EP0146573A1 - Compositions pharmaceutiques ayant une activite anthelmintique, leurs unites de dosage et procede de traitement de l'helminthiase chez les animaux - Google Patents

Compositions pharmaceutiques ayant une activite anthelmintique, leurs unites de dosage et procede de traitement de l'helminthiase chez les animaux

Info

Publication number
EP0146573A1
EP0146573A1 EP84902000A EP84902000A EP0146573A1 EP 0146573 A1 EP0146573 A1 EP 0146573A1 EP 84902000 A EP84902000 A EP 84902000A EP 84902000 A EP84902000 A EP 84902000A EP 0146573 A1 EP0146573 A1 EP 0146573A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
substituted
composition
radical
aryl
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Withdrawn
Application number
EP84902000A
Other languages
German (de)
English (en)
Inventor
Eva-Maria "Jingara" BENNET
Christopher Bryant
Carolyn Anne Behm
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoechst AG
Original Assignee
Hoechst AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hoechst AG filed Critical Hoechst AG
Publication of EP0146573A1 publication Critical patent/EP0146573A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/425—Thiazoles

Definitions

  • This invention relates to methods and compositions useful in the treatment of parasitic diseases in animals. More particularly, the invention relates to compositions containing a substituted benzimidazole carbamate, or a pro-drug there for, and levamisole in which the anthelmintic action of the composition is enhanced over that expected from the activity of either ingredient when used alone.
  • Helminthiasis is a widely occurring disease affecting animals, causing substantial economic losses in both game and the domesticated animal industry. Particularly susceptible to the disease are sheep, cattle, goats, horses and mules. Many anthelminitc agents have been discovered possessing varying degrees of efficacy on the particular helminths causing the infections.
  • mebendazole (1) (of. Formula sheet) is a broad-spectrum anthelmintic [Heath, D.D., Christie, M.J. and Chevis, RAF, 1975. Parasitology, 70, 273-285] and levamisole (2) (formula as. shown in claim 1) is effective against nematodes at low concentrations [Janssen, PAJ, 1976, Prog. Res., 20, 347-3533.
  • a first object of the present invention to provide compositions possessing a high degree of anthelmintic activity which overcome the above problems.
  • a second object is to provide compositions which contain substituted benzimidazole carbamates, or pro-drugs therefor, and levamisole in which the anthelmintic potency and efficacy of the composition is enhanced over the additive effect of th.e substituted benzimidazole carbamate, or a pro-drug therefor, and levamisole.
  • a third object is to provide a method for treating helminthiasis with compositions containing anthelmintically active substituted benzimidazole carbamates, or pro-drugs therefor, and levamisole wherein the dosage levels are substantially reduced over those required when each is administered alone.
  • a method of treating helminthiasis by the administration of a composition having a high degree of anthelmintic activity said composition comprising I) levamisole and II) a substituted benzimidazole carbamate of the general formula (3) (of. Claim 1) wherein
  • R 1 represents a 5- or 6-membered heterocyclic ring containing at least one hetero atom selected from O, N and S, or a radical -NHCO 2 R 2 , wherein R 2 represents alkyl; R 3 preferably is in 5-position and represents alkyl, a radical -NHCO 2 R 2 or a radical -XR 4 , wherein X represents O, CO, S, SO, SO 2 , -SO 2 -O- or -O- SO 2 - and R 4 represents a hydrocarbon group, eg alkyl, cyclo alkyl, aryl or aryl hydrocarbon, or substituted aryl, ie aryl substituted by alkoxy, halogen or alkyl groups substituted in turn by at least one halogen atom, with the proviso that when R 3 is in the 5-position and R 1 represents -NHCO 2 CH 3 and X represents CO, R 4 does not represent phenyl and with the further proviso that at least one of R 1 and
  • heterocyclic '' alkyl ",” substituted alkyl “,” cycloalkyl “,” aryl “and” substituted aryl “are used to denote the following:” heterocyclic "5- or 6-membered aliphatic or aromatic rings containing at least one hetero atora selected from O, N and S; preferred examples include furan, thiophene, tetrahydrofuran, pyrrolidine, isoxazole, piperidine, pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyridazine , pyrimidines, pyrazine and pyran; "alkyl” straight or branched-chain hydrocarbons of 1 to
  • cycloalkyl alicyclic rings containing from 3 to 6 carbon atoms; preferred examples are cyclopropyl, cyclopentyl and cyclohexyl; "aryl” 6- or more-membered aromatic rings which may or may not be fused to further 6- or more-membered aromatic or 5- or more-membered aliphatic rings; preferred examples include benzene, naphthalenes, indene and tetrahydronaphthalenes; "aryl hydrocarbon” aryl substituted by one or more, preferably at most three hydrocarbon groups separately selected from the group consisting of alkyl having from 1 to 4 carbon atoms, alkenyl and alkynyl; a preferred example is methylindene; "substituted aryl” aryl which is substituted by one or more, preferably at most three, radicals separately selected from the group consisting of alkoxy, halogen and alkyl substituted by
  • aryls those having from 6 to 10 carbon atoms and more especially phenyl and substituted phenyl and among the aryl hydrocarbons and substituted hydrocarbons those which contain at most three substitents to the aromatic skeleton, are preferred.
  • non-toxic salt denotes pharmaceutically acceptable salts which do not produce undesired side effects when administered at effective dosage levels.
  • addition salts include the hydrohalic, sulfuric, nitric, phosphoric, citric, acetic and oxalic acid salts.
  • pro-drug therefor is used to denote a compound having a structural formula different from the substituted benzimidazole carbamate which, after administration to the animal, is converted to the substituted benzimidazole carbamate.
  • Suitable pro-drugs are compounds having the general formula (4) (of. Claim 4) wherein X is O or S and both X may be equal or different;
  • R 5 and R 6 represent the same or different alkyl or cycloalkyl radicals; and R 8 represents H or R 3 , wherein R 3 is as inbefore defined.
  • Further examples of pro-drugs according to the present invention are compounds having the general formula (5) (of.
  • R 7 represents a radical selected from the group consisting of amino, unsubstituted alkyl, and alkyl substituted by one or more, preferably at most three, radicals separately selected from the group consisting of alkenyl, al kynyl, alkoxy or halogen; most preferably one alkenyl or alkynyl group or one or two alkoxy groups or halogen atoms, and X, R 3 , R 5 and R 6 are as defined before.
  • compositions for the treatment of helminthiasis comprising levamisole and a substituted benzimidazole carbamate of the general formula (3) or a pro-drug therefor or a non-toxic acid addition salt of said substituted benzimidazole carbamate or said pro-drug therfor.
  • Compounds of the general formula (3) are either known or can be prepared from known compounds by Standard reactions well known in the art.
  • Fenbendazole (3a), Cambendazole (3b), Parbendazole (3c), Albendazole (3d), Oxfendazole (3e), Oxibendazole (3f), Flubendazole (3g) and Ciclobendazole (3h) are all coramercially available.
  • pro-drugs examples include Thiophanate (4a) and Febantel (5a) both of which are commercially available (cf. formula sheet).
  • a ratio of active components of the order of about 1 to 10 parts of the benzimidazole carbamate, or pro-drug therefor, or their acid addition salt, to about 0.1 to 5 parts of levamisole is effective in removing the parasites.
  • compositions of the present invention exhibit a synergistic effect at combined dosage levels lower than those employed when using each active component separately.
  • the compositions are normally administered in daily amounts of 1 to 50 mg / kg body weight for a period of 1 to 14 days.
  • the compositions of the present invention are effective against helminths and especially effective against Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Chabertia, Strongyloides, Oesophagostomum, Hyostrongylus, Ancylostoma, Dictyocaulus, Ascaris, Heterakis and Fasciola. Particularly impressive is their activity against helmintic infections of the intestinal tract and against liver flukes. Therefore, the compositions are very useful for the treatment of infections in animals.
  • each component in the composition will vary according to the type of treatment to be employed, the host animal, and the particular parasitic disease being treated.
  • compositions of the present invention may be administered as a feed or feed supplement.
  • the compositions of the present invention could therefore be mixed with the animal's normal feed ingredients. It is preferred to administer the composition in dosage units corresponding to the daily doses or a certain fraction thereof (divided dosage). Suitable dosage units are 1 to 50 mg / kg body weight.
  • Each active component of the composition of the present invention may be administered simultaneously or sequentially provided that the administration of the second active component is during the period of biological activity in the animal of the first active component.
  • the compositions of the present invention may be administered as a single dose or in any suitable sustained release device.
  • compositions of the present invention may include other, nonactive ingredients, such as the usual carriers.
  • the carrier may be an orally ingestible container for the composition, for example, a gelatin capsule, or it may be an excipient of the kind normally used in medicaments of this character including maize starch, terra alba, lactose, sucrose, calcium phosphate, gelatin, stearic acid, agar, pectin or the like.
  • a solid carrier is used, the composition can be administered in tablet or capsule form.
  • a liquid carrier like peanut oil, sesame oil or water is used, the composition may be in the form of a soft gelatin capsule or in a liquid suspension.
  • the additional ingredients may be any other acceptable vehicle (s) convenient in the preparation of such forms.
  • the composition may contain, where appropriate, agents which aid the subsequent suspending of the active ingredients in water, such as bentonite and the like, to form a dry pre-drench composition, and this pre- drench composition added to water just before use.
  • agents which aid the subsequent suspending of the active ingredients in water such as bentonite and the like, to form a dry pre-drench composition, and this pre- drench composition added to water just before use.
  • agents which aid the subsequent suspending of the active ingredients in water such as bentonite and the like, to form a dry pre-drench composition, and this pre- drench composition added to water just before use.
  • further possible additives include preservatives and anti-foaming compounds.
  • Parasite free animals were each infected by injection with a parasitic larvae, either selected or not selected by benzimidazole anthelmintics. After a period of infection, the animals were split into four groups based on similar body weight and a similar random faecal nematode egg count. Alternatively, aftef a shorter period of infection, the animals were split on basis of similar body weight only, and the subsequent treatment effected on the fourth parasitic larval stage of the parasite. The first group was not subjected to anthelmintic treatment and was used as a comparison control. A second group was administered a dose of levamisole. A third group was treated with a substituted benzimidazole carbamate of formula (3).
  • the final test group was administered a composition comprising 1 to 10 parts of a substituted benzimidazole carbamate of general formula (3) to 0.1 to 5 parts levamisole. All dosage levels were administered orally and calculated on the basis of the mean body weight of each group such that a
  • the worm count was greatly reduced, with the maximum effect being the complete removal of the parasitic nematodes. Further, the administration of levamisole in combination with a benzimidazole carbamate of formula (3) was found to be particularly effective against strains of parasitic larvae which are resistant to treatment with benzimidazple carbamates of formula (3) alone.
  • worm-free ⁇ heep were infected by intrar ⁇ minal injection with infective larvae of a laboratory selected, benzimidazole resistant strain of the gastro-intestinal nematode Haemonchus contortus. After 21-28 days of infection, the sheep were allocated to the four groups based on similar body weight and a random faecal nematode egg count. Group 1 was used as the comparison control. Group 2 was administered a dose of levamisole (LMS). Group 3 was treated with fenbendazole (FBZ). Group 4 was administered a composition comprising fenbendazole and levamisole. Several experiments were conducted, in which various dose rates were used. The results of those experiments are given in Table I.
  • worm-free sheep were infected with a mixture of 3 nematode species - Haemonchus contortus (1), Ostertagia circumcincta (2) (laboratory selected and benzimidazole resistant) and Trichostrongylus Colubriformis (3) (a field strain), and then treated at dosage levels substantially below the normal therapeutic dose rates for each individual component of the composition. It was found that, by combining FBZ and LMS at the ⁇ e lower dose rates, complete removal of the parasitic nematodes was possible. The results of these experiments are given in Table III.
  • Example A Following the general method described in Example A, two separate experiments were undertaken in which worm-free sheep were infected with benzimidazole susceptible Haemonchus contortus or Trichostrongylus colubriformis. After 7 days of infection, the sheep were allocated to the four groups to test the effect of the present compositions on the fourth parasitic larval stage of the parasite. The results of those experiments are given in Tables V and VI, which illustrate the synergistic effect of FBZ / LMS compositions against the fourth larval stage.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compositions pharmaceutiques ayant une forte activité anthelmintique et comprenant I) la levamisole de formule (2) et IIa) des carbamates de benzimidazole substitué de formule (3), où R1 représente un anneau hétérocyclique à 5 ou 6 membres ou un radical -NHCO2R2, où R2 représente un alkyle; R3 représente un alkyle, ou un radical -NHCO2R2 ou un radical -XR4, où X représente O, CO, S, SO, SO2-O- ou -O-SO2- et R4 représente un groupe hydrocarbure ou un aryle substitué par des groupes alcoxy, allogènes ou alkyles qui sont à leur tour substitués par au moins un atome d'allogène, à condition que lorsque R1 se trouve en position 5 et R1 représente -NHCO2CH3 et X représente CO, R4 ne représente pas un phényle et à la condition supplémentaire qu'au moins l'un de R1 et R3 doit représenter le radical -NHCO2 alkyle, (IIb) des pro-médicaments ou (IIc) des sels d'addition acide non toxiques de ces carbamates de benzimidazole substitué ou des pro-médicaments. L'invention concerne également une unité de dosage d'une telle composition et un procédé pour traiter l'helminthiase chez les animaux en leur administrant une quantité effective d'une telle composition.
EP84902000A 1983-05-27 1984-05-24 Compositions pharmaceutiques ayant une activite anthelmintique, leurs unites de dosage et procede de traitement de l'helminthiase chez les animaux Withdrawn EP0146573A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU956983 1983-05-27
AU9569/83 1983-05-27

Publications (1)

Publication Number Publication Date
EP0146573A1 true EP0146573A1 (fr) 1985-07-03

Family

ID=3700328

Family Applications (1)

Application Number Title Priority Date Filing Date
EP84902000A Withdrawn EP0146573A1 (fr) 1983-05-27 1984-05-24 Compositions pharmaceutiques ayant une activite anthelmintique, leurs unites de dosage et procede de traitement de l'helminthiase chez les animaux

Country Status (2)

Country Link
EP (1) EP0146573A1 (fr)
WO (1) WO1984004677A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7059281B2 (en) 2004-07-12 2006-06-13 General Motors Corporation Four stroke engine auto-ignition combustion

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3325356A (en) * 1965-08-20 1967-06-13 Merck & Co Inc Compositions and method for treating helminthiasis
FR2461495A1 (fr) * 1979-07-23 1981-02-06 Vincent Andre Medicament antiparasitaire a effet retard

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7059281B2 (en) 2004-07-12 2006-06-13 General Motors Corporation Four stroke engine auto-ignition combustion

Also Published As

Publication number Publication date
WO1984004677A1 (fr) 1984-12-06

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Inventor name: BENNET, EVA-MARIA"JINGARA"

Inventor name: BRYANT, CHRISTOPHER

Inventor name: BEHM, CAROLYN, ANNE