CN101289423A - 7-chlorine -4-(1- piperazinyl)chinoline and applications thereof in preparation of anti-malaria medicaments - Google Patents

7-chlorine -4-(1- piperazinyl)chinoline and applications thereof in preparation of anti-malaria medicaments Download PDF

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CN101289423A
CN101289423A CNA2008100288691A CN200810028869A CN101289423A CN 101289423 A CN101289423 A CN 101289423A CN A2008100288691 A CNA2008100288691 A CN A2008100288691A CN 200810028869 A CN200810028869 A CN 200810028869A CN 101289423 A CN101289423 A CN 101289423A
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piperazinyl
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quinoline
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gained
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宓穗卿
刘昌辉
陈沛泉
黄小桃
***
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Guangzhou University of Chinese Medicine
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Abstract

The invention provides a new compound which is one of the metabolites of peraquine phosphate in human bodies and is named as 7-chlorine-4-(1-piperazinyl) quinoline with the molecular structure shown in the formula I. The compound of the invention which has effects of inhibiting the development of plasmodium schizont and the growth of plasmodium falciparum can be used for preparing anti-malarial drugs.

Description

7-chloro-4-(1-piperazinyl) quinoline and the application in the preparation anti-malaria medicaments thereof
Technical field
The present invention relates to organic chemistry filed, be specifically related to a kind of new compound that contains the quinoline ring.
Background technology
Quinoline (quinoline) is the compound of a kind of pyridine and benzo connection, and molecular formula is C 9H 7N, be mainly used in preparation dyestuff or as medicine intermediate, its derivative is of a great variety, and wherein piperazine quinoline (Piperaquine) and phosphoric acid salt thereof, chloroquine (chlorquine), quinine (quinine), Mefloquine hydrochloride (mefloquine) and primaquine (primaquine) are antimalarial medicines commonly used.
Piperazine quinoline and phosphoric acid salt thereof are a kind of preferably at present antimalarial medicines, for anti-chloroquine pernicious malaria the radical cure effect are arranged, but effect slowly." Piperaquine bioanalysis, drug metabolism and pharmacokinetics " literary composition done more deep research to the piperazine quinoline in the pharmacodynamics and the drug metabolism of human body, find that the piperazine quinoline has 5 kinds of main meta-bolitess after the utilization that is absorbed by the body, wherein also contain the quinoline ring in the molecular structure of two kinds of meta-bolitess, suc as formula 1 and formula 2 shown in, the structure of other 3 kinds of meta-bolitess is not clear and definite as yet, and this article is not done further research to chemical property, biological activity and the purposes of these compounds.
Figure A20081002886900031
Summary of the invention
The object of the present invention is to provide a kind of new compound.
Compound provided by the present invention is 7-chloro-4-(1-piperazinyl) quinoline, and its molecular formula is C 13H 14N 3Cl 1, molecular weight is 247.0867, molecular structure is suc as formula shown in the I.Under this compound normality is yellow powder, is soluble in methyl alcohol, can be dissolved in ethyl acetate, chloroform, methylene dichloride, but water insoluble.
Figure A20081002886900041
Compound of the present invention be piperaquine phosphate at one of intravital meta-bolites of people, be from the healthy people's that takes peroxophosphoric acid piperazine quinoline urine, to separate, concrete steps are as follows:
(1) collecting the healthy people's take peroxophosphoric acid piperazine quinoline urine, concentrate, is 15: 10: 1 methylene dichloride, ether and isopropyl alcohol mixed solvent extraction then with the volume ratio of 3 times of volumes, water intaking layer;
(2), divide water intaking layer and n-butanol layer with the n-butanol extraction of step (1) gained water layer with 3 times of volumes;
(3) get the water layer or the n-butanol layer purifying of step (2); When getting step (2) gained water layer, purifying according to the following steps:
1. the gained water layer is concentrated, cross the AB macroporous resin, first water wash-out is used 5～30% ethanol gradient elutions then, collects 10～30% alcoholic acid elutriants;
2. with step 1. the ethanol eluate of gained concentrate, cross the ODS column chromatography, first water wash-out is used 5%～30% methyl alcohol gradient elution then, collects, merges the elutriant of 10～30% methyl alcohol;
3. 2. the gained meoh eluate is concentrated with step, crosses dextrane gel Sephadex LH-20, uses 250mL 30% methanol-eluted fractions then, collects the 150th～250mL elutriant;
4. 3. the gained elutriant is concentrated with step, crosses the C18 liquid-phase chromatographic column, with 10% methanol-eluted fractions that contains 0.1%CF3COOH, collects elutriant then;
5. with 4. gained elutriant drying under reduced pressure of step, crystallization, The compounds of this invention;
During n-butanol layer in getting step (2), successively 1. the gained n-butanol layer is separated through AB macroporous resin, ODS post with method 2. by above-mentioned steps, the gained elutriant is crossed dextrane gel Sephadex LH-20, use 30% methanol-eluted fractions then, collect whole elutriants, cross the C18 liquid-phase chromatographic column at last, with 10% methanol-eluted fractions that contains 0.1%CF3COOH, collect the elutriant drying under reduced pressure, crystallization.
Compound of the present invention can suppress growth of malaria parasites and schizont is grown, and has anti-malarial activity preferably, can be used for preparing antimalarial medicine.Described medicine is made up of 7-chloro-4-(1-piperazinyl) quinoline and acceptable accessories.Described medicine can be an oral preparation, and wherein the weight percent content of 7-chloro-4-(1-piperazinyl) quinoline is 20%～50%.
Medicine of the present invention, antimalarial effective dose is calculated by user's body weight, and during oral administration, consumption every day of 7-chloro-4-(1-piperazinyl) quinoline is 19.8mg/kg～39.6mg/kg.
To prove the technique effect of The compounds of this invention by experiment in vitro and pharmacodynamics test below.
One, experiment in vitro
1, experiment material
Plasmodium: the FCC-1/HN strain, draw from Guangdong Province's preventing and treating verminosis institute.
Piperaquine phosphate: pharmaceutcal corporation, Ltd provides available from Chinese and Western, Shanghai, and content is 99.4%.
Chloroquini phosphas: pharmaceutcal corporation, Ltd provides available from Chinese and Western, Shanghai, and content is 99.4%.
The compounds of this invention: press the preparation of embodiment 1 method.
2, experimental technique and grouping:
(1) piperaquine phosphate treatment group (PQP group): piperaquine phosphate is configured to the solution of following concentration with dimethyl sulfoxide (DMSO): 5000 μ mol/L, 1000 μ mol/L, 100 μ mol/L, 50 μ mol/L, 10 μ mol/L, 5 μ mol/L, 1 μ mol/L, 0.5 μ mol/L, 0.1 μ mol/L and 0.05 μ mol/L, the piperaquine phosphate solution 20 μ L with above concentration handle plasmodium respectively.
(2) chloroquini phosphas treatment group (CQP group): chloroquini phosphas is configured to the solution of following concentration with dimethyl sulfoxide (DMSO): 5000 μ mol/L, 1000 μ mol/L, 100 μ mol/L, 50 μ mol/L, 10 μ mol/L, 5 μ mol/L, 1 μ mol/L, 0.5 μ mol/L, 0.1 μ mol/L and 0.05 μ mol/L, the chloroquini phosphas solution 20 μ L with above concentration handle plasmodium respectively.
(3) The compounds of this invention treatment group (M3 group): the solution that is configured to following concentration with dimethyl sulfoxide (DMSO): 5000 μ mol/L, 1000 μ mol/L, 100 μ mol/L, 50 μ mol/L, 10 μ mol/L, 5 μ mol/L, 1 μ mol/L, 0.5 μ mol/L, 0.1 μ mol/L and 0.05 μ mol/L, the The compounds of this invention solution 20 μ L with above concentration handle plasmodium respectively.
(4) blank group (H 2The O group): use water treatment plasmodium with said medicine equivalent.
(5) solvent control group (1%DMSO group): use 1%DMSO processing plasmodium with said medicine equivalent.
3, experimental result
The result is as shown in table 1, and The compounds of this invention has the obvious suppression effect to the growth of plasmodial schizont, and its effect and piperaquine phosphate are suitable.
The influence that table 1 The compounds of this invention is grown the plasmodium schizont
Figure A20081002886900051
Annotate: "-" representative is that the growth of plasmodial schizont is suppressed in the sheet; "+" representative is to exist plasmodial schizont or schizont to grow division in the sheet.
Two, pharmacodynamic experiment
1, material and method
(1) medicine: The compounds of this invention is pressed the method preparation of embodiment 1, and water is made into the suspension of required different concns, and drug dose is pressed 7-chloro-4-(1-piperazinyl) quinoline and calculated.
(2) plasmodium falciparum inhibition test
Laboratory animal is a kunming mouse, body weight (20 ± 2) g.Mouse is divided into 4 groups (10/group) at random: The compounds of this invention low dose group (M3 low dose group, 90mg/kg), (the dosage group among the M3 of dosage group in the The compounds of this invention, 180mg/kg), The compounds of this invention high dose group (M3 high dose group, 360mg/kg) and positive drug control group (PQP group, 160mg/kg).Every mouse respectively abdominal injection (ip) FCC-1/HN (plasmodium falciparum is drawn from Guangdong Province's preventing and treating verminosis institute) contain worm blood (red corpuscle 5 * 10 6Individual), infect inferior in the future by the administration of group filling stomach (ig).Administration time is respectively 0h (the first administration time is designated as 0h), 6h, 24h, 32h.Get blood from mouse tail the next day of last administration, and film-making dyeing microscopic examination and counting draw average inhibiting rate.
2, result
Table 2 The compounds of this invention oral administration is to the inhibiting rate of plasmodium falciparum
Group Dosage n Inhibiting rate (%)
The M3 low dose group 90mg/kg 10 80.2
Dosage group among the M3 180mg/kg 10 93.8
The M3 high dose group 360mg/kg 10 96.5
The PQP group 160mg/kg 10 94.0
The plasmodium falciparum inhibiting rate of oral dose administration in the The compounds of this invention is 93.8%, and near the inhibiting rate (94.0%) of positive control drug PQP, visible The compounds of this invention oral medication has significant inhibitory effect to plasmodium falciparum.
Description of drawings:
Fig. 1 is the UV spectrogram of The compounds of this invention.
Fig. 2 is the MS spectrogram of The compounds of this invention.
Fig. 3 is a The compounds of this invention 1The H-NMR spectrogram.
Fig. 4 is a The compounds of this invention 1The partial enlarged drawing of H-NMR spectrogram.
Fig. 5 is a The compounds of this invention 13The C-NMR spectrogram.
Fig. 6 is a The compounds of this invention 13The partial enlarged drawing of C-NMR spectrogram.
Fig. 7 is a The compounds of this invention 1390 ° of local figure of 135 ° of C-NMR DEPT and DEPT, wherein DEPT135 and DEPT90 represent the angle of methylene radical.
Fig. 8 is a The compounds of this invention 13The DEPT135 of C-NMR ° of local figure.
Fig. 9 is a The compounds of this invention 13The DEPT135 of C-NMR ° of local figure.
Embodiment
Example 1
The preparation of The compounds of this invention:
1, experiment 45 health volunteers not taking any medicine in the last week, age 20-30 year, body weight 45-75kg is by 0,6,24 and continuous four the clothes Artekin tablets of 32h, each two, 5 days urine is received the about 155L of urine collection urine altogether behind the collection medicine, uses for compartment analysis.
2. the separation and purification of meta-bolites M1 in the human urine sample
Method one: (1) is concentrated into 4L with collected urine, is 15: 10: 1 methylene dichloride, ether and isopropyl alcohol mixed solvent extraction then with the volume ratio of 3 times of volumes, the water intaking layer;
(2), divide water intaking layer and n-butanol layer with the n-butanol extraction of step (1) gained water layer with 3 times of volumes;
(3) step (2) gained water layer is concentrated, cross the AB macroporous resin, first water wash-out is used 5～30% ethanol gradient elutions then, collects 10～30% alcoholic acid elutriants;
(4) ethanol eluate with step (3) gained concentrates, and crosses the ODS column chromatography, and first water wash-out is used 5%～30% methyl alcohol gradient elution then, collects, merges the elutriant of 10～30% methyl alcohol;
(5) step (4) gained meoh eluate is concentrated, cross Sephadex LH-20, use the 250ml30% methanol-eluted fractions then, collect the 150th～250mL elutriant;
(6) step (5) gained elutriant is concentrated, cross the C18 liquid-phase chromatographic column, then with containing 0.1%CF 310% methanol-eluted fractions of COOH is collected elutriant;
(7) with step (6) gained elutriant drying under reduced pressure, crystallization gets yellow powder 3.3mg.
Method two: the n-butanol layer in access method one step (2) separates through AB macroporous resin, ODS post by the method for step (3) in the method one and (4) successively, the gained elutriant is crossed Sephadex LH-20, use 30% methanol-eluted fractions then, collect elutriant, cross the C18 liquid-phase chromatographic column at last, with containing 0.1%CF 310% methanol-eluted fractions of COOH is collected the elutriant drying under reduced pressure, and crystallization gets yellow powder 6.8mg.
Method one and the whole yellow powders of method two gained are mixed, detect evaluation in order to following method:
1, UV spectrum analysis
With the methanol-water dissolving, use PDA-100 diode-array detector (DAD) scanning then.The result as shown in Figure 1, institute's test sample product have uv-absorbing at 240nm, 226.2nm, 347nm place, three-way normalizing on the UV collection of illustrative plates, the expression sample purity is more than 98%, visible step (7) and step (8) gained yellow powder all are with a kind of compound.
2, HR-FTEI-MS spectrum analysis
Adopt the ionization method analysis with U.S. Thermo mass spectrograph (model: MAT95XP, resolving power＞2000): the EI source; Aperture temperature: 250 ℃; Sample introduction temperature: 350 ℃; Gas: nitrogen; Electronic attack source: 70eV; Sweep limit: m/z 50-600.The MS spectrogram of described compound determines that by the software analysis that the Thermo mass spectrograph carries the molecular weight of this compound is 247.0867 as shown in Figure 2, and molecular formula is C 13H 14N 3Cl 1, shown in table 3 and table 4.
Table 3
m/z Intensity Relative(％) Relative abundance (%)
29 850506.0 0.58
30 1556216.0 1.06
42 3367905.0 2.29
43 1246176.0 0.85
44 744972.0 0.51
51 986680.0 0.67
54 1212022.0 0.82
55 485688.0 0.33
56 14525184.0 9.88
57 6850820.0 4.66
58 802351.0 0.55
63 819374.0 0.56
65 436323.0 0.30
68 739107.0 0.50
69 794151.0 0.54
70 527097.0 0.36
71 805594.0 0.55
73 685220.0 0.47
74 2764386.0 1.88
75 3855226.0 2.62
76 1183601.0 0.81
77 1905986.0 1.30
78 555152.0 0.38
81 403170.0 0.27
83 631149.0 0.43
84 578374.0 0.39
85 1081572.0 0.74
87 548505.0 0.37
88 629680.0 0.43
89 806998.0 0.55
91 1030120.0 0.70
97 452200.0 0.31
98 1039169.0 0.71
99 11081984.0 7.54
100 3959967.0 2.69
101 4735081.0 3.22
102 1695158.0 1.15
105 938426.0 0.64
106 965753.0 0.66
109 527259.0 0.36
109 413676.0 0.28
111 528014.0 0.36
113 741821.0 0.50
114 1568341.0 1.07
115 1077889.0 0.73
116 438577.0 0.30
123 1425264.0 0.97
124 663137.0 0.45
125 832907.0 0.57
126 3984597.0 2.71
127 6923159.0 4.71
128 11294976.0 7.68
129 2396789.0 1.63
135 5752353.0 3.91
136 1870155.0 1.27
137 1759353.0 1.20
138 686756.0 0.47
140 1212239.0 0.82
141 1579179.0 1.07
142 1037017.0 0.71
149 2144973.0 1.46
150 974353.0 0.66
151 839484.0 0.57
152 626747.0 0.43
153 142491.0 0.97
155 30900480.0 21.02
156 6992748.0 4.76
157 874197.0 0.59
161 838938.0 0.57
162 12344064.0 8.40
163 7002216.0 4.76
164 6819153.0 4.64
165 2214965.0 1.51
166 1922054.0 1.31
167 2111283.0 1.44
169 40449536.0 27.5
170 57763072.0 39.29
171 6463566.0 4.40
172 406889.0 0.28
176 5484889.0 3.73
177 1658474.0 1.13
178 2844782.0 1.93
179 1096882.0 0.75
180 815578.0 0.55
181 2118393.0 1.44
182 2704924.0 1.84
183 958128.0 0.65
188 516414.0 0.35
189 9633536.0 6.55
190 7720808.0 5.25
191 13042688.0 8.87
192 8794112.0 5.98
193 3575321.0 2.43
194 2074433.0 1.41
195 449700.0 0.31
201 940994.0 0.64
202 1193546.0 0.81
203 5028390.0 3.42
203 2952407.0 2.01
205 147028736.0 100.00
206 19550720.0 13.30
207 40022272.0 27.22
208 4858820.0 3.30
209 436313.0 0.30
210 472449.0 0.32
211 686126.0 0.47
212 838702.0 0.57
215 419156.0 0.29
217 1284799.0 0.87
218 490615.0 0.33
219 430571.0 0.29
232 1937936.0 1.32
234 563948.0 0.38
244 592849.0 0.40
245 1491102.0 1.01
245 450927.0 0.31
247 44903424.0 30.54
248 8126167.0 5.53
249 12742656.0 8.67
250 1935865.0 1.32
Table 4
Mass Relative Intensity Theoretical Mass Delta[ppm] Delta[mmu] RDB Composition
247.0867 100.0 247.0871 -1.5 -0.4 8.0 C 13H 14N 2C1 1
247.0852 5.9 1.5 13.0 C 14H 9N 5
247.0889 -8.9 -2.2 3.0 C 12H 19N 1Cl 2
247.0763 42.0 10.4 3.5 C 11H 17N 2C1 2
247.0978 -45.0 -11.1 12.5 C 15H 11N 4
3, nuclear magnetic resonant analysis
Analytical instrument is a U.S. Bruker 500MHz nuclear magnetic resonance analyser, model: AV500; Probe: 5mm BBO BB-1H; Pulse: zg30 (hydrogen spectrum) and zgdc30 (carbon spectrum); Solvent: DMSO; Sampling number: 8; Sampled data points: 32K; Spectrum width: 10000Hz.
Through nucleus magnetic resonance 1H-NMR (MeOD 500MHz) analyzes, and shown in Fig. 3～4, analytical results is: and δ 2.73 (2H, t, H-1), 3.29 (2H, t, H-2), 3.57 (2H, t, H-2 ', 6 '), 3.37 (2H, t, H-3 ', 5 '), 8.71 (1H, d, J=5.4Hz, H-2 "), 7.16 (1H, d, J=5.4Hz, H-3 "), 8.15 (1H, d, J=9.0Hz, H-5 "), 7.62 (1H, dd, J=9.0Hz; J=2.1Hz, H-6 "), 8.00 (1H, d, J=2.1Hz, H-8 ").
Through nucleus magnetic resonance 13(MeOD 500MHz) analyzes C-NMR, and shown in Fig. 5～9, analytical results is: δ 30.9 (C-1), 50.2 (C-2), 176.6 (C-3), 54.6 (C-2 ', 6 '), 52.5 (C-3 ', 5 '), 148.1 (C-2 "), 109.7 (C-3 "), 145.1 (C-4 "); 128.9 (C-5 "), 124.1 (C-6 "), 139.3 (C-7 "), 127.8 (C-8 "), 121.0 (C-9 "), 160.4 (C-10 ").
Example 2
Prescription: example 1 gained compound 70g N.F,USP MANNITOL 48g
Microcrystalline Cellulose 32g low-substituted hydroxypropyl cellulose (L-HPC) 8g
Micropowder silica gel 1g Magnesium Stearate 1g
Method for making: get Microcrystalline Cellulose in 80 ℃ of dry 4h, evenly the back adds Magnesium Stearate, micropowder silica gel mixes with L-HPC, N.F,USP MANNITOL, example 1 gained compound successively, with suitable pressure direct compression, makes 200 altogether, every middle 0.8g contains 7-chloro-4-(1-piperazinyl) quinoline 350mg.
Example 3
Prescription: example 1 gained compound 30g starch 56g
Microcrystalline Cellulose 54g croscarmellose sodium (CCNa) 4.5g
Micropowder silica gel 4.5g sodium lauryl sulphate 0.8g
Method for making: taking by weighing medicinal powder and various auxiliary material by prescription, is tamanori with the 5%PVP-60% alcoholic solution, uses fluidized bed granulation, and compressing tablet promptly.Make 400 altogether, every 0.375 gram contains 7-chloro-4-(1-piperazinyl) quinoline 75mg.
Example 4
Prescription: example 1 gained compound 40g starch 30g
Microcrystalline Cellulose 54g croscarmellose sodium (CCNa) 4.5g
Micropowder silica gel 4.5g sodium lauryl sulphate 0.8g
Method for making: taking by weighing medicinal powder and various auxiliary material by prescription, is tamanori with the 5%PVP-60% alcoholic solution, uses fluidized bed granulation, and compressing tablet is promptly made 400 altogether, and every 0.335 gram contains 7-chloro-4-(1-piperazinyl) quinoline 100mg.

Claims (4)

1,7-chloro-4-(1-piperazinyl) quinoline, its molecular structure is suc as formula shown in the I.
Figure A2008100288690002C1
2, the application of 7-chloro-4-(1-piperazinyl) quinoline in the preparation anti-malaria medicaments.
3, a kind of anti-malaria medicaments, this medicine is made up of 7-chloro-4-(1-piperazinyl) quinoline and acceptable accessories.
4, medicine as claimed in claim 3 is characterized in that this medicine is an oral preparation, and wherein the weight percent content of 7-chloro-4-(1-piperazinyl) quinoline is 20%～50%.
CNA2008100288691A 2008-06-17 2008-06-17 7-chlorine -4-(1- piperazinyl)chinoline and applications thereof in preparation of anti-malaria medicaments Pending CN101289423A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105330601A (en) * 2015-11-03 2016-02-17 重庆康乐制药有限公司 Preparation method of piperaquine derivative

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105330601A (en) * 2015-11-03 2016-02-17 重庆康乐制药有限公司 Preparation method of piperaquine derivative

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