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 PDFInfo
- 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
- Authority
- AP
- ARIPO
- Prior art keywords
- riminophenazine
- compound
- dihydro
- radicals
- use according
- Prior art date
Links
- 201000004792 malaria Diseases 0.000 title claims description 16
- 238000000034 method Methods 0.000 title claims description 16
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 50
- 229960003677 chloroquine Drugs 0.000 claims description 45
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 37
- WDQPAMHFFCXSNU-UHFFFAOYSA-N clofazimine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC(Cl)=CC=3)C(=NC(C)C)C=C2N1C1=CC=C(Cl)C=C1 WDQPAMHFFCXSNU-UHFFFAOYSA-N 0.000 claims description 34
- 238000011282 treatment Methods 0.000 claims description 24
- -1 aikyl Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 230000000069 prophylactic effect Effects 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000000078 anti-malarial effect Effects 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 claims description 3
- 229960001962 mefloquine Drugs 0.000 claims description 3
- RHQTYDDJBYBCQV-UHFFFAOYSA-N phenazin-2-amine Chemical compound C1=CC=CC2=NC3=CC(N)=CC=C3N=C21 RHQTYDDJBYBCQV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- 241001024304 Mino Species 0.000 claims 1
- 239000003430 antimalarial agent Substances 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 description 23
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 20
- 244000045947 parasite Species 0.000 description 20
- 241000223960 Plasmodium falciparum Species 0.000 description 19
- 239000000460 chlorine Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- 210000003743 erythrocyte Anatomy 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 230000035945 sensitivity Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 230000002141 anti-parasite Effects 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 6
- 239000003096 antiparasitic agent Substances 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 206010035500 Plasmodium falciparum infection Diseases 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000005936 piperidyl group Chemical group 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 108091006112 ATPases Proteins 0.000 description 3
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 2
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 2
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 2
- 241000224016 Plasmodium Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005534 hematocrit Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000000051 modifying effect Effects 0.000 description 2
- 230000036457 multidrug resistance Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- NFCPRRWCTNLGSN-UHFFFAOYSA-N 2-n-phenylbenzene-1,2-diamine Chemical compound NC1=CC=CC=C1NC1=CC=CC=C1 NFCPRRWCTNLGSN-UHFFFAOYSA-N 0.000 description 1
- RUKISNQKOIKZGT-UHFFFAOYSA-N 2-nitrodiphenylamine Chemical compound [O-][N+](=O)C1=CC=CC=C1NC1=CC=CC=C1 RUKISNQKOIKZGT-UHFFFAOYSA-N 0.000 description 1
- NALREUIWICQLPS-UHFFFAOYSA-N 7-imino-n,n-dimethylphenothiazin-3-amine;hydrochloride Chemical compound [Cl-].C1=C(N)C=C2SC3=CC(=[N+](C)C)C=CC3=NC2=C1 NALREUIWICQLPS-UHFFFAOYSA-N 0.000 description 1
- IHQHTEWQXKMXNC-UHFFFAOYSA-N C1CCCCC1N=C1C=C2N(C=3C=CC=CC=3)C3=CC=CC=C3N=C2C(NC=2C=CC=CC=2)=C1 Chemical compound C1CCCCC1N=C1C=C2N(C=3C=CC=CC=3)C3=CC=CC=C3N=C2C(NC=2C=CC=CC=2)=C1 IHQHTEWQXKMXNC-UHFFFAOYSA-N 0.000 description 1
- 241000256113 Culicidae Species 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 102220625554 PLAC8-like protein 1_F79S_mutation Human genes 0.000 description 1
- 208000009182 Parasitemia Diseases 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PCSUEZZVJSFJOC-UHFFFAOYSA-N [2-(trifluoromethyl)quinolin-4-yl]methanol;hydrochloride Chemical compound Cl.C1=CC=C2C(CO)=CC(C(F)(F)F)=NC2=C1 PCSUEZZVJSFJOC-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 229940125687 antiparasitic agent Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- WDQPAMHFFCXSNU-BGABXYSRSA-N clofazimine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC(Cl)=CC=3)C(=N/C(C)C)/C=C2N1C1=CC=C(Cl)C=C1 WDQPAMHFFCXSNU-BGABXYSRSA-N 0.000 description 1
- 229960004287 clofazimine Drugs 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100001223 noncarcinogenic Toxicity 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ACOJCCLIDPZYJC-UHFFFAOYSA-M thiazole orange Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1=CC=C2C(C=C3N(C4=CC=CC=C4S3)C)=CC=[N+](C)C2=C1 ACOJCCLIDPZYJC-UHFFFAOYSA-M 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic 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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- Y—GENERAL 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against 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.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ZA95749 | 1995-01-31 |
Publications (2)
Publication Number | Publication Date |
---|---|
AP9600778A0 AP9600778A0 (en) | 1996-01-31 |
AP603A true AP603A (en) | 1997-07-28 |
Family
ID=66218533
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1996/000778A AP603A (en) | 1995-01-31 | 1996-01-25 | A method of treating malaria by administering a product containing reminophenazine. |
Country Status (8)
Country | Link |
---|---|
US (1) | US5763442A (en) |
EP (1) | EP0729757A1 (en) |
JP (1) | JPH08231401A (en) |
KR (1) | KR960028909A (en) |
AP (1) | AP603A (en) |
AU (1) | AU704048B2 (en) |
CA (1) | CA2168139A1 (en) |
ZA (1) | ZA96588B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
WO2006034219A2 (en) * | 2004-09-17 | 2006-03-30 | The General Hospital Corporation | Inactivation of microorganisms with multidrug resistance inhibitors and phenothiaziniums |
EP2200613B1 (en) | 2007-09-21 | 2018-09-05 | The Johns Hopkins University | Phenazine derivatives and uses thereof |
JP2016164125A (en) * | 2013-07-02 | 2016-09-08 | 国立大学法人帯広畜産大学 | Therapeutic agent and prophylactic agent of babesiosis |
EP3124028B1 (en) | 2014-03-25 | 2019-06-26 | National University Corporation Kagawa University | Malaria transmission prevention agent having rare sugar as effective component thereof and malarial parasite growth regulating agent |
Citations (3)
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 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
-
1996
- 1996-01-25 US US08/591,032 patent/US5763442A/en not_active Expired - Lifetime
- 1996-01-25 EP EP96300525A patent/EP0729757A1/en not_active Withdrawn
- 1996-01-25 ZA ZA96588A patent/ZA96588B/en unknown
- 1996-01-25 AU AU42190/96A patent/AU704048B2/en not_active Ceased
- 1996-01-25 AP APAP/P/1996/000778A patent/AP603A/en active
- 1996-01-26 CA CA002168139A patent/CA2168139A1/en not_active Abandoned
- 1996-01-27 KR KR1019960001788A patent/KR960028909A/en not_active Application Discontinuation
- 1996-01-31 JP JP8015294A patent/JPH08231401A/en active Pending
Patent Citations (3)
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 |
Also Published As
Publication number | Publication date |
---|---|
AU4219096A (en) | 1996-08-08 |
US5763442A (en) | 1998-06-09 |
ZA96588B (en) | 1996-08-16 |
JPH08231401A (en) | 1996-09-10 |
EP0729757A1 (en) | 1996-09-04 |
AP9600778A0 (en) | 1996-01-31 |
CA2168139A1 (en) | 1996-08-01 |
AU704048B2 (en) | 1999-04-15 |
KR960028909A (en) | 1996-08-17 |
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