CN101293871A - 7-chlorine-4-[4'-(7''-chloroquine-4''-base)diethylenediamine-1'-base]quinoline and uses thereof - Google Patents

7-chlorine-4-[4'-(7''-chloroquine-4''-base)diethylenediamine-1'-base]quinoline and uses thereof Download PDF

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CN101293871A
CN101293871A CNA2008100288687A CN200810028868A CN101293871A CN 101293871 A CN101293871 A CN 101293871A CN A2008100288687 A CNA2008100288687 A CN A2008100288687A CN 200810028868 A CN200810028868 A CN 200810028868A CN 101293871 A CN101293871 A CN 101293871A
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quinoline
mol
chloroquine
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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 piperaquine phosphate in human body, with chemical name being 7-chloro-4-[4'-(7''-chloroquine-4''-base)piperazine-1'-base]quinoline and molecular structure shown in Formula I. The inventive compound has the effects of inhibiting development of Plasmodium schizont and growth of Plasmodium falciparum; and can be used for preparing antimalarial drugs.

Description

7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] quinoline and uses 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 A20081002886800031
Summary of the invention
The object of the present invention is to provide a kind of new compound.
Compound provided by the present invention be 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] quinoline, molecular formula is C 22H 18N 4Cl 2, molecular weight is 408.0894, and yellow powder can be dissolved in chloroform, methylene dichloride, DMSO etc., is insoluble to methyl alcohol, water, and molecular structure is suc as formula shown in the I.
Figure A20081002886800041
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 that 15: 10: 1 methylene dichloride, ether and isopropyl alcohol mixed solvent extracts with the volume ratio of 3 times of volumes then, gets organic layer;
(2) organic layer is concentrated, cross the ODS column chromatography, first water wash-out is used 5%～50% methyl alcohol gradient elution then, collects, merges the elutriant of 30～50% methyl alcohol;
(3) step (2) gained meoh eluate is concentrated, cross Sephadex LH-20, use 30% methanol-eluted fractions then, collect the elutriant of 50-150mL;
(4) step (3) gained elutriant is concentrated, cross the C18 liquid-phase chromatographic column, with 50% methanol-eluted fractions that contains 0.1% formic acid, collect elutriant then;
(5) with step (4) gained elutriant drying under reduced pressure, crystallization gets The compounds of this invention.
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 can be an oral preparation, wherein 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] weight percent content of quinoline is 20%～40%.
Medicine of the present invention, antimalarial effective dose is calculated by user's body weight, during oral administration, 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] consumption every day of quinoline is 16.5mg/kg～33mg/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, 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, 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 (M1 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, 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 top medicine equivalent.
(5) solvent control group (1%DMSO group): use 1%DMSO processing plasmodium with top 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 A20081002886800051
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: 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] quinoline is by the method preparation of example I, water is made into the suspension of required different concns, drug dose press 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] quinoline calculates.
(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 (M1 low dose group, 75mg/kg), (the dosage group among the M1 of dosage group in the The compounds of this invention, 150mg/kg), The compounds of this invention high dose group (M1 high dose group, 300mg/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 n Inhibiting rate (%)
M1 low dose group 75mg/kg 10 82.5
Dosage group 150mg/kg among the M1 10 94.2
M1 high dose group 300mg/kg 10 97.0
PQP organizes 160mg/kg 10 94.0
The result is as shown in table 2, and the plasmodium falciparum inhibiting rate of oral dose administration among the The compounds of this invention M1 is 94.2%, near the inhibiting rate (94.0%) of positive control drug PQP; The plasmodium falciparum inhibiting rate of high dose oral administration is 97.0%, than the inhibiting rate height of positive control drug PQP, shows that the 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.
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 presses D, 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
(1) collected urine being concentrated into 4L, is 15: 10: 1 methylene dichloride, ether and isopropyl alcohol mixed solvent extraction then with the volume ratio of 3 times of volumes, gets organic layer;
(2) organic layer is concentrated into 250mL, crosses the ODS column chromatography, first water wash-out is used 5%～50% methyl alcohol gradient elution then, collects, merges the elutriant of 30～50% methyl alcohol;
(3) step (2) gained meoh eluate is concentrated 10ml, cross Sephadex LH-20, use 30% methanol-eluted fractions then, collect elutriant;
(4) step (3) gained elutriant is concentrated into 10ml, crosses the C18 liquid-phase chromatographic column, with 50% methanol-eluted fractions that contains 0.1% formic acid, collect elutriant then;
(5) with step (4) gained elutriant drying under reduced pressure, crystallization gets The compounds of this invention 4.5mg.
The evaluation of The compounds of this invention:
1, UV spectrum analysis: The compounds of this invention dissolves with methanol-water, uses PDA-100 diode-array detector (DAD) scanning then.The result as shown in Figure 1, this compound has uv-absorbing at 225.0nm and 358.5nm place, illustrates that compound has the quinoline structure, three-way normalizing on the UV collection of illustrative plates, the expression sample purity more than 98%.
2, 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 analysis software that the Thermo mass spectrograph carries the molecular weight of this compound is 408.0894 as shown in Figure 2, and molecular formula is C 22H 18N 4Cl 2, as shown in Table 1 and Table 2.
Table 1
m/z Intensity Relative
30 807403.0 2.38
41 945971.0 2.79
42 5602497.0 16.50
43 1835126.0 5.40
44 940027.0 2.77
45 1492769.0 4.40
54 2644772.0 7.79
55 7324968.0 21.57
56 13114624.0 38.62
57 6146096.0 18.10
58 988887.0 2.91
63 760261.0 2.24
68 1553427.0 4.57
69 876008.0 2.58
70 17139200.0 50.47
71 1116007.0 3.29
72 2003257.0 5.90
73 3281954.0 9.66
74 6274345.0 18.48
75 2641160.0 7.78
76 854403.0 2.52
77 956949.0 2.82
82 988830.0 2.91
83 5607769.0 16.51
84 5940427.0 17.49
85 1096194.0 3.23
86 4340283.0 12.78
97 1509093.0 4.44
98 1184517.0 3.49
99 9658368.0 28.44
100 3989892.0 11.75
101 6484872.0 19.10
102 2102738.0 6.19
112 1026406.0 3.02
113 1098011.0 3.23
114 1823006.0 5.37
115 1553418.0 4.57
116 2273774.0 6.70
123 737193.0 2.17
124 842484.0 2.48
125 975006.0 2.87
126 4258808.0 12.54
127 7302569.0 21.50
128 33960192.0 100.00
129 4751753.0 13.99
130 2734392.0 8.05
131 725126.0 2.14
134 2307359.0 6.79
135 2645274.0 7.79
136 1581534.0 4.66
137 1469488.0 4.33
140 1061382.0 3.13
141 1580099.0 4.65
142 1002415.0 2.95
149 1116134.0 3.29
150 909426.0 2.68
153 1227124.0 3.61
155 24769536.0 72.94
156 4854301.0 14.29
157 747953.0 2.20
162 11977472.0 35.27
163 6065407.0 17.86
164 4334244.0 12.76
165 1886423.0 5.55
166 1082656.0 3.19
167 2060626.0 6.07
168 3943681.0 11.61
169 6299272.0 18.55
170 61511459.0 18.11
171 829832.0 2.44
176 4329299.0 12.75
177 2334502.0 6.87
178 2182039.0 6.43
179 1380968.0 4.07
180 1000596.0 2.95
181 3433162.0 10.11
182 6475904.0 19.07
183 1827963.0 5.38
188 808571.0 2.38
189 8453120.0 24.89
190 11502848.0 33.87
191 14286848.0 42.07
192 18909184.0 55.68
193 5962017.0 17.56
194 5133391.0 15.12
195 867315.0 2.55
201 682932.0 2.01
202 1728682.0 5.09
203 6234804.0 18.36
204 8232710.0 24.24
205 14352128.0 42.26
206 3978390.0 11.71
207 3954020.0 11.64
210 874787.0 2.58
215 702121.0 2.07
217 9332224.0 27.48
218 2404011.0 7.08
219 2999181.0 8.83
220 691468.0 2.04
232 1198739.0 3.53
244 735803.0 2.17
245 3397369.0 10.00
246 1932651.0 5.69
247 5088145.0 14.98
248 1192834.0 3.51
249 1308383.0 3.85
258 2498638.0 7.36
260 26140416.0 76.97
261 4877938.0 14.36
262 7296453.0 21.49
263 1328712.0 3.91
304 5023317.0 14.79
305 1035461.0 3.05
306 1503257.0 4.43
317 1132541.0 3.33
318 7066083.0 20.81
319 28047104.0 82.59
320 7872458.0 23.18
321 8975104.0 26.43
322 1865860.0 5.49
Table 2
Figure A20081002886800101
3, nuclear magnetic resonant analysis: U.S. Bruker 500MHz nuclear magnetic resonance analyser, model: AV500; Probe: 5mm BBOBB-1H; Pulse: zg30 (hydrogen spectrum); Zgdc30 (carbon spectrum); Solvent: DMSO; Sampling number: 8; Sampled data points: 32K; Spectrum width: 10000Hz.
Through nucleus magnetic resonance 1H-NMR (DMSO-d 6, 500MHz) analyze, shown in Fig. 3～4, analytical results is: δ 8.67 (2H, d, J=6.7Hz, H-2,2 "), 7.10 (2H, d, J=6.7Hz, H-3; 3 "), 8.30 (2H, d, J=9.0Hz, H-5,5 "); 7.10 (2H, dd, J=9.0Hz, J=2.0Hz, H-6,6 "), 8.05 (2H, d, J=2.0Hz, H-8,8 "), 4.13 (8H; d, H-2 ', 3 ', 5 ', 6 ').
Through nucleus magnetic resonance 13(MeOD 500MHz) analyzes C-NMR, and shown in Fig. 5～7, analytical results is: δ 105.2 (C-3; 3 "), 143.9 (C-4,4 "), 128.7 (C-5; 5 "), 126.2 (C-6,6 "), 137.3 (C-7; 7 "), 126.2 (C-8,8 "); 158.6 (C-10,10 "), 49.9 (C-2 ', 3 ', 5 ', 6 ').
4, infrared absorption spectrum analysis The compounds of this invention: 3106～2982cm -1Show and have Ar-H, 1624～1501cm -1Show and have aromatic ring, 1160～1016cm -1Show and have aryl-halogen, 824～555cm -1Show and have C-Cl.
Example 2
Prescription: example 1 gained compound 60g 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, make 200 altogether, every 0.75g, contain 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] quinoline 300mg.
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% ethanolic soln, uses fluidized bed granulation, and compressing tablet promptly.Make 400 altogether, every 0.375 gram, contain 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] 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, every 0.335 gram, contain 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] quinoline 100mg.

Claims (4)

1,7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] quinoline, its molecular structure is suc as formula shown in the I.
Figure A2008100288680002C1
2,7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] application of quinoline in the preparation anti-malaria medicaments.
3, a kind of anti-malaria medicaments, this medicine by 7-chloro-4-[4 '-(7 "-chloroquine-4 "-yl) piperazine-1 '-yl] quinoline and acceptable accessories form.
4, medicine as claimed in claim 3 is characterized in that this medicine is capsule or tablet.
CNA2008100288687A 2008-06-17 2008-06-17 7-chlorine-4-[4'-(7''-chloroquine-4''-base)diethylenediamine-1'-base]quinoline and uses thereof Pending CN101293871A (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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