GB2195333A - 4-/4-(4-Ethylpiperazinyl-1)-phenylamino/-benzo(g)-quinoline and method for preparing same - Google Patents
4-/4-(4-Ethylpiperazinyl-1)-phenylamino/-benzo(g)-quinoline and method for preparing same Download PDFInfo
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- GB2195333A GB2195333A GB08622150A GB8622150A GB2195333A GB 2195333 A GB2195333 A GB 2195333A GB 08622150 A GB08622150 A GB 08622150A GB 8622150 A GB8622150 A GB 8622150A GB 2195333 A GB2195333 A GB 2195333A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract
4-/4-(4-Ethylpiperazinyl-1)-phenylamino-benzo(g)-quinoline according to the present invention has the formula: <IMAGE> and has antimalarial activity. A method for preparing this compound resides in that 1-ethyl-4-(4-nitrophenyl)piperazine of the formula: <IMAGE> is reduced in an organic solvent by hydrogen in the presence of a catalyst-palladium supported on carbon at a temperature of 80-100 DEG C with the formation of a solution of 1-ethyl-4-(4-aminophenyl)piperazine. The resulting product is reacted with 2,3-dihydrobenzo(g)quinolin-4(IH)-one of the formula: <IMAGE> in the presence of nitrocompounds of the benzene series. This reaction is carried out upon refluxing of the reaction mass with the removal of the formed water from the reaction zone. The desired product is isolated.
Description
SPECIFICATION 4/4-(4-Ethylpiperazinyl- 1 )-phenylamino/-benzo(g))quinoline and method for preparing same
The present invention relates to biologically active compounds, and, more particuiarly, to 4-/4 (4-ethylpiperazinyl- 1 )-phenylamino/-benzo(g)quinoline exhibiting improved antimalarial properties and to a method for preparing same.
The organic compound according to the present invention is novel and hitherto unknown in the literature.
The compound according to the present invention comprises 4-/4-(4-ethylpiperazinyl-1)-pheny- iamino/-benzo(g)quinoline of the formula:
The compound according to the present invention is a fine-crystal powder-like yellow substance insoluble in water, soluble in organic solvents upon heating; the compound is stable upon long-term storage in the dark at room temperature.
The study of the antimaiarial effect of 4-/4-(4-ethylpiperazinyl-1)-phenylamino/-benzo(g)quinoline in experimental conditions on -animals was carried out on a model of rodent malaria (mice) induced by Plasmodium berghei-"normal" drugsensitive strain in experiments of therapeutic" and "prophylactic type. White non-inbred mice of both sexes with a bodymass of 12-14 g were used for the experiments. The comparison compound is 4-(1-methyl-4-diethylaminobutylamino)-7- chloroquinolinophosphate (chloroquine). For chloroquine the doses are given as calculated for the base. The data of the final experiments are given hereinbelow.
In therapeutical experiments the compounds were administered per os in a single dose at the time of a developed infection, in the instant case two days after the test animals were infected intraperitoneally with the blood containing malarial parasites. The experiment covered 4 groups of animals of 8 mice in each. The animals of group I were given the compound according to the present invention in the dose of 75 mg/kg of the bodymass; those of Group 2-with the same compound in the dose of 50 mg/kg of the bodymass; Group 3-the comparison compound chioroquine in the dose of 50 mg/kg of the bodymass; Group 4-no compounds at all (control).
Chloroquine was administered as an aqueous solution, the compound according to the present invention-as a suspension in a starch aqueous solution. The compounds were given to the mice in accordance with their bodymass so that the dose per 20 g of the bodymass is contained in 0.2 ml of liquid. The progress of infection was assessed using Romanovsky-Giemsa coloured blood films taken from the tail (thin smears) by counting malaria parasites according to the
Sh.D.Moshkovsky method in points ("Medical Parasitology and Parasitogenic Diseases", 1964,
No. 4, Moscow USSR).
For the assessment of the antimalarial effect of the compounds in a therapeutical experiment 5 criteria were used (see Table 1 hereinbelow).
As it is seen from the experimental data shown in Table 1 the compound according to the present invention in the dose of 75 mg/kg of the bodymass produces an effect matching that of chloroquine.
The advantage of the compound according to the present invention is assessed by a chemotherapeutic quotient (0); the Q value of the standard reference (choroquine) is assumed as being equal to 1. The chemotherapeutic quotient reflects, the scope of a therapeutic effect of the test compound ration in comparison with the standard reference.
The 0 value for the compound according to the present invention is calculated from the formula:
e 0=-, wherein: e-ratio of a relative activity calculated t from the formula:
t
DEst e=
DEp t-ratio of a relative toxicity calculated from the formula:
DTst
T=
DTp
DEst DTst i.e. O is the ratio : , wherein:
DEp DTp
DE -dose of the compound providing a conventional effect;
DT -dose of the compound characterizing its toxicity st -standard reference compound; p -test preparation.
The dose of the compound according to the present invention producing a conventional effect (DE) was 75 mg/kg (for chloroquine it was 50 mg/kg); The dose of the compound illustrating its toxicity (DT), in the instant case the maximum tolerable dose determined on experimental animals was 1 800 mg/kg (for chloroquine it was 192.6 mg/kg).Therefore, Q in the calculation of toleration of the compound according to the present invention by the mice is equal to:
DEst DTst 50 192.0 -- : -- = -- = ----- = 6.2 DEp DTp 75 1,800.0
The comparison of the effects shown in Table 1 hereinbelow and of the 0 values points to the advantage of the compound according to the present invention over chloroquine as regards the scope of its therapeutic effect, even despite the fact that the dose of the compound according to the present invention producing a conventional effect (DE) is higher than that for chloroquine (75 mg/kg and 50 mg/kg respectively) due to a far lower toxicity of the compound of this invention.
In prophylacting experiments protective properties of the compounds were assessed, i.e.
duration of their effect in the animal's organism (the ability of inhibit the infection development).
The compound according to the present invention and chloroquine were administered per os in equal single doses prior to the
Table 1
Effectiveness of the compound according to the present invention in therapeutic experiments
(P.berglii - mice)
- - - D - - - NnEer compound Dose, of pa- ' Mean value for the group accord mg/kg rasites ing to tie assesstnent criteria on the 4 I ttle I day of | nq x o o o admini- I :: d a, strati- as a, a, strati- H h e a) 4) aJ MBcdk E) on of > m < 3 a) C Oakd the com- < H (d w a a, c pound o Ei art o g:4 c o a qq (in Or on wo s t points) as as o m U o o me an cr 0 mean zone 4AoOJ2 value 4 o oo o 00) 4) 0)H for B.C( t( qq k h as ha, o each : cd o as o as a, 04,0 4) as H group m as as U H' 4 X e o o 9 V A5 o O O -H as e c) o bD C) n EQ 1 2 3 4 5 6 7 Compound of the present inventi- Equal Equal on 75 4.6 -3.5a effect 1.5 effect
Ditto 50 4.8 -2.8a Equal 1.4c Equal
effect effect
Chloroquine 50 4.7 3.2a 1.8
Control 4.7 +1.0b Table 1 (cont.) Mean value for each group according to tie assessment
criteria
Nos. II a, as 'a O -H C r' 0-H 0 0 'a 0-H a) o 4) a) cH 'a -H H'a 600C a, rcca -H -H H rlr( 0 a) ':::I 'a Fe 4) o 040 H 04) H 0 1) $ H 0 a, as 0 d 'a 004 -HG)4) 004a,4) o ao oTi h 8 or d 50) C as o 0 ka zoo H as oo o a .o 0 0 a, as H as m a, 0 0 o 0 m CI) -H CI) o as -H 0 'a rld '1, 'a ri d d k C E! as d ~d L 4) 'a O0a) Fe 434) S aso-H as o ri d-C > -H as 0 aP 'H 04,0 t S 04'o 4) 4) 'H d 04,0-H 9 4) S sr: mo S QO OH OH-H 04 OH III IV V
1 8 9 10 11 12 13
1. 4.5 Quail 9.1 Equal 13.1 equal
effect effect effect
2. 27c Lesser 77c Lesser Lesser effect effect 10.8 effect 3. 4.3 9.2 13.7
4. - 6.5 a-decrease of the level of parasitemia; b-increase of the level of parasitemia; c-parasites disappeared in 6 mice out of 8, in 2 mice a sharp reduction of the number of parasites is observed without their disappearance; d-the level of parasitemia of 4 points is regarded as crucial, since at a lower level a parasite does not fall within the field of vision of a microscope, thus impairing the possibility of a more accurate assessment of the level of parasitemia.
infection of the animals (the animals infection, administration and dissolution of the compounds were carried out as described hereinbefore). The experiment covered three groups. of mice of 50 animals in each. The animals of Group I were given the compound according to the present invention in the dose of 150 mg/kg of the bodymass; Group 2-chloroquine in the dose of 150 mg/kg of the bodymass; Group 3 animals were not given any compound. Then 3 to 6 mice out of each group are successively infected with the interval of 24 hours. The examination of the blood films and the number of parasites was counted daily, beginning with the day following the date of infection of the animals over the period of 30 days. The protective effect is assessed according to the criteria shown in Table 2.
Table 2
Effectiveness of the compound according to the present
invention in prophylactic experiments (P.berghei,mice) Time bet- Num- I eriterion II criterion
Compound ween admini- ber III criterion stration of of
the compound mice full time of time of
and infecti- in preven- appea- death of
on, days the tion of rance mice
group the in- of days
fection para-.
develop- sites,
ment, num- days
ber of
mice
1 2 3 4 5 6
Compound
of this in- 1 4 4 30+# 30+# vention Chloroquine 1 4 0 6.7+ 12.0+
Control 5 0 1.0+ 6.2
Compound of
this inven
tion 2 4 4 39 302 Chloroquine 2 5 0 1.0- 6.6- Control 4 0 1.0 6.5
Compound of
this inven
tion 3 6 0 6.7e 12.0+ Chioroquine 3 5 0 1.0 6.6 Control 5 0 1.0 6.4 Compound of
this invention 4 5 0 3.2+ 9.0+
Control 5 1.0 5.6
Compound of
this inven
tion 5 6 0 1.5 7.5+
Control 5 0 1.2 6.4
Compound of th
this inven
tion 6 6 0 1.0 6.3-
Control 5 0 1.0 6.0
Note: + - there is the effect
- no effect - - parasites did not appear within the observation
period (30 days) As is seen from Table 2 when the animall were infected in 1 and 2 days after administration of the compound according to the present invention it caused a full prevention of the infection development in all of the animals in the group within the observation period-30 days. No such effect was observed in the groups of animals treated with chloroquine. The obtained experimental data show that a certain degree of the protective effect of the compound according to the present invention is noticed within the period of 5 days, whereas the effect of chloroquine ceases to be manifested already after 2 days.
The toxic effect of the compound according to the present invention has been also studied in comparison with chloroquine.
The experiments were carried out on outbred white mice of both sexes with a bodymass of 16-17 g. The compounds were administered orally as a suspension in a 1% starch aqueous solution. Mean lethal doses LD16 were determined by the methods of Litchfield, Wilcoxon, maximum tolerated doses-directly on the basis of the experimental data. The compounds were tested in different 5-7 doses. For each dose 6 animals were used. The control group consisted of 12 animals. The control group was given a 1% aqueous starch solution. Observations over of the test and control animals continued 10 days since the moment of administration of the compounds. The results of the thus-performed tests are shown in Table 3 hereinbelow.
Table 3
Results of investitation on acute toxicity of
the compound according to the present invention
in comparison with chloroquine
Compound Acute toxicity parameters, gZkg ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ..;maximum tolerated LD16 LD50
dose compound of
the present inention 1.8 2.05 2.45 (2.l6-2.78 Chloroquinex 0.192 0.26X 0.34 (C.29-0.41)X (x) For chloroquine the doses are given as calculated for the base.
The results of investigation on the toxic effect produced by the compound according to the present invention in comparison with chloroquine(Table 3) also point out to the advantage of the compound according to this invention over chloroquine. The compound of this invention proved to be much less toxic for laboratory animals than chloroquine. The maximum tolerated doses and medium-lethal doses of the compound according to the present invention are by 7-9 times higher than those for chloroquine.
In accordance with the present invention, the method of preparing 4-/4-(4-ethylpiperazinyl
1)phenylamino)/-benzo(g)quinoline resides in that 1-ethyl-4-/4-(4-nitrophenyl)piperazine of the formula:
is reduced in an organic solvent with hydrogen in the presence of a catalyst-palladium supported on carbon at a temperature within the range of from 80 to 100"C to give a solution of 1-ethyl4-(4-aminophenyl)-piperazine which is reacted with 2,3-dihydrobenzo(g)-quinoline-4-(IH)-one in the presence of a nitro compound of the benzene series upon heating the reaction mass at reflux with the removal of the forming water from the reaction zone, followed by isolation of the desired product.
The synthesis of the compound according to the present invention can be presented by the following scheme:
It is advisable to use, as the organic solvents, cyclohexanol or 3-methylbutanol-1.
As the nitrocompounds of the benzene series it is advisable to make use of nitrobenzene, ortho-nitrophenol of 1 -ethyl-4-(4-nitrophenyl)-piperazine.
The method according to the present invention makes it possible to obtain the desired product with a sufficient purity grade and in a good yield. The process to be implemented according to the method of the present invention necessitates no use of a special equipment.
The method for preparing 4-/4-(4-ethylpiperazinyl-1)-phenylamino/-benzo(g)quinoline is simple and can be performed in the following manner:
Into a round-bottom flask provided with a thermometer and a pipe for hydrogen supply 1ethyl-4-(4-nitrophenyl)piperazine an organic solvent and a hydrogenation catalyst are charged.
Then hydrogen is admitted into the flask to displace the air, whereafter the flask contents are heated to a temperature within the range of from 80 to 100"C under a continuous admission of hydrogen. The hydrogenation reaction is completed when absorption of hydrogen is stopped.
The reaction mass is cooled, the catalyst is removed therefrom, e.g. by filtration. 1-Ethyl-4-(4aminophenyl)piperazine formed as a result of hydrogenation is placed, in a solvent, into a threeneck flask provided with a stirrer and a reflux condenser with a water separator of the Dean
Stark type. Into the same flask 2,3-dihydrobenzo(g)quinoline-4(1H)-one and an organic oxidizing agent are charged. The flask contents are heated to reflux and the refluxing is continued till water stops to evolve, this water being continuously removed from the reaction zone. Then the flask contents are cooled and the desired product is recovered by conventional techniques such as dilution with ether or vacuum distilling-off of the solvent.
For a better understanding of the present invention the following specific examples are given hereinbelow by way of illustration.
Example 1
In a 250 ml round-bottom flask provided with a thermometer and a gas-supplying pipe 11.75 g (0.05 mol) of 1-ethyl-4-(4-nitrophenyl)piperazine, 40 ml of cyclohexanol and 0.3 g of a 10% palladium catalyst supported on carbon are charged. The air is displaced from the flask by means of hydrogen, where after hydrogenation is effected under normal pressure and at a temperature of 80-85"C till abscorption of the theroretically required amount of hydrogen. The catalyst is filtered-off.
The cyclohexanolic solution of the resulting 1-ethyl-4-(4-aminophenyl)-piperazine is placed into a 1 50 ml three-neck round-bottom flask provided with a mechanical stirrer, thermometer and a refiux condenser with Dean-Stark packing for separation of water evolving in the reaction.
Charged into the flask are 9.86 g (0.05 mol) of 2,3-dihydrobenzo(g)quinolin-4(1H)-one and 3 ml of nitrobenzene. The reaction mass is heated at reflux till water stops to evolve in the Dean
Stark packing, whereafter the flask contents are cooled, diluted with 3 volumes of ethyl ether and allowed to stand for 12 hours in a refrigerator. The precpitate is filtered-off, washed with ether and airdried. The resulting commercial-purity product is crystallized from p-xylene to give 11.7 g (61.1%) of 4-/4-(4-ethylpiperazinyl-1) phenylamino/benzo(g)quinoline in the form of yellow crystals melting at 250-252"C.
Elemental analysis:
Found, % C 78.1, H 6.8; N, 14.7; C2SH26N4 Calculated, %: C 78.5, H 6.8; N 14.6
Example 2
The desired product is obtained following the procedure described in the foregoing Example 1, except that cyclohexanol is replaced with 3-methylbutanol-1. The resulting product, i.e. 4-/4-(4ethylpiperazinyl-1)-phenylamino/-benzo(g)quinoiine melting at 250-252"C, in the yield of 58.2%.
Example 3
The desired product is obtained in a manner similar to that described in Example 1 hereinabove, except that instead of nitrobenzene o-nitrophenol is used; 4-/4-(4-ethylpiperazinyl-1)pheny- lamino/benzo(g)quinoline melting at 250-2520C is obained in the yield 57.0%.
Example 4
To a solution of 18.8 g (0.08 mol) of 1-ethyl-4-(4-nitrophenyl)-piperazine in 70 ml of cyclohexanol heated to 80"C 0.5 g of a 10% palladium catalyst supported on carbon is added and hydrogen is passed under normal pressure and at a temperature of 90-100 C till a theoretically calculated amount of hydrogen is absorbed. The catalyst is filtered-off. To the cyclohexanolic solution of 1-ethyl-4-(4-aminophenyl)piperazine 19.72 g (0.1 mol) of 2,3-dihydrobenzo(g)quinolin 4(lH)-one and 4.7 g (0.02 mol) of 1-ethyl-4-(4-nitrophenyl)piperazine are added and the reaction mass is refluxed using a reflux condenser with Dean-Stark packing till water evolving in the reaction stops to liberate.Thereafter, the flask contents are treated in a manner similar to that described in Example 1 hereinbefore to give 4-/4-(4-ethylpiperazinyl-1)-phenylamino/benzo(g)quinoline melting at 250-252 C as the desired product in the yield of 62.3%.
Example 5
The desired product is obtained in a manner similar to that described in the foregoing Example 4, except that instead of cyclohexanol an equal volume of 3-methylbutanol-1 is used 4-/4-(4ethylpiperazinyl-1)phenylamino/benzo(g)quinoline melting at 250-252"C is obtained in the yield of 59.1%.
The starting product, viz. 1-ethyl-4-(4-nitrophenyl)piperazine can be obtained in the following manner: a mixture of 141.6 g (0.9 mol) of 4-chloronitrobenzene, 124.2 g (0.9 mol) of anhydrous potash, 136.8 g (1.2 mol) of 1-ethylpiperazine and 150 ml of dimethylformamide are refluxed under vigorous stirring for 10 hours, whereafter the reaction mass is cooled and poured into 1.5
I of cold water. The residue is separated, washed with water and, while crude, is dissolved in 2
I of a 18% hydrochloric acid upon heating to the temperature of 50"C. The insoluble impurities are filtered-off, the filtrate is added with a 25% aqueus solution of ammonia till an alkaline reaction; the formed yellow precipitate is separated, washed with water and air dried to give 185.0 g of 1-ethyl-4-(4-nitrophenyl)piperazine in the form of yellow crystals melting at 68-70"C.
Claims (5)
1. 4-/4-(4-Ethylpiperazinyl- 1 )-phenylamino/-benzo(g)quinoline of the formula:
2. A method for preparing a compound according to Claim 1, comprising reducing 1-ethyl-4 (4-nitrophenyl)piperazine of the formula:
in an organic solvent by hydrogen in the presence of a catalyst-palladium supported on carbon at a temperature within the range of from 80 to 100"C to give a solution of 1-ethyl-4-(4aminophenyl)-piperazine which is reacted with 2,3-dihydrobenzo(g)quinolin-4(1H)-one of the formula:
in the presence of nitrocompounds of the benzene series upon refluxing of the reaction mass with the removal of the formed water out of the reaction zone, followed by isolation of the desired product.
3. A method according to Claim 2, wherein as the organic solvent cyclohexanol or 3-methylbutanol-1 is used.
4. A method according to Claims 2 and 3, wherein as the benzene series nitrocompounds nitrobenzene, orthonitrophenol or 1-ethyí-(4-nitrophenyl)-piperazine are used.
5. A method according to the foregoing Claims 2 to 4, substantially as described in the
Specification and Examples 1 through 5 hereinbefore.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8622150A GB2195333B (en) | 1986-09-15 | 1986-09-15 | 4/4-(4-ethylpiperazinyl-1)-phenylamino/-benzo(g)-quinoline and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8622150A GB2195333B (en) | 1986-09-15 | 1986-09-15 | 4/4-(4-ethylpiperazinyl-1)-phenylamino/-benzo(g)-quinoline and method for preparing same |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8622150D0 GB8622150D0 (en) | 1986-10-22 |
| GB2195333A true GB2195333A (en) | 1988-04-07 |
| GB2195333B GB2195333B (en) | 1990-03-28 |
Family
ID=10604199
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8622150A Expired - Fee Related GB2195333B (en) | 1986-09-15 | 1986-09-15 | 4/4-(4-ethylpiperazinyl-1)-phenylamino/-benzo(g)-quinoline and method for preparing same |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2195333B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995017471A1 (en) * | 1993-12-23 | 1995-06-29 | Zeneca Limited | Disazo compound |
| WO1995017472A1 (en) * | 1993-12-23 | 1995-06-29 | Zeneca Limited | Disazo compound |
| WO2001014331A2 (en) * | 1999-08-24 | 2001-03-01 | Regents Of The University Of California | Non-quinoline inhibitors of malaria parasites |
-
1986
- 1986-09-15 GB GB8622150A patent/GB2195333B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995017471A1 (en) * | 1993-12-23 | 1995-06-29 | Zeneca Limited | Disazo compound |
| WO1995017472A1 (en) * | 1993-12-23 | 1995-06-29 | Zeneca Limited | Disazo compound |
| WO2001014331A2 (en) * | 1999-08-24 | 2001-03-01 | Regents Of The University Of California | Non-quinoline inhibitors of malaria parasites |
| WO2001014331A3 (en) * | 1999-08-24 | 2001-09-07 | Univ California | Non-quinoline inhibitors of malaria parasites |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8622150D0 (en) | 1986-10-22 |
| GB2195333B (en) | 1990-03-28 |
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| PCNP | Patent ceased through non-payment of renewal fee |