CN102617569A - Beta-carboline derivative having antitumor activity and preparation method thereof - Google Patents

Abstract

The invention discloses a beta-carboline derivative having antitumor activity and a preparation method thereof. The chemical general formula of the beta-carboline derivative is shown in the specifications. The invention further discloses a preparation method of the beta-carboline derivative. In the beta-carboline derivative having antitumor activity disclosed by the invention, different substitution groups are introduced on the basis of the chemical structure of beta-carboline, so that the beta-carboline derivative plays a role in inhibiting the activity of Hela human body lung cancer cells and MCF-7 cancer cells, and has high antitumor activity.

Description

A kind of β-Ka Lin analog derivative and preparation method thereof with anti-tumor activity

Technical field

The present invention relates to a kind of β-Ka Lin analog derivative and preparation method thereof, especially relate to a kind of β-Ka Lin analog derivative and preparation method thereof with anti-tumor activity.

Background technology

At present, malignant tumour has replaced cardiovascular and cerebrovascular diseases gradually, becomes human No.1 killer.

The main means of existing treatment malignant tumour have: operative treatment, radiotherapy and pharmacological agent.But medicine ubiquity clinically is to the weak curative effect of noumenal tumour, and therefore shortcoming such as toxic side effect is big, is studied new low-poison efficient antineoplastic medicine and become the task of top priority.

The β-Ka Lin analog derivative is one type of vegeto-alkali that contains indole ring that nature exists, and has good biological activity, and its anti-tumor activity that shows has caused people's attention.At present, about the compound method of β-Ka Lin analog derivative, a lot of bibliographical informations are arranged both at home and abroad (referring to Tetrahedron Lett., 2004,45,5411-5413; Tetrahedron Lett., 2005,46,3831-3834; Tetrahedron, 2006,62,10900-06; Tetrahedron Lett., 2007,48,1379-1383; Org. Biomol. Chem, 2006,4,4478-4484; Org. Lett., 2008,10,3485-3488; Organic Lett., 2010,12,1540-1543; Tetrahedron, 2004,60,5315-5318; Tetrahedron, 2010,66,1496-1502; Chem. Commun., 2003,916-917; J. Org. Chem, 2005,70,4889-4892; Chem. Rev, 2004,104,3341-3370.).But the biological activity of existing discovery and synthetic β-Ka Lin analog derivative also is not very high, and other β-Ka Lin analog derivatives of finding do not have activity, and perhaps activity is not high yet.

Summary of the invention

The technical problem that the present invention will solve is, overcomes the deficiency of prior art, and higher β-Ka Lin analog derivative of a kind of anti-tumor activity and preparation method thereof is provided.

The present invention solve the technical problem the technical scheme that is adopted,

The present invention's β-Ka Lin analog derivative with anti-tumor activity, its chemical general formula is shown in chemical compounds I:

Wherein R is cyclopropyl, phenyl or is with substituent phenyl,

Said substituting group can be bromine, fluorine, methoxyl group, methyl, nitro, ethanoyl or aldehyde radical etc.;

The present invention has β-Ka Lin analog derivative of anti-tumor activity and preparation method thereof, and its synthetic route is:

The present invention's the β-Ka Lin analog derivative with anti-tumor activity is the basis with the chemical structure of β-Ka Lin, introduces different substituting groups, and the activity of Hela human hepatoma cell and MCF-7 cancer cells is had restraining effect, has good antineoplastic activity.

Embodiment

Below in conjunction with specific embodiment the present invention is done further explain.

With the 2 methyl indole is raw material, at first reference literature (Tetrahedron Lett., 1995,36,3103-06; Chem. Pharm. Bull, 1999,47,1740-1743; Synthetic Commun., 2004,34,1325 – 35) the synthetic compound 1-benzenesulfonyl-2-methyl-3-iodo-indoles (4) that obtains, replace through Sonogashira coupling, wohl-ziegler bromine again, the iodine cyclization obtains compound VIII Compound VIII obtains target compound through the Suzuki linked reaction again.

Embodiment 1

3, the 4-phenylbenzene- bSynthesizing of-carboline.

Its preparation method:

(1) 1-benzenesulfonyl-2-methyl-3-iodo-indoles (compound IV) is synthetic: with the 2 methyl indole is raw material, reference literature (Tetrahedron Lett., 1995,36,3103-06; Chem. Pharm. Bull, 1999,47,1740-1743; Synthetic Commun., 2004,34,1325 – 35) the synthetic compound 1-benzenesulfonyl-2-methyl-3-iodo-indoles (IV) that obtains;

(2) 1-benzenesulfonyl-2-methyl-3-benzyne base indoles (compound V) is synthetic: get 11.91g (30 mmol) step (1) gained compound IV, be dissolved in 40 ml N, NIn-the N, add 1.8g (2.6 mmol) bi triphenyl phosphine dichloride palladium, 0.9g (5mmol) cuprous iodide, 4.5g triethylamine and 4.59g (45mmol) phenylacetylene, logical nitrogen protection was reacted 12 hours down at 35 ℃; Thin-layer chromatography monitoring reaction terminal point, after reacting completely, suction filtration, washing; Ethyl acetate extraction, anhydrous sodium sulfate drying, underpressure distillation removes organic solvent; The resistates column chromatography gets faint yellow solid 9.16 g, yield 82.3%, m.p.93.7-94.5 ℃;

(3) 1-benzenesulfonyl-2-benzyl bromo-3-benzyne base indoles (compound VI) is synthetic: get 7.42g (20 mmol) step (2) gained compound V and be dissolved in the 40 ml tetracol phenixin, under nitrogen protection, be heated to backflow, add 5.34 g (30 mmol) again N-bromo-succinimide, the 50mg Diisopropyl azodicarboxylate is when the N-bromo-succinimide is suspended in the tetracol phenixin fully; React completely, reaction solution is washed through suction filtration; Anhydrous sodium sulfate drying, underpressure distillation extracts organic solvent, obtains the yellow oily crude product; Use sherwood oil again: tetracol phenixin (2:1) recrystallization gets yellow solid 8.1g, yield 90.0%;

(4) 1-benzenesulfonyl-2-benzyl nitrine-3-benzyne base indoles (compound VII) is synthetic: get 6.75g (15 mmol) step (3) gained compound VI and be dissolved in the 50ml sherwood oil, be dissolved in 1.3g (20mmol) sodiumazide in the 4 ml water again and join in the petroleum ether solution of compound VI, add the 0.1g 4-butyl ammonium hydrogen sulfate at last; Be heated to 90 ℃, back flow reaction 12 hours, suction filtration after reaction finishes; Filtrating is washed twice with deionized water; Separatory, underpressure distillation extracts organic solvent then, obtains red solid 5g; Productive rate 81.0%, m.p.80.0-83.6 ℃;

(5) 3-phenyl-4-iodo-9-benzenesulfonyl- bSynthesizing of-carboline (compound VIII): with 4.94g (12mmol) step (4) gained compound VII, be dissolved in the 50ml Nitromethane 99Min., add 1.01g (12 mmol) sodium hydrogencarbonate and 7.62 g (60 mmol) iodine again; Reacted 20 hours down at 105 ℃, TLC monitoring reaction terminal point, reaction solution is with 30ml saturated sodium thiosulfate solution washing; The 30ml ethyl acetate extraction; Washing, anhydrous magnesium sulfate drying, silica gel column chromatography (Yi Suan Yi Zhi ︰ sherwood oil=1 ︰ 5) gets the 2.68g product; White solid, yield 43.9%; ¹H NMR (CDCl ₃) d: 7.4 (t, J=8.00 Hz, 2H), 7.45-7.47 (m, 1H), 7.48-7.53 (m, 4H), 7.55-7.58 (m, 2H), 7.72-7.75 (m, 1H), 7.89-7.91 (m, 2H), 8.47 (d, J=8.50 Hz, 1H), 9.15 (d, J=8.00 Hz, 1H), 9.66 (s, 1H); ¹³C NMR (CDCl ₃) d:86.47,114.80,122.89,123.37,125.52,126.66,127.95,128.39,129.41,129.70,130.66,133.65,134.44,135.05,135.45,137.33,139.61,142.51,157.67; MS (EI): 510 (M ⁺+ 1), 369 (100), 242,214,77.

(6) compound 3,4-phenylbenzene-9-benzenesulfonyl- b-carboline (a) synthetic of compound IX: in the round-bottomed flask of one 25 ml, add 153mg (0.3 mmol) step (5) gained compound VIII; (54.9mg 0.45 mmol) phenylo boric acid, 9 mg (0.9% mmol) bi triphenyl phosphine dichloride palladium and 304.5 mg (0.9 mmol) potassiumphosphate add 10 ml toluene at last and make solvent; Reacted 20 hours down at 45 ℃; The thin-layer chromatography monitoring back suction filtration that reacts completely, underpressure distillation extracts organic solvent, and (ETHYLE ACETATE: sherwood oil=1:5) must faint yellow solid with silica gel column chromatography for crude product; 103.6 mg, yield 75.1%;

¹H?NMR?(CDCl ₃)?d:?6.81?（d,? J?=?8.00?Hz,?1H）,?7.08?(t,? J?=?7.50?Hz,?1H),?7.20?(t,? J?=?3.00?Hz,?3H),?7.24?(d,? J?=?2.50?Hz,?1H),?7.25?(s,?1H),?7.33,?7.35?(dd,? J?=?2.00,?3.30Hz,?2H),?7.38-7.44?(m,?5H),?7.53?(d,? J?=?8.50Hz,?1H),?7.56?(d,? J?=?7.00Hz,?1H),?7.96?(d,? J?=?7.50?Hz,?2H),?8.39?(d,? J?=?8.50?Hz,?1H),?9.75?(S,?1H); ^?13C?NMR?(CDCl ₃)?d:?114.75,?116.42,?123.70,?123.89,?124.71,?126.75,?127.28,?127.60,?127.63,?128.08,?128.79,?129.36,?129.38,?129.47,?129.51,?129.66,?130.01,?131.70,?133.57,?134.22,?134.26,?135.65,?136.86,?136.89,?137.58,?137.65,?139.33,?139.76,?152.06;?MS(EI)?460?(M ⁺+1):?319(100),?291,?77.

(7) compound 3, the 4-phenylbenzene- b-carboline (a) synthetic of chemical compounds I: in the round-bottomed flask of a 25ml, add 80mg IX a successively, 10 ml 1,4-dioxane; 1 ml massfraction is 40% sodium hydroxide solution, 80 ℃ down reaction after 3 hours underpressure distillation extract 80% 1, the 4-dioxane; Add 10 ml deionized waters again, use ethyl acetate extraction at last, separate organic phase; Underpressure distillation extracts solvent, and resistates gets I a with ETHYLE ACETATE and sherwood oil recrystallization (1:1);

¹H?NMR?(CDCl ₃)?d:?6.94?(t,? J?=?7.50?Hz,?1H),?7.02?(d,? J?=?8.00?Hz,?1H),?7.20-7.24?(m,?3H),?7.33-7.44?(m,?8H),?9.19?(s,?1H),?10.00?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d:?111.62,?119.55,?121.64,?123.44,?126.71,?127.58,?127.68,?127.98,?128.53,?130.05,?130.25,?130.36,?132.07,?135.30,?138.06,?140.74,?141.32,?147.30;?MS?(EI)?319?(M ⁺+1),?319?(100),?277,?169,?69,?57.?Anal.?Calc.?for?C ₂₃H ₁₆N _2?:?C?86.22,?H?5.03,?N?8.74;?found?C?86.40，H?4.90，N?8.70.

Embodiment 2

3-phenyl-4-(4-aminomethyl phenyl)- bSynthesizing of-carboline.

Its preparation method:

Step (1) to step (5) working method is with embodiment 1.

Step (6) 3-phenyl-4-(4-aminomethyl phenyl)-9-benzenesulfonyl- bSynthesizing of-carboline (compound IX b): with reference to the compound method of compound IX a among the embodiment 1; Used phenylo boric acid when difference is to use to methylphenylboronic acid replacement synthetic compound IX a after adding toluene is made solvent, reacts 24h down at 60 ℃; Suction filtration after the TLC monitoring reacts completely; Underpressure distillation extracts organic solvent, and column chromatography obtains faint yellow solid 96 mg, productive rate 61%.

¹H?NMR?(CDCl ₃)?d:?2.42?(s,?3H),?6.88?(d,? J?=?8.0Hz,?1H),?7.08-7.13?(m,?3H),?7.18?(s,?1H),?7.19-7.22?(m,?4H),?7.34-7.36?(m,?2H),?7.42?(t,? J?=?7.75Hz,?2H),?7.52-7.56?(m,?2H),?7.95?(t,? J?=?1.50?Hz,?1H),?7.97?(d,? J?=?1.00?Hz,?1H),?8.39?(d,? J?=?8.50?Hz,?1H),?9.73?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d:?21.36,?114.73,?123.79,?123.84,?124.86,?126.75,?127.18,?127.59,?129.34,?129.40,?129.48,?129.77,?129.85,?130.02,?131.83,?133.59,?133.73,?133.77,?133.79,?134.16,?134.19,?135.50,?137.69,?137.73,?137.76,?139.33,?139.34,?139.97,?152.23；

Step (7) 3-phenyl-4-(4-aminomethyl phenyl)- bSynthesizing of-carboline (compounds): the concrete operations step is synthetic with embodiment 1 chemical compounds I a's; Obtain faint yellow solid 64 mg, productive rate 82.3%. ¹H?NMR?(CDCl3)?d:?2.43?(s,?3H),?6.91?(t,? J?=?5.75?Hz,?1H),?6.95?(t,? J?=?6.75?Hz,?1H),?7.13?(d,? J?=?8.00?Hz,?1H),?7.19-7.27?(m,?7H),?7.32?(t,? J?=?7.00?Hz,?1H),?7.44?(s,?1H),?7.45?(d,? J?=?1.50?Hz,?1H),?9.21?(s,?1H),?10.32?(s,?1H);? ¹³C?NMR?(CDCl3)?d:?21.41,?111.65,?113.94,?119.40,?121.69,?123.48,126.63,?127.75,?127.86,?128.65,?129.24,?130.06,?130.20,?130.41,?131.38,131.84,134.92,?135.44,?137.14,?140.92,?141.42,?147.31；MS?(EI)?333?(M ⁺+1),?333(100),?319,?159,?83,?57

Embodiment 3

3-phenyl-4-(4-p-methoxy-phenyl)- bSynthesizing of-carboline.

Its preparation method:

Step (1) to step (5) working method is with embodiment 1;

Step (6) 3-phenyl-4-(4-p-methoxy-phenyl)-9-benzenesulfonyl- bSynthesizing of-carboline (compound IX c): used when difference is to use to methoxyphenylboronic acid replacement synthetic compound IX b with reference to the compound method of compound IX b among the embodiment 2 to methylphenylboronic acid, obtain product 105mg, yield 80.3%;

¹H?NMR?(CDCl ₃)?d:?3.85?(s,?3H),?6.92?(t,? J?=?9.50?Hz,?3H),?7.11?(t,? J?=?7.50?Hz,?1H),?7.14?(d,? J?=?8,50?Hz,?2H),?7.21?(d,? J?=?6.00?Hz,?3H),?7.35?(t,? J?=?4.00?Hz,?2H),?7.41?(t,? J?=?8.00?Hz,?2H),?7.54?(t,? J?=?7.75?Hz,?2H),?7.95?(d,? J?=?7.50?Hz,?2H),?8.39?(d,? J?=?8.50?Hz,?1H),?9.73?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d:?55.19,?114.18,?114.71,?123.75,?123.88,?124.83,?126.71,?127.16,?127.63,?128.91,?129.33,?129.43,?129.99,?131.16,?131.99,?133.56,?134.19,?135.43,?137.44,?137.59,?139.27,?139.92,?152.39,?159.29;?MS(EI)?490?(M ⁺+1):?350,?83?(100)；

Step (7) 3-phenyl-4-(4-p-methoxy-phenyl)- bSynthesizing of-carboline (chemical compounds I c): the concrete operations step is synthetic with embodiment 1 chemical compounds I a's, obtains product 73mg, yield 89.3%.

¹H?NMR?(CDCl ₃)?d:?3.87?(s,?3H),?6.95?(t,? J?=?9.00?Hz,?4H),?7.17?(d,? J?=?8.50?Hz,?1H),?7.20-7.25?(m,?5H),?7.33?(t,? J?=?9.00?Hz,?1H),?7.42?(d,? J?=?6.00?Hz,?2H),?9.17?(s,?1H),?10.32?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d:?55.26,?111.73,?113.99,?119.49,?121.73,?123.51,?126.68,?127.78,?127.95,?128.87,?129.89,?130.24,?130.44,?131.42,?131.84,?135.50,?140.90,?141.49,?147.46,?159.00;?MS?(EI)?349?(M ⁺+1):?349?(100),?334,?306,?167,?159.

Embodiment 4

3-phenyl-4-(2-p-methoxy-phenyl)- bSynthesizing of-carboline.

Its preparation method:

Step (1) to step (5) working method is with embodiment 1;

Step (6) 3-phenyl-4-(2-p-methoxy-phenyl)-9-benzenesulfonyl- bSynthesizing of-carboline (compound IX d): used when difference is to use to O-methoxy phenylo boric acid replacement synthetic compound IX b with reference to the compound method of compound IX b among the embodiment 2 to methylphenylboronic acid, obtain product 87mg, yield 84.0%;

¹H?NMR?(CDCl ₃)?d:?3.45(s,?3H),?6.88-6.96?(m,?3H),?7.07-7.10?(m,?2H),?7.18-7.20?(m,?3H),?7.35-7.43?(m,?5H),?7.50-7.55?(m,?2H),?7.95?(d,? J?=?1.50?Hz,?1H),?7.97?(d, ?J?=?1.00?Hz,?1H),?8.36?(d,? J?=?8.50?Hz,?1H),?9.72?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d:?55.36,?111.26,?114.71,?121.03,?123.28,?123.92,?125.02,?125.84,?126.22,?126.81,?127.25,?127.49,?129.35,?129.99,?131.38,?132.08,?133.70,?134.16,?135.44,?137.84,?139.32,?140.32,?152.90,?157.17.

Step (7) 3-phenyl-4-(2-p-methoxy-phenyl)- bSynthesizing of-carboline (chemical compounds I d): the concrete operations step is synthetic with embodiment 1 chemical compounds I a's, gets product 61mg, yield 90.0%.

¹H?NMR?(CDCl ₃)?d?:?3,51?(s,?3H),?6.93-7.02?(m,?4H),?7.09?(d,? J?=?8.00?Hz,?1H),?7.20-7.24?(m,?4H),?7.33?(t,? J?=?7.75?Hz,?1H),?7.41?(t,? J?=?7.75?Hz,?1H),?7.47?(d,? J?=?6.00?Hz,?2H),?9.18?(s,?1H),?10.02?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d?:?55.41,?111.13,?111.61,?119.50,?120.90,?121.90,?123.08,?125.04,?126.44,?126.72,?127.08,?127.55,?127.83,?128.92,?129.48,?129.73,?131.66,?131.99,?135.39,?141.27,?141.39,?148.06,?157.25;?MS?(EI)?350?(M ⁺+1),?350?(100),?335,?319,?159?,113,?71,?43.

Embodiment 5

3-phenyl-4-cyclopropyl- bSynthesizing of-carboline.

Its preparation method:

Step (1) to step (5) working method is with embodiment 1;

Step (6) 3-phenyl-4-cyclopropyl-9-benzenesulfonyl- bSynthesizing of-carboline (IX e): used when difference is to use to cyclopropylboronic acid replacement synthetic compound IX b with reference to the compound method of compound IX b among the embodiment 2 to methylphenylboronic acid, obtain product 78mg, yield 68.7%;

¹H?NMR?(CDCl ₃)?d:?0.24-0.28?(m,?2H),?0.99-1.04?(m,?2H),?2.33-2.37?(m,?1H),?7.35-7.42?(m,?3H),?7.45-7.52?(m,?4H),?7.66-7,69?(m,?1H),?7.71?(s,?1H),?7.72?(d, ?J?=?1.50?Hz,?1H),?7.90(d,? J?=?1.5Hz,?1H),?7.91?(d,? J?=?1.5Hz，1H),?8.47?(d,? J?=?8.5Hz,?1H),?8.52?(d,? J?=?8.0Hz,?1H),?9.62?(s,?1H)；

(7) 3-phenyl-4-cyclopropyl- bSynthesizing of-carboline (chemical compounds I e): the concrete operations step is synthetic with embodiment 1 chemical compounds I a's, obtains product 52mg, yield 88.7%.

¹H?NMR?(CDCl ₃)?d?:?0.34-0.37?(m,?2H),?1.03-1.07?(m,?2H),?2.47-2.52?(m,?1H),?7.27?(s,?1H)?,7.31?(t,? J?=?7.50?Hz,?1H),?7.39?(t,? J?=?7.25?Hz,?1H),?7.46?(t,? J?=?7.50?Hz,?2H),?7.52?(t,? J?=?7.50?Hz,?1H),?7.76?(d,? J?=?7.50?Hz,?2H),?8.57?(d,? J?=?8.00?Hz,?1H),?8.96?(s,?1H),?9.44?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d?:?10.58,?14.18,?21.06,?111.44,?119.68,?121.94,?125.20,?126.96,?127.78,?129.47,?129.97,?130.77,?131.06,?135.05,?141.07,?141.94,?149.96,?171.20;?MS?(EI)?284?(M ⁺+1):?269,?256,?159,?127,?121,?97,?83,?71,?57?(100),?43.

Embodiment 6

3-phenyl-4-(3-oil of mirbane)- bSynthesizing of-carboline.

Its preparation method:

Step (1) to step (5) working method is with embodiment 1;

Step (6) 3-phenyl-4-(3-nitrophenyl)-9-benzenesulfonyl- bSynthesizing of-carboline (IX f): in the round-bottomed flask of one 25 ml, add 153 mg (0.3 mmol) steps (5) gained compound VIII successively; 75 mg (0.45 mmol) 3-oil of mirbane boric acid, 9 mg (0.9% mmol) bi triphenyl phosphine dichloride palladium and 293 mg (0.9 mmol) cesium carbonate and 10 ml 1,4-dioxane; Reacted 30 hours down at 80 ℃; Suction filtration after reacting completely, underpressure distillation extracts solvent, the resistates silica gel column chromatography; Get yellow solid 94.7 mg, yield 62.5%;

¹H?NMR?(CDCl ₃)?d?:?6.76?(d,? J?=?8.00Hz,?1H),?7.11?(t,? J?=?7.50?Hz,?1H),?7.22?(t,? J?=?3.75Hz,?3H),?7.25-7.28?(m,?2H),?7.45?(t,? J?=?8.00?Hz,?2H),?7.56-7.62?(m,?4H),?7.96?(t,? J?=?1.50?Hz,?1H),?7.97?(d,?J?=?1.00?Hz,?1H),?8.16?(t,? J?=?1.50?Hz,?1H),?8.27,8.29?(dd,? J?=?2.00?Hz,?2Hz,?1H),?8.43?(d,? J?=?8.50?Hz,?1H),?9.81?(s,1H);? ¹³C?NMR?(CDCl ₃)?d:?115.07,?122.96,?123.11,?123.88,?124.16,?125.21,?126.72,?126.88,?127.73,?127.95,?129.47,?129.88,?129.96,?130.01,?131.25,?133.58,?134.45,?136.49,?136.53,?137.39,?138.82,?138.95,?139.39,?148.29,?152.28；

(7) compound 3-phenyl-4-(3-oil of mirbane)- bSynthesizing of-carboline (chemical compounds I f): the concrete operations step is synthetic with embodiment 1 chemical compounds I a's, obtains product 56mg, and yield is 78.5%.

¹H?NMR?(CDCl ₃)?d?:?6.97-7.02?(m,?2H),?7.23?(d,? J?=?7.00?Hz,?4H),?7.34?(d,? J?=?6.00?Hz,?2H),?7.43?(t,? J?=?7.25?Hz,?1H),?7.61?(t,? J?=?8.25?Hz,?1H),?7.71?(d,? J?=?7.50?Hz,?1H),?8.29?(d,? J?=?7.00?Hz,?2H),?9.17?(s,?1H),?9.57?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d?:?111.89,?120.09,?120.97,?122.71,?122.81,?125.41,?127.22,?128.0,?128.54,?129.61,?130.32,?133.03,?135.10,?136.72,?139.88,?140.05,?141.23,?147.70,?148.27;?MS?(EI)?365?(M ⁺+1):?319?(100),?159,?144.

Embodiment 7

3-phenyl-4-(3-formyl radical phenyl)- bSynthesizing of-carboline.

Its preparation method:

Step (1) to step (5) working method is with embodiment 1;

Step (6) 3-phenyl-4-(3-formyl radical phenyl)-9-benzenesulfonyl- bSynthesizing of-carboline (IX g): with reference to the compound method of compound IX f among the embodiment 6, used 3-oil of mirbane boric acid when difference is with 3-formylphenylboronic acid replacement synthetic compound IX f obtains glassy yellow solid 48mg, and yield is 57.2%;

¹H?NMR?(CDCl ₃)?d:?2.48?(s,?3H),?6.79?(d,? J?=?8.00?Hz,?1H),?7.08?(t,? J?=?7.75?Hz,?1H), 7.20?(t,? J?=?3.00?Hz,?3H),?7.28,7.29?(dd,? J?=?2.50?Hz,?3Hz,?2H),?7.43-7.59?(m,?6H),?7.84?(s,?1H),?7.97?(d,? J?=?7.50?Hz,?2H),?8.0?(d,? J?=?7.50?Hz,?1H),?8.41?(d,? J?=?8.50?Hz,?1H),?9.79?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d:?26.68,?114.91,?123.29,?124.01,?124.33,?126.73,?127.45,?127.77,?127.88,?128.43,?129.16,?129.43,?129.73,?130.00,?130.20,?131.45,?133.58,?134.36,?134.83,?136.03,?137.33,?137.41?137.45,?139.33,?139.39,?152.25,?197.62;?MS(EI)?489?(M ⁺+1):?348(100),?304,?77,?40；

(7) 3-phenyl-4-(3-formyl radical phenyl)- bSynthesizing of-carboline (chemical compounds I g): the concrete operations step is synthetic with embodiment 1 chemical compounds I a's, obtains product 32mg, yield 86.2%.

¹H?NMR?(CDCl ₃)?d?:?6.96?(t,? J?=?7.50?Hz,?1H),?7.06?(d,? J?=?8.00?Hz,?1H),?7.20-7.24?(m,?4H),?7.35?(d,? J?=?5.50?Hz,?2H),?7.41?(t,? J?=?7.50?Hz,?1H),?7.53?(t,? J?=?7.50?Hz,?1H),?7.60?(d,? J?=?7.00?Hz,?1H),?7.96?(s,?1H),?8.02?(d,? J?=?7.50?Hz,?1H),?9.13?(s,?1H),?9.57?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d?:?111.74,?119.89,?119.96,?121.42,?123.16,?126.95,?127.37,?127.83,?128.21,?128.29,?128.77,?128.97,?130.39,?130.74,?132.59,?135.15,?135.22,?137.27,?138.61,?140.39,?141.26,?147.68,?198.00;?MS?(EI)?348?(M ⁺+1)?:?348?(100),?304,?230,?77,?40。

Embodiment 8

3-phenyl-4-(4-fluorophenyl)- bSynthesizing of-carboline.

Its preparation method:

Step (1) to step (5) working method is with embodiment 1;

Step (6) 3-phenyl-4-(4-fluorophenyl)-9-benzenesulfonyl- bSynthesizing of-carboline (compound IX h): with reference to the compound method of compound IX f among the embodiment 6, used 3-oil of mirbane boric acid when difference is with 4-fluorophenyl boric acid replacement synthetic compound IX f obtains faint yellow solid 39mg, yield 42.8%;

¹H?NMR?(CDCl ₃)?d:?6.87?(d,? J?=?8.00?Hz,?1H),?7.08-7.14?(m,?3H),?7.21-7.23?(m,?5H),?7.31?(d,? J?=?4.00?Hz,?2H),?7.43?(t,? J?=?7.75?Hz,?2H),?7.55-7.58?(m,?2H),?7.97?(d,? J?=?8.00?Hz,?2H),?8.41?(d,? J?=?8.50?Hz,?1H),?9.76?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d:?114.85,?115.88,?116.05,?123.51,?123.97,?124.50,?126.76,?127.41,?127.76,?128.58,?129.40,?129.67,?129.98,?131.79,?131.86,?132.77,?133.55,?134.30,?135.80,?137.55,?139.34,?139.54,?139.81,?152.26；

Step (7) 3-phenyl-4-(4-fluorophenyl)- bSynthesizing of-carboline (chemical compounds I h): the concrete operations step is synthetic with embodiment 1 chemical compounds I a's, obtains product 28mg, yield 84.8%.

¹H?NMR?(CDCl ₃)?d?:?6.98?(t,? J?=?7.50?Hz,?1H),?7.04?(d,? J?=?8.00?Hz,?1H),?7.12?(t,? J?=?7.75?Hz,?3H),?7.24?(d,? J?=?6.50?Hz,?3H),?7.32-7.40?(m,?5H),?9.18?(s,?1H),?9.99?(s,?1H);? ¹³C?NMR?(CDCl ₃)?d?:?111.70,?115.55,?115.72,?119.65,?121.45,?123.23,?126.82,?128.11,?128.51,?128.94,?130.32,?131.91,?131.97,?132.21,?133.95,?133.98,?135.26,?140.53,?141.31,?147.50,?161.29,?163.26;?MS?(EI)?337?(M ⁺+1),?210,?105?(100),?77,?65.

The pharmacology test result

Prepare in selected part the foregoing description b-carboline compound carries out external anticancer shaker test; But be not limited only to these several kinds, select Hela (cervical cancer cell) respectively for use, MCF-7 (human breast cancer cell); A549 (lung carcinoma cell) cell strain; Adopt mtt assay to test, obtain the IC50 value of each sample by graphing method, control compound is a yageine.

Anticancer inhibition with respect to yageine is active, and the present invention's compound improves a lot to the inhibition activity of Hela and MCF-7.

Claims (4)

1. β-Ka Lin analog derivative with anti-tumor activity is characterized in that chemical general formula is shown in chemical compounds I:

Wherein R is cyclopropyl, phenyl or is with substituent phenyl.

2. the β-Ka Lin analog derivative with anti-tumor activity according to claim 1 is characterized in that said substituting group is bromine, fluorine, methoxyl group, methyl, nitro, ethanoyl or aldehyde radical.

3. the β-Ka Lin analog derivative with anti-tumor activity according to claim 1 is characterized in that, R is following group:

。

4. preparation method with β-Ka Lin analog derivative of anti-tumor activity as claimed in claim 1 is characterized in that its synthetic route is:

。