Synthesis and antiviral activity of 5-heteroaryl-substituted 2'-deoxyuridines

The synthesis of 5-heteroaryl-substituted 2'-deoxyuridines is described. The heteroaromatics were obtained from three different 5-substituted 2'-deoxyuridines. Cycloaddition reaction of nitrile oxides on the 5-ethynyl derivative 1 gave the isoxazoles 4a-e. The thiazole derivatives 14a-c were obtained from the 5-thiocarboxamide 11, while 5-pyrrol-1-yl-2'-deoxyuridine (17) could be synthesized directly from 5-amino-2'-deoxyuridine. The compounds were evaluated for antiviral activity. Selective activity against herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) was noted for 5-(3-bromoisoxazol-5-yl)-2'-deoxyuridine (4c). The compound was inactive against herpes simplex virus type 2, cytomegalovirus, and thymidine kinase (TK)-deficient mutants of HSV-1 and VZV, which indicates that, most likely, its antiviral activity depends on phosphorylation by the virus-specified TK.     

Synthesis and antiviral properties of 5-(2-substituted vinyl)-6-aza-2'-deoxyuridines

The following 5-(2-substituted vinyl)-6-aza-2'-deoxyuridines were synthesized: (E)-5-(2-bromovinyl) (2) (6-aza-BVDU), 5-(2-bromo-2-fluorovinyl) (a mixture of E and Z isomers) (3), (E)-5-(2-chlorovinyl) (4), (E)-5-[2-(methylthio)vinyl] (5), 5-(2,2-dibromovinyl) (6), and 5-(3-furyl) (7). The synthesis of 2-6 utilized Wittig-type reactions on 5-formyl-1-(2'-deoxy-3', 5'-di-O-p-toluoyl-beta-D-erythro-pentofuranosyl)-6-azauracil (16). 6-Aza-BVDU (and its alpha-anomer) was also synthesized from (E)-5-(2-bromovinyl)-6-azauracil (12) by using standard deoxyribosidation methodology. Compound 7 was prepared from 5-(3-furyl)-6-azauracil (33) via a ribosidation/deoxygenation sequence. An attempt to prepare the corresponding 5-(2,2-difluorovinyl) analogue afforded instead a mixture of the 5-[(2,2-difluoro-2-methoxy)ethyl] and 5-(2,2,2-trifluoroethyl) derivatives 29 and 30. Compounds 2-7, 29, and 30 were tested for in vitro activity against herpes simplex virus types 1 and 2 (HSV-1, HSV-2). 6-Aza-BVDU (2) exhibited ID50s of 8 micrograms/mL vs. HSV-1 and 190 micrograms/mL vs. HSV-2. BVDU (1) had ID50s of 0.015 and 1.6 micrograms/mL against HSV-1 and HSV-2, respectively. Compound 4 showed a similar profile of activity, but the other analogues were either weakly active or inactive.     

Synthesis and antiviral activity of the carbocyclic analogues of 5-ethyl-2'-deoxyuridine and of 5-ethynyl-2'-deoxyuridine

The carbocyclic analogue of the antiviral agent 5-ethyl-2'-deoxyuridine (EDU) was synthesized by two routes. The pivotal step in the first route is the reaction of lithium dimethylcuprate with the carbocyclic analogue of 5-(bromomethyl)-2'-deoxyuridine dibenzoate (6). The second route is based on the synthesis of the carbocyclic analogue of 5-ethynyl-2'-deoxyuridine (12) by a coupling reaction catalyzed by bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide, a method reported recently (Robins and Barr) for the synthesis of the true nucleoside 5-ethynyl-2'-deoxyuridine (1b). The carbocyclic analogue of EDU inhibits the replication of type 1 and type 2 herpes simplex viruses in Vero cells. The carbocyclic analogue of 5-ethynyl-2'-deoxyuridine has modest activity against herpes simplex virus, types 1 and 2.     

Synthesis of 5-[1-hydroxy(or methoxy)-2-bromo(or chloro)ethyl]-2'-deoxyuridines and related halohydrin analogues with antiviral and cytotoxic activity

A series of new 5-(1-hydroxy-2-haloethyl)-2'-deoxyuridines (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2'-deoxyuridines (2, 5, 7). Treatment of 3a,b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2'-(deoxyuridines (4a,b). The 5-(1-hydroxy-2-chloroethyl) (3b), 5-(1-methoxy-2-bromoethyl) (4a), 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl) (6a), and 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl) (6b) derivatives exhibited in vitro antiviral activity (ID50 = 0.1-1 microgram/mL range) against herpes simplex virus type 1 (HSV-1). 5-(1-Hydroxy-2-bromo-2-(ethoxycarbonyl)-ethyl)-2'-deoxyuridine (6a) was the most active cytotoxic agent in the in vitro L1210 screen exhibiting an ED50 of 11 micrograms/mL relative to melphalan (ED50 = 0.15 micrograms/mL).     

Synthesis and antiviral activity of (E)-5-(2-bromovinyl)uracil and (E)-5-(2-bromovinyl)uridine

(E)-5-(2-Bromovinyl)uracil (BVU) and (E)-5-(2-bromovinyl)uridine (BVRU) were synthesized starting from 5-formyluracil via (E)-5-(2-carboxyvinyl)uracil or starting from 5-iodouridine via (E)-5-(2-carbomethoxyvinyl)uridine and (E)-5-(2-carboxyvinyl)uridine, respectively. Depending on the choice of the cell system, BVU and BVRU exhibited a marked activity against herpes simplex virus type 1 (HSV-1) in vitro. Although BVU and BVRU were less potent than the reference compound (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), their antiviral activity spectrum was remarkably similar to that of BVDU. The latter findings suggest that BVU and BVRU are metabolically converted to BVDU or a phosphorylated product thereof. In vivo, BVU protected mice against a lethal disseminated HSV-1 infection.     

Fluoro carbocyclic nucleosides: synthesis and antiviral activity of 2'- and 6'-fluoro carbocyclic pyrimidine nucleosides including carbocyclic 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-methyluracil and carbocyclic 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil

The racemic carbocyclic 2'-fluoroarabinosyl pyrimidine nucleosides 8, 9 (C-FIAU), 12, and 13 (C-FMAU) and the 2'-fluororibosyl pyrimidine nucleosides 17, 20, and 21 were prepared from their respective protected 2'-fluoro amino diols 5 and 14. The carbocyclic 2'-2'-difluorothymidine analogue 27 was obtained from the protected difluoro amino diol 24 which was prepared from the ketone 23 and (diethylamino)sulfur trifluoride (DAST). The chiral carbocyclic 2'-deoxy-6'-fluorouridines 33, 34, 38, and 39 were synthesized from the protected 6'-fluoro amino diols 30 and 36, which were prepared by reduction of the azides 28 and 35. C-FMAU (13) and C-FIAU (9) were active in vitro against HSV-1 with ID50 values of 4.4 and 11 micrograms/mL, respectively, but they were inactive against HSV-2. The cytidine analogues 12 and 20 displayed modest activity in vitro against HSV-1 and HSV-2 but were inactive against human influenza A virus.     

Synthesis, antiviral and cytotoxic activity of 2'-deoxyuridines, 2'-fluoro-2'-deoxyuridines and 2'-arabinouridines containing 5-(1-hydroxy-2-halo-2-ethoxycarbonylethyl)-, 5-(1-hydroxy-2-iodo-2- carboxyethyl)- and 5-[1-hydroxy (or methoxy)-2-iodoethyl] substituents.

The 5-[1-hydroxy-2-chloro-2-(ethoxycarbonyl)ethyl]-2'-deoxyuridine (7) and 5-[1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl]-2'- fluoro-2'-deoxyuridine/uridine nucleosides (8, 9) were synthesized by the regiospecific addition of HOX (X = Br or Cl) to the vinyl substituent of the respective (E)-5-[2-(ethoxycarbonyl)-vinyl]-2'-deoxyuridines (6a-b) and uridine (6c). A related reaction of (E)-5-(2-carboxyvinyl)-2'-deoxyuridines (10a-b) and uridine (10c) with iodine and potassium iodate afforded the 5-(1-hydroxy-2-iodo-2-carboxyethyl) derivatives (11-13). 5-(1-Hydroxy-2-iodoethyl)-arabinouridine (18) was obtained by the reaction of (17) with iodine in the presence of the oxidizing agent iodic acid. Treatment of (18) with methanolic sulfuric acid afforded 5-(1-methoxy-2-iodoethyl)-arabinouridine (19) in 65% yield. Of the newly synthesized compounds, 7, 11 and 12 showed activity in vitro against HSV-1. The most active compound (12, ID50 = 0.1 microgram/ml) was 10 times less active than acyclovir (ID50 = 0.01 microgram/ml) against HSV-1. Compounds 7 and 11 were cytotoxic to L1210 cells in culture, exhibiting an ED50 of 7.2 and 4.7 micrograms/ml respectively, relative to melphalan (ED50 = 0.15 microgram/ml), but were inactive against the KB cell line.     

Synthesis and antiviral properties of (E)-5-(2-bromovinyl)-2'-deoxycytidine-related compounds

Treatment of 3',5'-di-O-acetyl-(E)-5-(2-bromovinyl)-2'-deoxyuridine (2) with p-chlorophenyl phosphorodichloridate and 1,2,4-triazole gave 1-(3,5-di-O-acetyl-2-deoxy-beta-D-erythro-pentofuranosyl)-(E)-5-(2-br o movinyl)- 4-(1,2,4-triazol-1-yl)pyrimidin-2(1H)-one (3). Reaction of 3 with ammonia gave (E)-5-(2-bromovinyl)-2'-deoxycytidine (1), the overall yield from 2 being 60%. A similar 4-(1,2,4-triazol-1-yl) derivative (4) was obtained from 3',5'-di-O-acetyl-thymidine by the use of phosphoryl chloride as the condensing agent. Treatment of thymidine with trimethylsilyl chloride and then with phosphoryl chloride and 1,2,4-triazole gave upon workup 1-(2-deoxy-beta-D-erythro-pentofuranosyl)-5-methyl-4(1,2,4-triazol -1-yl) pyrimidin-2(1H)-one (5). (E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU) when similarly treated gave the corresponding (E)-5-(2-bromovinyl) compound 7. A minor product formed in both cases was a 4-(1,2,4-triazol-1-yl) derivative in which the nucleoside 5'-hydroxyl group had been replaced by chlorine (6 and 8). Whereas compounds 4-6 and 8 did not exhibit a selective antiviral effect, compounds 1-3 and 7 proved almost as active as the reference compound BVDU. In particular, compound 7, the 4-triazolyl derivative of BVDU, would seem worth pursuing for its potential as an inhibitor of herpes simplex virus type 1 and varicella-zoster virus.     

Synthesis and antiviral activity of the enantiomeric forms of carba-5-iodo-2'-deoxyuridine and carba-(E)-5-(2-bromovinyl)-2'-deoxyuridine

Both enantiomers of the carbocyclic analogues of 5-iodo-2'-deoxyuridine (14 and ent-14) and of (E)-5-(2-bromo-vinyl)-2'-deoxyuridine (16 and ent-16) were synthesized by using (+)- or (-)-endo-norborn-5-en-2-yl acetate or butyrate, respectively, as starting materials. Against herpes simplex virus type 1 (+)-C-BVDU (16) was only slightly less active than BVDU itself, whereas (-)-C-BVDU (ent-16) proved to be 10-400-fold less effective, depending on the strain investigated. Against HSV-2 both (+)- and (-)-C-BVDU as well as (+)- and (-)-C-IDU showed minor activity. All carbocyclic analogues were inactive against TK-HSV-1 strains, pointing to the prerequisite of phosphorylation (activation) by the viral thymidine kinase (TK).     

5-(Haloalkyl)-2'-deoxyuridines: a novel type of potent antiviral nucleoside analogue

Syntheses of 5-(2-haloethyl)-2'-deoxyuridines, 5-(3-chloropropyl)-2'-deoxyuridines, and 5-(2-chloroethyl)-2'-deoxycytidine are described. The antiviral activities of these compounds were determined in cell culture against herpes simplex virus types 1 and 2. All compounds were shown to possess significant and selective antiviral activity. The most potent derivative, 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), inhibited HSV-1 at concentrations below 0.1 microgram/mL. It exerted measurable inhibitory effects on cell proliferation only at concentrations higher than 100 micrograms/mL. In vivo CEDU reduced the mortality rate of HSV-1-infected mice at concentrations lower than 5 mg/kg per day when given intraperitoneally and orally. Thus, it proved to be more effective in this in vivo model than the reference compounds (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 9-[(2-hydroxyethoxy)methyl]guanine (ACV).     

Synthesis and antiviral activity of 1-cyclobutyl-5-(2-bromovinyl)uracil nucleoside analogues and related compounds.

A series of racemic (1 alpha (E), 2 beta, 3 alpha)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-(2-halovinyl)uracils was synthesized and evaluated in cell culture. The bromovinyl, iodovinyl, and chlorovinyl analogues, 13, 15, and 16, respectively, are all potent inhibitors of varicella zoster virus (VZV), but are less inhibitory to the replication of human cytomegalovirus (HCMV) and herpes simplex viruses 1 and 2 (HSV-1, HSV-2). The excellent anti-VZV activities of 13, 15, and 16 coupled with their virtual inability to inhibit WI-38 cell growth indicate high in vitro therapeutic indices. VZV thymidine kinase readily converts these compounds to their respective monophosphates but not to their corresponding diphosphates. Compound 13a, the (1'R) enantiomer of the bromovinyl analogue 13, was also synthesized, and its potency is comparable to that of the racemate. A lower homologue 14, (1 alpha (E),2 beta, 3 alpha)-1-[2-hydroxy-3-(hydroxymethyl)cyclobutyl]-5- (2-bromovinyl)uracil, was found to be inactive against VZV, HCMV, HSV-1, and HSV-2.     

Synthesis and antiviral activity of novel 5-(1-cyanamido-2-haloethyl) and 5-(1-hydroxy(or methoxy)-2-azidoethyl) analogues of uracil nucleosides

A new class of 5-(1-cyanamido-2-haloethyl)-2'-deoxyuridines (4-6) and arabinouridines (7, 8) were synthesized by the regiospecific addition of halogenocyanamides (X-NHCN) to the 5-vinyl substituent of the respective 5-vinyl-2'-deoxyuridine (2) and 2'-arabinouridine (3). Reaction of 2 with sodium azide, ceric ammonium nitrate, and acetonitrile-methanol or water afforded the 5-(1-hydroxy-2-azidoethyl)-(10) and 5-(1-methoxy-2-azidoethyl)-2'-deoxyuridines (11). In vitro antiviral activities against HSV-1-TK(+) (KOS and E-377), HSV-1-TK(-), HSV-2, VZV, HCMV, and DHBV were determined. Of the newly synthesized compounds, 5-(1-cyanamido-2-iodoethyl)-2'-deoxyuridine (6) exhibited the most potent anti-HSV-1 activity, which was equipotent to acyclovir and superior to 5-ethyl-2'-deoxyuridine (EDU). In addition, it was significantly inhibitory for thymidine kinase deficient strain of HSV-1 (EC(50) = 2.3-15.3 microM). The 5-(1-cyanamido-2-haloethyl)-2'-deoxyuridines (4-6) all were approximately equipotent against HSV-2 and were approximately 1.5- and 15-fold less inhibitory for HSV-2 than EDU and acyclovir, respectively. Compounds 4-6 were all inactive against HCMV but exhibited appreciable antiviral activity against VZV. Their anti-VZV activity was similar or higher to that of EDU and approximately 5-12-fold lower than that of acyclovir. The 5-(1-cyanamido-2-haloethyl)-(7,8) analogues of arabinouridine were moderately inhibitory for VZV and HSV-1 (strain KOS), whereas compounds 10 and 11 were inactive against herpes viruses. Compounds 5 and 6 also demonstrated modest anti-hepatitis B virus activity against DHBV (EC(50) = 19.9-23.6 microM). Interestingly, the related 5-(1-azido-2-bromoethyl)-2'-deoxyuridine (1n) analogue proved to be markedly inhibitory to DHBV replication (EC(50) = 2.6-6.6 microM). All compounds investigated exhibited low host cell toxicity to several stationary and proliferating host cell lines as well as mitogen-stimulated proliferating human T lymphocytes.     

Synthesis and antiviral activity of novel acyclic nucleoside analogues of 5-(1-azido-2-haloethyl)uracils.

We present the discovery of a novel category of 5-substituted acyclic pyrimidine nucleosides as potent antiviral agents. A series of 1-[(2-hydroxyethoxy)methyl] (5-7), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] (8-10), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl] (11-13) derivatives of 5-(1-azido-2-haloethyl)uracil were synthesized and evaluated for their biological activity in cell culture. 1-[4-Hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azido-2-chloroethyl)uracil (12) was the most effective antiviral agent in the in vitro assays against DHBV (EC(50) = 0.31-1.55 microM) and HCMV (EC(50) = 3.1 microM). None of the compounds investigated showed any detectable toxicity to several stationary and proliferating host cells.     

Synthesis and antiviral evaluation of carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine

Carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine, compounds 8 and 9, were synthesized by an eight-step synthesis from (+/-)-(1 alpha,2 alpha,3 beta,5 beta)-3-amino-5-(hydroxymethyl)-1,2- cyclopentanediol (1), which was prepared from cyclopentadiene via an eight-step route. These compounds were tested in vitro against herpes simplex virus type 1 (HSV-1). The 2'-amino analogue was found to show moderate antiviral activity, with an ED50 of 50 microM. However, the 2'-azido analogue was not active at a concentration up to 400 microM.     

Synthesis of (E)-5-(3,3,3-trifluoro-1-propenyl)-2'-deoxyuridine and related analogues: potent and unusually selective antiviral activity of (E)-5-(3,3,3-trifluoro-1-propenyl)-2'-deoxyuridine against herpes simplex virus type 1

Syntheses of (E)-5-(3,3,3-trifluoro-1-propenyl)-2'-deoxyuridine (TFPe-dUrd) (1), 5-(3,3,3-trifluoro-1-propyl)-2'-deoxyuridine (11), 5-(3,3,3-trifluoro-1-methoxy-1-propyl)-2'-deoxyuridine (8), and 5-(3,3,3-trifluoro-1-hydroxy-1-propyl)-2'-deoxyuridine (10) from 5-chloromercuri-2'-deoxyuridine are described. The antiviral activity of TFPe-dUrd was determined in cell culture against herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and vaccinia virus and compared concurrently with 5-(1-propenyl)-2'-deoxyuridine, 5-(2-bromovinyl)-2'-deoxyuridine, 5-iodo-2'-deoxyuridine, and 5-(trifluoromethyl)-2'-deoxyuridine. TFPe-dUrd demonstrated a potent and unusually selective activity against HSV-1, with a 2-log reduction in virus yield at 0.03 micrograms/mL (0.09 microM); L-1210 cell growth was inhibited by 50% only at 290 micrograms/mL. Isopycnic centrifugation of 32P-labeled DNA indicated that if 0.5 or 2 microM TFPe-dUrd was present for 0-6 h postinfection, viral DNA synthesis was reduced by ca. 50 and 85%, respectively; concomitantly, a new DNA band appeared at lower density than normal cellular or viral DNA.     

Synthesis and antiviral activity of 2-benzyl(isobutyl)-5-hydroxybenzofuran derivatives

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 23, No. 7, pp. 843–847, July, 1989.     

Synthesis and antiviral evaluation of carbocyclic analogues of 2-amino-6-substituted-purine 3'-deoxyribofuranosides

Carbocyclic analogues of 2-amino-6-substituted-purine 3'-deoxyribofuranosides were synthesized by beginning with (+/-)-(1 alpha,3 alpha,4 beta)-3-amino-4-hydroxycyclopentanemethanol and 2-amino-4,6-dichloropyrimidine. The route parallels the earlier syntheses of the corresponding ribofuranoside and 2'-deoxyribofuranoside analogues. The 2-amino-6-chloropurine, guanine, and 2,6-diaminopurine derivatives and the analogous 8-azapurines were prepared. The analogue (3'-CDG) of 3'-deoxyguanosine is active in vitro against a strain of type 1 herpes simplex virus (HSV-1) that induces thymidine kinase and is modestly active against a thymidine kinase inducing strain of type 2 HSV. 3'-CDG is not active against a strain of HSV-1 that lacks the thymidine kinase inducing capacity, whereas the carbocyclic analogue of 2-amino-6-chloropurine 3'-deoxyribofuranoside is active against that strain. The carbocyclic analogue of 2,6-diaminopurine 3'-deoxyribofuranoside displayed modest activity in vitro against influenza virus.     

Phosphonoformate and phosphonoacetate derivatives of 5-substituted 2'-deoxyuridines: synthesis and antiviral activity

The synthesis of potential "combined prodrugs" wherein phosphonoformate or phosphonoacetate was attached to the 5'-position of 2'-deoxyuridine, 2'-deoxythymidine, 5-iodo-2'-deoxyuridine (IDU), 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), or 5-(2-bromovinyl)-2'-deoxyuridine (BVDU) or to the 3'-position of CEDU is described. The antiviral activities of these derivatives and of reference compounds were compared in Vero, HEp-2, and primary rabbit kidney cells against herpes simplex virus types 1 and 2 (HSV-1 and -2). The CEDU and BVDU analogues were also evaluated against systemic and intracutaneous HSV-1 infection in mice. The nature of the 5-substituent proved critical for antiviral activity, since only the 5-iodo-, 5-(2-bromovinyl)-, and 5-(2-chloroethyl)-substituted derivatives were inhibitory to the herpesviruses. Furthermore, the type specificity is determined by the nature of the 5-substituent: the IDU analogues were similarly inhibitory to HSV-1 and -2 whereas the CEDU and BVDU analogues inhibited HSV-2 replication only at considerably higher concentrations than HSV-1. In vivo, several derivatives were shown to possess significant antiviral activity; however, none surpassed its respective parent compound, CEDU or BVDU, in potency. It seems improbable, therefore, that a synergistic effect between PFA or PAA and the nucleoside analogue occurred. The extent of in vitro and in vivo activity of the CEDU and BVDU 5'-phosphonoformates and 5'-phosphonoacetates is most plausibly explained by the ease by which the "combined prodrugs" are hydrolyzed and the parent compound, CEDU and BVDU, respectively, is released.     

2-(E)-亚苄基-5-氨甲基环戊醇类化合物的合成及抗炎活性研究

目的设计合成2-(E)-亚苄基-5-氨甲基环戊醇类化合物,并对其抗炎活性进行初步的评价。方法以环戊酮为起始原料,通过Stork烯胺反应、Mannich反应、选择性还原制备目标化合物;以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果共合成了12个新化合物,经1H-NMR、MS和IR确证结构。初步药理实验结果显示10个目标化合物具有较强的抗炎活性。结论目标化合物稳定性有所提高并且保留了抗炎活性。     

2-（E）-亚苄基-5-芳氨基甲基环戊醇类化合物的合成及其抗炎活性研究

目的设计合成2-（E）-亚苄基-5-芳氨基甲基环戊醇类化合物，并对其抗炎活性进行初步的评价。方法以环戊酮为起始原料，通过Stork烯胺反应、Mannich缩合反应、胺交换反应和选择性还原制备目标化合物；以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果共合成16个新化合物，其结构经^1H-NMR和MS谱确证。结论初步药理实验结果显示，4个目标化合物具有较强的抗炎活性。