TW201202256A - Selenolopyrazole derivatives and use thereof as anticancer agents - Google Patents

Abstract

The present invention synthesizes a series of selenolo[3, 2-c]pyrazole and selenolo[2.3-c]pyrazole derivatives, and discovers their anticancer activity.

Description

201202256 VI. Description of the invention: [Technical field to which the invention pertains] and [°, azole and porphin [2, 3-and] The present invention synthesizes a series of porphin [3, 2 ° ratio sitting derivatives, and reveals Anticancer activity. [Prior Art] New fused pyrazole compounds and their details are disclosed in the reference US 7,378,532 B2

The use of inhibiting the growth of cancer cells is incorporated into the present specification. The inventors of the present invention continued to study the fused pyrazole compound of us 7,378,532 B2, which can be used to find pharmacologically active derivatives. SUMMARY OF THE INVENTION The main object of the present invention is to provide a series of novel porphin [3,2·and]pyrazole and porphin [2,indole]pyrazole compounds. Another object of the present invention is to provide an anticancer pharmaceutical composition and a method for inhibiting the growth of sputum cancer cells. According to the novel synthesis of the present invention. Western orders. ratio. The sitting compound has the following formula (I) or (Π): 201202256

Wherein R1 is hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, fluorine, gas or bromine; R2 is hydrogen or methyl; R3 is -COOR2, -CR2HOH, -CR2H(CO)-(CH2) m-COOH, -CH2-〇-C(0)-(CH2)m-NH2 or -CH2-0-C(0)-(CH2)m-C00H ' wherein R2 is as defined above and m=l or 2;

Ar^ is phenyl or 'X, where x is 〇, s or se;

^R4

Ar2 is wherein R4 is hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, fluoro'a or bromine; η = 〇, 1 or 2 〇 The present invention also provides an anti-cancer pharmaceutical composition comprising The aforementioned compound (I) or (II) of the present invention which is an effective amount of a therapeutically effective amount of a cancer, or a pharmaceutically acceptable salt thereof. The present invention also provides a use of the aforementioned compound (I) or (II) of the present invention, or a pharmaceutical salt thereof, for the manufacture of an anticancer drug. Preferably, Ar! is 2-furan. 201202256 Preferably, R3 is 5-CH2OH or S-CHz-O-CCOHCH^-COOH, where m=l or 2. More preferably, R3 is 5-CH2OH. Preferably, R3 is 5-CH2-〇-C(〇)-(CH2)2-COOH. Preferably, η = 0 or 1. Preferably, preferred 'R2 and R4 are hydrogen ' and Ri is hydrogen or methyl. The compound of the present invention has the formula (I). The compound of the present invention has the formula (II). The cancer is lung cancer or kidney cancer. [Embodiment] In a preferred embodiment of the present invention, a series of novel porphin [3 2_ and ] pyrazole and porphin [2,3_and] pyrazole compounds are synthesized and they are directed against non-small cell lung cancer cells. The in vitro cytotoxic activity of strain NCI-H226 and renal cancer cell line A498 was measured. 201202256 Example

OH 1,R = Η 2,R = CH3 SOCI2 CH2CI2

8, R2 = h, r3 = h, r4 = H 9, R2 = Cl, R3 = h, r4 = H 10 r2 = h, r3 = Cl, r4 11 r2 = h, r3 = h, r4 = ci 12 K2 =5 F, R3 = :h,r4= H 13 = h,r, = H,R4 = =F 14 r2 =〇ch3 R3=H,R4=H 15 = H,R? = h,r4 = = OCH ,

AcOH/ toluene

Pb(OAc)4 -► ch2ci2 16, 25,34,43,48 17, 26,35,44,49 18.27.36.45 19, 28,37 20, 29,38 21.30.39.46 22,31,40 23.32.41.47 24,33,42

R = H, R2 = H, R3 = H, R4 = HR = CH3J R2 = H, R3 — H, R4 = HR = H, R ==Cl, R3 = H, R4 = HR = H, R2 = H, R.3 = Cl, R4 = HR = H, R2 = H, R3 = H, R4 = C1 R = H, R2 = F, R3 = H, R4 = HR = H, R2 = H, R3 = H, R4 = FR = H, R2 = OCH3, R3 = H, R4 = HR = H, R2 = H, R3 == H, R4 = OCH3 Scheme 1 Scheme 1 shows the reaction pathways, starting reactants for the synthesis of the compounds of the invention And intermediates. 6 201202256 5 - Synthesis of methoxyl-yl-2-pyranyl 2-°® phenophenone (6) Weigh 1 (5 g, 0.026 mol) in a three-necked flask and add 5〇 ML dichloromethane' and SOCI2 (1 〇g), heated to reflux for 20 hours, SOC12 was removed under reduced pressure to produce intermediate 3, and then 50 mi of dioxane was added, with methyl 2-furancarboxylate (methyl- 2-furoate) (5.4 g), finally added FeCl3 (4.6 g), heated to reflux for 4 hours 'monitored by TLC (dichloropyrene. hexane 4:1). After the reaction was completed, pour into water to stop the reaction. The mixture was extracted with a gas-fired product. The organic layer was removed with anhydrous sulfate anhydrous. The filtrate was concentrated under reduced pressure to give a solvent-free distillation. The crude product was purified by column chromatography (Shishijiao). Oxygen enthalpy: Zhengjiyuan = 4: 1), and finally recrystallized from dioxane to give compound 6 (5.0 g), white needle crystals, yield 62%, melting point 115-118 °C. Compound 6 : (1) MS (m/z) : 284 (M+) (2) IR, vmax (KBr) cm'1 : 1716 (C = 0), 1618 (C = 0) (3) UV : λ: Πιαχ (MeOH) nm (loge) : 332 (3.73) (4) ^-NMR (DMSO-i/6, 200 MHz) d (ppm): 3.84 (s, 3H), 7.44-7.42 (m, 1H), 7.57-7.52 (w, 2H), 8.42-8.40 (w, lH), 8.78 (i/, lH). (5) 13C-NMR (DMSO-^6, 50 MHz) d (ppm): 52.94, 1 19.61 , 1 19.96, 132.15, 137.76, 143.91, 146.439, 147.74, 158.41, 174.33. Synthesis of 5-nonyloxycarbonyl-2-furyl 5-indenyl-2-nonylphenyl ketone (7) 201202256 2 (5 g, 0.026 mol) was added to the three-necked flask with % ml of di-ethane ethane and then added to SOCh (10 g) and heated to reflux for 20 hours. The S0C12' was removed under reduced pressure to give intermediate 4, then 50 ml. Methane was calcined with 5 4 g of 2-methyl-2-furoate, and finally FeCl3 (46 g) was added and heated under reflux for 4 hours, monitored by TLC (dioxane: hexane = 4 : 1) After the reaction is completed, the reaction solution is poured into water to terminate the reaction, and the mixture is extracted with dioxane. The organic layer is removed with anhydrous magnesium sulfate, and the mixture is decompressed and concentrated to no dissolution. Distilled, the crude product was separated and purified by column chromatography (Miaojiao) (two gas ablation: Zhengjiyuan = 4:1), and finally recrystallized by two gas to obtain compound 7 (3.87 g), white needle Crystallization, yield 50%, melting point 101-1〇4. (:. Compound 7: (1) MS (m/z): 298 (M + ) (2) IR, vmax (KBr) cm*1 : 1735 (C = 0) (3) UV : λιηβχ (MeOH) nm (loge) : 317 (3.80) (4) 'H-NMR (DMSO-i/5, 200 MHz) d (ppm): 2.58 (5} 3H), 3.84 (s, 3H), 7.23 (d, 1H) , 7.44-7.46 (d, 1H), 7.51-7.52 {d, 1H), 8.24-8.26 (df 1H). (5) 13C-NMR (OUSO-d6> 50 MHz) d (ppm): 18.96, 52.88, 1 19.49, 13 1.23, 138.28, 145.56, 146.23, 1 52.80, 158.40, 159.89, 173.73. 3-(5-decyloxycarbonyl-2-furanyl)_i_phenyl porphin [3,2-and]. Synthesis of azole (34) Weighed compound 6 (3.8 g, 0.013 mol) in a three-necked flask, adding 1 〇〇201202256 ml toluene, acetic acid 1 ·5 ml catalysis, after heating, Then add 8 (5.0 g, 0.046 mol) reaction, heat to reflux for 4 hours, remove toluene by concentration under reduced pressure, then add 50 ml of dichloromethane (liquid a), take another shape, weigh 25 g of four Lead tetraacetate and boron trifluoride etherate 100 ml (b liquid), stir in an ice bath, quickly add (a liquid) to (b liquid), carry out cyclization reaction for 30 minutes, TLC sheet monitoring (dichlorosilane: n-hexane:=7:1), after the reaction is completed, the reaction solution is poured into water to terminate the reaction, and extraction is carried out with di-methane, and the organic layer φ is removed with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to a solvent-free solvent. The crude product was purified by column chromatography (di-methane: n-hexane = 7:1) and finally recrystallized from dioxane to give compound 34 (0.727 g ). White needle crystals, yield 14%, melting point 144-147 °C. Compound 34: (1) MS (m/z): 372.0 (M + ) (2) IR, vmax (KBr) cm'1 : 1724 (C = 0) (3) UV : λ max (MeOH) nm (loge ) : 326 (4.01) ( (4) *H-NMR (DMSO-J6, 200 MHz) d (ppm): 3.83 (s, 1H), 7.06-7.05 (d, 1H), 7.59-7.37 (m, 4H) ), 7.84-7.78 (m, 3H), 8.40-8.37 (d, 1H). (5) 13C-NMR (DMS0-i/6, 50 MHz) d (ppm): 52.40, 109.32, 1 14.50, 1 19.48 , 120.86, 127.38, 130.20, 137.64, 139.61, 139.94, 143.71, 149.51, 1 5 1.03, 158.63. 3-(5-decyloxy-2-ylpropanyl)-1-phenyl-5-indole Base D West [3, 2 - and]. In comparison with 201202256 嗤(35), weighed compound 7 (3.8 g, 0.013 mol) in a three-necked flask, added ι〇〇ml toluene' acetic acid 1.5 ml, and then added compound 8 (5 〇g, 〇 after heating) 〇46 Moer)'heated under reflux for 4 hours, concentrated to remove benzene from benzene, added 5 liters of dioxane (liquid a), and another bottle of eggplant was weighed 25 grams of tetraacetic acid and trifluoride 100 ml (b solution), stir in an ice bath, add (3) liquid to the liquid (b), carry out the cyclization reaction (CyCuzati〇n) for 3 minutes, monitor with tlc tablets (diqi methane: positive Alkane = 7 : 1) 'After the reaction is completed, the reaction solution is poured into water to terminate the reaction, and the mixture is extracted with di-methane, the organic layer is removed with anhydrous magnesium sulfate, and the filtrate is concentrated under reduced pressure to dryness without solvent. The product was isolated and purified by column chromatography (dichloromethane: n-hexane = 7 : hexane) and finally recrystallized from di-methane to give compound 35 (0.486 g). White needle crystals, yield 9 %, melting point 1 5 5 -1 5 7 . (:. Compound 35: (1) MS (m/z): 386 (M+) (2) IR, Vmax (KBr) cm·1 : 1732 (C = 0) (3) UV : λ max (MeOH) nm (loge) : 329 (4.09) (4) !H-NMR (DMSO-rf6, 200 MHz) d (ppm): 2.59 (s, 1H), 3.80 (s, 1H), 6.90-6.92 (d, 1H) , 7.44-7.37 (m, 2H), 7.76-7.50 (w, 3H), 7.80-7.76 (d, 2H). (5) 丨3C-NMR (DMSO-4 50 MHz) d (ppm): 19.79, 52.36 , 109.17, 1 12.72, 1 17.30, 120.76, 127.26, 130.1 1, 137.509, 139.94, 143.61, 148.18, 1 5 1.05, 154.29, 158.60. 201202256 3-(5-methoxycarbonyl-2-furanyl)-1 -(2-Phenylphenyl) 3⁄4 phen[3,2-and]"Biazole (36) Synthesis Weighed compound 6 (3.8 g, 0.013 mole) in a three-necked flask, adding 100 ml of toluene' and 1.5 nU of acetic acid, after heating, weighed compound 9 (5 g, 0.035 mol) was added to the reaction 'heated reflux for 4 hours, concentrated under reduced pressure to remove benzene, and then added 50 ml of di-methane (a liquid), take another For the eggplant-shaped bottle, weigh 25 g of lead tetraacetate and 1 〇〇ml of boron trifluoride (b liquid), stir it in an ice bath, and quickly add (a liquid) φ to (b liquid), and carry out a cyclization reaction for 30 minutes. Monitored by TLC film (two Gas decane: n-hexane = 7: 1), after the reaction is completed, the reaction solution is poured into water to terminate the reaction, and the mixture is extracted with di-methane, the organic layer is removed with anhydrous magnesium sulfate, and the filtrate is concentrated under reduced pressure. The crude product was purified by column chromatography (dioxane: n-hexane = 7: hexane), and then recrystallized from di-methane to give compound 36 (0-107 g). Rate 2% ' Melting point 134-136 ° C. Compound 36 : ® (1) IR, vmax (KBr) cm.1 : 1737 (C = 0) (2) UV : λ max (MeOH) nm (logs) : 318 (4.16 (3) 'H-NMR (DMSO -d6, 200 MHz) d (ppm): 3.81 (s, 1H), 7.03-7.01 (d, 1H), 7.27-7.24 (d, 1H), 7.70-7.42 5H ), 8.32-8.29 (d, 1H). (4), 3C-NMR (DMSO-c/tf, 50 MHz) d (ppm): 52.42, 109.37, 1 13.98, 1 17.59, 1 19.79, 120.30, 120.81, 128.94, 129.53, 13 1.04, 132.16, 137.09, 137.09, 137.93, 11 201202256 139.51, 143.70, 150.97, 152.44, 158.64· 3-(5-decyloxy). Synthesis of ketone)-1-(3-phenylphenyl) 3⁄4 phen[3,2·and] squat (37) Weighed compound 6 (3.8 g, 0.013 mol) in a three-necked flask, added 1 〇〇ml toluene, 1.5 mi of acetic acid, after heating, weighed compound 1 〇 (5 g, 〇〇39 mol) into the reaction, heated under reflux for 4 hours, concentrated under reduced pressure to remove toluene, and then added 50 ml of dioxane Alkane (liquid a), take another eggplant bottle, weigh 25 g of tetraacetic acid and 100 ml of trifluoride side (b liquid) and mix it in an ice bath, and quickly add (a liquid) (b liquid) The cyclization reaction was carried out for 30 minutes, and monitored by TLC tablets (一气曱院.正己院=7: 1). After the reaction was completed, the reaction solution was poured into water to terminate the reaction. The layer was dehydrated with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to dryness without solvent. The crude product was purified by column chromatography (dioxane: n-hexane = 7 : 丨), and finally dichloro hexane. Crystallization gave Compound 37 (0.107 g). White hairy crystals, yield 1 g/〇, m.p. 107-109. Compound 3 7 : (1) IR, vmax (KBr) cm-1 : .1732 (C = 0) (2) UV : λ max (MeOH) nm (loge) : 320 (4.12) (3) 'H-NMR (OMSO-d6, 200 MHz) d (ppm): 3.81 (s, 3H), 6.98-6.97 (d, 1H), 7.53-7.33 (m, 3H), 7.77-7.70 (m, 3H), 8.37-8.34 (d, 1H). (4) 13C-NMR (DMSO-rftf, 50 MHz) d (ppm): 52.36, 109.59, 1 14.48, 1 18.87, 120.03, 120.25, 120.64, 12 201202256 126.91,13 1.74, 134.52, 138.03, 140.01, 140.93, 143 8〇, 149.3 1, 150.65, 158.54. 3-(5-decyloxycarbonyl-2-furanyl)-1-(4-phenylphenyl) porphin [3,2_ and Synthesis of β-pyrazole (38). Weigh compound 6 (3.8 g, 〇.〇13 molar) and add 1 〇〇ml 曱 ' ' and acetic acid 1,5 ml to the three-necked flask, heat, and weigh The compound ^ (5 g, 〇〇39 mol) was added to the reaction, refluxed under heating for 4 hours, concentrated under reduced pressure to remove toluene, • 50 ml of dichloromethane Q solution was added, and another eggplant bottle was weighed and weighed 25 g Tetraacetate lead and boron trifluoride 100 ml (b liquid) were stirred in an ice bath, and (a liquid) was quickly added (b liquid) for cyclization reaction for 30 minutes, and monitored by TLC sheet (two gas methane: positive Alkane = 7 : 1 ), after the reaction is completed, the reaction solution is poured into water to terminate the reaction, and the mixture is extracted with di-methane, and the organic layer is removed by anhydrous sulfuric acid. The filtrate is concentrated under reduced pressure until solvent-free distillation. The crude product was separated and purified by column chromatography (di-methane: n-hexane = 7:1), and finally recrystallized from dioxane to give compound 38 (0.03 7 g). White hairy crystals, yield 1%, _ melting point 146-148 ° C ° Compound 38 : (1) IR, vmax (KBr) cm·1 : 1728 (C = 0) (2) UV : λ max (MeOH) Nm (loge) : 322 (4.17) (3) !Η-ΝΜΚ (OMSO-d6, 200 MHz) d (ppm): 3-82 (^,1H), 7.04-7.03 (d, 1H), 7.43-7.41 (d, 1H), 7.58-7.54 (^, 2H), 7.85-7.77 (m, 3H), 8.40-8.38 (d, 1H). (4) 13C-NMR (DMSO-i/5, 200 MHz) d (ppm): 13 201202256 52.40,1G9.5G, 114.45,119.82,120.72,122.21,130.03, 131.32,137.85,138.66,139.94,143.77,149.36,150.76, 158.58 3-(5-methoxycarbonyl-2-furan Synthesis of fluorophenyl) hydrazine 2 | pheno[3,2 and ] ij azole (39) Weighed compound 6 (3.8 g, 0·013 mol) in a three-necked flask, adding 1 〇〇 ml of toluene' And 1.5 ml of acetic acid catalyzed, after heating, weighed compound 12 (5 g, 0.039 mol) was added to the reaction, refluxed under heating for 4 hours, concentrated under reduced pressure to remove toluene, and then added 50 ml of di-methane (liquid a). Take another eggplant-shaped bottle, weigh 25 g of lead tetraacetate and boron trifluoride 1〇〇mi (b solution), stir in an ice bath, and add (a liquid) quickly (in liquid b) The cyclization reaction was carried out for 3 minutes and monitored by TLC tablets (di-methane: n-hexane = 7: i). After the reaction was completed, the reaction solution was poured into water to terminate the reaction with dioxane (dioxane). The extraction was carried out 'the organic layer was removed with anhydrous magnesium sulfate'. The filtrate was concentrated under reduced pressure until solventless distillation. The crude product was purified by column chromatography (di-methane: hexane = 7:1). The dioxane was recrystallized to give compound 39 (0.085 g). White hairy crystals, yield 4%, melting point 1 58-161 e. Compound 39: (1) IR, vmax (KBr) cm'1 : 1712 (C = 0) (2) UV : λ max (MeOH) nm (loge) : 322 (4.12) (3) 'H-NMR (OMSO -d6, 200 MHz) d (ppm): 3.81 (s, 3H), 7.04-7.02 (d, 1H), 7.54-7.36 (m, 5H), 7.73 (t, 1H), 8.34-8.31 (¢/, 1H). 201202256 (4) 13C-NMR (DMSO-heart, 200 MHz) d (ppm): 52.43, 109.53, 114.17, 117.38, 117.76, 118.25, 120.83, 126.02, 127.47, 130.64, 130.79, 138.38, 139.68, 143.80 , 1 50.84, 15 1.71, 158.63. 3-(5-decyloxycarbonyl _.2_furanyl)-^(4-fluorophenyl hydrazine, 2·and]. Synthesis of azole (40) Take compound 6 (3.8 g, 0.013 mol) in a three-necked flask, add ι〇〇φ ml 曱 benzene, acetic acid 1.5 ml 'heated, and weigh compound I3 (5 g, 〇〇39 mol) into the reaction, 'Reheated by heating for 4 hours, concentrated under reduced pressure to remove benzene, and then added 50 ml of di-methane (a liquid)' to take another eggplant-shaped bottle, weighed 25 g of tetraacetic acid and trifluorochemical shed 100 ml (b liquid Stir in an ice bath, add (a liquid) to the (b liquid), carry out the cyclization reaction for 30 minutes, and monitor with TLC (dichloromethane: N-hexane = 7: 1). After the reaction is completed, the reaction mixture is poured into water to terminate the reaction, and the mixture is extracted with dioxane. The organic layer is dried over anhydrous magnesium sulfate, and the filtrate is concentrated under reduced pressure to solvent. The product was evaporated, and the crude product was purified by column chromatography (dioxane: n-hexane = 7:1), and then recrystallized from hexane to afford compound 40 (0.063 g). Rate 3% ' Melting point 160-1631. Compound 4〇: (1) IR, vmax (KBr) cm·1 : 1707 (00) (7) UV : λ max (MeOH) nm (loge) : 300 (4.09) (3) lH-NMR (OMSO-d6, 200 MHz) d (ppm): 3·82 3H), 7.04-7.02 (d, 1H), 7.44-7.32 (m, 3H), 7.87-7.70 15 201202256 (m, 2H) , 8.39-8.36 (d, 1H). (4) 13C-NMR (DMSO-i/6, 200 MHz) d (ppm): 52.41, 109.37, 1 14.31, 1 16.74, 1 17.20, 120.80, 123.04, 123.21, 136.41, 137.64, 139.81, 143.72, 149.62, 150.93, 158.61. 3 _(5·methoxycarbonyl-2-furanyl)-1-(2-methoxyphenyl)- porphin [3,2- ° ° than the wow (41) synthesis Weighed compound 6 (3.8 g, 0.013 mol) in a three-necked bottle, add 1 〇〇ml of stupid, and acetic acid 1. 5 ml, After the heat, weighed 14 (5 g, 0.039 mol), added the reaction, refluxed by heating for 4 hours, concentrated under reduced pressure to remove toluene, and then added 50 mi of di-methane (a liquid), and then took another eggplant-shaped bottle. Take 25 g of tetraacetic acid and boron trifluoride 100 ml (b solution) and stir it in an ice bath. Add (a liquid) to the liquid (b liquid) for cyclization for 30 minutes, and monitor with TLC tablets. Calcination: n-hexane = 7: 1 ). After the reaction is completed, the reaction solution is poured into water to terminate the reaction. 'Extraction with dioxane'. The organic layer is removed with anhydrous sulfuric acid. The filtrate is concentrated under reduced pressure. The solvent was distilled off, and the crude product was separated and purified by column chromatography (di-methane: n-hexane = 7:1), and finally recrystallized from dioxane to give compound 41 (0.037 g). Mucilage, yield ι%, melting point 72-76 ° C. Compound 41 : (1) IR, ax (KBr) cm·1 : 1716 (00) (2) UV : χ max (Me〇H) nm (loge) : 320 (4.22) (3) 'H-NMR (DMSO - D6, 200 MHz) d (ppm): 16 201202256 • 3.78 (5, 3H), 3.81(5, 3H)} 6.99-6.97 (d, 1H), 7.28-7.〇8 (m, 3H), 7.51- 7.42 (m, 3H), 8.24-8.21 (d, 1H). (4) 13C-NMR (DMSO-heart, 50 MHz) d (ppm): 52.37, 56.21, 108.92, 1 13.33, 1 14.92, 120.85, 121.28 , 127.58, 128.48, 130.46, 137.40, 138.13, 143.52, 151 39 152.17, 153.12, 158.68. 3-(5-decyloxyweiyl-2-fluoropropanyl)-1-(4-methoxyphenyl) Synthesis of n-Shen [3 2_and] φ pyrazole (42) Weighed compound 6 (3_8 g, 0.013 mol), and added 1 〇〇ml of the nail to the three-necked flask, and 1.5 ml of acetic acid. 'Weighed compound 15 (5g 0039 mole) was added to the reaction, refluxed by heating for 4 hours, concentrated under reduced pressure to remove toluene, then 50 ml of di-methane (a solution) was added, another eggplant bottle was taken, and 25 g was weighed. Lead tetraacetate and boron trifluoride i 00 ml (b liquid) were stirred in an ice bath, and (a liquid) was quickly added to (b liquid) for cyclization reaction for 30 minutes, and monitored by TLC sheet (two gas armor) Alkane: n-hexane = 7: 1). After the reaction is completed, the reaction mixture is poured into water ▼ to terminate the reaction. The mixture is extracted with dioxane (di-methane), and the organic layer is removed with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to dryness crystals eluted eluted elution elution elution elution elution elution elution elution elution Mucilage, yield 1%, melting point 89-92. (:. Compound 42: (1) IR, vmax (KBr) cm'1 : 1721 (C = 0) (2) UV : λ max (MeOH) nm (loge) : 316 (4.25) 17 201202256 (3) ' H-NMR (DMSO -d6, 200 MHz) d (ppm): 3.77 (5, 3H), 3.86-3.81 (w, 3H), 7.01-6.96 (m, 2H), 7.56-7.46 (m, 2H,) , 7.78-7.67 (m, 3H), 8.41-8.39 (m, 1H). 3-(5-methyl-ethyl-2-pyranyl)-1-phenyl. Western [3,2_ and] n Synthesis of η sitting (43) Pre-mix THF with sodium metal to reflux and remove water, and use benzophenone as an indicator to boil to dark blue. Weigh 7.5 g (0.068 mol) anhydrous chlorinated | bow (caiciuin chloride, Granular), 5.0 g (0.132 mol) of sodium borohydride (S0) and 100 ml of anhydrous tetrahydrofuran, reacted at room temperature for 4 hours to form calcium borohydride (calcium borohydride) Ca(BH4)2) white suspension, and then weighed the reactant 34 (3 g, 0.008 mol) for reduction reaction 'heated reflux for 24 hours, monitored by TLC sheet (EA: n-hexane = 3: 2)' After the reaction is completed, it is cooled to room temperature, concentrated under reduced pressure to remove thF, and the reaction solution is poured into water to terminate the reaction. Gas extraction (chi〇roform) extraction 'The organic layer was removed with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure until solventless distillation. The crude product was purified by column chromatography (EA: hexane = 3: 2 Finally, it was recrystallized from ethyl acetate to give compound 43 (2,09 g), mucus, yield 72%. Compound 43: (1) MS (m/z): 344.1 (M + ) (2) IR , vmax (KBr) cm'1 : 3 100-3500 (OH) (3) UV : λ max (MeOH) nm (loge) : 262 (4.19), 3 1 8 (4.1 1) (4) 'H-NMR (DMSO-J5, 200 MHz) d (ppm)): 18 201202256 • 4.47-4.45 (d, 2H), 5.34 (t, 1H), 6.46-6.45 (d, 1H), 6.79-6.77 (d, 1H) , 7.37-7.33 (m, 1H), 7.57-7.49 (w, 2H), 7.82-7.77 (m, 3H), 8.37-8.34 (d, 1H). (5) 13C-NMR (DMSO-4 50 MHz) d (ppm): 56.18, 108.47, 109.72, 114.60, 118.63, 120.46, 126.88, 130.17, 138.87, 139.10, 140.17, 146.61, 149.1 1, 156.44. 3-(5-Hydroxymethyl-2-furyl)-i _Phenyl_5_methyl porphin [3, 2_ and]. Synthesis of azole (44) Weigh 7.5 g (0.068 mol) of anhydrous calcium carbonate, 5.0 g (0.132 mol) of hydrogenated sodium hydride and 1 〇〇 ml of anhydrous tetrahydrofuran, and react at room temperature for 4 hours. Hydrogen boronation mother white suspension, and then weighed the reactant 35 (3 g, 0.008 mp) for reduction reaction, heated back to 24 hours, and monitored by TLC (EA: n-hexane == 3: 2) After completion, the THF was concentrated under reduced pressure, and the mixture was poured into water to terminate the reaction. The mixture was extracted with an air-purification. The organic layer was taken to remove water with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to dilute without solvent. Purification by column chromatography (EA: hexane = 3: 2), and then crystallised from ethyl acetate to afford compound 44 (1.91 g). Mucilage, yield 66%. Compound 44: (1) MS (m/z): 356 (M + ) (2) IR, Vmax (KBr) cm'1 : 3200-3400 (OH) (3) UV : λ max (MeOH) nm (loge ) : 266 (4.25), 318 (4.30) (4) !H-NMR (DMSO-i/65 200 MHz) d (ppm): 2-62 (5, 3H), 4.46-4.43 (d, 2H), 5.35-5.30 (/, 1H), 6.45-6.43 19 201202256 (d, 1H), 6.73-6.71 {d, 1H), 7.35-7.32 (/, 1H), 7.74-7.51 (m> 3H), 7.79-7.74 (d, 2H). (5) 13C-NMR {OMSO-d6, 50 MHz) d (ppm): 19.87, 56.15, 108.39, 109.66, 1 12.92, 126.81, 120.42, 130.13, 140.18, 146.61, 147.82, 153.809, 156.30. 3-(5-Mmethyl-2-pyranyl)-1 - (2-phenylphenyl) 3⁄4 phen[3,2-and]» is more than <» sitting (45) 7.5 g (0.068 mol) anhydrous calcium carbonate, 5·〇g (0.132 mol) sodium borohydride and 100 ml of anhydrous tetrahydrofuran, reacted at room temperature for 4 hours to form a white suspension of calcium borohydride, and then The reactant 36 (3 g, 0.0077 mol) was weighed and subjected to a reduction reaction, and the mixture was heated under reflux for 24 hours, and monitored by TLC (EA: n-hexane = 3:2). After the reaction was completed, the temperature was lowered to room temperature. Concentrate to remove THF, pour the reaction into water to make the end The reaction was carried out by gas-purification, and the organic layer was evaporated to dryness with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to a solvent-free distillation. The crude product was purified by column chromatography (EA: hexane ~ 3: 2). Finally, it was recrystallized from ethyl acetate to give Compound 45 (0.04 g). Hairy crystals, yield 71%. Compound 45: (1) IR, vmax (KBr) cm'1 : 3 100-3500 (〇H) (2) UV : λ max (MeOH) nm (logs) : 3i〇(4·〇8) (3) 'H-NMR (DMSO-heart, 200 MHz) d (ppm): 46~4.43 {dy 1H), 5.33(ί, 1H), 6.45-6.43 (d, 1H), 6.75-6.73 (dt iH), 7.23 -7.20 (d, 1H), 7.55-7.23 (m, 2H), 7.73-7.62 {m, 2H), 20 201202256 ' 8.28-8.25 (d, 1H). (4) 13C-NMR (DMSO-c?6 , 50 MHz) d (ppm): 56.16, 108.35, 109.65, 1 14.07, 1 16.71, 128.86, 129.46, 13 1.02, 137.37, 138.80, 139.16, 146.60, 151.63, 156.35. 3-(5-1^(11' 〇\丫1^11^1-2-furyl)_1_(2-fluorophenyl) porphin [3,2-and] D ratio. Sit (4 6) synthesis weighed 7.5 g (0.068 mol) Anhydrous calcium carbonate, 5.0 g (0.132 mol) φ sodium borohydride and 100 ml of anhydrous tetrahydrofuran, reacted at room temperature for 4 hours to form a white suspension of calcium borohydride, and weighed the reactant 39 (3 g, The reaction was carried out, and the mixture was heated under reflux for 24 hours, and monitored by TLC (EA: n-hexane = 3: 2). After the reaction was completed, the mixture was cooled to room temperature, and concentrated under reduced pressure to remove THF. Stop the reaction in water and extract with chloroform The organic layer was extracted with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to dryness without solvent. The crude product was purified by column chromatography (EA: n-hexane = 3: 2). Crystallization gave Compound 46 (0.025 g).jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs (2) UV : λ max (MeOH) nm (logs) · 322 (4.06) (3) i-NMR (DMSO-heart, 200 MHz) d (ppm): 4.48 (d, 1H), 5.37 (t, 1H ), 6.46 (d, 1H), 6.77 (d, lH) 7.47-7.35 (m, 4H), 7.70 {t, 1H), 8.30-8.28 (d, 1H). (4) ,3C-NMR (DMSO- i/6, 50 MHz) d (ppm): 21 201202256 56.18,1 08.58,109.68,114.13,114.24,117.30,117.42,117.69,125.91,127.22,130.07,130.23,1 38.94, 39.61, 146.48,151.26,152.50, 156.50,157.46. Synthesis of 3-(5-hydroxyindol-2-furanyl)-1 _(2-decyloxyphenyl) porphin [3,2-and]pyrazole (47) Weigh 7.5 g (0.068 mol) anhydrous calcium carbonate, 5 〇g (〇" 32 mol) sodium borohydride and 100 ml of anhydrous tetrahydrofuran, reacted at room temperature for 4 hours to form calcium borohydride white The liquid was floated, and the reactant 41 (3 g, 0.008 mol) was weighed and added to the reaction. After heating and refluxing, the reaction was carried out for 24 hours, and monitored by TLC (EA: n-hexane = 3:2). After thawing to a room temperature, the THF was concentrated to remove the THF. The reaction mixture was poured into water to terminate the reaction, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The crude product was purified by column chromatography (yield: hexane = 3: 2), and then crystallised from ethyl acetate to afford compound 47 (0.033 g). Compound 47: (1) IR, vmax (KBr) cm·1 : 3100-3500 (OH) (2) UV : λ max (MeOH) nm (loge) · 312 (4.27) (3) 'H-NMR (OUSO-d6 , 200 MHz) d (ppm): 3-78 (s, 3H), 4.45 (s, 2H), 6.43 (d, 1H), 6.70 (d, 1H), 7.26-7.07 (m, 3H), 7.45- 7.39 (m, 2H), 8.19-8.17 (d, 1H). (4) 13C-NMR (DMSO-i/6, 50 MHz) d (ppm): 56.15, 107.85, 109.60, 113.24, 115.05, 116.26, 121.23 , 22 201202256 127.42,128.77,129.98,1 37.43,138.61,146.94,151.72 152.96, 156.09. 3-(5-Hydroxycarbonyl-2-furanyl)-1-phenyl porphin [3,2-and]pyrazole (48) Synthesis Weighing compound 34 (1.49 g, 0.004 mol) and 10% NaOH for hydrolysis, heating and refluxing for 2 hours, monitoring with TLC (EA), after the reaction is completed, the reaction solution Pour into water to terminate the reaction, extract with toluene, take the water layer to neutralize with 1 〇% HC1, make the solution acidic, g take ethyl acetate vinegar, take the organic layer to remove water with anhydrous sulphuric acid, take the liquid through The organic layer was concentrated under reduced pressure to dryness crystals eluted eluted eluted eluted elution Brown columnar crystals, yield 78%, mp 234-237 〇 C, Compound 48: (1) MS (m/z): 358 (M+) (2) IR, vmax (KBr) cm'1 : 1673 (C = 0), 2400-3200 (OH) (3) UV : λ max (MeOH) nm (loge) : 316 (4.19) φ (4) 'H-NMR (DMSO-d6, 200 MHz) d (ppm): 3.41 (br, 1H), 7.03-7.02 {d, 1H), 7.36-7.34 (m, 2H), 7.58-7.51 (ί, 2H), 7.83-7.79 (d, 3H), 8.40-8.37 (d, 1H (5) 13C-NMR (DMSO-c?6, 50 MHz) d (ppm): 109.19, 1 14.52, 1 19.39, 120.20, 120.83, 127.35, 130.21, 137.86, 139.59, 139.97, 144.96, 149.49, 150.58 , 159.61. 3-(5-Phaseyl-2-pyrene-e-n-yl)-1-phenyl-5-fluorenyl 0δ-pheno[3,2-and]d than spit (49) 23 201202256 The compound 35 (1·49 g, 0.004 mol) was subjected to a hydrolysis reaction with 1% by weight of Na〇H. The reaction was heated under reflux for 2 hours, and monitored by TLC (EA). After the reaction was completed, the reaction solution was poured into water. The reaction was terminated, and the mixture was extracted with a stupid step. The aqueous layer was neutralized with 10% HCl to make the solution acidic. The mixture was extracted with ethyl acetate. The organic layer was evaporated over anhydrous magnesium sulfate. Steamed out, most Recrystallized from ethyl acetate to give compound 49 (1, 〇98 g). The yield of brown columnar crystals was 73% with a dazzling point of 236-239 °C. Compound 49: (1) MS (m/z): 372.1 (M+) (2) IR, vmax (KBr) cm·1 : 1671 (〇0), 2400-3200 (OH) (3) UV : λ max ( MeOH) nm (loge) : 326 (4.19) (4) 'H-NMR (DMSO-£/5, 200 MHz) d (ppm): 2.63 (s, 3H), 3.65 {br, 1H), 6.96-6.94 (d, 1H), Ί.34-1.32 (m, 2H), 7.35(^, 1H,), 7.56-7.48(m, 3H), 7.79-7.75 (d, 2H) (5) 13C-NMR (DMSO) -A, 50 MHz) d (ppm): 19.84,109.14,112.78,117.19,120.21,120.79,130.19,127.31, 137.75, 139.95, 144.87, 148.22, 150.57, 154.399, 159.62. 24 201202256

Scheme 2 Scheme 2 shows the reaction pathways, starting reactants and intermediates for the synthesis of compounds 55-60 of the invention. Synthesis of 1-benzyl-3-(5-nonyloxycarbonyl-2-furanyl) porphin [3,2-and]«biazole (55) 25 201202256 Scale compound 6 (5.66 g, 0.02 Mo The ear is dissolved in 1 ml of toluene, and 1.5 ml of glacial acetic acid is added as a catalyst, and the temperature is raised to reflux. At this time, benzylhydrazine (50) (4 88 g, 〇〇 4 mol) is added dropwise. The reaction was carried out for 3 hours, and the mixture was cooled to room temperature. The filtrate was concentrated under reduced pressure to dryness without solvent, and the crude product was isolated by column chromatography to give a crude product (E/Z forms). Next, lead tetraacetate (26 6 g, 莫 mol) was placed in an eggplant bottle, and 100 ml of boron trifluoride was added. Under ice bath, the crude product (E/z forms) of Compound 51 in 50 ml of di-methane was quickly poured into the reaction mixture for 30 minutes, and then the reaction solution was poured into ice water to terminate the reaction. The methane was extracted, and the organic layer was washed with water, 5% aqueous sodium carbonate, and water to neutral. The organic layer was dehydrated with anhydrous magnesium sulfate (MgS〇4). The filtrate was concentrated under reduced pressure to a solvent-free distillation. The crude product was purified by column chromatography (purpuration/gum) and recrystallized with n-hexane. Compound 55 (1.5 g) was obtained as pale pink crystals, yield 20.1%, m.p. Compound 55: (1) MS (m/z): 385.8 (M + ) (2) IR, vmax (KBr) cm'1 : 1724 (C = 0) · (3) UV : λ max (MeOH) nm ( Loge) : 314 (4.2) (4) 'H-NMR (CDC13, 600 MHz) d (ppm): 3-9l (s, 3H), 5.53 (s, 2H), 6.81 (d, 1H, J = 4.2 Hz), 6.96 (d, 1H> 6.0 Hz), 7.23- 7.26 (m, 2H), 7.28 (d, 1H, y = 4.2 Hz), 7-2 8-7.34 (m, 3H), 7.91 (d, 1H, / = 5.4 Hz) (5) 13C-NMR (CDC13, 150 MHz) d (ppm): 51-84, 55.53, 107.38, 1 12.21, 117.45, 1 19.99, 127.51 (x 2), 26 201202256 128.16, 128.83 (χ 2), 1 35.57, 135.82, 136.55, 143.47, 150.52, 151.67, 159.07. 1-Benzyl-3-(5-decyloxy-2-ylf-yl)-5-methyl . Xishen [3, 2_ and ] ° ratio. Sit on compound (56) and take compound 7 (5.9.4 g, 0.02 mol) dissolved in 1 ml of toluene, add 1.5 ml of glacial acetic acid and benzoquinone (50) (4.88 g, 〇〇4) The reaction and treatment were carried out under the same conditions as Compound 55 to give Compound 56 (1.56 g), white crystals, yield: 19.5%, 142-145. Compound 56 : (1) MS (m/z): 400.1 (M+) (2) IR, vmax (KBr) cm'1 : 1730 (C = 0) (3) UV : λ max (MeOH) nm (loge) : 314 (3.4) (4) 'H-NMR (CDC13, 200 MHz) d (ppm): 2-56 (s, 3H), 3.89 (s, 3H), 5.46 (s, 2H), 6.62 (s, 1H), 7.76 (d, !H, J = 3.6 Hz), 7.18-7.32 (m, 6H) (5) 13C-NMR (CDC13, 50 MHz) d (ppm): !9.68, 51.84, 55.34, 107.46, 110.09, 115.72, 120.02, 127.43 128.10, 128.84, 136.01, 136.46, 143.45, 149.57, 1 51.75, 152.52, 159.12. 1 methyl-3-(5-pyridyl-2-0.n.) The order [3,2 -and]u is superior to the person of Jun (57). The gas is fed first (1.98 g '0.018 mol) and hydrogen oxidized sodium (ι377 27 201202256 g '0.036 mol) and 50 ml of THF. The reaction was carried out for 4 hours at room temperature to form Ca(BH4)2. Further, compound 55 (〇. 772 g, 0.002 mol) was added, and the mixture was heated under reflux for 6 hours. The reaction was stopped by pouring into ice water, and the mixture was extracted with two gas smolders. Dehydrated with anhydrous magnesium sulfate (MgS〇4), and the filtrate was reduced. The mixture was concentrated to a solvent-free distillation, and the crude product was purified by column chromatography (ethyl acetate: hexane = 1 : 1 / yel). Recrystallization from n-hexane to give compound 57 (7). Columnar crystals, yield 74. 2 ° /. , 126- 129 ° C. Compound 57 : (1) MS (m/z) : 358 (M + ) (2) IR, vmax (KBr) cm'1 : 3200- 3400 (OH) (3) UV : λ max (MeOH) nm (loge ) : 303 (3.8) (4) ^-NMR (CDC13, 200 MHz) d (ppm): 4.41 (d, 2H, J = 5.6 Hz), 5.29 (t, 1H, J = 5.6 Hz), 5.53 (s 2H), 6.38 (d, 1H, J = 3.0 Hz), 6.59 (d, 1H, J = 3.0 Hz), 7.25- 7.33 (m5 5H), 7.48 (d, 1H, J = 5.8 Hz), 8.11 (d , 1H, 5.8 Hz) (5) 13C-NMR (CDCI3, 50 MHz) d (ppm): 54.46, 56.11, 107.11, 109.49, 113.53, 115.37, 127.99, 128 19 129.09, 137.22, 137.62, 147.28, 151.24, 155.68 1-Benzyl-3-(5-hydroxymethyl-2-furyl)-5-fluorenyl porphin [3,2-and]. ratio. The compound 56 (0·800 g, 0.002 mol) was taken from the synthesis of (58) and reacted and treated under the same conditions as the compound S7 to obtain Compound 58 (0.612 g), 28 201202256 • White needle crystals. Rate 82.5%, 147-148 °C. Compound 58 : (1) MS (m/z) : 372.1 (M + ) (2) IR, vmax (KBr) cm'1 : 3200- 3400 (OH) (3) UV : λ max (MeOH) nm (loge ) : 262 (3.6) (4) ^-NMR (CDC13, 200 MHz) d (ppm): 2.54 (s, 3H), 4.39 (d, 2H, J = 3.6 Hz), 5.27 (t, 1H, J = 3.6 Hz), 5.46 (s, 2H), 6.36 (d, 1H, / = 3.0 Hz), 6.54 (d, 1H, / = • 3.0 Hz), 7.19- 7.33 (m, 6H) (5) 13C-NMR (CDCI3, 50 MHz) d (ppm): 19.78, 54.36, 56.09, 107.05, 109.45, 11 1.56, 113.32, 127.90, 128.16, 129.09, 137.14, 137.66, 147.28, 149.90, 15 1.90, 1 55.59. 1-Benzene Synthesis of 3-(5-hydroxymethyl-2-furanyl) porphin [3,2-and]pyrazole (59) _ Weighing compound 55 (0. 772 g, 0.002 mol), placed In 20 ml of 10% aqueous NaOH, the reaction was heated under reflux for 2 hours, and the temperature of the reaction solution was lowered to room temperature. Then, a 10% aqueous solution of HCl was added dropwise to an ice bath to precipitate solid particles, and the solid was recrystallized from ethanol to give compound 59 (0.595 g) of white crystals, yield: 80.2%, 243-244 °C. Compound 59 : (1) MS (m/z): 372.0 (M+) (2) IR, vmax (KBr) cm'1 : 1697 (C = 0) ; 2500- 3400 (OH) 29 201202256 (3) UV : λ max (MeOH) nm (loge) : 310 (4.2) (4) 'H-NMR (CDC13j 200 MHz) d (ppm): 5.58 (s, 2H), 6.82 (d, 1H, /= 3.6 Hz), 7.18-7.35 (m, 6H), 7.52 (d, 1H, 7 = 5.6 Hz), 8.1 8 (d, 1H, 7 = 5.6 Hz) (5) 13C-NMR (CDC13j 50 MHz) d (ppm): 54.69 , 108.03, 1 13.52, 1 16.44, 1 19.55, 128.07, 128.29, 129.13, 136.37, 137.33, 137.75, 145.30, 150.86, 1 5 1.5 1, 160.03. Succinic acid mono-[5-(1-phenylhydrazinyl-fluorene) Synthesis of pheno[3,2-andypyrazol-3-yl)furan-2-yl]methyl ester (60). Compound 57 (1. 071 g, 0.003 mol), succinic anhydride (0. 9 g, 0.009 mol) and 4-dimethylaminopyridinium (DMAP) (〇. 403 g, 0.0033 mol) were placed in a three-necked flask, and 75 ml of THF was added as a solvent and heated to reflux. After reacting for 2 hours, the reaction was quenched by the addition of water and the THF was evaporated. The aqueous layer was added dropwise with a 10% aqueous HCl solution to pH = 2, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to evaporate without solvent. Ethyl acetate / ruthenium acetate, recrystallized from ethyl acetate / n-hexane to give compound 60 (yield: 548 g), white crystals, yield 40%, 111-1140 C. Compound 60: (1) MS (m/z): 457 (M + ) (2) IR, vmax (KBr) cm·1 : 1717 (C = O); 2700-3300 (OH) (3) UV : λ Max (MeOH) nm (loge) : 303 (3.9) 30 201202256 '· (4) ]H-NMR (CDC13, 200 MHz) d (ppm): 2.40-2.48 (m, 4H), 5.09 (s, 2H) , 5.55 (s, 2H), 6.61 (d, 1H, J = 3.4 Hz), 6.66 (d, 1H, / = 3.4 Hz), 7.18-7.33 (m, 5H), 7.4 8 (d, 1H, / = 5.8 Hz), 8.15 (d, IK, J = 5.8 Hz) (5) 13C-NMR (CDCI3, 50 MHz) d (ppm): 29.09, 54.54, 58.18, 107.27, 113.24, 113.51, 115.74, 127.97, 128.20, 129.09, 136.87, 137.37, 137.52, 148.54, 149.44, 1 5 1.33, 1 72.30, 173.73.

〇-(CH2)nNHNH2

64, n = 0 65, n = 1

68, n = 0 69, n = 1

31 201202256 Scheme 3 Scheme 3 shows the reaction pathways, starting reactants and intermediates for the synthesis of the compound 66·7〇 of the present invention. Methoxycarbonylphenyl 2-. The synthesis of phenoxy ketone (63) was taken from porphin (61) (5.0 g, 0. 〇38 mol) and 4-methoxycarbonyl carbamide (62) (8.34 g, 0.042 mol) ) Dissolve in 5 ml of ^ 2 · dichloroethane, then add anhydrous aluminum trioxide (1 〇 19 g, 〇〇76 mol). After refluxing for 30 minutes, cool to room temperature and pour the reaction solution. The reaction was terminated by entering about 25 ml of ice water. Then, it was extracted with dioxane, and the organic layer was washed with water in a regular manner with β water, 5% sodium carbonate (NaaCO 3 ) aqueous solution to neutrality. The organic layer was dehydrated with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to dryness without solvent. The crude product was purified by column chromatography (purpuration / hydrazine) and recrystallized from n-hexane to give compound 63 (4.78 g). ), yellow crystals, yield 43%, 124-127.0 °C. Compound 63: (1) MS (m/z): 294.0 (Μ+) φ (2) IR, vmax (KBr) cm'1 : 1618, 1715 (C = O) (3) 'H-NMR (CDC13, 200 MHz) d (ppm): 3.94 (s, 3H), 7.41 (dd, 1H, J= 4.0, 5.4 Hz), 7.79 (d, 1H, / = 4.0 Hz); 7.85 (d, 2H, /= 8.6 Hz), 8.13 (d, 2H, /= 8.6 Hz); 8.47 (d, 1H, J = 5.4 Hz) (4) l3C-NMR (CDC13, 50 MHz) d (ppm): 52.46, 128.95, 129.63, 130.89 , 133.06, 137.77, 141.23, 32 201202256 141.51, 150.01, 166.29, 188.77. 1-Phenyl-decyloxyphenyl) 3⁄4 phen[3,2 -and]° ratio (66) Compound 63 (5.86 g, 0_02 mol) was dissolved in 1 mL of toluene, and 1.5 ml of glacial acetic acid and phenylhydrazine (8) (4.36 g, 0.04 mol) were reacted under the same conditions as compound 55. Treatment gave Compound 66 (1.93 g), white crystals, yield: 25.3%, 165-166. Compound 66 : ^ (1) MS (m/z) : 382 (M+) (2) IR, vmax (KBr) cm*1 : 1713 (C = O) (3) 'H-NMR (DMSO-i/6 , 200 MHz) d (ppm): 3.85 (d, 3H), 7.37 (t, 1H, J = 7.2 Hz), 7.56 (t, 2H, J = 8.2 Hz), 7.81-7.89 (m, 3H), 7.95 -8.11 (m, 4H), 8.40 (d, 1H, J = 5.8 Hz) (4) 13C-NMR (DMSO-^65 5 0 MHz) d (ppm): 52.67, 114.64, 1 19.47, 120.84, 125.99, 127.27, 129.45} _ 130,23,130.57,136.57,139.25,140.13,144.47, 149.93 166.36 1-Benzyl-3-(p-decyloxy-rebellant phenyl [3,2_and]u than saliva (67) Synthetic weighing compound 63 (5.86 g, 〇.〇2 Mo) dissolved in 00 ml of hydrazine, 1.5 ml of glacial acetic acid and benzyl hydrazine (5 〇) (4 88 g, 〇 〇4 Mohr), reacted and treated under the same conditions as Compound 55, to obtain 33 201202256 Compound 67 (2.49 g), white crystals, yield 31.4% '150- 153 ° C. Compound 67 : (1) MS (m/z): 396.0 (M + ) (2) IR,vmax (KBr) cm-丨:1717 (C = Ο) (3) UV : λ max (MeOH) nm (loge) : 310 (3.8) (4) 'H-NMR (CDC13, 200 MHz) d (ppm): 3.91 (s, 3H), 5.53 (s, 2H), 7.0 0 (d, 1H, J = 5.8 Hz), 7.21-7.38 (m, 5H), 7.85- 7.95 (m, 3H), 8.10 (d, 2H, J = g.6 Hz) (5) 13C-NMR ( CDCI3, 50 MHz) d (ppm): 52.12, 55.48, 112.51, 117.20, 125.41, 127.52, 128.13, 128.86, 130.16, 1 34.83, 136.12, 137.11, 143.55, l5〇91 166.95. 1-phenyl-3 -Hydroxymethylphenyl) porphin [3,2-and]pyrazole (68) Synthesis of compound 66 (0. 764 g, 0_002 mol), the same compound ^

The reaction and the treatment were carried out under the same conditions to give Compound 68 (yield: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Compound 68: (1) MS (m/z): 354 (M+) (2) IR, vmax (KBr) cm·1 : 3 100- 3500 (OH) (3) 'H-NMR (DMSO-i/6 , 200 MHz) d (ppm): 4.53 (d, 2H, J = 5.8 Hz), 5.28 (t, 1H, /= 5.8 Hz) 7 , (t, 1H, /= 7.0 Hz), 7.45 (d, 2H , /= 8.0 Hz), 7.55 (t, 2H, j == 8 〇H^5 34 201202256 7.79- 7.86 (m, 5H) , 8.37 (d, 1H, /= 5.8 Hz) (4) 13C-N' MR (DMSO-i/6, 50 MHz) d (ppm): 63.13, 1 14.70, 1 18.89, 120.53, 125.70, 126.84, 127.61, 130.17, 130.65, 138.72, 140.31, 143.34, 145.59, 149.55 1-phenylhydrazine -3-(/7-hydroxydecylphenyl) porphin [3,2-and]. Synthesis of azole (69). Take compound 67 (0-792 g, 0.002 mol) under the same conditions as compound 57. The reaction and the workup gave Compound 69 (0.564 g), g, white crystals of white crystals, yield: 76.8%, 158-160oC. Compound 69: (1) MS (m/z): 368.1 (M+) (2 IR, vmax (KBr) cm'1 : 3100- 3500 (OH) (3) UV : λ max (MeOH) nm (loge) : 292 (3.9) (4) ]H-NMR (CDC13j 200 MHz) d ( Ppm): 4.49 (d, 2H, J = 5.2 Hz), 5.21 (t, 1HS J = 5.2 Hz), 5.56 (s, 2H), 7.20- 7.33 (m, 5H), 7.39 (d, 2H, J= 8.0 Hz), 7.51 (d • 1H, /= 5.8 Hz), 7.68 (d, 2H, / = 8.2 Hz), 8.16 (d, 1H, J = 5 8

Hz) (5) l3C-NMR (CDCI3, 50 MHz) d (ppm): 54.49, 63.12, 113.68, 115.57, 125.24, 127.49, 128.05, 128.16, 129.08, 13 1.27, 1 36.85, 137.70, 142.57, 143.91 1 5 1.635. Synthesis of 1-benzyl-3-(/7-pyruyl) pharynphin [3,2-and]d than 嗤(7〇) 35 201202256 Scale compound 67 (0. 792 g, </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Compound 70: (1) MS (m/z): 382.0 (M+) (2) IR, vmax (KBr) cm*1 : 1684 (C = O); 2400-3200 (OH) (3) UV : λ max (MeOH) nm (loge): 302 (3.8) (4) 'H-NMR (CDC13, 200 MHz) d (ppm): 5.60 (s, 2H), 7.20- 7.38 (m, 5H), 7.55 (d, 1H, J = 5.8 Hz), 7.82 (d, 2H, J = 8.2 Hz), 8.01 (d, 2H, J = 8.2 Hz), 8.20 (d, 1H, 7 = 5.8 Hz) (5) 13C-NMR ( CDCI3, 50 MHz) d (ppm): 54.66, 1 13.65, 1 16.42, 125.36, 128.08, 128.26, 129.13, 130.21, 130.64, 136.72, 137.38, 143.01, 151.91, 167.53.

36 201202256

&lt;Q-(CH2)nNHNH2

AcOH / Toluene

75, n = 1

Scheme 4 Scheme 4 shows the reaction pathways, starting reactants and intermediates for the synthesis of compounds 78-8i of the invention. Synthesis of _ 5 -decyloxy-yl-2-pyranyl- 3- °® phenotype (73) Weigh the reactant 71 (5 g, 0.026 mol) in a three-necked flask, add 5 〇 ml Dichloromethane' and SOCh (1〇g), heated to reflux for 2 hours, decompressed S0C12' under reduced pressure to produce intermediate 72, then add 50 ml of dioxane, with methyl 2-furancarboxylate (5.4 g Finally, FeCl3 (4·6 g) was added and heated under reflux for 4 hours. Monitored by TLC (dichloromethane: n-hexane = 4:1). 'After the reaction was completed, 'pour into water to terminate the reaction. The organic layer was extracted with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to 37 201202 256 solvent-free distillation. The crude product was purified by column chromatography (dichloromethane) (dioxane: n-hexane = 4: 1) 'Recrystallized from dioxane methane to give compound 73 (3.0 g), white needle crystals, yield 40.6%, mp. (:. Compound 73: (1) MS (m/z) 284 (M + ) (2) IR, vmax (KBr) cm·1 : 1720 (C = 0), 1629 (C = 0) (3) ' H-NMR (CDC13, 200 MHz) d (ppm): 3.94 (5, 3H), 7.24 (d, 1H, J = 3.8 Hz), 7.34 (d, IH, J = 3.8 Hz), 7.92-8.10 (m (2) 13C-NMR (CDC13, 50 MHz) d (ppm): 52.44, 1 18.63, 1 1 8.92, 130.5 1, 130.80, 142.12, 142.58 , 146.27, 154.59, 158.64, 175.30. 3-(5-methoxyl-yl-2-carboxyl)-1-phenylpheno[2,3·and]_. Compound 73 (3.8 g, 0.013 mol) was placed in a three-necked flask, catalyzed by adding 100 ml of toluene and acetic acid (15 ml). After heating, phenyl hydrazine 8 (5. 〇g, 0.046 mol) was added to react. After refluxing for 4 hours, remove the residue by decompression under reduced pressure and then add 50 ml of dioxane (liquid a), and take another eggplant-shaped bottle and weigh 25 g of tetraacetic acid and three gasifications to remove 1 〇〇ml (b liquid) The mixture was stirred in an ice bath, and (a liquid) was quickly added to the liquid (b liquid), and the cyclization reaction was carried out for 3 minutes, and monitored by a tlC sheet (diqi methane: n-hexane = 7:1), after the reaction was completed. , pour the reaction solution The reaction was terminated in water, and extracted with di-methane. The organic layer was separated from water by anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to solventless distillation. The crude product was purified by column chromatography. Alkane: n-hexane = 7: 1), and finally recrystallized from di-methane to give compound 78 (0.62 g). White needle crystals, yield 12.8% mp 167-169 ° C. Compound 78: (1) MS (m/z) : 372.0 (M + ) (2) IR, vmax (KBr) cm-1 : 1725 (C = 0) (3) !H-NMR (OMSO-d6, 200 MHz) d (ppm): 3.83 (5, 3H), 7.22 (d, 1H, J = 3.6 Hz), 7.36 (t, 1H, /= 7.0 Hz), 7.45 (d, 1H, "/= 3.8 Hz), 7.50-7.72 (m , 3H), 7.77 (d, 2H, /=8.2 Hz), 7.93 (d, 1H, / = 5.8 Hz). (4) 13C-NMR (DMSO-i/5, 50 MHz) d (ppm): 52.42 , 110.48, 118.30, 120.67, 127.03, 130.54, 131.37, 136.34, 139.54, 141.80, 143.79, 151.12, 158.71. 39 201202256 After the reaction was carried out for 30 minutes, the reaction solution was poured into ice water to terminate the reaction, and the reaction was carried out. The extraction was carried out, and the organic layer was washed successively with water, a 5% aqueous solution of sodium carbonate, and washed with water until neutral. The organic layer was dehydrated with anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure to dryness without solvent. The crude product was purified by column chromatography (purpuration / hydrazine) and recrystallized from n-hexane to obtain compound 79 (0 82 g), white crystals 'yield 10.6%, melting point 121-123 ° C. Compound 79: (1) MS (m/z): 385.8 (M+) (2) IR, Vmax (KBr) cm'1 : 1724 (C = O) (3) ^-NMR (CDC13, 600 MHz) d ( Ppm): 3.89 (s, 3H), 5.42 (s, 2H), 6.85 (d, 1H, J = 3.6 Hz), 7.11- 7.65 (m, 8H). 3-(5-hydroxymethyl-2-furan Synthesis of keto-1-phenyl porphin [2,3 _]pyrazole (8 〇) Weigh 1.98 g of '(0.018 mol) anhydrous calcium carbonate, (1 377 g, 〇〇36 mol) Sodium borohydride and 100 ml of anhydrous tetrahydroaluminium fluorene, reacted at room temperature for 4 hours to form a white suspension of calcium borohydride (Ca(BH4)2)' and weigh the reactant Μ (〇·744 g , 0.002 mol) to carry out the reduction reaction 'heated reflux 24

In an hour, the mixture was cooled to room temperature, and concentrated under reduced pressure to remove THF. The reaction mixture was poured into water to terminate the reaction, and the mixture was extracted with a methylene chloride. The organic layer was evaporated over anhydrous magnesium sulfate. The crude product was isolated and purified by column chromatography (hexane: <RTI ID=0.0># </RTI> </RTI> <RTIgt; The white precipitate was finally recrystallized from ethyl acetate to give a yield of 88.9%, m.p. 136-138. Compound 80: (1) MS (m/z): 344.1 (M + ) (2) IR, vmax (KBr) cm-1 : 3200-3600 (OH) (3) 'H-NMR (DMSO-i/6 , 200 MHz) d (ppm)): 4.48 (d, 2H, J= 5.6 Hz), 5.35 (t, 1H, /= 5.8 Hz), 6.46 (d, 1H, J = 3.0 Hz), 6.98 (d, 1H, J= 3.0 Hz), 7.31 (t, 1H, j= 7.5 Hz), 7.50-7.70 (m, 3H), 7.75 (d, 2H, J = 8.0 Hz), 7.85 (d, 1H, J = • 5.6 Hz). (4) 13C-NMR (DMSO-c?^ 50 MHz) d (ppm): 56.20,109.49,117.86,118.84,126.43,130.03,13〇45, 130.72, 137.79, 139.69, 141.18, 146.77, 156.51. 1-Methyl- 3- (5-methyl- 2-[---------]. The synthesis of calcium (1.98 g, 0.018 mol) than the synthesis of saliva (81) The ear and sodium borohydride (1377 keke '0.036 mol) and 50 ml of THF were reacted at room temperature for 4 hours to form Ca(BH4)2. Compound 79 (0·772 g, 0.002 mol) was added. After heating and refluxing for 6 hours, the reaction was stopped by pouring into ice water, and the mixture was extracted with methylene chloride. The mixture was dehydrated with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to a solventless distillation. The crude product was purified by column chromatography (acetic acid). Ethyl ester: n-hexane = 1 : 1 / Ethyl rubber) 'recrystallized with n-hexane' gave compound 81 (0.457 g), white crystals, yield 6 3. 8 %, 1 3 0.2 - 1 3 1.3 C. Compound 81 : 201202256 (1) MS ( m/z) : 358 (M + ) (2) IR, vmax (KBr) cm'1 : 3 100- 3400 (OH) (3) 'H-NMR (DMSO-i/^ 200 MHz) d (ppm) ): 4.42 (d, 2H, J = 5.6 Hz), 5.31 (t? ih, J = 5.6 Hz), 5.43 (s, 2H), 6.38 (d, 1H, J = 3.2 Hz), 6.76 (d, 1H) , J = 3.2 Hz), 7.20-7.50 (m, 6H), 7.57 (d, 1H, J = 5.8 Hz). (4) 3C-NMR (DMSO-^(Jj 5〇MHz) d (ppm): 56.01 , 56.15, 107.73, 109.31, 1 18.73, 128.73, 129.03, 129.22, 135.74, 135.86, 143.39, 147.59, 155.60. · Human tumor cell strains and human tumor cell lines used in the culture experiments, purchased from ATCC or BCRC. The total volume of the cultured cultivator cultured in 24-well was 1 ml/weU; and the compounds of various concentrations were added and cultured in an incubator at 37 ° C, 95% humidity, and 5% CO 2 for 48 hours, respectively. Proliferation analysis experiments. Analysis of cytotoxicity of compounds using MTT_ First, remove 800 μΐ of cells from each well (1200 rpm, 5 min), then remove the supernatant, wash with 200 μΐ HBSS, and centrifuge again (1200 rpm, 5 min) After removing the supernatant, add 200 μΐ HBSS. 50 μΐ of the cell culture medium from which the medium was removed from each well was placed in a 96-well plate. Add 10 μΐ of guanidine solution (5 mg/ml) for 4 hours at 37 ° C; remove DMSO (150 μΐ/ Well) dissolves the purple-black particles of the cells, and finally measures the OD57 〇 value with the ELISΑ reader at 570 nm. 42 201202256 Table 1. Cytotoxicity of porphin [3,2-and]pyrazole and porphin [2,3-and]pyrazole derivatives on NCI-H226 and A498 tumor cell lines

IC50a_ Compound R5 n R5, NCI-H226 A498 34 Η 0 COOCH3 &gt; 100 &gt; 100 35 ch3 0 COOCH3 &gt; 100 &gt;100 36 Η 0 COOCH3 &gt; 100 &gt; 100 37 Η 0 COOCH3 &gt; 100 &gt; 100 38 Η 0 COOCH3 &gt; 100 &gt; 100 39 Η 0 COOCH3 &gt; 100 &gt; 100 40 Η 0 COOCH3 &gt; 100 &gt; 100 41 Η 0 COOCH3 &gt; 100 &gt; 100 42 Η 0 COOCH3 &gt; 100 &gt;100 43 Η 0 ch2oh 29.5 2.2 44 ch3 0 ch2oh 25.0 1.98 48 Η 0 COOH &gt; 100 &gt;100 49 ch3 0 COOH &gt; 100 &gt; 100 43 201202256 55 Η 1 COOCHs &gt; 100 &gt; 100 56 ch3 1 COOCH3 &gt; 100 &gt; 100 57 Η 1 ch2oh 1.4 0.4 58 ch3 1 ch2oh 8.7 0.9 59 Η 1 COOH &gt; 100 &gt; 100 60 Η 1 CH2OCO(CH2)2COOH 2.2 0.8 66 Η 0 COOCH3 &gt; 100 &gt; 100 67 Η 1 COOCH3 &gt; 100 &gt; 100 68 Η 0 CH2OH &gt; 100 &gt; 100 69 Η 1 CH2OH &gt; 100 &gt; 100 70 Η 1 COOH &gt; 100 &gt; 100 78 Η 0 COOCH3 &gt;100 &gt; 100 79 Η 1 COOCH3 &gt; 100 &gt; 100 81 Η 1 ch2oh _ 0.14

a Definition of IC5〇--The concentration required to inhibit 50% of proliferation during compound treatment. Data were expressed as mean SD of three independent experiments, and Student's t test was used to analyze the statistical significance of the difference, where a ΠΡ" value of less than 0.05 was considered statistically significant. Compounds 43, 44, 57, 58, 60 and 81 have significant inhibitory activities against proliferation of human lung cancer (NCI-H226) and renal cancer (Α498) cell lines.

Claims (1)

201202256 ' VII. Patent application scope: 1. A porphin-pyrazole compound having the following formula (I) or (Π): Wherein R1 is hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, fluoro, chloro or bromo; R2 is hydrogen or methyl; R3 is -COOR2, -(CR2H)jOH, -(CR^Hh- C^OVCCHdn^COOH, -(CR2H)j-0-C(0)-(CH2)m-NH2 or -(CR2H)j-0-C(0)-(CH2)m-C00H, where R2 is defined Same as above, j = 1-6 and l-i Ari are phenyl or Wherein X is 0, S or Se Ar2 is wherein R4 is hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, fluoro, chloro or bromo; and η = 0, 1 or 2. 45 201202256 2. A compound according to claim 1 wherein Ar is 2-furan. 3. A compound according to claim 1 or 2 wherein R3 is 5-CH2OH or 5-CH2-0-C(0)-(CH2)m-C00H, wherein m = 1 or 2. 4. A compound as claimed in claim 3, wherein R3 is 5-CH2OH. 5. A compound as claimed in claim 3, wherein R3 is 5-CH2-0-C(0)-(CH2)2-C00H. 6. A compound as claimed in claim 3, wherein n = 0 or 1. 7. The compound of claim 6 wherein R2 and R4 are hydrogen and R1 is hydrogen or sulfhydryl. 8. The compound of claim 1 or 2, wherein the compound has the formula (I). 9. The compound of claim 1 or 2, wherein the compound has the formula (II). 46 1 0. An anti-cancer pharmaceutical composition comprising an effective amount for treating cancer 201202256 • As an active ingredient, as described above, please cite the compound described above, or a pharmaceutically acceptable salt thereof. u• A composition as claimed in claim 10, lung cancer or kidney cancer. 12. Use of a compound according to the above-mentioned patent application, or a pharmaceutically acceptable salt thereof, for the manufacture of an anticancer 13. The use of the invention of claim 12, cancer or kidney cancer. Among the nine items, the cancer is used for any of the nine medicines. The cancer is lung 47 201202256 IV. Designated representative map: (1) The representative representative of the case is: ( ). (2) A brief description of the symbol of the representative figure: [None] ❹ 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: