CN111138361B - Substituted phenoxy-2-azabicyclo [3.2.1] octane compounds and preparation method and application thereof - Google Patents

Substituted phenoxy-2-azabicyclo [3.2.1] octane compounds and preparation method and application thereof Download PDF

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CN111138361B
CN111138361B CN202010004479.1A CN202010004479A CN111138361B CN 111138361 B CN111138361 B CN 111138361B CN 202010004479 A CN202010004479 A CN 202010004479A CN 111138361 B CN111138361 B CN 111138361B
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azabicyclo
octane
benzyl
substituted phenoxy
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CN111138361A (en
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孟繁浩
张毅
张廷剑
涂顺
张振豪
李馨阳
王琳
赵楠
孙琦
梁经纬
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China Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to substituted phenoxy-2-azabicyclo [3.2.1]Octane compounds and a preparation method and application thereof. The substituted phenoxy-2-azabicyclo [3.2.1]The general structural formula I of the octane compound is as follows:

Description

Substituted phenoxy-2-azabicyclo [3.2.1] octane compounds and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a substituted phenoxy-2-azabicyclo [3.2.1] octane compound, and a preparation method and application thereof.
Background
Cancer is a malignant tumor that originates in epithelial tissues, and is characterized by rapid proliferation and metastasis of cells, with mortality rates leading to all diseases. Cancer has biological characteristics of abnormal cell differentiation and proliferation, uncontrolled growth, infiltrative and metastatic properties, and the occurrence of cancer is a complex process with multiple factors and multiple steps. According to the latest cancer data published by the international agency for research on cancer (IARC), 1810 ten thousand cancer cases are newly added in 2018 all over the world, the number of deaths reaches 960 ten thousand, and the global cancer burden is further increased. Lung cancer, breast cancer in women, and colorectal cancer have become the three most prevalent cancers worldwide, with mortality rates ranked first, fifth, and second, respectively.
Plants of the genus aconitum of the family ranunculaceae have been widely noticed as toxic plants and medicinal plants, and there are about more than 300 species in the whole world, more than half of which are distributed in china. The main pharmacological component of Aconitum plant is diterpene alkaloid, mainly including aconitine (aconitine), mesaconine (mesaconine) and hypaconine (hypaconine). Previous studies have focused on the pharmacological effects of aconite diterpene alkaloids on the cardiovascular system, such as the treatment of hypertension, tachycardia and arrhythmia. However, the efficacy of aconite diterpene alkaloids in anti-tumor therapy has recently attracted extensive attention from researchers. In order to evaluate the antitumor efficacy of aconitoid alkaloids, the subject group screened potential antitumor targets of aconitoid alkaloids by molecular docking studies and found the potential of aconitoid alkaloids as PARP-1 inhibitors and HSP90 inhibitors for cancer treatment (Med Chem Res,2016,25(6): 1-10.). However, aconite alkaloids have strong neurotoxicity and cardiotoxicity, and direct administration is limited in clinical application. The inventor further studies the structure-activity relationship of aconite alkaloids, and finds out the activity and toxicity change mechanism when different substituents exist on the aconite alkaloid skeleton (Molecules,2018,23(9): 2385.).
In order to search for aconitine antineoplastic drugs with high activity and low toxicity, the inventor selects 2-azabicyclo [3.2.1] octane (b) which retains an active low-toxicity part in an aconitine mother nucleus (a).
Figure BDA0002354731980000011
Meanwhile, in order to enhance the stability of the compound, the inventor connects benzyl on the nitrogen of a seven-membered ring to form a tertiary amine structure, connects phenoxy on the 4-position of the seven-membered ring to form an ether structure to delay the metabolism of the medicament in vivo, finds a series of substituted phenoxy-2-azabicyclo [3.2.1] octane compounds with novel structures and good antitumor activity, and does not report the prior art.
Disclosure of Invention
Aiming at the problems, the invention aims to provide a substituted phenoxy-2-azabicyclo [3.2.1] octane compound, a preparation method and application thereof, wherein the compound shows good effect in an in vitro anti-tumor activity test and can be used for preparing anti-tumor drugs.
In order to achieve the purpose, the invention adopts the following technical scheme.
A substituted phenoxy-2-azabicyclo [3.2.1] octane compound has a structural general formula I shown as follows,
Figure BDA0002354731980000021
wherein R is methyl, methoxy, cyano, fluorine, chlorine, bromine or nitro.
The substituted phenoxy-2-azabicyclo [3.2.1] octane compound is characterized in that the compound of the general formula I, the isomer, the pharmaceutically acceptable salt, the hydrate or the prodrug thereof is any one of the following compounds:
(1) (1R, 4R, 5S) -2-benzyl-4- (o-tolyloxy) -2-azabicyclo [3.2.1] octane (ZY 01);
(2) (1R, 4R, 5S) -2-benzyl-4- (m-tolyloxy) -2-azabicyclo [3.2.1] octane (ZY 02);
(3) (1R, 4R, 5S) -2-benzyl-4- (p-tolyloxy) -2-azabicyclo [3.2.1] octane (ZY 03);
(4) (1R, 4R, 5S) -2-benzyl-4- (o-methoxyphenoxy) -2-azabicyclo [3.2.1] octane (ZY 04);
(5) (1R, 4R, 5S) -2-benzyl-4- (m-methoxyphenoxy) -2-azabicyclo [3.2.1] octane (ZY 05);
(6) (1R, 4R, 5S) -2-benzyl-4- (p-methoxyphenoxy) -2-azabicyclo [3.2.1] octane (ZY 06);
(7) (1R, 4R, 5S) -2-benzyl-4- (2-cyanophenoxy) -2-azabicyclo [3.2.1] octane (ZY 07);
(8) (1R, 4R, 5S) -2-benzyl-4- (3-cyanophenoxy) -2-azabicyclo [3.2.1] octane (ZY 08);
(9) (1R, 4R, 5S) -2-benzyl-4- (4-cyanophenoxy) -2-azabicyclo [3.2.1] octane (ZY 09);
(10) (1R, 4R, 5S) -2-benzyl-4- (2-fluorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 10);
(11) (1R, 4R, 5S) -2-benzyl-4- (3-fluorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 11);
(12) (1R, 4R, 5S) -2-benzyl-4- (4-fluorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 12);
(13) (1R, 4R, 5S) -2-benzyl-4- (2-chlorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 13);
(14) (1R, 4R, 5S) -2-benzyl-4- (3-chlorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 14);
(15) (1R, 4R, 5S) -2-benzyl-4- (4-chlorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 15);
(16) (1R, 4R, 5S) -2-benzyl-4- (2-bromophenoxy) -2-azabicyclo [3.2.1] octane (ZY 16);
(17) (1R, 4R, 5S) -2-benzyl-4- (3-bromophenoxy) -2-azabicyclo [3.2.1] octane (ZY 17);
(18) (1R, 4R, 5S) -2-benzyl-4- (4-bromophenoxy) -2-azabicyclo [3.2.1] octane (ZY 18);
(19) (1R, 4R, 5S) -2-benzyl-4- (2-nitrophenoxy) -2-azabicyclo [3.2.1] octane (ZY 19);
(20) (1R, 4R, 5S) -2-benzyl-4- (3-nitrophenoxy) -2-azabicyclo [3.2.1] octane (ZY 20);
(21) (1R, 4R, 5S) -2-benzyl-4- (4-nitrophenoxy) -2-azabicyclo [3.2.1] octane (ZY 21);
however, the compound is not limited to the above compounds, and the compound structure satisfies the general structural formula, which is defined in the present invention.
A preparation method of substituted phenoxy-2-azabicyclo [3.2.1] octane compounds specifically comprises the following steps.
(1) The method comprises the steps of taking benzylamine hydrochloride as a starting material to react with ethyl glyoxylate to form Schiff base, and carrying out Diels-Alder addition on the Schiff base and cyclopentadiene to obtain the (1S, 3S, 4R) -2-benzyl-2-azabicyclo [2.2.1] hept-5-ene-3-carboxylic acid ethyl ester.
(2) The (1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] hept-5-ene-3-carboxylic acid ethyl ester is reduced by hydrogen and alkylated by benzyl chloride to prepare the (1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid ethyl ester.
(3) Reducing 1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid ethyl ester by lithium aluminum hydride, reacting with methylsulfonyl chloride, rephotographing, and expanding ring to obtain (1R, 4R, 5S) -2-benzyl-4-chlorine-2-azabicyclo [3.2.1] octane.
(4) The compound shown in the general formula I is obtained by alkylation reaction of (1R, 4R, 5S) -2-benzyl-4-chloro-2-azabicyclo [3.2.1] octane and substituted phenol.
A pharmaceutical composition comprises any one of the substituted phenoxy-2-azabicyclo [3.2.1] octane compounds, pharmaceutically acceptable salts, hydrates or solvates thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient, and is prepared into clinically acceptable dosage forms.
Further, the pharmaceutical composition, the pharmaceutically acceptable carrier or excipient comprises a diluent, an adjuvant and/or a carrier used in the pharmaceutical field.
Furthermore, the clinically acceptable dosage forms of the pharmaceutical composition comprise injections, tablets, capsules, aerosols, suppositories, membranes, dropping pills, external liniments and ointments.
The substituted phenoxy-2-azabicyclo [3.2.1] octane compound, and pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition thereof can be applied to the preparation of antitumor drugs.
Further, the substituted phenoxy-2-azabicyclo [3.2.1] octane compound, pharmaceutically acceptable salt, hydrate or solvate thereof or the composition is applied to preparation of antitumor drugs, wherein the drugs are drugs for resisting human lung cancer A549 cells, human liver cancer HepG2 cells and human breast cancer MCF-7 cells.
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the invention are derivatives of formula I which may themselves have poor or no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis, or otherwise) to the corresponding biologically active form.
The 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.
Compared with the prior art, the invention has the following beneficial effects.
(1) The invention designs and synthesizes a novel anti-tumor compound of substituted phenoxy-2-azabicyclo [3.2.1] octane.
(2) The compound has obvious effect in-vitro antitumor activity test and can be used for preparing antitumor drugs. Opens up a new way for the deep research and development of the anti-tumor drugs in the future.
(3) The preparation method of the compound is simple, convenient to operate and suitable for industrial production.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are provided to illustrate the present invention, but these examples are only for illustrating the present invention and the present invention is not limited to these.
A substituted phenoxy-2-azabicyclo [3.2.1] octane compound has a chemical structure general formula I:
Figure BDA0002354731980000041
wherein each R group is independently methyl, methoxy, cyano, fluoro, chloro, bromo, nitro.
The preparation of substituted phenoxy-2-azabicyclo [3.2.1] octanes is further illustrated by the following examples. Example 1 preparation of substituted phenoxy-2-azabicyclo [3.2.1] octanes.
Preparation of ethyl (1S, 3S, 4R) -2-benzyl-2-azabicyclo [2.2.1] hept-5-ene-3-carboxylate.
Into a 250mL reaction flask were charged benzylamine hydrochloride (29.0g,0.21mol), ethyl glyoxylate 50% toluene solution (50.0g,0.24mol) and water (25mL), and after stirring and dissolution, freshly distilled cyclopentadiene (26.0g,0.4mol) was added and the reaction was stirred at room temperature for 35 hours. After the reaction was complete, the reaction mixture was washed with diethyl ether and the aqueous layer was NaHCO3Adjusting pH to 9-10, extracting with ethyl acetate, washing the organic layer with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtain yellow oily product 30.3g, with yield: 53.1 percent.
Preparation of ethyl (1R, 3S, 4S) -2-azabicyclo [2.2.1] heptane-3-carboxylate.
(1S, 3S, 4R) -2-benzyl-2-azabicyclo [2.2.1] in a 100mL reaction flask]Hept-5-ene-3-carboxylic acid ethyl ester (10.0g,38.86mmol), 10% palladium on carbon catalyst (1.0g) and ethanol (70mL) in H2And stirring and reacting for 48 hours at normal temperature under the environment. After the reaction is finished, performing suction filtration, washing a filter cake for 2 times by using ethanol, performing column chromatography separation after decompression concentration to obtain a light yellow oily product 2.6g, wherein the yield is as follows: 39.5 percent.
Preparation of ethyl (1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylate.
To a 100mL reaction flask were added ethyl (1R, 3S, 4S) -2-azabicyclo [2.2.1] heptane-3-carboxylate (2.5g,14.77mmol), benzyl chloride (2.0g,16.25mmol) and acetonitrile (50mL), and anhydrous potassium carbonate (3.0g,22.16mmol) was added with stirring, followed by reaction with stirring at room temperature for 24 h. After the reaction is finished, performing suction filtration, washing a filter cake for 2 times by using acetonitrile, performing column chromatography separation after decompression concentration to obtain a colorless oily product 3.2g, wherein the yield is as follows: 83.5 percent.
Preparation of ((1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] hept-3-yl) methanol.
To a 250mL reaction flask were added (1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid ethyl ester (3.5g,13.50mmol) and tetrahydrofuran (100mL), -lithium aluminum hydride (2.0g,53.90mmol) was added slowly in portions with stirring at 10 deg.C, and after the reaction was continued for 1h with stirring at that temperature, it was taken out and reacted for 12h with stirring at room temperature. After the reaction is finished, slowly and sequentially dripping 2mL of water, 2mL of 10% NaOH solution and 6mL of water under stirring at-10 ℃, taking out, stirring at room temperature for 30min, carrying out suction filtration, washing a filter cake for 2 times by using tetrahydrofuran, and carrying out column chromatography separation after reduced pressure concentration to obtain 2.1g of a light yellow oily product, wherein the yield is as follows: 71.7 percent.
Preparation of (1R, 4R, 5S) -2-benzyl-4-chloro-2-azabicyclo [3.2.1] octane.
In a 100mL reaction flask were added ((1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] hept-3-yl) methanol (2.5g,11.50mmol), triethylamine (1.28g,12.65mmol) and dichloromethane (40mL), -methanesulfonyl chloride (1.58g,13.81mmol) in dichloromethane (10mL) was added dropwise with stirring at 5 ℃ and after stirring at that temperature for 1 hour, the reaction was taken out and stirred at room temperature overnight. After the reaction, water was added to separate an organic layer, a water layer was extracted with dichloromethane for 2 times, the organic layers were combined, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and then subjected to column chromatography to obtain 1.9g of a yellow oily product, yield: 70.1 percent.
Preparation of (1R, 4R, 5S) -2-benzyl-4- (substituted phenoxy) -2-azabicyclo [3.2.1] octane.
Adding (1R, 4R, 5S) -2-benzyl-4-chloro-2-azabicyclo [3.2.1] octane (0.3g,1.27mmol), substituted phenol (0.89mmol), potassium carbonate (0.53g,3.82mmol) and DMF (15mL) into a 100mL reaction bottle, carrying out reflux reaction at 80 ℃ for 12h, completely reacting, pouring into water, extracting an aqueous layer with ethyl acetate for 2 times, combining organic layers, washing the organic layers with saturated saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and carrying out column chromatography separation to obtain an oily product.
(1) (1R, 4R, 5S) -2-benzyl-4- (o-tolyloxy) -2-azabicyclo [3.2.1] octane (ZY 01).
Light brown oil, yield: 85.1 percent.1H NMR(500MHz,CDCl3)δ7.40(d,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,2H),7.24(t,J＝7.1Hz,1H),7.01–6.82(m,4H),4.13(s,1H),3.89(s,3H),3.57(d,J＝5.7Hz,2H),3.23(s,1H),2.94(d,J＝13.4Hz,1H),2.61(d,J＝4.2Hz,1H),2.46(dd,J＝39.7,11.9Hz,2H),1.93(s,1H),1.80–1.72(m,1H),1.43(d,J＝6.4Hz,2H),1.27–1.22(m,1H).13C NMR(126MHz,CDCl3)δ150.74,146.62,128.42,127.47,126.10,121.57,120.28,118.15,112.34,77.05,58.90,58.14,55.52,49.03,37.31,31.98,25.66,21.18。
(2) (1R, 4R, 5S) -2-benzyl-4- (m-tolyloxy) -2-azabicyclo [3.2.1] octane (ZY 02).
Light brown oil, yield: 82.7 percent.1H NMR(500MHz,CDCl3)δ7.39–7.27(m,5H),7.18(d,J＝7.1Hz,1H),7.10(d,J＝8.0Hz,1H),6.86(t,J＝7.2Hz,1H),6.78(d,J＝8.1Hz,1H),4.17(s,1H),3.58(t,J＝23.8Hz,2H),3.24(s,1H),2.89(dd,J＝13.0,7.3Hz,1H),2.63(s,1H),2.38(s,3H),2.27(s,1H),1.80(s,1H),1.40(s,1H),1.28(s,3H),0.98–0.80(m,1H).13C NMR(126MHz,CDCl3)δ152.73,148.76,129.43,128.46,127.11,122.67,121.78,119.96,113.43,79.21,59.02,57.45,56.24,48.31,36.12,32.86,26.15,20.08。
(3) (1R, 4R, 5S) -2-benzyl-4- (p-tolyloxy) -2-azabicyclo [3.2.1] octane (ZY 03).
Light brown oil, yield: 84.4 percent.1H NMR(500MHz,CDCl3)δ7.34(d,J＝7.3Hz,2H),7.27(t,J＝7.2Hz,2H),7.20(t,J＝7.1Hz,1H),7.04(d,J＝7.8Hz,2H),6.82(d,J＝7.6Hz,2H),4.07(s,1H),3.53(q,J＝13.4Hz,2H),3.19(s,1H),2.88(d,J＝13.2Hz,1H),2.55(d,J＝4.2Hz,1H),2.44(d,J＝13.0Hz,1H),2.36(d,J＝11.4Hz,1H),2.27(s,3H),1.89(s,1H),1.77–1.69(m,1H),1.39(d,J＝10.6Hz,2H),1.22–1.15(m,1H).13C NMR(126MHz,CDCl3)δ155.09,129.46,129.32,129.23,128.38,127.48,126.12,116.05,114.70,75.73,58.98,58.16,49.20,37.04,31.90,25.63,21.26,19.86。
(4) (1R, 4R, 5S) -2-benzyl-4- (o-methoxyphenoxy) -2-azabicyclo [3.2.1] octane (ZY 04).
Yellow oil, yield: 87.2 percent.1H NMR(500MHz,CDCl3)δ7.40(d,J＝7.2Hz,2H),7.31(t,J＝7.2Hz,2H),7.24(t,J＝7.1Hz,1H),7.01–6.81(m,4H),4.13(s,1H),3.89(s,3H),3.57(d,J＝5.7Hz,2H),3.23(s,1H),2.94(d,J＝13.4Hz,1H),2.61(d,J＝4.2Hz,1H),2.50(d,J＝11.3Hz,1H),2.42(d,J＝12.5Hz,1H),1.93(s,1H),1.81–1.73(m,1H),1.43(d,J＝6.4Hz,2H),1.27–1.22(m,1H).13C NMR(126MHz,CDCl3)δ150.74,128.42,127.47,126.10,121.57,120.28,118.15,112.34,58.90,58.14,55.52,49.03,37.31,25.66。
(5) (1R, 4R, 5S) -2-benzyl-4- (m-methoxyphenoxy) -2-azabicyclo [3.2.1] octane (ZY 05).
Yellow oil, yield: 88.6 percent.1H NMR(500MHz,CDCl3)δ7.38(d,J＝7.2Hz,2H),7.28(t,J＝7.2Hz,2H),7.20(t,J＝7.1Hz,1H),7.08–6.91(m,4H),4.09(s,1H),3.98(s,3H),3.75(d,J＝5.7Hz,2H),3.32(s,1H),2.49(d,J＝13.4Hz,1H),2.43(d,J＝4.2Hz,1H),2.40(d,J＝11.3Hz,1H),2.38(d,J＝12.5Hz,1H),1.93(s,1H),1.85–1.70(m,1H),1.33(d,J＝6.4Hz,2H),1.26–1.19(m,1H).13C NMR(126MHz,CDCl3)δ151.45,129.32,128.52,125.17,122.47,119.28,117.67,110.56,58.90,58.14,55.52,50.35,37.41,24.57。
(6) (1R, 4R, 5S) -2-benzyl-4- (p-methoxyphenoxy) -2-azabicyclo [3.2.1] octane (ZY 06).
Yellow oil, yield: 90.2 percent.1H NMR(500MHz,CDCl3)δ7.42–7.29(m,4H),7.27(d,J＝6.6Hz,1H),6.92(d,J＝8.0Hz,2H),6.84(d,J＝8.0Hz,2H),4.05(s,1H),3.80(s,3H),3.57(d,J＝16.2Hz,2H),3.25(s,1H),2.91(d,J＝13.4Hz,1H),2.58(s,1H),2.42(d,J＝10.5Hz,2H),1.93(s,1H),1.78(s,1H),1.44(s,2H),1.01–0.80(m,1H).13C NMR(126MHz,CDCl3)δ153.45,131.76,129.74,126.85,125.06,118.48,116.85,111.74,58.18,57.52,54.36,51.64,38.25,25.66。
(7) (1R, 4R, 5S) -2-benzyl-4- (2-cyanophenoxy) -2-azabicyclo [3.2.1] octane (ZY 07).
Light yellow oil, yield: 67.8 percent.1H NMR(500MHz,CDCl3)δ7.53(d,J＝7.6Hz,1H),7.44(t,J＝8.0Hz,1H),7.36(dd,J＝28.4,7.3Hz,4H),7.30–7.19(m,2H),6.96(t,J＝7.6Hz,1H),4.02–3.71(m,2H),3.66(t,J＝8.7Hz,1H),3.59(d,J＝5.9Hz,1H),3.26(d,J＝13.7Hz,1H),2.62–2.45(m,2H),2.06(d,J＝11.3Hz,1H),1.82(t,J＝15.6Hz,1H),1.71(dd,J＝14.7,10.2Hz,1H),1.42(dd,J＝17.8,10.7Hz,2H),1.29(d,J＝9.2Hz,2H).13C NMR(126MHz,CDCl3)δ160.10,133.57,133.02,128.94,128.50,127.63,126.39,119.88,115.89,114.81,111.70,54.77,39.45,34.88,28.32,21.89。
(8) (1R, 4R, 5S) -2-benzyl-4- (3-cyanophenoxy) -2-azabicyclo [3.2.1] octane (ZY 08).
Light yellow oil, yield: 65.4 percent.1H NMR(500MHz,CDCl3)δ7.33(dt,J＝15.4,8.4Hz,5H),7.22(dd,J＝25.3,17.5Hz,4H),4.17(s,1H),3.54(dd,J＝39.0,13.2Hz,2H),3.24(s,1H),2.85(d,J＝13.4Hz,1H),2.57(d,J＝4.0Hz,1H),2.48(d,J＝13.1Hz,1H),2.32(d,J＝11.5Hz,1H),1.93(s,1H),1.85–1.76(m,1H),1.45(d,J＝10.6Hz,2H),1.30–1.24(m,1H).13C NMR(126MHz,CDCl3)δ157.36,129.71,128.23,127.55,126.27,123.78,120.86,118.54,118.17,112.56,58.96,58.28,48.79,36.81,25.57,21.02。
(9) (1R, 4R, 5S) -2-benzyl-4- (4-cyanophenoxy) -2-azabicyclo [3.2.1] octane (ZY 09).
Light yellow oil, yield: 63.1 percent.1H NMR(500MHz,CDCl3)δ7.57–7.52(m,2H),7.35(s,4H),7.27(s,1H),6.98–6.91(m,2H),4.50(s,1H),3.53(dd,J＝38.6,13.2Hz,2H),3.18(s,1H),3.01(s,1H),2.54(s,1H),2.25(t,J＝10.2Hz,1H),1.84(d,J＝9.3Hz,2H),1.71(d,J＝11.4Hz,1H),1.63–1.51(m,2H),1.44(d,J＝3.6Hz,1H).13C NMR(126MHz,CDCl3)δ160.42,138.12,133.37,128.28,127.68,126.43,118.60,115.64,103.11,74.14,58.75,57.76,49.70,37.23,35.91,22.42,21.29。
(10) (1R, 4R, 5S) -2-benzyl-4- (2-fluorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 10).
Light brown oil, yield: 89.7 percent.1H NMR(600MHz,CDCl3)δ7.37–7.33(m,2H),7.27(dd,J＝10.3,4.7Hz,2H),7.20(t,J＝7.3Hz,1H),7.08–7.03(m,1H),7.00–6.94(m,2H),6.92–6.86(m,1H),4.10(s,1H),3.57(d,J＝13.5Hz,1H),3.49(d,J＝13.5Hz,1H),3.20(t,J＝4.6Hz,1H),2.87(d,J＝13.6Hz,1H),2.55(d,J＝6.0Hz,1H),2.47–2.39(m,2H),1.92–1.85(m,1H),1.73(dt,J＝12.6,7.1Hz,1H),1.46–1.36(m,2H),1.24–1.19(m,1H).13C NMR(151MHz,CDCl3)δ155.22,153.58,145.60,139.12,128.91,128.13,126.74,124.18,122.04,119.61,116.61,78.50,59.55,58.95,49.49,37.98,32.50,26.24,21.91。
(11) (1R, 4R, 5S) -2-benzyl-4- (3-fluorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 11).
Light brown oil, yield: 90.5 percent.1H NMR(500MHz,CDCl3)δ7.38–7.28(m,4H),7.23(dd,J＝16.2,8.0Hz,2H),6.72(d,J＝8.2Hz,1H),6.65(d,J＝9.9Hz,2H),4.14(s,1H),3.56(d,J＝15.8Hz,2H),3.24(s,1H),2.90(d,J＝13.4Hz,1H),2.63–2.42(m,2H),2.36(d,J＝11.4Hz,1H),1.93(s,1H),1.78(dd,J＝13.9,7.6Hz,1H),1.44(d,J＝10.5Hz,2H),1.27–1.22(m,1H).13C NMR(126MHz,CDCl3)δ164.03,162.08,129.52,128.32,127.53,114.89,111.36,106.75,103.10,75.54,58.92,58.20,48.93,36.88,25.57。
(12) (1R, 4R, 5S) -2-benzyl-4- (4-fluorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 12).
Light brown oil, yield: 87.0 percent.1H NMR(600MHz,CDCl3)δ7.34–7.30(m,2H),7.26(dd,J＝10.2,4.7Hz,2H),7.22–7.18(m,1H),6.95–6.88(m,2H),6.83(ddd,J＝9.6,4.9,2.7Hz,2H),4.02(t,J＝3.6Hz,1H),3.54(d,J＝13.4Hz,1H),3.47(d,J＝13.4Hz,1H),3.20(t,J＝4.7Hz,1H),2.87–2.81(m,1H),2.52(d,J＝6.0Hz,1H),2.43–2.32(m,2H),1.91–1.85(m,1H),1.77–1.70(m,1H),1.40(dddd,J＝14.9,12.3,9.5,3.4Hz,2H),1.23–1.18(m,1H).13C NMR(151MHz,CDCl3)δ158.16,156.58,153.88,153.87,138.74,129.06,128.17,126.88,118.01,117.96,115.85,115.70,77.02,59.69,58.95,49.60,37.62,32.64,26.26,21.71。
(13) (1R, 4R, 5S) -2-benzyl-4- (2-chlorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 13).
Brown oil, yield 92.8%.1H NMR(600MHz,CDCl3)δ7.40–7.33(m,3H),7.28–7.23(m,2H),7.19(t,J＝7.3Hz,1H),7.14–7.08(m,1H),6.91–6.83(m,2H),4.15(t,J＝3.4Hz,1H),3.65(d,J＝13.5Hz,1H),3.53(d,J＝13.5Hz,1H),3.22(t,J＝4.7Hz,1H),2.86(d,J＝13.7Hz,1H),2.59(dd,J＝10.6,4.7Hz,1H),2.53(d,J＝11.5Hz,1H),2.46(dd,J＝13.7,3.1Hz,1H),1.93–1.87(m,1H),1.79–1.70(m,1H),1.52–1.40(m,2H),1.21(dd,J＝10.7,5.1Hz,1H).13C NMR(101MHz,CDCl3)δ153.51,139.27,130.52,128.85,128.13,127.44,126.72,124.81,121.79,116.75,77.47,59.38,59.17,48.93,37.89,32.16,26.21,22.67。
(14) (1R, 4R, 5S) -2-benzyl-4- (3-chlorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 14).
Brown oil, yield 93.4%.1H NMR(500MHz,CDCl3)δ7.43–7.28(m,5H),7.26–7.10(m,2H),6.94(s,1H),6.83(d,J＝8.3Hz,1H),4.14(s,1H),3.69–3.44(m,2H),3.23(s,1H),2.90–2.84(m,1H),2.58(s,1H),2.35(d,J＝11.4Hz,1H),1.93(s,1H),1.82–1.75(m,1H),1.69(s,1H),1.45(s,2H),0.97–0.80(m,1H).13C NMR(101MHz,CDCl3)δ154.76,138.72,130.52,129.51,128.13,127.44,126.72,121.81,120.81,117.79,78.74,59.38,58.80,47.32,37.34,32.14,25.71,22.64。
(15) (1R, 4R, 5S) -2-benzyl-4- (4-chlorophenoxy) -2-azabicyclo [3.2.1] octane (ZY 15).
Brown oil, yield 92.2%.1H NMR(500MHz,CDCl3)δ7.35(d,J＝7.1Hz,3H),7.29(d,J＝7.6Hz,2H),7.22(d,J＝8.0Hz,2H),6.85(d,J＝8.1Hz,2H),4.11(s,1H),3.55(d,J＝17.6Hz,2H),3.24(s,1H),2.88(d,J＝13.5Hz,1H),2.47(d,J＝13.2Hz,2H),1.93(s,1H),1.44(d,J＝10.4Hz,4H),1.25(s,1H).13C NMR(101MHz,CDCl3)δ152.89,137.57,130.62,128.80,128.45,126.89,125.12,124.43,121.71,116.35,76.89,59.38,59.15,49.05,37.89,32.16,26.22,22.98。
(16) (1R, 4R, 5S) -2-benzyl-4- (2-bromophenoxy) -2-azabicyclo [3.2.1] octane (ZY 16).
Light yellow oil, yield 92.8%.1H NMR(500MHz,CDCl3)δ7.59(d,J＝7.8Hz,1H),7.41(d,J＝7.3Hz,2H),7.30(t,J＝7.6Hz,2H),7.26–7.18(m,2H),6.85(dd,J＝13.5,7.6Hz,2H),4.20(s,1H),3.73(d,J＝13.5Hz,1H),3.60(d,J＝13.3Hz,1H),3.28(s,1H),2.91(d,J＝13.7Hz,1H),2.62(dd,J＝23.0,8.0Hz,2H),1.95(s,1H),1.80(dd,J＝11.8,6.2Hz,1H),1.52(dt,J＝35.1,11.0Hz,2H),1.26(dd,J＝18.1,12.3Hz,2H).13C NMR(126MHz,CDCl3)δ153.71,132.97,128.16,127.54,127.49,126.07,121.47,115.44,113.44,58.68,58.64,48.12,37.21,31.44,25.54,22.31。
(17) (1R, 4R, 5S) -2-benzyl-4- (3-bromophenoxy) -2-azabicyclo [3.2.1] octane (ZY 17).
Pale yellow oil, yield 93.5%.1H NMR(500MHz,CDCl3)δ7.39–7.22(m,5H),7.19–7.01(m,3H),6.88(d,J＝8.1Hz,1H),4.14(s,1H),3.56(dd,J＝31.3,13.7Hz,2H),3.23(s,1H),2.88(d,J＝13.3Hz,1H),2.58(d,J＝4.3Hz,1H),2.49(d,J＝13.2Hz,1H),2.35(d,J＝11.5Hz,1H),1.93(s,1H),1.83–1.74(m,1H),1.45(t,J＝8.8Hz,2H),1.27–1.21(m,1H)。
(18) (1R, 4R, 5S) -2-benzyl-4- (4-bromophenoxy) -2-azabicyclo [3.2.1] octane (ZY 18).
Pale yellow oil, yield 93.6%.1H NMR(500MHz,CDCl3)δ7.79(d,J＝7.8Hz,1H),7.61(d,J＝7.3Hz,2H),7.57–7.41(m,1H),7.34(d,J＝4.2Hz,4H),7.28(d,J＝4.4Hz,1H),4.35(t,J＝6.7Hz,1H),4.20–4.10(m,1H),3.51(dd,J＝31.5,13.3Hz,2H),3.15(d,J＝4.2Hz,1H),2.99(dd,J＝11.3,5.5Hz,1H),2.49(s,1H),2.31(t,J＝11.0Hz,1H),1.98–1.92(m,1H),1.81–1.73(m,2H),1.41(s,1H),1.21(s,1H).13C NMR(126MHz,CDCl3)δ167.05,133.39,131.77,130.28,128.24,128.15,127.65,126.40,115.00,76.73,76.48,76.23,58.58,57.57,53.45,42.04,37.99,22.71,21.62。
(19) (1R, 4R, 5S) -2-benzyl-4- (2-nitrophenoxy) -2-azabicyclo [3.2.1] octane (ZY 19).
Light yellow oil, yield 73.7%.1H NMR(500MHz,CDCl3)δ7.80(d,J＝8.1Hz,1H),7.74(d,J＝1.2Hz,1H),7.41–7.33(m,3H),7.31–7.22(m,4H),4.26(s,1H),3.55(dd,J＝37.4,13.4Hz,2H),3.25(s,1H),2.88(d,J＝14.0Hz,1H),2.60(d,J＝4.4Hz,1H),2.51(d,J＝13.2Hz,1H),2.34(d,J＝11.5Hz,1H),1.94(s,1H),1.82(d,J＝5.7Hz,1H),1.49(d,J＝10.6Hz,2H),1.27(d,J＝10.6Hz,1H).13C NMR(126MHz,CDCl3)δ157.81,148.63,129.29,128.24,127.54,126.26,122.58,115.03,109.79,75.94,58.96,58.27,48.82,36.81,25.59,21.00。
(20) (1R, 4R, 5S) -2-benzyl-4- (3-nitrophenoxy) -2-azabicyclo [3.2.1] octane (ZY 20).
Light yellow oil, yield 69.1%.1H NMR(500MHz,CDCl3)δ7.80(d,J＝8.0Hz,1H),7.58(d,J＝1.3Hz,1H),7.50-–7.41(m,3H),7.34–7.28(m,4H),4.29(s,1H),3.65(dd,J＝37.6,12.4Hz,2H),3.34(s,1H),2.73(d,J＝14.0Hz,1H),2.57(d,J＝4.2Hz,1H),2.47(d,J＝13.2Hz,1H),2.36(d,J＝11.5Hz,1H),1.82(s,1H),1.79(d,J＝5.7Hz,1H),1.43(d,J＝10.6Hz,2H),1.31(d,J＝10.5Hz,1H).13C NMR(126MHz,CDCl3)δ159.27,147.45,128.81,127.51,126.334,125.73,121.94,113.49,107.08,73.50,58.76,57.89,47.37,35.29,23.52,20.40。
(21) (1R, 4R, 5S) -2-benzyl-4- (4-nitrophenoxy) -2-azabicyclo [3.2.1] octane (ZY 21).
Pale yellow oil, yield 71.6%.1H NMR(500MHz,CDCl3)δ7.81(dd,J＝32.5,4.7Hz,2H),7.46(t,J＝8.1Hz,1H),7.40(d,J＝7.7Hz,2H),7.36–7.23(m,4H),4.30(s,1H),3.63(d,J＝13.3Hz,1H),3.55(d,J＝13.4Hz,1H),3.29(s,1H),2.91(s,1H),2.60(dd,J＝45.1,8.8Hz,2H),2.37(t,J＝16.0Hz,1H),2.04–1.81(m,2H),1.53(d,J＝10.6Hz,2H),1.32(d,J＝10.6Hz,1H).13C NMR(126MHz,CDCl3)δ158.14,149.32,128.989,127.41,126.42,126.26,121.85,114.36,108.93,74.82,57.68,56.71,49.29,37.14,25.51,21.17。
Example 2 tumor cell proliferation inhibition assay of the target compound.
The compound of the invention is subjected to tumor cell proliferation inhibition experiments, and the test method adopts a conventional MTT method.
Culturing of tumor cells: the cell strain is cultured by using A549 (human lung cancer cell), HepG2 (human liver cancer cell) and MCF-7 (human breast cancer cell) in a culture solution of RPMI1640+ 10% FBS + double antibody (penicillin 100 unit/ml, streptomycin 100 mu g/ml).
Sample preparation: after dissolution in DMSO (Merck), media (-) is added to make a 1000. mu.g/ml solution or homogeneous suspension, which is then diluted with DMSO-containing media (-). The final concentrations were: 0.5. mu.M, 0.25. mu.M, 0.125. mu.M, 0.0625. mu.M, 0.03125. mu.M. Pemetrexed (PTX) was used as a control.
Test methods for inhibition of cell proliferation: the adding concentration of each hole of the 96-hole plate is 4-5 multiplied by 104Mu.l of cell suspension per ml, placed at 37 ℃ in 5% CO2In the incubator. After 24 hours, the sample solution and the control solution were added to each well at 10. mu.l/well in duplicate, 37 ℃ with 5% CO2The reaction was carried out for 24 hours. Adding 20 μ l of 5mg/ml MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide) solution into each well, reacting for 4 hr, adding DMSO solution into each well, placing in incubator at 150 μ l/well, dissolving, measuring 570nm OD value with MK-2 full-automatic enzyme standard instrument, and calculating inhibitory concentration IC50. The results are shown in Table 1.
TABLE 1 in vitro proliferation inhibition Activity of samples on human tumor cells IC50Value of
Figure BDA0002354731980000111
Figure BDA0002354731980000121
Experiments prove that the compounds show good effects in-vitro tumor cell proliferation inhibition experiments.

Claims (8)

1. A substituted phenoxy-2-azabicyclo [3.2.1] octane compound shown as a general formula I or a pharmaceutically acceptable salt thereof, which is characterized in that: formula I is shown below:
Figure DEST_PATH_IMAGE001
，
wherein R is methyl, methoxy, cyano, fluorine, chlorine, bromine or nitro.
2. The substituted phenoxy-2-azabicyclo [3.2.1] octane of claim 1 or pharmaceutically acceptable salt thereof wherein the compound of formula i is any one of the following:
(1R, 4R, 5S) -2-benzyl-4- (o-tolyloxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (m-tolyloxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (p-tolyloxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (o-methoxyphenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (m-methoxyphenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (p-methoxyphenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (2-cyanophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (3-cyanophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (4-cyanophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (2-fluorophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (3-fluorophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (4-fluorophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (2-chlorophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (3-chlorophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (4-chlorophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (2-bromophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (3-bromophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (4-bromophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (2-nitrophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (3-nitrophenoxy) -2-azabicyclo [3.2.1] octane;
(1R, 4R, 5S) -2-benzyl-4- (4-nitrophenoxy) -2-azabicyclo [3.2.1] octane.
3. A method for preparing a substituted phenoxy-2-azabicyclo [3.2.1] octane compound according to claim 1, comprising the steps of:
(1) reacting benzylamine hydrochloride serving as a starting material with ethyl glyoxylate to form Schiff base, and carrying out Diels-Alder addition on the Schiff base and cyclopentadiene to obtain (1S, 3S, 4R) -2-benzyl-2-azabicyclo [2.2.1] hept-5-ene-3-carboxylic acid ethyl ester;
(2) the (1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] hept-5-ene-3-carboxylic acid ethyl ester is reduced by hydrogen and alkylated by benzyl chloride to prepare (1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid ethyl ester;
(3) reducing (1R, 3S, 4S) -2-benzyl-2-azabicyclo [2.2.1] heptane-3-carboxylic acid ethyl ester by lithium aluminum hydride, and then carrying out rearrangement reaction with methylsulfonyl chloride to expand rings to obtain (1R, 4R, 5S) -2-benzyl-4-chlorine-2-azabicyclo [3.2.1] octane;
(4) the compound shown in the general formula I is obtained by alkylation reaction of (1R, 4R, 5S) -2-benzyl-4-chloro-2-azabicyclo [3.2.1] octane and substituted phenol.
4. A pharmaceutical composition comprising the substituted phenoxy-2-azabicyclo [3.2.1] octane compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient, and formulated into a clinically acceptable dosage form.
5. A pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable carrier or excipient comprises diluents, adjuvants and/or carriers useful in the pharmaceutical field.
6. The pharmaceutical composition of claim 4, wherein the clinically acceptable dosage form comprises injections, tablets, capsules, aerosols, suppositories, films, dropping pills, liniments for external use, ointments.
7. Use of a substituted phenoxy-2-azabicyclo [3.2.1] octane compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 4-6 in the preparation of an anti-neoplastic drug.
8. The use of claim 7, wherein the anti-tumor drug is a drug against human lung cancer a549 cells, human liver cancer HepG2 cells, and human breast cancer MCF-7 cells.
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Publication number Priority date Publication date Assignee Title
CN102452981A (en) * 2010-11-03 2012-05-16 上海药明康德新药开发有限公司 1,3-disubstituted-3-azabicyclo [3,2,1] octane derivatives and preparation method thereof
CN106061973A (en) * 2013-12-05 2016-10-26 辉瑞公司 Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102452981A (en) * 2010-11-03 2012-05-16 上海药明康德新药开发有限公司 1,3-disubstituted-3-azabicyclo [3,2,1] octane derivatives and preparation method thereof
CN106061973A (en) * 2013-12-05 2016-10-26 辉瑞公司 Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Novel chiral bridged azepanes: stereoselective ring expansion of 2-azanorbornan-3-yl methanols";Elzbieta Wojaczynska等;《Tetrahedron》;20120720;第68卷;第7848-7854页 *

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