IE52296B1

IE52296B1 - Veterinary medicament based on benzoquinolizine carboxylic acids and their derivatives

Info

Publication number: IE52296B1
Application number: IE712/80A
Authority: IE
Original assignee: Riker Laboratories Inc
Priority date: 1979-04-10
Filing date: 1980-04-09
Publication date: 1987-09-02
Also published as: AU5728280A; FR2453647B1; GB2049420A; IT1111918B; NZ193374A; IT7921723A0; IE800712L; FR2453647A1; ZA802088B

Abstract

For use in treating or preventing microbial infection of the circulatory, digestive, or respiratory system of an animal, a compound selected from benzoquinolizine carboxylic acids and their derivatives corresponding to the formula: where each Y is a lower alkyl, lower alkoxy, halegeno, hydroxyl, nitro, cyano, trifluoromethyl, amino, lower alkanamido, trifluoracetamido or lower N,N-dialkylamino radical; each R is a methyl, ethyl or trifluoromethyl radical; n is 0, 1 or 2 and, when n is equal to 2, Y can be a, methylene-dioxy (-OCH2O-) or ethylenedioxy (-OCH2CH2O-) radical connected to adjacent positions of the nucleus; m is 0, 1 or 2 and, when R is a trifluoromethyl radical, m equals 1.

Description

The present invention relates to a veterinary medicament which is particularly useful in the treatment of pigs, goats, sheep, cattle, poultry, and primates to prevent or cure diseases or pathological conditions caused by micro-organisms such as gram-negative bacteria and some gram-positive bacteria, fungi such as Candida albicans and Aspergillus niger etc., and coccidae.

The medicament according to the invention belongs to the family of benzoquinolizine carboxylic acids and their derivatives corresponding to the general formula: where each Y is a lower alkyl, lower alkoxy, halogen, hydroxyl, nitro, cyano, trifluoromethyl, amino, lower alkanamido, trifluoracetamido or lower Ν,Ν-dialkylamino radical; each R is a methyl, ethyl or trifluoromethyl radical; n is a whole number from 0 to 2 and, when n is equal to 2, Y can be a methylene-dioxy (-OCHgO-) or ethylenedioxy (-OCHgCHgO-) radical connected to adjacent positions of the nucleus; m is a whole number from 0 to 2 and, when R is a trifluoromethyl radical, m equals 1.

Derivatives of the acids include lower alkyl esters, acyl halides, acyl hydrazides, lower alkylamides, morpholides piperidides and pharmaceutically acceptable salts.

The expressions lower alkyl or lower alkoxy as used herein denote radicals of 1 to 4 carbon atoms of linear or branched chain configuration.

Particular compounds for use in the medicament according to the invention are illustrated by the following: 6.7- dihydro-5 ,10-d1 methyl-1-oxo-1H,5H-benzo [ij]-quinol1zine-2-carboxylic acid; 9- chi oro-6,7-dthydro-5-methyl-l-oxo-lH,5Hbenzo-[1j] quinol1zine-2-carboxylic acid; hydrated sodium 6,7-dihydro-9-fluoro-5-methyl1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylate; methyl 6,7-dihydro-9-fluoro-5-methyl-1-oxo-IH, 5H-benzo[ij]-quinol1z1ne-2-carboxylate; 6.7- di hydro-9-fluoro-5-methyl-1-oxo-1H.5Hbenzo[1j]-qui nolizi ne-2-carboxamide; - acetamido-6,7-dihydro-5-methyl-l-oxo-lH,5Hbenzo[1j]-quinolizine-2-carboxyl1c acid; 6.7- di hydro-5,8,10-trimethyl-1-oxo-1H,5H-benzo[ij]-qu1nolizine-2-carboxylic acid; 8-chloro-6,7-di hydro-5-methyl-1-oxo-1H,5H-benzo[1j]-quinolizine-2-carboxylIc acid; 6.7- dihydro-8-methoxy-5-methyl-l-oxo-lH,5H-benzo[ij]-quinolIzine-2-carboxylIc acid; 6.7- di hydro-5,7-dimethyl -9-f1uoro-1-oxo-lH,5Hbenzo[i j]-quinolizine-2-carboxylic acid; 6.7- dihydro-5,8-dimethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid; - 4 2,3-d1 hydro-3-methyl-7-oxo-lH,7H-1,3-dioxo [9,10]-benzo [ij] quinolizine-6-carboxylic acid; 3-methyl-7-oxo-2,3,10,11-tetrahydro-1H.7H-1 ,4dioxino[9,10]benzo[ij]quinolizine-6-carboxylic acid; 6,7-dihydro-9-fluoro-1-oxo-5-trifluoromethyllH,5H-benzo[ij]quinolizine-2-carboxylic acid; and in particular, 6,7-dihydro-9-fluoro-5-methyl-l-oxo-lH,5Hbenzo[ijjquinolizine-2-carboxylic acid.

The compounds for use in the medicament according to the invention may be obtained, for example, by first reacting a substituted tetrahydroquinoline of the formula: (where Y, R, n and m are as defined above) with a dialkyl alkoxymethylene-malonate at a temperature between ahout 100° and 200°C to form a tetrahydroquinoline bearing a dialkyl methylene-malonate substituent on the nitrogen corresponding to the formula: - 5 This compound Is In admixture with polyphosphoric acid at a temperature between about 100° and 140°C to form an ester derived from a substituted 6,7-dihydro-benzoquinolizine2-carboxylic acid of the following formula, which ester is either isolated or saponified to the acid: It is known from our Patent Specification No. 37050 that the above compounds have useful pharmacological activity in humans due to their pre10 ferential and almost total elimination from the body through the urinary tract [90% in conjugated form (inactive), 10% in active form (free or as hydroxide)]. This observation has made these compounds useful in particular for the treatment of urinary tract infections in humans. Knowing this phenomenon, one could also have expected to be able to treat animals for such diseases. However, urinary tract infections in animals such as pigs, goats, sheep, beef cattle, poultry and non-human primates are relatively infrequent, thereby suggesting little utility for these products in the veterinary field. But, surprisingly, this Is not the case. These compounds have been shown to be particularly effective for the prevention or treatment of disorders such as gastrointestinal, circulatory and pulmonary infections in animals caused by gram-negative bacteria and certain gram-positive - 6 bacteria, fungi and coccidiae.

This property 1s particularly important today considering the increasing interest that society places on the industrial rearing of animals. These animals are exposed to many pathological organisms against which there is little protection due either to the absence of effective therapeutic agents, or to the toxicity of therapeutic agents which would otherwise be effective.

The present invention provides effective 10 therapeutic agents which have a high therapeutic coefficient.

In fact, the LD 50 for the 6,7-dihydro-9-fluoro-5-methyl-loxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid compound when administered orally to rats, is 2450 mg/kg and 700 mg/kg by the intraperitoneal route. The LD 50 in the rat by the oral route is approximately 400 times greater than a daily therapeutic dosage of 6 mg/kg. Hence, a very wide margin of safety and an excellent therapeutic coefficient (ED 50/LD 50) is provided, although systematic tests to determine the LD 50 have not been carried out in animals of the species concerned for comprehensible economic reasons. Nonetheless, dosages corresponding to 10 to 50 times the therapeutic dose have been administered to these species without significant toxic side effects such as disorders or lesions in various organs or anomalies in the biological, blood, urinary constants or the like.

To demonstrate the effectiveness and the advantage of the compounds for use in the medicament according to the invention, results of experiments obtained in human therapeutics were can52296 - 7 pared with those obtained 1n certain of the animals belonging to the species concerned. These tests were carried out utilizing, in particular, the compound 6,7-dihydro-9fluoro-5-methyl-1-oxo-1H,5H-benzo-[ij]quinolizine-2carboxyllc acid. A daily treatment of 1200 mg of the compound was administered to human subjects. In 24 hours, between 80 and 100% of the dose administered was eliminated by the urinary route. On the other hand, in a primate like the baboon (papio-papio), the compound was eliminated between 20 to 30% by the urinary route and 70 to 80% by the Intestinal route. Goats, sheep, bovine cattle, poultry and pigs are situated between these two extremes. Thus, for example, pigs eliminate 15 to 25% of the compound in the feces, 75 to 85% by the urinary route. This observation shows that the compound is eliminated more slowly in the species concerned and thus higher levels are available to its therapeutic use at the level of the parts, members, glands, or biological fluids which could be afflicted by the germs or the infections to be combatted, such as the digestive system (intestinal tract), the respiratory system (pulmonary tract), the liver (biliary tract), the blood, the embryos and eggs (reproductive organs), the mammary glands, etc.

The compounds for use in the medicament according to the invention are suitable for canbatiiig microorganisms suoh as: AEROMONAS ESCHERICHIA COLI PROTEUS KLEBSIELLA SALMONELLA ENTEROBACTER YERSINIA-PSEUDOTUBERCULOSIS PASTEURELLA STAPHYLOCOQUES STREPTOCOQUES PSEUDOMONAS The compounds for. use in the medicament according to the invention are of particular interest since microorganisms of the type mentioned above are observed to be more and more prolific in the animal species concerned. Infections by these microorganisms are manifested by loss of produce for the breeder. 1 The compounds for use in the medicament according to the invention can be formulated by incdrporating them into conventional organic or inorganic pharmaceutical vehicles or excipients suitable for oral, Intraperitoneal, topical, local or external administration. The daily dosage is between about 5 and 50 mg/kg. Thus, in the case, for example, of 6,7-dihydro9-fluoro-5-methyl-1-oxo-1H,5H-benzo [ij]quino!izi ne-225 carboxylic acid, this compound can be administered: (1) as a soluble powder of 0.5 to 3% of active compound in a mixture of lactose and sodium carbonate containing 99.2% to 95.2% and 0.3% to 1.8% respectively; (2) as a tablet with 150 to 1000 mg of active 30 compound in a tabletting excipient; - 9 (3) as an Injectable solution such as; An injectable aqueous suspension (use in all animals) containing 30 mg/ml of active compound in excipient such as polysorbate 80, sodium carboxymethylcellulose, saline, or water for injectable preparations; (4) as an oral paste with 0.8% of active compound in an excipient paste; and (5) milk flow-stopping cream in the form of cannular syringes with 50 mg of active compound in the excipient customarily used for this purpose.

These formulations, used experimentally in animals afflicted with colibacilloses, salmonelloses, pasteurelloses, diarrheas, septicemias, adaption stress or pathology of separation, have led to a cure in less than 5 days of treatment at a daily dosage of 6 mg of active compound per kilogram of body weight.

In any event, the various formulations of the compounds enable, in their administration, a maximum blood level to be rapidly reached, e.g., 30 minutes after oral administration, two hours after administration by the intramuscular route.

The compounds for use in.the medicament according to the invention may also be administered as a preventative at the same dosages against disorders caused by the stress of separation, change of diet, transportation, change of site, the stress occurring at certain periods of growth of indefinite or indeterminate origin. In fact, it is well established that, on the occasion of these various stress situations, -1010 certain micro-organisms present in a particular organ in insufficient number to cause disorders, proliferate suddenly and abruptly produce pathological disorders which can cause death. Since these states are known and foreseeable, compounds of the invention can be administered at the desired time and for a predetermined period to combat them. In fact, used under these conditions, they produce satisfactory results without modification or slowing down of the digestive functions and growth.

It goes without saying that the present invention has only been described by way purely of explanation and in no way limiting and that any useful modification could be introduced therein without departing from its scope as defined by the appended claims.

Claims

CLAIMS :

1. Use of a benzoquinolizine carboxylic acid or a derivative thereof corresponding to the formulas 5 where each Y is a lower alkyl, lower alkoxy, halegeno, hydroxyl, nitro, cyano, trifluoromethyl, amino, lower alkanamido, trifluoracetamido or lower N,N-dialkylamino radical; each R is a methyl, ethyl or trifluoromethyl radical; n is a whole number from 0 to 2 and, when π is 10 equal to 2, Y can be a methylene-dioxy (-0CH 2 0-) or ethylenedioxy (-0CH 2 CH 2 0~) radical connected to adjacent positions of the nucleus; m is a whole number from 0 to 2 and, when R 1s a trifluoromethyl radical, m equals 1 for the manufacture of a veterinary medicament for treating and 15 preventing microbial infections of the circulatory, digestive and respiratory systems.

2. Use according to claim 1, wherein said compound is selected from: 6,7-dihydro-5,10-dimethyl-l-oxo-lH,5H-benzo 20 [ij]-quinolizine-2-carboxylic acid; 9-chloro-6,7-dihydro-5-methyl-l-oxo-lH,5H52296 - 12 benzo-[ij]quinol izi ne-2-carboxyl ic acid ; hydrated sodium 6,7-dihydro-9-fluoro-5-methyl1-oxo-1H,5H-benzo [ij] quinolizine-2-carboxylate; methyl 6,7-di hydro-9-fluoro-5-methyl-1-oxo-1H,5 5H-benzo[ij]-quinolizine-2-carboxylate; 6.7- dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizi ne-2-carboxamide; 10-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5Hbenzo[ij]-quinolizine-2-carboxylic acid; 10 6,7-di hydro-5,8,10-trimethyl-1-oxo-1H,5H-benzo[ij] quinolizine-2-carboxylic acid; 8-chloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij] quinolizine-2-carboxylic acid; 6.7- di hydro-8-methoxy-5-methyl-1-oxo-1H-5H-benzo15 [ij] quinolizine-2-carboxylic acid; 6.7- di hydro-5,7-di methyl-9-fluoro-1-oxo-lH,5Hbenzo[ij]quinolizine-2-carboxylic acid; 6.7- dihydro-5,8-dimethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid; 20 2,3-di hydro-3-methyl-7-oxo-1H,7H-1,3-dioxo[9,10]benzo[ij]quinolizine-6-carboxylic acid;

3. -methyl-7-oxo-2,3,10,11-tetrahydro-1H,7H-1,4dioxi no[9,10]benzo[ij]quinolizine-6-carboxylic acid ; 6.7- di hydro-9-fluoro-1-oxo-5-trifluoromethyl25 1H,5H-benzo[ij]quinolizine-2-carboxyl1c acid and, in particular, 6,7-di hydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo [ij]quinolizine-2-carboxylic acid. - 13 3. Use according to claim 1 or 2, wherein said compound is formulated for administration by the oral, peritoneal or topical route.

4. Use according to any one of the 5 preceding claims, wherein said compound is administered at doses between 5 and 50 mg/kg.

5. Use according to claim 1,