AP603A - A method of treating malaria by administering a product containing reminophenazine. - Google Patents

A method of treating malaria by administering a product containing reminophenazine. Download PDF

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Publication number
AP603A
AP603A APAP/P/1996/000778A AP9600778A AP603A AP 603 A AP603 A AP 603A AP 9600778 A AP9600778 A AP 9600778A AP 603 A AP603 A AP 603A
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Prior art keywords
riminophenazine
compound
dihydro
radicals
use according
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APAP/P/1996/000778A
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AP9600778A0 (en
Inventor
Constance Elizabeth Medlen
Ronald Anderson
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Univ Van Pretoria
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • A61P33/02Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides the use of a

Description

ANTI-PARASITIC ACTIVITY
Title of the invention
THIS INVENTION relates to anti-parasitic activity, to therapeutic treatments and substances or compositions for use against parasites, and to the use of substances or compositions in the manufacture of medicaments for prophylactic or for therapeutic treatment against parasites.
G
Background to the invention
A problem in the therapy of diseases caused by parasites 10 < is that the parasites become resistant to drugs used for treating the patient. This resistance may be intrinsic or may be acquired. A major world problem arising in countries where maleria is prevalent is the growing resistance to the drugs which have been used for the prophylactic or therapeutic treatment of malaria.
AP/F79S/ 0 0 7 78
AP . Q υ 6 ύ 3
Brief summary of the invention
We have found that riminophenazines possess activity against diseases caused by parasites, eg. malaria. The present invention provides a substance or composition for use in the treatment of infections caused by parasites, said substance or composition comprising a riminophenazine. The substance or composition may be used for prophylactic and/or therapeutic r- treatment.
The invention also provides the use of a riminophenazine in the manufacture of a medicament to treat infections caused by parasites, e.g. malaria carried by flying insects such as mosquitos.
The invention further provides a method for the prophylactic and/or therapeutic treatment of infections of the human or animal body caused by parasites which comprises administering an J
5 effective amount of a riminophenazine to the human or animal body.
' A riminophenazine is a phenazine containing a substituted imino substituent in one of the benzene rings. The imino group conveniently may be in the 2- (or 3- position depending on the nomenclature), the nitrogen atoms of Jhe_phenazine being in the 520 and 10- positions. Conveniently, there may also be an amino group in the same benzene ring as the imino group, preferably in the 3- (or
AF/r/9 6 / 0 0 7 78
AP. Ο 0 6 υ3
2- position, depending on the nomenclature). A presently preferred riminophenazine may have a 2-(substituted imino)-3-(substituted amino)-10-ary! grouping, (alternatively a 3-(substituted imino)-2(substituted aMino)-10-aryl grouping, depending on the nomenclature used) optionally with a further substituent in the 7- or 8-position), i.e.
a compound of the general formula:
co c
θ Following the nomenclature system used in chemical abstracts, such a compound would be known as a 7-(R2)-3-(R4n10 anilino)-10-(R1n-phenyl)-2,10-dihydro-2-(R3-imino)-phenazine.
Detailed description of the invention
The riminophenazine may be used in the invention in the form of a pharmaceutically acceptable salt, e.g. an acid addition salt.
AP/P/ 9 6 / 0 0 7 78
AP. Ο Ο 6 Ο 3
In general formula (I) ;
R1 is a hydrogen atom, a halogen atom or an alkyl, alkoxy or trifluoromethyl radical,
R2 is a hydrogen or halogen atom,
R3 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyi, or is a substituted or unsubstituted heterocyclic or heterocyclicalkyl radical,
R4 is a hydrogen or halogen atom or an alkyl, alkoxy or trifluoromethyl radical, and n is 1, 2 or 3.
c
G
The radicals R1 and R4 may, for example, be hydrogen, chlorine, methyl, isopropyl, methoxy or trifluoromethyl. R1 and R4 may conveniently be in the 3- and/or 4- positions. When n is 2 or 3, there are two radicals R1 and R4 in the phenyl rings and these radicals may be the same or different. R2 may conveniently be hydrogen or chlorine.
AP/P/ 9 6 / 0 0 7 78
The radical R3 in the above formula (I) may for example, be hydrogen, C, - C4 - lower alkyl, (e.g. methyl, ethyl, n-propyl or isopropyl), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclohexyl, hyroxycyclohexyl, cyclooctyl, cyclododecyl, N,N20
AP.00603 dialkylaminoalkyl, cylohexylmethyl, piperidyl, alkyl-substituted piperidyl or benzyl substituted piperidyl.
A particularly convenient radical R3 in the above formula (I) is a tetramethylpiperidyl (TMP) radical, e.g. a 4-TMP radical (i.e. 45 (2,2,6,6,-tetramethylpiperidyl) radical. Other preferred radicals for R3, are cyclohexyl and Ν,Ν-diethylamino propyl radicals.
r
The compounds of general formula (I) may be used in a method of treatment of infections of the human or animal body caused by parasites, particularly malaria. The riminophenazines may be used for prophylactic and for therapeutic treatment of such infections.
The invention particularly provides the use of a ( .
compound of formula (I) in the manufacture of a medicament to treat c
infections caused by parasites, particularly malaria infections, the 15 riminophenazines may be used alone or together with other compounds which have anti-parasitic activity. Such treatment may be by means of a single composition containing a riminophenazine and another anti-parasitic compound or by separate compositions, one containing a riminophenazine and the other containing another anti20 parasitic compound.
8Z L 0 0 / 9 6 Zd.'dV
AP.00603
Thus the invention also provides a pharmaceutical composition which comprises (a) a riminophenazine and (b) another anti-parasitic compound. A carrier or diluent may also be present.
Examples of anti-parasitic compounds are compounds which are used in the therapeutic treatment or prophylactic treatment of malaria, e.g. chloroquine, (i.e. the compound 7-Chloro-4-quinolinylΝ',N'-diethyl-1,4-pentanediamine) and mefloquine (i.e. the compound (
(R,S)( ± )o-2-piperidinyl-2,8-0/s(trifluoromethyl)-4-quinoline methanol hydrochloride.
Thus the invention particularly includes a pharmaceutical composition comprising a mixture of a riminophenazine and (a) chloroquine or mefloquine, together with a pharmaceutical carrier or diluent.
( c
The compositions may be in any suitable form, e.g. a tablet, capsule, solution, sterile solution, or the like. They may be . introduced orally, intravenously, transdermally, or in any other suitable manner. Typical compositions may contain from about 50 to 2000, more usually 100 to 600, e.g. 150 to 300 mg of active ingredient, together with one or more inert carriers. Any suitable carrier known in the art may be used. The riminophenazines may ba administered to adults in daily dosages of from about 5 to 30 mg/kg
AP/P/9 6 / 0 0 7 78
AP.00603 per week, more usually 10 to 20 mg/kg per week for an average adult for prophylactic purposes. For therapeutic treatment, the dosage can be increased substantially, e.g. to amounts of from 100 to 200 mg per day.
The riminophenazine in the composition preferably is cf the above general formula (I) in which R1, R2, R3, R4 and n have the meanings given above.
Presently preferred examples of R1 and R4 in the above formula (I) are hydrogen, chlorine, methyl and trifluoromethyl.
Presently preferred examples of R2 are hydrogen and chlorine.
Presently preferred examples of R3 are TMP, piperidyl, hydrogen, alkyl, cycloalkyl, dialkylaminoalkyl and alkylcycloalkyl.
c
Many of the riminophenazines of the above oenerai c
formula (I) are known compounds whose preparation has been described in the literature, e.g. including South African Patents Nos.
57/1249 and 57/3266. Alternatively other general methods of preparation described in the literature for the preparation of riminophenazines may be followed.
For example a 1-anilino-2-nitiobenzene of general formula (II) may be reduced, e.g. with hydrogen in the presence of a
AP/P/ 9 6 / 0 0 7 78
AP. Ο Ο δ Ο 3 palladium carbon catalyst, or in zinc and acetic acid, to form the corresponding 1 -anilino-2-aminobenzene (i.e. 2-amino-diphenyIamine) of general formula (III), in which R1, R2 and n have the meanings defined above. Heating at temperature of 40-55°C can be used.
AP/P/ 96/00778
The diphenylamine of formula (III) may be oxidatively condensed, e.g. with ferric chloride and concentrated hydrochloric ac<d or acetic acid to form a riminophenazins of general formula (IV), i.e. a compound of formula (I) in which R3 is hydrogen. Ethyl alcohol may be used as a solvent. Stirring at ambient temperatures of, preferably, below 15°C may be used.
AP.00603
(IV)
The other riminophenazines of general formula (I) can be formed from the riminophenazine of general formula (IV) by reaction with an amine of formula R3-NH2. Refluxing of the reactants, in solution in dioxane, for a period of 3 to 5 hours may be necessary.
C.
c
The 1-anilino-2-nitrobenzene starting material may be prepared by reacting a 2-halo-nitrobenzene containing a R2-radical in the 5-position, with a formulated aniline having a R1 substituent in the phenyl ring. The reaction may be carried out in the presence of anhydrous potassium carbonate and while boiling the reactants in dimethylformamide.
8Z L 0 0 / s 6;
AP . 0 0 6 0 3
Particular examples of compounds of general formula (I) are set out in the following Table I:
TABLE - 1
Compound R1 R2 R3 , 1 R !
B283 H H H ........ 1 '—' H
B628 4-CI H H H
Clofazimine (B663) 4-CI H -CH(CH3)2 4-CI
B669 H H -Cyclohexyl H
B67O H H -CH(CH3)2 H
B673 4-CI H Cyclohexyl 4-CI
B718 H H -C2H5 H
B729 H H Cycloheptyl Η i I
B741 4-CI H 4-methyl cyciohexyi 1 4-CI ί
B746 4-CI H -C2H5 4-CI
B749 4-CI H -{CH,)2N.(C2H5)2 4-CI |
B759 4-CI H -(CH2)3CH3 4-CI |
B796 H H -cyclopentyl H
B98O 4-F H -CH(CH3)2 4-F
B1865 H Cl -CH(CH3)2 H
B1912 H Cl -cyclohexyl H
B3677 4-me H -cyciohexyi 1 4-me
B3763 H H -cyclo’nexyl methyl i H
B3779 4-CI H 4-(N,N-diethylamino(- -2-methyl-butyl 4-CI 1 ί
B3786 Cl H 4Z-TMP ci !
B3825 4-CI H 4-hydroxy cyciohexyi 4-CI |
B3962 H H 4Z-TMP H
AP/PZ 9 6 / 0 0 7 78
AP . Ο Ο 6 Ο 3
TABLE - 1 (CONTINUED)
Compound R1 R2 R3 R4
B4019 H Cl 4Z-TMP H
B4021 H Cl -c2h5 H
B4070 4-me H -4-piperidyl 4-me
B4090 4-CI Ci 4Z-TMP 4-CI
B4100 3,4-di-CI H 4Z-TMP 3,4-di-CI
B4103 4-CF3 H 4Z-TMP 4-CF3
B4104 4-CI Cl Cyclohexyl 4-CI
B4112 3-CI H 4Z-TMP 3-CI
B4121 3,5-di-CI H 4Z-TMP 3,5-di-CI
B4123 3-CI Cl 4Z-TMP 3-CI
B4126 3-CF3 H 4Z-TMP 3-CF3
B4127 3-CF3 Cl 4Z-TMP 3-CF3 j
B4128 2,4-di-CI H 4Z-TMP Ί 2,4-di-CI
B4154 3,4-di-CI H -(CH2)3N.(C2H6)2 3,4-di-CI
B4158 4-CH(CH3)2 H 4Z-TMP ί 4-CH(CH3)2
B4159 4-CH(CH3)2 Cl 4Z-TMP 4-CH(CH,)2
B4163 3-CF3-4-CI H 4Z-TMP 3-CF3-4-CI
B4166 H H -cyclooctyl H
B4169 3,4,5-tri-CI H 4Z-TMP J 3,4,5-tri-CI
B4170 H H -cyclopropyl H
B4171 H H -cyclododecyl <H 1
B4172 H H -cyciobutyl H 1
B4173 H H 4Z-(N- benzylpiperidyl) H
B4174 4-OCH3 H 4Z-TMP 4-OCH3
B4175 3,4-di-CI H Cyclohexyi 3,4-di-CI
B4177 4-OCF3 H 4Z-TMP 4-OCF3
AP/P/9 6 / 0 0 7 78
AP. Ο Ο 6 Ο 3
In the above table, when R3 is 4/-TMP, the TMP radical is a 4-(2,2,6,6,-tetramethyl piperidine) radical, and me is used as an abbreviation for methyl.
The chemical names for some of the compounds of
Table I are set out in Table II below :
TABLE II
B663 N, 5-d/s-(4-chlorophenyl)-3,5-dihydro-3-[( 1 - methylethyl)imino]-2-phenazinamine;
B669 - Ni5-b/s(phenyl)-3,5-dihydro-3-(cyclohexylimino)-2- phenazinamine;
B796 - N,5-0/'s-phenyl-3,5-dihydro-3-(cyclopentylimino)- 2-phenazinamine;
B3677 - N,5-b/s(4-methylphenyl)-3,5-dihydro-3- (cyclohexylimino)-2-phenazinamine;
B3763 N,5-b/s(phenyl)-3,5-dihydro-3- t(cyclohexylmethyl)imino]-2-phenazinamine;
B3779 N, 5-Z?/s(4-chloropheny 1)-3,5-d i hydro-3-ί (4- diethylamino-2 - methy lbutvl)imino]-2- phenazinamine;
B3962 - N,5-0/s(phenyl)-3,5-dihydro-3-[(2',2',6',6'- tetramethyl-4-piperidyl)imino]-2-phenazinamine;
AP/P.' 9 6 / 0 0 7 78
AP.00603
B4070
B4100
B4103
Γ
B4104
B4112
B4121 <
c
B4123
B4126
N, 5-Z>/s(4-methylphenyl)-3,5-dihydro-3-[(4piperidyl)imino]-2-phenazinamine;
N,5-b/s(3,4-dichlorophenyl)-3,5-dihydro-3[(2',2',6',6’-tetramethyl-4-pipsridyl)-imino]-2phenazinamine;
N,5-Z?/s(4-trif!uoromethylphenyl)-3,5-dihydro3[(2',2',6',6'-tetramethyi-4-piperidyl)imino]-2phenazinamine;
N,5-Z>/s(4-ch!orophenyl)-8-chloro-3,5-dihydro-3(cyclohexyIimino)-2-phenazinamine;
N,5-0/s(3-chlorophenyl)-3,5-dihydro-3[(2',2',6'(6'-tetramethyl-4-piperidyi;-imino3-2phenazinamine;
N,5-6/s(3,5-dichiorophenyl)-3,5-dihydro-3[{2',2',6',6'-tetramethyl-4-piperidyl)-imino]-2phenazinamine.
N,5-h/s(3-chlorophenyl)-8-chloro-3,5-dihydro3[{2',2',6'/6'-tetramethyl-4-piperidyl)-imino]-2phenazinamine;
N,5-b/s(3-trifliJoromethyl-4-pheny!)-3,5-dihydro-3[(2',2',6',6'-tetramethy!-4-p;peridyl)-imino]-2phenazinamine;
AP/P/ 9 6 / 0 0 7 78
B4127
B4154
B4158
C
B4159
B4163
B4166 (
B4169
B4170
AP. 0 0 6 0 3
N,5-d/s(3-trifluoromethylphenyl)-8-chloro-3,5dihydro-3-[(2',2',6',6'-tetramethyl-4-piperidyl)imino]-2-phenazinamine;
N,5-0Zs(3,4-di-chlorophenyl)-3,5-dihydro-3-[(3'(N,N-diethylamino)-propylimino]-2-phenazinamine;
N,5-d/s(4-isopropylphenyl)-3,5-dihydro-3[(2',2',6',6'-ietramethyl-4-piperidyl)-imino]-2phenazinamine;
N,5-d/s(4-isopropylphenyl)-8-chloro-3,5-dihydro-3f(2',2',6',6'-tetramethyl-4-piperidyi)-imino]-2phenazinamine;
N,5-Z?/s[(3-trif!uorornetHyl)-4-chlorophenyl]-3,5dihydro-3-[(2',2',5'.,6'-tetramethylpiperidyl)imino]-2-phenazinamine
N,5-d/s(phenyl)-3,5-dihydro-3-(cyclooctylimino)-2phenazinamine;
N,5-Z?/s(3,4,5-tri-ch!orophenyl)-3,5-dihydro3[(2',2',6',6'-tetramethyl-4-piperidyi;-imino]-2phenazinamine;
N,5-Z?/s(phenyl)-3,5-dihydro-3-(cyclopropylimino)2-phenazinamine;
N,5-Z?/’s(pher:yl)-3,5-dihydro-3-(cyclododeAP/P/ 9 6 / 0 0 7 78 cylimino)-2-phenazinamine;
B4171
Β4172 - N,5-6/s(phenyl)-3,5-dihydro-3-(cyclobutylimino)-2phenazinamine;
Β4173 - N,5-6/s(phenyl)-3,5-dihydro-3-[4'-(Nbenzylpiperidyl)-imino]-2-phenazinamine;
B4174 - N,5-6/s(4-methoxyphenyl)-3,5-dihydro-3[(2',2',6',6'-tetramethyl-4-piperidyl)-imino]-2phenazinamine;
B4175 - N, 5-6/5(3,4-di-chlorophenyl)-3,5-dihydro-3(cyclohexylirnino)-2-phenazinamine.
Treatment of parasite-infected human erythrocytes with a compound of the above general formula (I) results in the reduction of resistance of the parasite to anti-parasitic compounds, and/or in anti-parasitic activity, particularly anti-malarial activity. Furthermore, treatment of non-infected humans with a compound of the above general formula (I) results in protection against infection by parasites.
Without being bound by theory, the possible reasons for the surprising activity of the compounds of formula (!) is that a relationship may exist between riminophenazine mediated enhancement of PLA2 (i.e. phosphclipose A2) activity and the inhibition of ATPase of P-glycoprotein, or the inhibition of Pglycoprotein activity may occur as a secondary consequence of the depletion of cellular ATP following prolonged inhibition of Na + , K/, ,'P, 9 6 / 0 0 7 78
AP.00603
ATPase activity. Thus, a reversal of resistance to anti-parasitic agents may occur, primarily via activation of PLA2 and consequent lysophospholipid-mediated inhibition of the ATPase activity of Pglycoprotein. Both of these mechanisms may be operative.
The riminophenazines of the above formula (I), contain an imino group. They are reasonably non-toxic and possess a potent r resistant modifying activity when administered in vitro. We have found that they inactivate the drug pump activity in cell lines with acquired multi drug resistance.
in addition to being relatively non-toxic, the compounds of the above general formula (!) are non-carcinogenic and nonmyelosuppressive. They possess direct antineoplastic activity as well as multi-drug resistance modifying potential.
c
Description of preferred embodiments, and the drawings
Particular riminophenazines which have shown good activity against the maleria microorganism Plasmodium faiciparium are B41 12, namely N,5-h/s(3-ch'oropheny!)-3,5-dihydro-3-(4'-TMP-imino)2-phenazinamine, B4158, namely N,5-d/s(4isoprophy!penyl',-3,5dihydro-3-(4'-TMP-imino)-2-phenazinamine, B4121, namely N,4d/s(3,5-dichlorophenyl)-3,5-dihydro-3-(4'-TMP-imino)-2phenazinamine, B4100, namely N,5-d/s(3,4-dichlorophenyl)-3,5AP/P/ 9 6 / 0 0 7 78
AP.00603 dihydro-3-(4'-TMP-imino)-2-phenazinamine and B669, namely N,5b/s(phenyl)-3,5-dihydro-3-(cyclohexylimino)-2-phenazinamine.
Certain of the results of experiments given in the Examples, below, are illustrated in the accompanying drawings in which Figure 1 is a graph of the percentage inhibition of Plasmodium falciparum resistance against chloroquine concentration, for the experiment described in Example 3; and
Figure 2 is a graph of the percentage inhibition of Plasmodium falciparum resistance against riminophenazine concentration for the experiment described in Example 4. It shows the direct anti-material activity of the riminophenazines used in that
Example.
The invention is illustrated in non-limiting manner by reference to the following Examples.
c
5 Example 1
THE REVERSAL OF CHLOROQUINE RESISTANCE OF PLASMODIUM
FALCIPARUM Bv B669
AP/P/9 6 / 0 0 7 78
B669 is the compound N,5-bis-(phenyl)-3,5-dihydro-3(cyclohexylimino)-phenazinamine.
AP . 0 0 6 0 3
Resistance to chloroquine by malaria parasites can be mediated by a type of P-glycoprotein homologue termed Pg H1 which is similar to the mammalian drug afflux pump (MDR-I present in multidrug resistant cancer cell lines). This type of resistance can be reversed by the calcium channel blocker, verapamil. The dose of this calcium channel blocker required to reverse this type of resistance in vitro would, however, cause severe side effects in vivo.
c
The activity of riminophenazines to reverse chloroquine resistance in Plasmodium falciparum was tested in the following manner;
Methods
A preliminary series of experiments were carried out (
using two laboratory strains of P. falciparum (RB-1 and Fac-9). These c
strains were obtained from the Medical Research Council, Durban, where they were characterised as being either mildly resistant or sensitive to chloroquine. The isolates were maintained in suspension culture in known manner (as described by Freese JA, Markus MB and
Golenser J, 1991; Bulletin of the World Health Organization 69: 707AP/P/ 9 6 / 0 0 7 78
712).
AP . 0 0 6 0 3
Infected erythrocytes were diluted with human 0positive red blood cells to a parasitaemia of 0.2 - 0.9 % and suspended to 3 % in RPMI containing 44 mg/1 hypoxanthine and 10% human type 0 serum. Aliquots (100 μ\) of the suspension were dispensed into the wells of 96-well microtitre plates. To these suspensions 100 μΐ of the medium were added containing either chloroquine or B669 alone or in combination. The final drug concentrations were 31, 62, 126, 250 500 and 1000 nM for r
chloroquine and 0.125, 0.25, 0.5 and 1.0 //g/ml for 3669. Relevant 10 solvent controls were included. The plates were incubated for 24 hours at 38 °C in a desiccator gassed with 5 % 02, 5 % CO2 and
90% N2. Thin blood smears were prepared from each well, stained with Giemsa stain and the percentage of red biood cells infected by at least one parasite determined microscopically.
c
Results c
The solvent systems had no effect cn the percentages of infected cells. B669 alone had a direct effect on both strains at
1.0 //g/ml. Although the percentage parasitaemia did not differ from the untreated control systems, a morphological deterioration of tha parasites was observed at this concentration (as set out in Table 1 below). The experimental agent (B669) however, did not increase the sensitivity of the chloroquine sensitive strain to chloroquine (Table 1,
AP/P/ 9 6 / 0 0 7 78
AP.00603 whereas, in the case of the chloroquine resistant strain sensitivity to 500 nM chloroquine was increased up to three fold in the presence of 0.25 pg/ml B66S (see Table 2 below) and up to two fold to 125 nM chloroquine in the presence of 0.1 25 pg/ml B669. In the tables, nd means not determined.
Conclusion r
The results of this study indicated the potential use of the riminophenazines in the treatment of, or prophylaxis against chloroquine resistant malaria.
AP/P/ 9 6 / 0 0 7 78
AP.00603
TABLE 1
The effect of B669 on the sensitivity to chloroquine of a chloroquine sensitive strain of Plasmodium falciparum (Fab-9) ( Percentage red blood cells infected with P. falciparum (Fab-9) after
Chloroquine treatment (nM) :
AP/P/ 9 6 / 0 0 7 78
B669 Treatment (gg/ml)
0 31 02 125 250 500 10
0 3.8 4.9 3.9 2.4* 3.1* 0.1* 0
0.125 4.0 3.9 nd nd nd 0.9 nd
0.25 4.4 3.1 nd 2.9 nd 0.1* nd
(K5 3.0 2.7* nd 3.0 nd 0.1* nd
LO 4.1* 2.9 nd 0.9 nd 0.1* nd
* parasites morphologically abnormal
AP.00603
TABLE 2
The effect of B669 on the sensitivity to chloroquine of a chloroquine resistant strain of Plasmodium falciparum (RB-1)
Percentage red blood cells infected 5 with P. falciparum (RB-1) after r
Chloroquine treatment (nM) ;
E ci =4.
δ ε
rt o
κH o
KO
KO ra
0 31 62 125 250 500 1000
0 3.5 3.5 3.3 3.3 3.1 3.0 0.4
0.125 3.6 nd nd 1.6* nd 1.3 nd
0.25 4.0 3.9 2.8* 1.9* nd 0.9* 0
OJ 3.2 nd nd nd 1.4* nd 0.1
1.0 2.6* 2.6* nd nd 0.1* nd 0
AP/P,'9 6 / 0 0 7 78 * parasites morphologically abnormal
AP.00603
Example 2
THE REVERSAL OF CHLOROQUINE RESISTANCE OF
PLASMODIUM FALCIPARUM BY B669
The following experiment was done to confirm previous 5 results w'hich were obtained microscopically and details of which are
C set out in Example 1.
Methods
For this experiment the same two strains of P. falciparum, as used in Example 1 (RB-1 and Fab-9) w'ere again used. Infected erythrocytes were diluted with human O-positive red blood cells to a c
parasitaemia of 0.2-0.9 % and suspended to 3 % in RPMI containing c
mg/1 hypxanthine and 10 % human type serum. Aliquots (100 μΐ) of the suspension were dispensed into the wells of 96-well microtitre plates. To these suspensions 100 μϊ of the medium A'ere added containing either chloroquine or B669 alone or a combination of chloroquine and B669. Relevant solvent controls were included. Negative control wells were also included containing uninfected red blood cells. The plates were incubated at 38°C in a desiccator gassed with 5 % O2, 5 % CO2 and 90 % N2. After 24 hours 100 μΐ culture
AP/P/ 9 6 / 0 0 7 78
AP.00603 medium of each well was replaced with 100 ml of hypoxathine - free medium containing 10% human serum and 0,5 μ Ci3H-hypoxanth:ne and incubated for a further 18 hours. The contents of the wells were then harvested on to glass fibre filters. The filters were washed with distilled water, dried, haemoglobin dissolved in a sodium bicarbonate solution and placed in scintillation vials containing 4 ml scintillation fluid and counted for 5 min in a liquid scintillation counter.
c
Results
The percentage inhibition was calculated as follows:
Percentage inhibition = 1 CPM (drug treated cells) - CPM (neg. control) x 100
CPM (untreated cells) - CPM (neg. control) (2 where CPM was the mean of two values of counts per minute for each
5 treatment. The percentage inhibition is shown in the following Tables.
AP/P/ 9 6 / 0 0 7 78
AP.00603
TABLE 3
The effect of B669 on the sensitivity to chloroquine of a chloroquine sensitive strain of Plasmodium falciparum (Fab-9) using the 3Hhypoxanthine uptake method
PERCENTAGE INHIBITION
CHLOROQUINE TREATMENT (nM)
0 0 0 31 52.5 62 23.5 125 48.7 250 66.9 500 100 1000 100
x—\. ε CD 0.125 29.8 12.9 7.4 68.3 81.4 100 100
c OJ ε 0.25 10.4 21.0 0 34.9 85.5 100 100
co JJ H sO 0.5 41.7 60.5 91.7 93.6 100 100 100
sC ca L0 46.6 98.8 95.9 100 100 100 100
8// 0 0 / 9 6 /d/dV
AP.00603
TABLE 4
The effect of B669 on the sensitivity to chloroquine of a chioroquine sensitive strain of Plasmodium falciparum (RB-9) using the 3H-hypoxanthine uptake method
PERCENTAGE INHIBITION
CHLOROQUINE TREATMENT (mM'
0 31 62 125 250 500 100'
0 0 0 0 8 33 100 100
E 0.125 0 15.2 12.2 0 100 100 100
c
e 0J5 0 0 26.4 0 100 98.S 95
rt o
H
CN NO NO CQ 0^ 0 0 16.6 92 95 100 100
LU 0 58.6 100 100 100 ICO 100
AP/P/ 9 6 / 0 0 7 78
C
The solvent systems had no effect on the percentages of infected celis. As can be seen from Table 3, only the chloroquine sensitive strain (RB-1) was sensitive to B669 alone (0.125 - 1.0 /xg/ml) while the experimental agent (B669) did not increase the sensitivity of o this strain to chloroquine. As can be seen from Table 3, in tlie case of the chloroquine resistant strain sensitivity to 250 nM chloroquine was increased up to three fold in the presence of 0.125 - 0.5 gg/ml B669
AP. Ο Ο 6 Ο 3 and sensitivity to 125 μΜ chloroquine up to ten fold in the presence of 0.5 and 1.0 pg/ml B669. Effects of the experimental drug was also seen at concentrations of chloroquine as low as 31 and 62 nM.
Discussion
These results, as well as the results obtained with the c microscopy method of Example 1 indicate the ability of riminophenazines to reverse chloroquine resistance in malaria. Direct anti-malaria activity, especially in the case of the chloroquine sensitive strain of P.falciparum, was also possessed hy B669.
c c
Example 3
THE REVERSAL OF CHLOROQUINE RESISTANCE
IN PLASMODIUM FALCIPARUM BY B4112
To test the activity of B4112 to reverse chloroquine resistance in Plasmodium falciparum, the following experiment was done:
AP/P' 9 6 / 0 0 7 78
Methods
A chloroquine resistant strain of P.falciparum (FAC 8) was obtained from Dr P Smith, University of Cape Town (originally from Dr A F Cowman, Royal Melbourne Hospital, Victoria, Australia).
AP. 0 0 6 0 3
Malaria infected erythrocytes (ring stage) were diluted with human O-positive red blood cells together with RPMI containing 44 mg/1 hypoxanthine and 10% human type A serum to a parasitaemia of 2% and a haematocrit of 5%. This suspension was incubated in a 5 gassed desiccator (5% O2, 5% CO2 and 905¾ N2) with serial dilutions of chloroquine ranging from 61 - 500 nM in 96-well microtitre culture plates for 48 hours in the presence or absence of a fixed concentration © of B4112 (100 ng/ml). Relevant solvent controls were included.
At the end of the incubation period, 100 μ\ of the medium 10 was removed from each well and replaced with a fixation solution containing 10 mM TRIS, 10 mM Na-Azide and 150 mM Na Cl. The plates were stored overnight at 4 °C and then 25 ul aliquots from each well were stained in test tubes with 0.5 ml thiazole orange at a c
concentration of 0.25 Mg/ml in phosphate-buffered saline (PBS). After c
5 an incubation period of 1 hour at room temperature (in the dark), (he tubes were placed on ice and the level of parasitaemia determined by flow cytometry using a Coulter Epics Profile II (Coulter Electronics
Ltd, Hialeah, PLA, USA).
Results
The solvent systems had no effect on the percentages of infected cells. Chloroquine per se inhibited the growth of the parasite
AP/P' 9 6 / 0 0 7 78
AP.ΟΟ6Ο3 at concentrations > 250 nM (Figure 1), whereas B4112 per se at 100 ng/ml inhibited parasite growth by 27 percent. However, B4112 (100 ng/ml) increased the sensitivity of this strain of P. falciparum to 125 nM chloroquine from 33 to 100 percent as is seen in Figure 1 of the accompanying drawings.
Conclusions
C In this experiment B4112 and cliloroquine clearly interacted synergistically.
Example 4
DIRECT ANTIMALARIAL ACTIVITY QF THF
RIMINOPHENAZINE
To investigate the direct antimalarial activity cf the riminophenazines B669, B4100, B4103, B4112, B4121, B4158 and c
B4169 against a laboratory strain of P.falciparum the following 15 experiment was done:
AP/F/ 9 6 / 0 0 7 78
Methods
A laboratory strain of P.falciparum (RB-1; obtained from
Dr B L Sharp, National Malaria Research Programme, MRC, Durban) was maintained.
AP. Ο Ο 6 Ο 3
For these experiments malaria cultures of haematocrit 5.0% and initial parasitemia 2.0% were used. The malaria infected erythrocytes (ring stage) were incubated in microtitre plates with serial dilutions of B669, B4100, B4103, B4112, B4121, B4158 and B4169 (0.125-2 ^g/ml) for 48 hours and processed for analysis on the flow cytometer as described in Example 3.
Results
The effects of B669, B4100, B4103, B4112, B4121,
34158 and B4169 on the growth of F.jaliparum can be seen from 10 Figure 2 of the accompanying drawings. Βό69, B4103, Β4Π2 and
B4158 inhibited the growth of this strain of the malarial parasite by more than 50% at a concentration of 0.5 ,ug/ml with the order of activity B4158 > B4112 > B4103 > B669 at this concentration as can be seen from Figure 2 of the accompanying drawings.
G
Conclusions
These results indicate once again the potential use of the
AP/P,' 9 6 / 0 0 7 78 riminophenazines, especially B4158 and B4112, in the treatment of prophylaxis of chloroquine resistant malaria.
Example 5
Some compositions of the invention are made up as follows:
CAPSULES rng/capsule
Riminophenazine 100 - 2000 mg
5 Diluent/Disintegrant 5 - 200 mg
C Glidants 0 - 15 mg
Disintegrants 0 - 20 mg
TABLETS mg/tablet
Riminophenazine 100 - 2000 mg
10 Diluent 5 - 200 mg
{ Disintegrant 2 - 50 mg
( Binder 5 - 100 mg
Lubricant 2 - 20 mg
SYRUP rrig/10 nil
15 Riminophenazine 100 - 2000 rag
Solvents, solubilisers, stabilisers 5 - 500 mg
Colouring agents 0,5 - 150 mg
Preservatives/Antioxidants 1-150 mg
Flavours 5 - 200 mg
ΑΡ/Ρ; 9 6 / 0 0 7 78
AP.00603
INTRAVENOUS
Riminophenaz ine 100 - 2000 mg
Alkali/buffer, Isotonically agents 5 - 100 Mg
Stabilisers, solubilisers 0 - 100 Mg
AP/P/9 6 / 0 0 7 78
AP.ύύ603

Claims (11)

1. A method for prophylactic or therapeutic treatment of malaria, comprising administering to a patient in need or such treatment, an effective amount of a riminophenazine of the general formula, wherein: R1 and R4 are independently selected from hydrogen atoms, halogen atoms, aikyl, alkoxy and trifluoromethyi radicals,
R* ia selected from hydrogen or halogen atoms,
R* is sefacted from hydrogen atoms, alkyl, substituted alkyl, cycloalkyl, cycloalkylaikyi, unsubstituted heterocyclic radicals, substituted heterocyclic radicals, unsubstituted heterocyciicalkyl and substituted heterocyclicaikyl radicals; with the proviso that when Ra is isopropyl, R’ and R4 are not both 4-chloro.
AP/P/ 96 / 00778
AP.00603 '-Λ
2, A method according to claim 1 wherein the riminophenazine is a compound listed in Table I herein, other than N,5'bis-{4-chforo phenyl) -3,5 dihydro -3-(sopropylimino -2-phenezinamine.
3, A method according to claim 2, wherein the riminophenazine
3 is the compound N,5-bis-(3-chloro phenyl)-3,5-dihydro-3-[2',2',6',6'tetramethyl-4- piperidyl) imino]-2-phenazinamine.
4, A method according to claim 2, wherein the riminophenazine isN,5-bis(4-isopropylphenyl)-3,3-dihydro-3-[{2',2',6',6'-tetramethyl4-piperidyl)’iminoJ-2-phana2inamine.
0 5. A method according to claim 2 wherein the riminophenazine le
N,5-bls(phenyl) -3,5-dihydro-3-(cyclopropyiimino) -2-phenazinamine.
β. A method according to any of claims 1 to 5, wherein a known prophylaotically or therapeutically active anti-material compound is also administered to the human or animal body.
3 . 7. The uae of a riminophenazine for the prophylactic or therapeutic treatment of malaria, wherein the riminophenazine le a compound of the general formula:
8 L L 0 0 / 9 6 /d/dV .
AP. Ο Ο 6 0 j wherein; R’ and R4 are independently selected from hydrogen atoms, halogen atoms, alkyl, alkoxy and trifluoromethyl
5 radicals,
R* is selected from hydrogen and halogen atoms,
R3 Ϊ9 selected from hydrogen atoms, alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, unsubstituted heterocyclic radicals, substituted heterocyclic radicals,
0 unsubstituted heterocycllcalkyl and substituted hsterocycilcalkyl radicals;
with the proviso that where R3 Is isopropyl, R’ and R4 are not both 4-ohloro,
Γ
8. Ths use according to claim 7, wherein tha riminophenazine is
5 a compound of Table 1 herein other than N,5-bis-{4-ohlorophsny(}-3,5· dihydro -3-(i30propyiimino)-2'p'nena2inamine.
AP/P/'
9 6 / 0 0 7 78
AP.00603 , 9. The use according to claim 7, wherein the riminophenazine is k
the compound N,5-biS’(3-cHloro phenyl)'3,5-d[hydra-3-[{2',2’,5',6'tetramethyl-4-piperldyl) f'mino]'2-phenazinamine.
10. The use according to claim 7 wherein the riminophenazine is
5 N,5-bia(4-iaopropylphenyl)-3,5-dihYdro-3-[i2',2',6',6'-tetramathy[-4plperidyl) •iminoj-2-phenazlnamine.
11. . The uee according to claim 7, wherein the riminophenazine is N,5-bis(phenyl)«3,5-dihydro-3’(cyclopropylimino)-2-phena2inamine.
12. The use according to any of claims 7 to 11 in conjunction with
10 a known prophylactically or therapeutically active anti-maiarial oompound.
1 3. The use in the manufacture of a medicament to treat or prevent nataria of a riminophenazine of a compound of the general formula :
8Z L 0 0 / 9 6 Zd/dV
AP. C 5 6 0 3
38' wherein; R’ and R* ara independently selected from hydrogen atoms, haicgen atoms, alkyl, aikoxy and trifluoromethyl <
5 radicals,
RJ is selected from hydrogen and halogen atoms,
R* is selected from hydrogen atoms, alkyl, substituted alkyl, cycioaJkyl, eycloalkylalkyl, unsubstituted heterocyclic radicals,'substituted heterocyclic radicals,
10 , unsubstltutsd heterccyctiealkyl and substituted heterocyolicalkyl radicals;
with the proviso that when R3 is isopropyl, R1 and R4, are not both 4-chloro.
β
14. The use according to claim wherein the riminophenazine is a compound of Table I herein other than N,5-bis-{4-chlorphenyl)-3,5dihydro'3’(isopropylimino) -l-phenazinamlne.
ID
AP/P/ 9 6 / 0 0 7 78
ΑΡ.00603
15. The use according to olalm 14 wherein the riminophenazlne Is the compound N,5-bia-(3-chlorophenyl) 3,5-dthydro-3-{(2',2',Q',9', tetramethyl-4-piperidyl) imino]-2-phenazinamine.
1 β, The use according to claim 13 wherein the compound is N,5«
5 bis(4-isopropylphenyl)-3,5'dihydrc-3[(2'/2',8,/6'-tetram9thyl-4piperidylHmlnol-2-phenazinamine.
17. The use according to claim 13 wherein the compound is N,5bis(phenyl)-3,5-dibydro-3ricycIopropyllrnino)-2-phena2inamina.
ι
13. The use according to any of claims 14 to 17, wherein the '£
10 product also contains a known prophylactically or therapeutically ' · active antj-meiarlal compound. f _
19. .The use according to claim 18, wherein the known prophylactically or therapeutically active anti-malarial compound is chloroqUine or mefloquine.
APAP/P/1996/000778A 1995-01-31 1996-01-25 A method of treating malaria by administering a product containing reminophenazine. AP603A (en)

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WO1997045120A1 (en) * 1996-05-24 1997-12-04 University Of Pretoria Use of riminophenazines as antimicrobial and antimalarial agents
US6734192B1 (en) 1999-08-23 2004-05-11 Mp-1 Inc. Treatment of viral infections
JP3904364B2 (en) 2000-03-03 2007-04-11 独立行政法人科学技術振興機構 Novel compounds with antimalarial activity
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EP2200613B1 (en) 2007-09-21 2018-09-05 The Johns Hopkins University Phenazine derivatives and uses thereof
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Publication number Priority date Publication date Assignee Title
DE1795323A1 (en) * 1967-10-26 1972-01-05 May & Baker Ltd New heterocyclic compounds
EP0374991A1 (en) * 1988-11-23 1990-06-27 Westmart Hill Limited New antimicrobial phenazine derivatives, method for their preparation, compositions containing them, and their use in therapy
EP0676201A2 (en) * 1994-04-05 1995-10-11 Adcock Ingram Limited Use of a riminophenazine for treating MDR resistance

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US2875204A (en) * 1954-11-08 1959-02-24 Geigy Chem Corp 2-amino-3-(p-chlorophenylimino)-3, 5-dihydro-5-(p-chlorophenyl)-phenazine and salts thereof
US2948726A (en) * 1956-04-27 1960-08-09 Geigy Chem Corp New phenazine derivatives
US2946792A (en) * 1956-10-04 1960-07-26 Geigy Chem Corp New phenazine derivatives
US2943089A (en) * 1957-04-15 1960-06-28 Geigy Chem Corp New phenazine derivatives
FR1579474A (en) * 1967-10-24 1969-08-29
US3859667A (en) * 1973-12-26 1975-01-14 Laura C Roy Garment constructions

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
DE1795323A1 (en) * 1967-10-26 1972-01-05 May & Baker Ltd New heterocyclic compounds
EP0374991A1 (en) * 1988-11-23 1990-06-27 Westmart Hill Limited New antimicrobial phenazine derivatives, method for their preparation, compositions containing them, and their use in therapy
EP0676201A2 (en) * 1994-04-05 1995-10-11 Adcock Ingram Limited Use of a riminophenazine for treating MDR resistance

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