CN101429174B

CN101429174B - Piperazine derivant with antineoplastic activity

Info

Publication number: CN101429174B
Application number: CN2008101540181A
Authority: CN
Inventors: 陈娇娇; 陈莉; 赵义平; 傅宏俊
Original assignee: Tianjin Polytechnic University
Current assignee: Tianjin Polytechnic University
Priority date: 2008-12-12
Filing date: 2008-12-12
Publication date: 2012-07-11
Anticipated expiration: 2028-12-12
Also published as: CN101429174A

Abstract

The invention discloses piperazine derivatives with anti-tumor activity, which have a structure as right, in the formula, when X is C=O, R is H or -CH3; and when X is -CHOH or -CH2, R is H. The compounds are obtained by using carvone as an initial raw material through chlorination reaction, condensation reaction, sodium borohydride reduction and Huang Min-lon reduction reaction. In vitro experiments show that the compounds have stronger propagation inhibiting effect on a cancer cell strain Lncap of human pancreas, are potential anti-tumor medicaments, and have application to preparing anti-tumor pharmaceutical preparations.

Description

One type of bridged piperazine derivatives with anti-tumor activity

Technical field

The present invention relates to one type of bridged piperazine derivatives with antitumor action; Be specially a kind of 2; 5-two replacement-N, N-two [2-(4-methyl-5 replaces hexamethylene-3-alkene) allyl group] piperazine, this compounds has characteristics such as good water solubility, anti-tumor activity height; Be a kind of potential antitumor drug, have the purposes of preparation anti-tumor medicinal preparation.

Background technology

Human life and health in the cancer serious threat, is one of the highest disease of mortality ratio.Although it is clinical that existing at present tens of kinds of effective cancer therapy drugs get into, in the treatment of malignant tumour, obtained good effect, still fail to reach satisfied effect for the treatment that accounts for the solid tumor of malignant tumour more than 90%.Therefore, the research of cancer therapy drug still is one of vital task of field of medicaments.

Nitrogen heterocyclic ring is present in many antitumor drug structures, like NSC 94600, vinealeucoblastine(VLB) and vincristine(VCR) etc.In addition, introducing this type group also is the method water-soluble commonly used that improves medicine.For example, Yakult company introduces two piperidyl synthetic irinotecans in the NSC 94600 structure, is improved owing to improved water-soluble its antitumour activity that makes, and becomes marketed drug.But nitrogen heterocyclic ring itself has strong toxicity, need transform its structure, to reduce toxicity, improves clinical applicability.

In recent years; Discover some monocyclic monoterpene compounds; For example PC 560 and analog Karvon, carveol etc. have better anti-tumor activity; Toxicity is low, better tolerance, and be at present known a few existing chemoprophylaxis effect has the natural product of chemotherapy effect again to tumour.The rodent breast tumor that PC 560 brings out for chemical factor, lymphoma, lung cancer, cancer of the stomach, liver neoplasm all have the chemoprophylaxis effect, under effective dose, host cell are not had toxicity.Simultaneously, PC 560 also is a kind of effectively chemotherapeutic, for the rat breast cancer that dimethylbenzanthracene and nitrosomethylurea bring out, its complete response rate＞80%.It is clinical to have got into the I phase at Britain's PC 560, is used to treat mammary cancer and straight colorectal carcinoma.

But PC 560 class monocyclic monoterpene compound is water insoluble, and bioavailability is low, thereby limits the performance of its antitumor action.Chen Jiaojiao etc. (Chinese pharmaceutical chemistry magazine, 2006,16 (6), 356-359) when the synthetic and anti-tumor activity of research Linonene anologs, find, nitrogen heterocyclic rings such as piperazine are introduced in the PC 560 structure, can improve the anti-tumor activity of compound.The research of this compounds at present is less, and N, the two substituted piperazine like compound of N-still do not have report.

Summary of the invention

The present invention aims to provide a kind of good water solubility, bridged piperazine derivatives that anti-tumor activity is high, and this compound can be used for developing the antitumor drug of better efficacy.

Bridged piperazine derivatives general structure according to the invention is following:

Wherein: when X=C=O, R=H or-CH ₃When X=-CHOH or-CH ₂-time, R=H.

Bridged piperazine derivatives according to the invention is to be starting raw material with Karvon (l-carvone), and through chlorination, condensation reaction, sodium borohydride reduction and Huang Ming dragon reduction reaction obtain, and the preparation route is following:

Among the figure: R=H or-CH ₃

Bridged piperazine derivatives provided by the invention has better water solubility, and the cell in vitro active testing shows that this compounds has inhibited proliferation to human pancreas cancer cell strain Lncap, and the result sees table 1.Experiment showed, that this compounds is a kind of potential antitumor drug, have the purposes of preparation anti-tumor medicinal preparation.

Embodiment

Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention in any way.

Embodiment 1:

Prepare chloro Karvon midbody with existing maturation method: Karvon 15.0g (0.1mol) is dissolved in the 300mL normal hexane, ice bath 0-5 ℃, stir down and drip hypochlorous acid trimethyl carbinol ester 13.3g (0.11mol), finish and rise to room temperature, continue to stir 3h.Reaction solution is used the saturated sodium sulfite aqueous solution, saturated common salt water washing successively, and anhydrous sodium sulfate drying concentrates, and gets yellow oil 10.7g, productive rate 72.7%. ¹H?NMRδ(ppm)：1.76(s，3H)，2.33-2.40(m，2H)，2.49-2.66(m，2H)，2.94(m，1H)，4.06(s，2H)，5.03(s，1H)，5.23(s，1H)，6.73(m，1H)。

Embodiment 2:

N, N-two [2-(4-methyl-5 oxo hexamethylene-3-alkene) allyl group] piperazine hydrochloride (1) synthetic

Chloro Karvon midbody 16.2mmol, salt of wormwood 8.9mmol, piperazine 8.1mmol are dissolved in the 15mL ethanol reflux 8h.Boil off ethanol, residuum is dissolved in the 30mL methylene dichloride, with 1N hydrochloric acid soln washing (30mL * 3), merges acid solution; Soda ash light is neutralized to pH9.0～10.0, and dichloromethane extraction (30mL * 5) merges organic layer, uses the saturated common salt water washing; Anhydrous sodium sulfate drying, concentrating under reduced pressure gets yellow oil; Be dissolved in acidic alcohol, leave standstill crystallization, get white crystalline solid.Product yield: 67.9%, mp:195-197 ℃. ¹H-NMRδ(ppm)：1.77(s，6H)，2.20-2.67(m，16H)，2.85(m，2H)，2.92(s，4H)，4.92(s，2H)，5.01(s，2H)，6.74(m，2H)；MS(EI)m/z：382(M ⁺，100).

Embodiment 3:

2-methyl-N, N-two [2-(4-methyl-5 oxo hexamethylene-3-alkene) allyl group] piperazine hydrochloride (2) synthetic

Reaction process is with embodiment 2.Product yield: 77.4%, mp:190-192 ℃. ¹H?NMRδ(ppm)：1.24(m，3H)，1.79(s，6H)，2.30-2.49(m，15H)，2.84(m，2H)，2.92(s，4H)，4.91(s，2H)，5.02(s，2H)，6.75(m，2H)；MS(EI)m/z：410(M ⁺，5)，192(100).

Embodiment 4:

2,5-dimethyl--N, N-two [2-(4-methyl-5 oxo hexamethylene-3-alkene) allyl group] piperazine hydrochloride (3) synthetic

Reaction process is with embodiment 2.Product yield: 74.9%, mp:170～172 ℃. ¹H-NMR(300MHz，CDCl ₃)，δ(ppm)：1.52(s，6H)，1.76(s，6H)，2.26～2.49(m，6H)，2.59(m，2H)，2.82(m，4H)，3.01(m，4H)，3.27(s，4H)，4.98(s，2H)，5.05(s，2H)，6.74(m，2H)。IR(KBr)，σ/cm ^-1：2934.0，2888.9，2797.6，2708.0，2553.5，2470.5，1667.6，1582.0，1463.4，1378.8，1312.2，1185.5，1137.9，1076.1，1056.4，905.6。

Embodiment 5

N, N-two [2-(3-hydroxy-4-methyl hexamethylene-3-alkene) allyl group] piperazine hydrochloride (4) synthetic

With the product N among the embodiment 2, N-two [2-(4-methyl-5 oxo hexamethylene-3-alkene) allyl group] piperazine 8.1mmol is dissolved in the 15mL methyl alcohol, and the ice bath cooling adds Peng Qinghuana 20mmol altogether down in batches in the 1h, finish and continue to stir 2h under the room temperature.Steam methyl alcohol, add saturated aqueous common salt 30mL, dichloromethane extraction (30mL * 3) merges organic layer, uses the saturated common salt water washing, and anhydrous sodium sulfate drying concentrates.Residuum separates (developping agent is petroleum ether-ethyl acetate-methyl alcohol of 10: 1: 0.1 of volume ratio) through silica gel column chromatography, and product adds acidic alcohol, leaves standstill crystallization, gets white solid.Yield 21.5%, mp180～182 ℃.EI-MS，m/z?386(M ⁺-2HCl)； ¹H-NMR(D ₂O)，δ(ppm)：1.33～1.40(m，2H)，1.58(s，6H)，1.80～1.83(m，2H)，2.06～2.10(m，4H)，2.20～2.25(m，2H)，3.20～3.60(m，8H)，3.78～3.81(q，2H，J＝13.6Hz)，4.15～4.16(m，1H)，5.28(s，1H)，5.36(s，1H)，5.46～5.47(m，1H)；IR(KBr)，σ/cm ^-1?3406.6，2925.7，1642.0，942.9。

Embodiment 6

N, N-two [2-(4-methyl cyclohexane-3-alkene) allyl group] piperazine hydrochloride (5) synthetic

With the product N among the embodiment 2, N-two [2-(4-methyl-5 oxo hexamethylene-3-alkene) allyl group] piperazine 8.1mmol, 80% Hydrazine Hydrate 80 1.6mL (40.0mmol), terepthaloyl moietie 15mL add in the reaction flask, calorify 120 ℃ of reaction 2h down.Be cooled to 70 ℃, add Pottasium Hydroxide 56mmol, react 4h down in 180～185 ℃.Stopped reaction is cooled to room temperature, adds saturated aqueous common salt 100mL, with dichloromethane extraction (30mL * 5), merges organic layer, uses the saturated common salt water washing, and anhydrous sodium sulfate drying concentrates.Residuum separates (developping agent is 15: 1 a petroleum ether-ethyl acetate of volume ratio) through silica gel column chromatography, and product adds acidic alcohol, leaves standstill crystallization, gets white crystalline solid.Yield 10.6%, mp156～168 ℃. ¹H-NMR(MHz，CDCl ₃)，δ(ppm)：1.45～1.53(m，2H)，1.65(s，6H)，1.78～1.82(m，2H)，1.86～1.92(m，2H)，1.95～1.96(m，2H)，2.02～2.08(m，2H)，2.12～2.15(m，2H)，2.18～2.24(m，2H)，2.39(s，8H)，2.89～2.94(m，2H)，4.85(s，1H)，4.93(s，1H)，5.39～5.40(m，1H)，7.22～7.25(m，1H)，7.28～7.32(m，4H)；IR，σ/cm ^-1：3079.6，2915.5，1643.7；EI-MS，m/z：354(M ⁺-2HCl，67)，233(100)。

With the positive contrast medicine of PC 560 (d-Limonene), measured the inhibited proliferation of compound with mtt assay to pancreas cancer cell strain Lncap, the result sees table 1.Compare with PC 560, these target compounds suppress the IC of pancreas cancer cell strain Lncap ₅₀Value increases, so this compounds is expected to develop the medicine that becomes the treatment drug-resistant tumor.

Table 1 compound is to the inhibited proliferation of human pancreas cancer cell strain Lncap

Compound	IC ₅₀(μM)	Compound	IC ₅₀(μM)
				d-Limonene	＞100	3	45
1	17	4	20
				2	15	5	51

Claims

1. one type has the active bridged piperazine derivatives of anti-carcinoma of the pancreas, it is characterized in that such structural formula of compound is following:

In the formula when X=C=O, R=H or-CH ₃When X=-CHOH or-CH ₂-time, R=H.

2. the hydrochloride of the described bridged piperazine derivatives of claim 1.

3. the application of the hydrochloride of described bridged piperazine derivatives of claim 1 or the described bridged piperazine derivatives of claim 2 in the anti-carcinoma of the pancreas pharmaceutical prepn of preparation.