EP0146556A1 - Potentiation of anthelmintics - Google Patents
Potentiation of anthelminticsInfo
- Publication number
- EP0146556A1 EP0146556A1 EP19840901726 EP84901726A EP0146556A1 EP 0146556 A1 EP0146556 A1 EP 0146556A1 EP 19840901726 EP19840901726 EP 19840901726 EP 84901726 A EP84901726 A EP 84901726A EP 0146556 A1 EP0146556 A1 EP 0146556A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- anthelmintic
- compound
- benzimidazole
- group
- vivo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
Definitions
- the present invention relates to a method of potentiating anthelmintic compounds and to anthelmintic preparations in which the anthelmintic properties of known anthelmintic coumpounds are potentiated. It is known that conventional orally administered anthelmintics rely upon absorption from the alimentary canal of the animal followed by a sustained concentration of anthelmintically active material in the bloodstream of the animal. In the case of the benzimidazole group of anthelmintic compounds the original member of this group, thiabendazole (TBZ), is metabolised and completely excreted within 36 hours of dosing.
- TTZ thiabendazole
- the present inventors have discovered that when conventional anthelmintic compounds are administered to animals in association with a microtubule inhibitor it results in an increase in the plasma level of the anthelmintic compounds and a corresponding increase in efficiency of the anthelmintic compound than when administered in the absence of the microtubule inhibitor.
- tubulin a dimer of ⁇ and ⁇ tubulin
- Microtubule inhibitors act to increase the rate and extent of depolymerisation of the microtubules to form the tubulin proteins and/or to decrease the rate and extent of polymerisation of the tubulin proteins to form microtubules.
- the present invention consists in an anthelmintic preparation containing as active components at least one anthelmintic benzimidazole carbamate or a compound which may be converted in vivo to such a benzimidazole carbamate and at least one microtubule inhibitor being a benzimidazole compound of the formula
- R 1 is a radical and R 5 is an alkyl group to a maximum size of C 8 H 17
- R 3 and R 4 are each selected from the group comprising H, OH, NH 2 , SH, F, Br, Cl, I, CH 3 , CH 2 CH 3 , NHCH 3 , N(CH 3 ) 2 , SCH 3 , NHCOCH 3 , NHCOCH 2 R 6 , NHCOOCH 3 , NHCOOCH 2 R 6 , C 6 H 5 , CF 3 , COOH, COOCH 3 and COOCH 2 R 6 ,
- R 6 is the same as R 3 and R 4 ,
- R 2 is XR 7 ,
- X is NH, S, O, CO, or CH 2 , and
- R 7 is an aliphatic or aromatic radical, or a compound which may be converted in vivo to any one of the abovementioned benzimidazole microtubule inhibitors.
- the present invention further consists in a method for potentiating in a mammalian animal the action of a benzimidazole carbamate anthelmintic compound or a compound which may be converted in vivo to such a compound, comprising administering the anthelmintic compound to the animal in association with at least one microtubule inhibitor being a benzimidazole compound of the formula
- R 1 , R 2 , R 3 and R 4 are as hereinabove defined.
- the activities of the potentiator will increase the toxicity of the anthelmintic to nematodes whether sensitive to or resistant to the anthelmintic;
- the potentiated combination results in an improved efficacy against species which are only marginally susceptible to present dosages (including Trematodes and Cestodes), and
- a lower dose of the anthelmintic can be used with a potentiator to achieve equipotent activity with a resultant cost saving.
- the anthelmintic compounds most preferably used in the present invention are the anthelmintically active benzimidazole carbamates and compounds which may be converted in vivo to such benzimidazole carbamates. Included in the latter category are the phenylguanidines, thioallophanates and 1-substituted benzimidazole carbamates.
- microtubule inhibitors for use in the present invention are drawn from the group of benzimidazole compounds having the structural formula shown in Figure 2.
- R 1 is optimally a carbamate of structure where R 5 is an alkyl group to a maximum size of
- R 1 may also be an amide of general structure or a thiocarbamate of general structures
- R 2 can be represented as in Figure 3, where X is either NH, S, O, CO or CH 2 and R 5 is as previously defined.
- R 2 can be also represented as in Figure 4.
- R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 can be any combination of the following substituents,
- R 2 can also be represented as in Figure 5.
- R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 are as previously defined
- R 11 and R 12 are defined as for R 3 , R 4 ' R 6 , R 7 ' R 8 ' R 9 or R 10 .
- R 2 substituent is non-critical to the activity of the compound and could in effect be almost any organic radical of small or medium size.
- microtubule inhibitors useful in the present invention also include compounds such as substituted phenylguanidines and thioallophanates which can be metabolically activated in vivo to any of the benzimidazole microtubule inhibitor compounds specified above.
- the constituents of the anthelmintic preparation according to this invention may be administered simultaneously or sequentially provided that the administration of a second one of the ingredients to the animal is during the period of biological activity in the animal of the other of the ingredients, i.e. they should be administered "in association" with one another.
- the anthelmintic and the microtubule inhibitor may be administered orally, intraruminally, intramuscularly, intravenously, subcutaneously or dermally. They may be administered as a single dose, an implant or a bolus type dosage including any sustained release devices including intraruminal sustained release devices and sustained release devices delivering a continuous or pulsed release.
- the potentiated anthelmintic preparation may be used against any parasite, insect or organism which is deleterously affected by the active anthelmintic alone.
- microtubule inhibitors are known themselves to have some anthelmintic properties.
- the microtubule inhibitors are used at concentrations at which the compounds have relatively little anthelmintic activity of their own. It has also been found that the potentiation is not merely an additive effect of the anthelmintic activity of the two compounds. There has been found to be a true potentiation in that the plasma concentration profiles are much greater than would be expected by the mere additions of the effects of the two compounds individually.
- the anthelmintic and the microtubule inhibitor are each preferably administered to the animal in an amount of from 0.1 to 20mg/kg, preferably 3 to 12 mg/kg.
- sheep in 7 of the 8 groups were orally administered with oxfendazole (hereinafter called OFZ) (Synanthic 22.65g OFZ/1; Batch No. 8179 Syntex Australia) at a dose rate of 4.53mg/kg.
- OFZ oxfendazole
- the 3 sheep in each of the 7 groups were co-administered with the microtubule inhibitor parbendazole (hereinafter called PBZ) (Wormguard 90g PBZ/1, Smith Kline Australia) at either 0, 1.35, 2.70, 4.5, 9.0, 18.0 and 36.0 mg/kg respectively.
- the remaining group of 3 sheep were given OFZ at lOmg/kg.
- Plasma to be assayed was allowed to thaw and OFZ and its metabolites exctracted following a method slightly modified from that described by Allan et al. (1981) J. Chromatography 183: 311-319 employing disposable Sep Pak C 18 cartridges (Part No. 519.10 Water Associates Milford, Massachusetts 01757 USA).
- the Sep Pak was prepared by washing successively with 5.0ml High Performance Liquid Chromatography (HPLC) grade methanol followed by 5.0ml 0.017M NH 4 H 2 PO 4 buffer pH 5.5.
- HPLC High Performance Liquid Chromatography
- TBZ-resistant Trichostrongylus colubriformis (VRGS-strain, Hogarth Scott et al, 1976, Res. Vet. Sci. 21: 232-237) with a resistance factor at egg hatch of 57 to TBZ and on LD 9 0 against adult worms of 150mg TBZ/kg were obtained from stock cultures.
- TBZ-resistant Haemonchus contortus (VRSG-strain) with an LD 90 against adult worms of 200mg TBZ/kg were obtained from exsheathed L 3 larvae stored in liquid nitrogen and then passaged through a sheep. Twenty, 5-month-old Merino-Border Leicester cross-bred ewes, raised under worm-free conditions, were each infected with 8000 T.colubriformis and 4140 H.contortus benzimidazole-resistant larvae per os. The sheep were held in group pens on a maintenance diet (600g/d) of equal portions of wheaten chaff, lucerne chaff and oats and water ad libitum.
- a maintenance diet 600g/d
- Group II Oxfendazole, orally administered as the commercial preparation Synanthic at 4.53mg/kg.
- Group IV Oxfendazole, 4.53mg/kg + Parbendazole, 4.5mg/kg.
- Six days after treatment faecal worm egg counts were taken, the sheep killed and their parasite population determined using standard parasitological procedures.
- OFZ Anthelmintic Efficacy Faecal worm egg counts, taken immediately prior to and 6 days after treatment, together with the total post mortem TBZ-resistant H. contortus and T.colubriformis counts, are shown in Table 2. Also shown are the relative efficacies of the treatment regimes. Oral administration of OFZ at 4.53mg/kg reduced
- PBZ had no effect of F.hepatica numbers, whereas ABZ reduced fluke population bY 85.6% (p ⁇ 0.01).
- Example 3 The effect of variation of benzimidazole potentiator was examined. Substitution of PBZ (I; Figure 4) with methyl (5(6) propyloxybenzimidazol-2yl) carbamate (II), methyl (5(6) phenoxybenzimidazol-2yl) carbamate (III), methyl (5 (6) (3',4'-dichlorophenoxybenzimidazol-2yl) carbamate (IV) and methyl (5(6) (2'-naphoxybenzimidazol-2yl) carbamate (V), compounds known to inhibit the polymerisation of tubulin, was shown to increase the area under the plasma concentration-time curve for ABZ-SO and ABZ-SO 2 (Table 4). Compound (V) was found to be more potent than PBZ, demonstrating a similar potentiation at less than one-quarter the PBZ dose rate.
Abstract
Préparation anthelmintique comportant un composé anthelmintique carbamate de benzimidazole et un inhibiteur à microtubule qui est un composé benzimidazole substitué. Procédé pour renforcer l'activité des composés anthelmintiques carbamates de benzimidazole chez les mammifères comprenant l'administration du composé anthelmintique à l'animal associé à un inhibiteur à microtubule qui est un composé benzimidazole substitué.Anthelmintic preparation comprising an anthelmintic benzamidazole carbamate compound and a microtubule inhibitor which is a substituted benzimidazole compound. A method of enhancing the activity of benzimidazole carbamate anthelmintic compounds in mammals comprising administering the anthelmintic compound to the animal in combination with a microtubule inhibitor which is a substituted benzimidazole compound.
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU9238/83 | 1983-05-09 | ||
AUPF923883 | 1983-05-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0146556A1 true EP0146556A1 (en) | 1985-07-03 |
EP0146556A4 EP0146556A4 (en) | 1985-09-16 |
Family
ID=3770123
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19840901726 Withdrawn EP0146556A4 (en) | 1983-05-09 | 1984-05-07 | Potentiation of anthelmintics. |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0146556A4 (en) |
NZ (1) | NZ208042A (en) |
WO (1) | WO1984004455A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA944191B (en) * | 1993-06-15 | 1995-02-08 | Univ Australian | Synergistic anthelmintic compositions |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4173632A (en) * | 1978-07-31 | 1979-11-06 | E. R. Squibb & Sons, Inc. | Fasciolicidal compositions |
US4299837A (en) * | 1979-12-05 | 1981-11-10 | Montedison S.P.A. | Anthelmintic benzimidazole-carbamates |
-
1984
- 1984-05-03 NZ NZ20804284A patent/NZ208042A/en unknown
- 1984-05-07 WO PCT/AU1984/000079 patent/WO1984004455A1/en not_active Application Discontinuation
- 1984-05-07 EP EP19840901726 patent/EP0146556A4/en not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO8404455A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP0146556A4 (en) | 1985-09-16 |
WO1984004455A1 (en) | 1984-11-22 |
NZ208042A (en) | 1987-07-31 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19850104 |
|
AK | Designated contracting states |
Designated state(s): DE FR GB |
|
17Q | First examination report despatched |
Effective date: 19870415 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Withdrawal date: 19880413 |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: PRITCHARD, ROGER, KINGSLEYC.S.I.R.O. DIVISION OF Inventor name: HENNESSY, DESMOND, RONALDC.S.I.R.O. DIVISION OF Inventor name: LACEY, ERNESTC.S.I.R.O. DIVISION OF ANIMAL HEALTH |