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Aromatic chlorethazine piperazine quaternary ammonium salt derivatives, and preparation and use thereof

A technology of aromatic nitrogen mustard and quaternary ammonium salt, which is applied in the direction of drug combination, pharmaceutical formula, medical preparations containing active ingredients, etc., and can solve problems such as limited application

Inactive Publication Date: 2009-05-27
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, side effects such as myelosuppression and gastrointestinal reactions have brought great pain to the patients taking the medication, which severely limited their clinical application.

Method used

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  • Aromatic chlorethazine piperazine quaternary ammonium salt derivatives, and preparation and use thereof
  • Aromatic chlorethazine piperazine quaternary ammonium salt derivatives, and preparation and use thereof
  • Aromatic chlorethazine piperazine quaternary ammonium salt derivatives, and preparation and use thereof

Examples

Experimental program
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preparation example Construction

[0097] Preparation of γ-(p-aminophenyl)butyric acid

[0098]

[0099] β-(4-Acetamidobenzoyl)-propionic acid (89g, 378mmol), potassium hydroxide (88g, 1.57mol), 65ml of 85% hydrazine hydrate and 450ml of diethylene glycol were heated to reflux (about 140°C) for 1.5 hours , remove the condensing tube to raise the temperature to 195°C, steam off excess hydrazine hydrate, and keep the temperature to continue reflux for 4 hours. After cooling to room temperature, the reaction system was diluted with about 400ml of water, and the pH was adjusted to neutrality with 6N hydrochloric acid. Crystals were precipitated, filtered, and washed with water to obtain 44 g of white crystals, with a yield of 65.0%. -120°C).

[0100] 1 H NMR (DMSO, 300MHz): 11.2-12.3 (b, 1H, COO H), 6.81 (d, 2H, J=8.0Hz, ArH), 6.47 (d, 2H, J=8.0Hz, ArH), 4.60-5.70 (bs, 2H, NH 2 ), 2.38(t, 2H, J=7.4Hz, Ph- CH 2 ), 2.15(t, 2H, J=7.4Hz, CH 2 -COOH), 1.68(m, 2H, Ph-CH 2 - CH 2 ).

[0101] Pre...

preparation Embodiment 1

[0131] Preparation Example 1 Preparation of Chlorinated 4-(4'-ethoxycarbonylpropylphenyl)-1,1-dimethyl-1,4-diazacyclohexane

[0132]

[0133] The mixed solution of CLBM (2.0g, 6mmol), dimethylamine hydrochloride (0.6g, 7mmol), 40ml ethanol and sodium bicarbonate (5.0g, 59mmol) was stirred and heated to reflux for 24 hours, and TLC showed that most of the raw materials had been After the reaction, excess sodium bicarbonate was removed by filtration, the filtrate was evaporated to dryness under reduced pressure, dissolved in 20ml of water, extracted twice with ethyl acetate (15ml×2), the water layer was evaporated to dryness under reduced pressure, and recrystallized from ethanol-ethyl acetate to obtain 1.4 g white needle crystals, yield 68.2%, Mp: 230-237°C.

[0134] 1 H NMR (D 2 O, 300MHz): 7.09(d, 2H, J=8.7Hz, ArH), 6.90(d, 2H, J=8.7Hz, ArH), 3.87(q, 2H, J=6.9Hz, CH 2 -CH 3 ), 3.43-3.47 (m, 4H, N- CH 2 ), 3.35-3.37 (m, 4H, N + - CH 2 ), 3.08(s, 6H, N + ...

preparation Embodiment 2

[0136] Preparation Example 2 Preparation of 2,4-dimethyl-9-(4'-ethoxycarbonpropylphenyl)-3-oxa-6,9-diazaspiro[5.5]undecane chloride

[0137]

[0138] The preparation was carried out according to the method in Preparation Example 1, CLBM and 2,6-dimethylmorpholine were reacted in equimolar amounts, and white flaky crystals were obtained after post-treatment, with a yield of 76.2%, Mp: 276-278°C.

[0139] 1 H NMR (D 2 O, 300MHz): 7.09 (d, 2H, J = 8.7Hz, ArH), 6.89 (d, 2H, J = 8.7Hz, ArH), 4.13 (m, 2H, O- CH ), 3.87(q, 2H, J=7.2Hz, CH 2 -CH 3 ), 2.91-3.77 (m, 12H, N- CH 2 , N + - CH 2 ), 2.44(t, 2H, J=7.2Hz, Ph- CH 2 ), 2.18(t, J=7.2Hz, 2H, Ph-CH 2 -CH 2 - CH 2 ), 1.72-1.79 (m, 2H, Ph-CH 2 - CH 2 ), 1.09 (d, 6H, J=6.3Hz, O-CH- CH 3 ), 1.04(t, 3H, J=7.2Hz, CH 2 - CH 3 ).

[0140] Elemental Analysis: C 22 h 35 ClN 2 o 3 , measured: C, 64.10; H, 8.48; N, 6.60; theoretical: C, 64.29; H, 8.58; N, 6.82.

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Abstract

The invention discloses an aryl nitrogen mustard piperazinium derivative with a general formula I or pharmaceutically acceptable salt thereof, wherein R<1> is H, a saturated or unsaturated straight-chain or branched-chain alkyl group, and aryl or substituted aryl, and the alkyl group can be freely substituted by substitutional groups selected from halogens, amino groups, substituted amino groups, hydroxyl groups, cyano groups, nitryl, aryl and substituted aryl; A is saturated or unsaturated straight-chain or branched-chain alkylene, and the alkylene can be substituted by amido; Ar is arylene; R<2> and R<3> is independently hydrogen or methyl; n and m are integers within the range of between 0 and 2, and the n and the m are not zero synchronously; B and D independently represent straight-chain or branched-chain alkyl groups of C1-C3, and straight-chain or branched-chain alkylenes of the C1-C3; Y is -CHR4-, -O-, -S-, -S(O)-, -SO2-, -NR<4>-, and substituted or unsubstituted phenylene, wherein R<4> is H, saturated or unsaturated alkyl groups with 1 to 6 carbon atoms, optionally substituted or unsubstituted aryl, or aromatic heterocyclic-substituted methyl or ethyl; or when the B and the D are alkyl groups, the Y does not exist, that is, the derivative is ring-opened and does not form a spiro ring; and X<-> is pharmaceutically acceptable inorganic or organic anions.

Description

technical field [0001] The invention relates to aromatic nitrogen mustard derivatives of piperazine quaternary ammonium salts and a preparation method and application thereof. Background technique [0002] For a long time, nitrogen mustard compounds and their derivatives have been used as antitumor drugs, mostly as chemotherapy drugs, and the clinical treatment effect is very good (Wang Zemin, "Complete Works of Contemporary Drug Structures", 1993, 2046-2186). They have obvious inhibitory activity against many malignant tumors, such as malignant lymphoma, malignant melanoma, chronic leukemia and the like. Especially among them, Cyclophosphamide, Chlorambucil and Melphalan are still used clinically as first-line drugs because of their good therapeutic effects. However, side effects such as myelosuppression and gastrointestinal reactions have brought great pain to patients, which severely limited their clinical application. [0003] [0004] Cyclophosphamide Lumcanine Mil...

Claims

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Application Information

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IPC IPC(8): C07D295/037C07D295/155C07D491/10C07D487/10A61K31/4985A61K31/5383A61P35/00
Inventor 李润涛孙崎李功崔景荣葛泽梅程铁明
Owner PEKING UNIV
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