4-(trifluoromethyl) benzyl bromide and N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine were replaced with benzyl chloride and N-(4-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine, respectively, as starting materials; the product was obtained as pale yellow solid in a yield of 21%, m.p. 215-216° C.
(120) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.36 (s, 1H, —NH), 8.38 (s, 1H, ArH), 7.83 (s, 1H, ArH), 7.63 (d, J=8.96 Hz, 2H, ArH), 7.48 (m, 2H, ArH), 7.41 (m, 2H, 7.35 (m, 1H, ArH), 7.14 (s, 1H, ArH), 7.04 (d, J=8.96 Hz, 2H, ArH), 5.12 (s, 2H, —CH.sub.2), 4.21 (brs, 4H, —CH.sub.2), 3.87 (brs, 2H, —CH.sub.2), 3.83 (brs, 2H, —CH.sub.2), 3.66 (s, 4H, —CH.sub.2), 3.65 (s, 4H, —CH.sub.2), .sup.13C NMR (100 MHz, DMSO-d.sub.6): δ 156.71, 154.79, 153.78, 153.18, 148.29, 146.93, 137.35, 132.63, 128.55, 128.55, 127.92, 127.80, 127.80, 124.36, 124.36, 114.76, 114.76, 108.89, 107.96, 103.29, 70.76, 70.76, 69.69, 69.60, 69.55, 68.96, 68.68, 68.53, 68.25. MS (ESI+) m/z: 518.8[M+H].sup.+
Example 28
Synthesis of N-(3-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(121) N-(3-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine was firstly synthesized in steps 28.1-28.7; steps 28.1-28.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 3-aminophenol and 4-chloro-6,7-(benzo-15-crown-5)-4-quinazoline, respectively, as starting materials.
28.8 Synthesis of N-(3-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(122) The synthesis procedure was similar to that in step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(3-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine as starting material; the product was obtained as white solid in a yield of 16%, m.p. 143-144° C.
(123) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.41 (s, 1H, —NH), 8.43 (s, 1H, ArH), 7.86 (s, 1H, ArH), 7.71 (m, 5H, ArH), 7.40 (d, J=8.8 Hz, 1H, ArH), 7.27 (t, J=8.0 Hz, 1H, ArH), 7.14 (s, 1H, ArH), 6.75 (d, J=8.4 Hz, 1H, ArH), 5.23 (s, 2H, —CH.sub.2), 4.20 (brs, 4H, —CH.sub.2), 3.85 (brs, 2H, —CH.sub.2), 3.82 (brs, 2H, —CH.sub.2), 3.63 (s, 8H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d.sub.6): δ 158.27, 156.38, 152.92, 152.89, 148.42, 147.15, 142.26, 140.99, 129.32, 128.55, 128.10, 125.74, 125.49, 125.46, 123.04, 114.85, 109.37, 109.11, 109.01, 107.99, 103.28, 70.77, 70.73, 69.66, 69.57, 68.99, 68.65, 68.50, 68.45, 68.27. MS (ESI+) m/z: 586.46 [M+H].sup.+
Example 29
Synthesis of N-(4-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(124) Structural formula of N-(4-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine is as follows:
(125) ##STR00019##
(126) N-(4-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine was firstly synthesized in steps 29.1-29.7; steps 29.1-29.7 were similar as steps 1.1-1.7 in Example 1, except that o-aminophenol and 4-chloro-6,7-(benzo-9-crown-3)-4-quinazoline were replaced with 4-aminophenol and 4-chloro-6,7-(benzo-15-crown-5)-4-quinazoline, respectively, as starting materials.
29.8 Synthesis of N-(4-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine
(127) The synthesis procedure was similar to that in Step 7.8 of Example 7 except that N-(2-hydroxyphenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine was replaced with N-(4-hydroxyphenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine as starting material; the product was obtained as pale yellow solid in a yield of 16%, m.p. 197-198° C.
(128) .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.34 (s, 1H, —NH), 8.36 (s, 1H, ArH), 7.82 (s, 1H, ArH), 7.75 (m, 2H, ArH), 7.65 (m, 3H, ArH), 7.11 (s, 1H, ArH), 7.04 (d, J=9.00 Hz, 2H, ArH), 5.22 (s, 2H, —CH.sub.2), 4.18 (brs, 4H, —CH.sub.2), 3.85 (brs, 2H, —CH.sub.2), 3.81 (brs, 2H, —CH.sub.2), 3.63 (s, 8H, —CH.sub.2). .sup.13C NMR (100 MHz, DMSO-d.sub.6): δ 156.67, 154.43, 153.80, 153.14, 148.29, 148.29, 146.93, 142.32, 132.88, 128.11, 128.11, 125.47, 125.44, 124.36, 124.36, 114.80, 114.80, 108.87, 107.98, 103.32, 70.78, 69.72, 69.72, 69.63, 69.63, 68.97, 68.97, 68.63, 68.29, 68.29. MS (ESI+) m/z: 586.8 [M+H].sup.+
Example 30
Synthesis of 2-(3-Fluoro-benzyloxy)-5-(7,8,10,11-tetrahydro-6,9,12-trioxa-1,3-diaza-cyclonona[b]naphthalen-4-ylamino)-benzonitrile
(129) Structural formula of 2-(3-Fluoro-benzyloxy)-5-(7,8,10,11-tetrahydro-6,9,12-trioxa-1,3-diaza-cyclonona[b]naphthalen-4-ylamino)-benzonitrile is as follows:
(130) ##STR00020##
(131) Steps 30.1-30.7 were similar with the steps 1.1-1.7 in Example 1.
(132) In the target compound of Example 30 represented by formula (I), n=0, R═CN; and ArCH.sub.2XC.sub.6H.sub.3RN— is 3-(((3-FC.sub.6H.sub.4)CH.sub.2O)C.sub.6H.sub.3CN)N—.
(133) The synthesis method for the compound of example 30 is as follows.
(134) ##STR00021##
(135) Into a 100 mL eggplant-shaped flask, 4-chloro-6,7-(benzo-9-crown-3) quinazoline (20 mmol) and isopropanol (15 mL) were sequentially added, heated to dissolve, and then 3-cyano-4-(3-fluorobenzyloxy) aniline (30 mmol) was added. The reaction mixture was heated to reflux. After reacting for about 2 h, yellow solid appeared, and the reaction was continued for 2 h. The completion of the reaction was monitored by TLC. The reaction solution was allowed to stand for cooling and then filtered with suction to give 0.22 g of pale yellow solid (yield: 28%) with a melting point of 220-222° C. .sup.1H NMR (400 MHz, DMSO-d6) δ 11.34 (d, J=23.6 Hz, 1H), 8.87 (s, 1H), 8.73 (d, J=9.3 Hz, 1H), 7.99 (d, J=2.5, 0.8 Hz, 1H), 7.78-7.66 (m, 1H), 7.54 (td, J=8.0, 6.0 Hz, 1H), 7.46 (d, J=2.9 Hz, 1H), 7.42-7.36 (m, 3H), 7.27 (dd, J=8.9, 2.1 Hz, 1H), 5.36 (s, 2H), 4.91-4.76 (m, 2H), 4.55-4.43 (m, 2H), 3.94 (dd, J=8.6, 5.7 Hz, 4H). .sup.13CNMR: 158.05, 156.85, 156.76, 156.58, 154.65, 153.87, 153.57, 151.52, 147.37, 145.18, 130.73, 128.37, 127.94, 125.55, 125.28, 117.76, 115.40, 115.16, 114.61, 111.00, 74.93, 72.72, 71.63, 71.54, 69.84. MS (ESI+) m/z: found 472.15 [M+H].sup.+
Example 31
Synthesis of 3-(3-Fluoro-benzyloxy)-5-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalen-4-ylamino)-benzonitrile
(136) Structural formula of 3-(3-Fluoro-benzyloxy)-5-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalen-4-ylamino)-benzonitrile is as follows:
(137) ##STR00022##
(138) Steps 31.1-31.7 were similar with the steps 1.1-1.7 in Example 1.
(139) In the target compound of Example 31 represented by formula (I), n=1, R═CN; and ArCH.sub.2XC.sub.6H.sub.3RN— is 3-(((3-FC.sub.6H.sub.4)CH.sub.2O)C.sub.6H.sub.3CN)N—.
(140) The synthesis method was similar to that of Example 30. The obtained product was a pale yellow solid with a melting point of 223-225° C. .sup.1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.90 (s, 1H), 8.70 (s, 1H), 7.98 (d, J=2.6 Hz, 1H), 7.73 (dd, J=8.9, 2.6 Hz, 1H), 7.55 (d, J=6.1 Hz, 1H), 7.48 (s, 1H), 7.43-7.35 (m, 3H), 7.29-7.21 (m, 1H), 5.36 (s, 2H), 4.42 (s, 4H), 3.92-3.77 (m, 4H), 3.67 (s, 4H). .sup.13CNMR: 158.24, 156.76, 156.35, 156.13, 154.75, 153.92, 153.80, 151.53, 147.29, 145.65, 131.24, 128.56, 127.82, 125.74, 125.42, 118.03, 116.12, 115.97, 114.71, 111.36, 73.16, 71.19, 70.97, 70.58, 69.18, 69.09, 68.93. MS (ESI+) m/z: found 516.18 [M+M].sup.+. Anal. calcd: C, 65.11; H, 4.88; F, 3.68; N, 10.85; O, 15.49.
Example 32
Synthesis of 4-(3-Fluoro-benzyloxy)-5-(2,5,8,11,14-pentaoxa-18,20-diaza-tricyclo[13.8.0.0.SUP.17,22.]tricosa-16,18,20,22-tetraen-21-ylamino)-benzonitrile
(141) Structural formula of 4-(3-Fluoro-benzyloxy)-5-(2,5,8,11,14-pentaoxa-18,20-diaza-tricyclo[13.8.0.0.sup.17,22]tricosa-16,18,20,22-tetraen-21-ylamino)-benzonitrile is as follows:
(142) ##STR00023##
(143) Steps 32.1-32.7 were similar with the steps 1.1-1.7 in Example 1.
(144) In the target compound of Example 32 represented by formula (I), n=2, R═CN; and ArCH.sub.2XC.sub.6H.sub.3RN— is 3-(((3-FC.sub.6H.sub.4)CH.sub.2O)C.sub.6H.sub.3CN)N—.
(145) The synthesis method was similar to that of Example 30. The obtained product was a pale yellow solid with a melting point of 217-218° C. .sup.1H NMR (400 MHz,) δ 11.04 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.65 (dd, J=8.9, 2.6 Hz, 1H), 7.44 (d, J=12.6, 7.1, 4.1 Hz, 1H), 7.24 (s, 4H), 7.17-7.11 (m, 1H), 5.24 (s, 2H), 4.28-4.15 (m, 4H), 3.84-3.78 (m, 4H), 3.60 (s, 8H). .sup.13CNMR: 157.17, 156.52, 156.24, 156.03, 154.77, 154.01, 153.59, 151.46, 146.90, 145.25, 130.84, 128.12, 127.98, 125.29, 125.06, 117.96, 115.72, 115.43, 114.61, 111.28, 70.85, 70.37, 69.55, 69.37, 68.42, 68.56, 68.47, 68.38, 68.17. MS (ESI+) m/z: found 562.22 [M+H].sup.+.
BIOLOGICAL EXAMPLES
Example 33
(146) In vitro anticancer activity of 35 target compounds was tested by MTT assay.
(147) Cell lines to be tested: human hepatoma cell line (HepG2), human lung cancer cell line (A549), human prostate cancer cell line (DU145), human breast cancer cell line (MCF-7), human neuroblastoma cell line (SH-SY5Y), human gastric mucosal cell line (Ges-1) and human embryonic lung fibroblast cell line (CCC-HPF-1) (the cells to be tested were purchased from the Cancer Hospital of Chinese Academy of Medical Sciences).
(148) The cells in logarithmic growth phase were treated to prepare a single cell suspension, with the cell density adjusted, which was seeded in a 96-well cell culture plate. About 2×10.sup.3 cells were contained in 100 μL per well, and cultured in a cell incubator at 37° C., 5% CO.sub.2, and saturated humidity for 24 h. The used medium was aspirated and abandoned, and then 100 μL of the target compound in different concentrations (0.1 μM-100 μM) were added for drug treatment. Five duplicate wells were prepared for each concentration. The background blank well, negative control well and positive control well were also prepared. All the wells were placed in a cell culture incubator at 37° C., 5% CO.sub.2, saturated humidity for another 72 h. Then, each well was added with 10 μL of MTT solution (5 mg/mL) and incubated for another 4 h. After that, each well was added with 100 μL of 10% SDS-0.1% NH.sub.4Cl (10% SDS purchased from Beijing Mengyimei Biotechnology Co., Ltd.) solution, and incubated at 37° C. for 10 h in the dark. Then, the absorbance OD was measured at 570 nm using a microplate reader at a reference wavelength of 650 nm. Cell proliferation inhibition was calculated according to the following formula: % inhibition=(OD.sub.control−OD.sub.treat)(OD.sub.control−OD.sub.blank)×100. IC.sub.50 value, i.e., 50% proliferation inhibition concentration, was calculated by SPSS 16.0 software. Each group was performed at least three times in parallel.
(149) The inhibitory activities of 35 target compounds against tumor cell strains HepG2, A549, MCF-7, DU145 and SH-SY5Y were tested by MTT assay (Table 1). Some compounds with optimal antitumor activity were selected. Among them, compounds 3, 5 and 13 have strong specific inhibitory activity on A549; compound 17 has a strong specific inhibitory effect on MCF-7; compound 23 has a strong specific inhibitory effect on DU145; compound 11 has a strong specific inhibitory effect on SH—SY5Y; compounds 29, 31, 34, and 35 have a good inhibitory effect on proliferation of at least three of the five tumor cells; especially, compound 35 has high anticancer activity on all the five tumor cells.
(150) Experiment of Compound 35 Against Hepatocellular Carcinoma HepG2 In Vivo
(151) Biological evaluation of exemplary compound 35 shown in formula (I) of the present invention (the serial number is shown in Table 1) and its combination with regorafenib or sorafenib in the treatment of nude mice bearing HepG2 cancer
(152) Compound 35 is N-(4-((4-trifluoromethylphenyl) methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine.
(153) Its structural formula is as follows:
(154) ##STR00024##
(155)
(156)
(157) As shown in
(158)
(159)
(160)
(161)
(162) The compound numbers shown in Table 1 below correspond to the following compounds:
(163) N-(2-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (1), N-(3-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (2), N-(4-((4-nitrophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (3), N-(2-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (4), N-(3-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (5), N-(4-((p-fluorophenyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (6), N-(2-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (7), N-(3-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (8), N-(4-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (9), N-(3-((4-cyanophenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (10), N-(4-((4-cyanophenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (11), N-(2-((4-pyridyl)methoxy)phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (12), N-(2-((3-chloro,4-fluorophenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (13), N-(3-((3-chloro,4-fluorophenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (14), N-(4-((3-chloro,4-fluorophenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine (15), N-(3-((p-fluorophenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (16), N-(4-((p-fluorophenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (17), N-(2-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (18), N-(3-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (19), N-(4-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (20), N-(3-((phenyl)methoxy)phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (21), N-(2-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (22), N-(3-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (23), N-(4-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine (24), N-(3-((p-fluorophenyl)methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (25), N-(4-((p-fluorophenyl)methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (26), N-(2-((phenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (27), N-(3-((phenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (28), N-(4-((phenyl)methoxy)phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (29), N-(2-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (30), N-(3-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (31), N-(4-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (32), N-(2-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (33), N-(3-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (34), N-(4-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-15-crown-5)-4-quinazolinamine (35), 2-(3-Fluoro-benzyloxy)-5-(7,8,10,11-tetrahydro-6,9,12-tri oxa-1,3-diaza-cyclonona[b]naphthalen-4-ylamino)-benzonitrile (36), 3-(3-Fluoro-benzyloxy)-5-(7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1,3-diaza-cyclododeca[b]naphthalen-4-ylamino)-benzonitrile (37), 4-(3-Fluoro-benzyloxy)-5-(2,5,8,11,14-pentaoxa-18,20-diaza-tricyclo[13.8.0.0.sup.17,22]tricosa-16,18,20,22-tetraen-21-ylamino)-benzonitrile (38), and Gefitinib. Their IC.sub.50 values for five common cells are also shown in Table 1.
(164) TABLE-US-00001 TABLE 1 Test results of tumor cell proliferation inhibition activity for some exemplary compounds of formula (I) of the present invention and the positive drug Tumor inhibition rate (IC.sub.50, μM) Compounds HepG2 SH-SY5Y A549 MCF-7 DU145 1 50.158 >100 28.424 >100 85.647 2 65.330 36.587 15.471 42.419 >100 3 >100 55.183 6.619 39.684 >100 4 >100 84.522 14.354 >100 >100 5 >100 55.320 7.843 78.235 >100 6 >100 82.683 43.256 65.217 >100 7 87.433 >100 >100 >100 >100 8 >100 19.273 >100 >100 >100 9 >100 30.422 >100 >100 >100 10 >100 >100 >100 >100 >100 11 67.384 9.886 81.339 >100 >100 12 31.256 >100 >100 >100 >100 13 >100 >100 9.429 >100 88.612 14 43.582 22.663 >100 >100 90.065 15 76.540 >100 >100 >100 >100 16 >100 22.835 >100 >100 >100 17 >100 20.669 >100 8.306 >100 18 60.765 75.493 29.86 >100 >100 19 >100 >100 >100 >100 >100 20 19.396 58.633 >100 66.505 >100 21 >100 22.835 >100 >100 >100 22 >100 >100 >100 >100 >100 23 33.956 20.026 24.893 17.625 2.756 24 >100 >100 >100 >100 >100 25 19.023 20.036 >100 >100 >100 26 55.468 39.282 43.949 >100 >100 27 29.244 24.000 48.531 >100 >100 28 55.468 39.282 43.949 >100 >100 29 11.863 5.254 29.454 11.965 8.798 30 48.055 >100 >100 >100 >100 31 9.817 8.416 19.785 6.410 13.846 32 >100 >100 >100 >100 >100 33 >100 >100 30.662 28.468 >100 34 5.696 8.561 8.516 8.478 26.87 35 3.336 2.138 8.564 10.025 8.803 36 >100 >100 3.518 >100 0.310 37 19.568 >100 0.455 >100 >100 38 2.770 1.287 14.464 2.797 0.803 Gefitinib 29.790 18.216 14.803 >100 >100
Example 34
(165) Effect of compound 3 of Formula (I) of the present invention (as listed in Table 1) on cell cycle
(166) Experiment procedure: A549 cells in logarithmic growth phase (purchased from the Cancer Hospital of Chinese Academy of Medical Sciences) were seeded into 6-well cell culture plates, adjusted to 5×10.sup.5 cells per well, and cultured in an incubator at 37° C., 5% CO.sub.2, and saturated humidity for 24 h. The used medium was discarded. The cells were treated with the target compounds in different concentrations for 48 h, and grouped to an administration group and a control group (non-administered). The cells were digested with 0.25% trypsin to form a single cell suspension, centrifuged at 1500 r/min for 5 min. The supernatant was discarded, and the cells were collected. The cells were washed twice with precooled PBS buffer, centrifuged at 1500 r/min for 5 min, added to 5 mL of precooled 70% ethanol, and placed at 4° C. for at least 24 h. After centrifugation, the supernatant was discarded, and the cells were washed twice with PBS and collected by centrifugation. The cells were suspended in 400 μL PBS, added with 30 μL of RNaseA (purchased from Corning Inc., USA) at the concentrations from 1 mg/mL to 50 μg/mL, and incubated at 37° C. for 30 min. The centrifuge tube was then inserted into an ice bath to stop digestion. After the tube was cooled, 50 μL of PI staining solution (500 μg/mL) (purchased from Corning Inc., USA) was added to a final concentration of 50 μg/mL. The tube was immersed in an ice bath to perform straining in the dark for 30 min-40 min, filtered through a 300 mesh nylon mesh, and tested by flow cytometer (FACS Vantage SE: BD, USA).
Compound 3: N-(4-((4-nitrophenyl) methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(167) TABLE-US-00002 TABLE 2 Effect of compound 3 of Formula (I) of the present invention on A549 cell cycle Groups Cell proportion, % (μM) G.sub.0/G.sub.1 G.sub.2/M S 0 83.71 ± 0.21 .sup.a 4.03 ± 0.10 .sup.a 12.25 ± 0.11 5 84.51 ± 0.32 .sup.a 3.06 ± 0.12 .sup. 12.42 ± 0.10 10 85.58 ± 0.44 .sup.a 3.05 ± 0.19 .sup. 11.39 ± 0.64 20 87.23 ± 0.31 .sup.a 1.41 ± 0.05 .sup.a 11.68 ± 0.26 40 90.08 ± 0.62 .sup.a 2.04 ± 0.14 .sup.a .sup. 7.90 ± 0.50 .sup.a Note: .sup.a indicates a comparison between experiment groups, P < 0.05.
(168) The present invention investigated compound 3 (as listed in Table 1) by cell cycle experiments. The cell cycle results indicate that the percentages of cells in G.sub.0/G.sub.1 phase increases gradually as the drug concentration increased. The percentage of cells in G.sub.0/G.sub.1 phase increases from 83.71% to 90.08% as the concentration increases from 0 μM to 40 μM, and the difference between the groups is significant (P<0.05). That is, compound 3 can block A549 in G.sub.0/G.sub.1 phase.
(169) It can be seen that compounds of formula (I) provided by the present invention can kill tumor cells in G.sub.0/G.sub.1 phase, indicating that the target compounds of formula (I) provided by the present invention belongs to a targeted medicine.
Example 35
(170) Biological evaluation of exemplary compound 3 of formula (I) of the present invention on nude mice bearing A549 cancer cells
Compound 3: N-(4-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine
(171) Structural formula of N-(4-((4-nitrophenyl)methoxy) phenyl)-6,7-(benzo-9-crown-3)-4-quinazolinamine is as follows:
(172) ##STR00025##
(173) The results in
(174)
(175) Both
Example 36
(176) Biological evaluation of exemplary compound 23 (as listed in Table 1) of formula (I) of the present invention on nude mice bearing DU145 cancer cells
Compound 23: N-(3-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine
(177) Structural formula of N-(3-((4-trifluoromethylphenyl)methoxy) phenyl)-6,7-(benzo-12-crown-4)-4-quinazolinamine is as follows:
(178) ##STR00026##
(179)
(180)
(181)
(182) Combining the experiment results of
(183) The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements, etc., made within the spirit and principle of the invention are intended to be included within the scope of the invention.