AP645A - Benzamine derivative, compositions containing said derivative and use thereof. - Google Patents

Benzamine derivative, compositions containing said derivative and use thereof. Download PDF

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Publication number
AP645A
AP645A APAP/P/1996/000866A AP9600866A AP645A AP 645 A AP645 A AP 645A AP 9600866 A AP9600866 A AP 9600866A AP 645 A AP645 A AP 645A
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compound
formula
agent
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APAP/P/1996/000866A
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AP9600866A0 (en
Inventor
Jean-Francois Rossignol
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Romark Laboratories Lc
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Priority claimed from US08/227,033 external-priority patent/US5387598A/en
Priority claimed from US08/301,407 external-priority patent/US5578621A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/58—Nitro radicals
    • 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
    • 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
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Food Preservation Except Freezing, Refrigeration, And Drying (AREA)

Abstract

The present invention relates to a new compound formula

Description

Ap 00645
BENZAMIDE DERIVATIVE, COMPOSITIONS CONTAINING SAID
DERIVATIVE AND USE THEREOF
Abstract zf the disclosure
The present invention relates to a newccmcound ct formula Σ
with one of the symbols R,, R;, R3, R4 and Rj representing OH, whereas the remaining symbols represent H ; to a pharmaceutical composition containing the said 15 compound, and to the use of said compound as anti-parasital, anti-bacterial, anti-fungal agent, antiviralagent. ’T’V*» O**·* 3"** Ax* — 20
Nitrothiazole compound PH 5775 (2- (acetclyioxy)-N-(5-nitro 2-thiazolyl) benzamide) is acompound of formula Σ
AP/P/ 9 6 / 00 8 66 30 1. in which R, = O-COCH3
= R3 = R< = R< — H
The preparation and uses of this compound(called hereafter Compound S - formula II) are disclosedin' US 3,= = 0,251, as well as in publication made byAoolicant.
In US 3,950,351, the compound B of formula II.s crecared tv reactino 15 with 20
Hal -
N
Hal = halide NO- z NH.
This reaction is not suitable for the25 preparation of pure compound of formula I
in which one o: therepresents symbols R,, R,, R3, R4 and Rj CH, whereas the remaining symbols 30 AP 00645
Moreover, contrary to what could be expectedfrom the prior art, i.e. that the presence of an acyloxycroup was necessary fcr rendering the compound activeand efficient against bacteria, parasites, ..., it hasnew been found that the compound of formula I
with one of the symbols R,, R,, R,, R4 and Rj representing 15 CK, whereas the remaining symbols represent H ; had an excellent efficiency against parasites, bacteria,fungus although it does not contain an acyloxy group.The said compound I had a substantially immediate actionagainst parasite, fungus, bacteria. 20 It has also been found that said compound was activeagainst viruses.
It has also been found that compositioncontaining the said compound I also advantageouslycontains a wetting agent. Most preferred compositions 25 are those containing a wetting agent and a starchderivative.
Tests made by applicant have also shownthat by using simultaneously the compound of theinvention and a wetting agent, the efficiency of the 3 0 compound is drastically increased and that by using sucha mixture, it is possible to treat affections of thelower abdomen, such as intestinal affections (diarrhea),gastrointestinal infections, enteric infections,sexually transmitted infections, vaginal infections and 35 urinocenital infections. AP/P/ 9 6 / 0 0 8 66 J .
The invention relates therefore also to acomposition for combatting affections of the lowerabdomen, said composition containing :
* an effective amount of an active agent of formula I
* and a wetting agent, said composition comprising preferably also a starchderivative. AP 00645 r„- the Invention
The present invention relates to a newcompound C of formula I
in which one of the symbols R,, R:, R3, R< and Rj represents OK, whereas the remaining symbols 1= represent K.
Preferably, Rj = OH
The invention relates also to a pharmaceuticalcomposition comprising as active agent, a compound offormula I as described hereabove, preferably a compound 20 of formula I in which R, = OH (formula III) .
According to an embodiment, the compositioncomprises, as active ageu\, a mixture of Compound A offormula AP/P/ 9 6 / 0 0 8 66
20 25 30
Such a composition combines a substantiallyimmediate action against parasite, fungus, bacteria,virus or a substiantially immediate treatment ofintestinal affection and a some what retarded action ortreatment.
Such a composition is thus suitable fortreating human affections or for preventing humanaffections, such as parasitic infections, bacterialinfections, fungal infections, diarrhea and otherintestinal affections, such as affections due toviruses .
In said composition, the weight content ofCompound A of formula III
N
AP 00645 with respect to the weight of the mixture of compound Aof formula Ill - -4
and compound B of formula
AP/P/ 9 6 / 0 0 8 66 2 0 is comprised between 0.5 and 2 0 %, preferably between0.5 and 10 %, more preferably between 0.5 and 5 %.
The invention relates also to the use of acompound according to the invention, especially acomposition according to the invention as anti-parasital 25 agent, anti-bacterial agent, anti-fungal agent, antiviral agent.
The composition may contain further activeas anthelmintic agents,agent,. suer. agent, and anti-viral
The composition may also contain a wettingagent and/cr a starch derivative and/cr an excipient. A composition, preferably a solidcomposition, for oral administration for combattingaffections or infections of the lower abdomen,preferably intestinal and vaginal conditions, contains : 30 * an effective amount of Ccmoound B of formula 20 25
* a wetting agent, and possibly, but preferably ♦ at least one starob derivative.
The latter composition may also contain otheractive agents, fcr example an anthelmintic agent such asfebantel, praziquantel, levamisole, albendazole,oxfendazole, mcxidectin, ivermectin, milbemycins, etc.
The preparation and use of compound B isdisclosed in US 3,950,351 and US 4,315,018.
The wetting agent present in the compositioncontaining compound C of formula I (such as compound A)and/or compound B is advantageously an anionicsurfactant, and is preferably selected among the groupconsisting of sugar esters, polyoxyethylene,polyoxyprcpylene, anhvdrohexitol derivatives, fattyalkanol amides, fatty amine oxides, sucrose, mannitol,sorbitol, lecithins, polyvinylpyrrolidones, fatty acidesters, glycerides of sucrose, esters of xylose,polyoxyethylene glycerides, esters of fatty acids andpolyoxyethylene ether of fatty alcohols and acid esters of sorbitan, polyoxyethylene fattypolyoxvethyelene esters of acids of sorbitan, glyceridepolyglycides, esters cf alcohol polyglycidesand mixture thereof .
Particularly suitable wetting agents aresaccharose distearate, ?V? (polyvinylpyrrolidone), etc. 30 35 AP u u 6 4 5
The composition according to the invention containspreferably a starch derivative, especially a carboxyderivative of starch, such as carboxymethyl starch,natrium derivative thereof or a salt thereof. 5 The composition contains, for example, up to 20 % by weight, advantageously 1 to 10 % by weight ofsurfactant with respect to the weight of activeagent (s), and up to 2 0 % by weight, advantageously 1 to10 % by weight of starch derivative with respect to the 1C weight of active agent (s).
The invention relates also to a galenic formulation for oral administration against virusesand/or for combatting affections of the lower abdomen,such as intestinal, vaginal or urogenital conditions or 15 disorders, said galenic formulation comprising a corecontaining a composition containing : * an effective amount of an active agent of compoundC and/or compound A and/or compound B, * a wetting agent, and possibly, but preferably 20 * a starch derivative or a salt thereof, the water content of said composition being less than25 % by weight, the said core being preferably coatedwith a membrane. Such a membrane can be a membraneinsoluble in the acid gastric medium, but soluble in the 25 intestine.
The preferred compositions, wetting agents,etc of the galenic formulation are those disclosedhereabove for the composition according to theinvention. 3 0 The invention relates yet to the use of the composition or the galenic formulation for the treatmentof diarrhea, for the treatment of liver troubles,..
The invention relates also to an ointment orgel, cream or suppositories for the treatment of organs 25 of the lower abdomen, such as vaginal or urogenital AP/P/ 9 6 / 0 0 8 6 6
At 10 conditions or disorders, disorders of the rectum. Theointment, preferably in the gel form, comprises acompound of formula ~ and/or compound B, a wetttngagent, as well as excipient. - The wetting agent is preferably one of those listed above for the composition and/or galenicformulation.
Furthermore, the invention relates to an anti-bacterial composition containing a compound C of formula 1C I and/cr compound 3, and a wetting agent. Such acomposition is active against aerobic, as well anaerobicbacteria, the composition having thus a very largespectra of activity.
The invention relates thus also to a process 15 for killing bacteria or for preventing the presence orgrowth of bacteria in a medium. In said process, thebacteria or medium is treated with a bactericidalcomposition according to the invention, for example byspraying the composition on the bacteria, by immersing 20 a support into a medium, etc.
The invention relates also to a process for treating diarrhea affections of animals, preferablyhumans, in which a composition containing : * an effective amount of an active agent of compound
25 C and/or of compound B * a wetting agent * a starch derivative is orally administered.
The invention relates furthermore to a food 3 0 .composition such as a food pasta or a yaourt comprising,as preserving agent,
* an effective amount of a compound C of formula I(preferably compound A) and/or compound B * possibly, but advantageously a wetting agent, and 35 possibly, but preferably together with a wetting AP 00645 11 agent ; a starch derivative
Description cf the Drawings
Figure 1 is the UV spectrum of compound A offormula Ill
Figure 2 is the IF spectrum of compound A offormula Ill, and
Figure 3 is the HPLC mass spectrum of compound A offormula III. 20
Description of the invention
Th·
9 9 8 0 0 / 9 6 /d/dV
preparation of pure compound of formula I
in which one of the symbols R,, R,r RJ( R4 and Rs represents OH, whereas the remaining symbols 35
represent H 12
can be made from compounds of formula I
in which one ci the symbols R,, R:, R3, R4 and R, is anIS acylcxv croup, whereas the remaining symbols represent hydrogen.
The said compound is put in suspension in aweak mixture of hvdrochlcridric acid and water. The sotreated compound is then filtered and washed with water. IS The washed compound is then possibly dried.
EXAMPLE Of PREPARATION
Preparation of compound A20 ........................- A specific example of preparation is givenhereafter : 2 g of 2- (acetclyloxy) -N- (5-nitro 2-thiazolyl) benzamide(i.e. PH 5776) - compound B prepared according to the 25 method disclosed in US 2,950,251 is put in suspension in20 ml of a 27 % HOI solution. The medium was kept at50°0 during 24 hours and was slowly stirred.
After said treatment, the medium was filteredso as to obtain solid particles. Said particles have 3 0 . then been washed with water until pH 7 and dried in an oven at 50°C.
The resulting product appears as yellowmicrocristalline needles, the melting point of which was254°C (melting point measured according to the capillary 25 determination cn a Mettler FP aooaratus) . AP 00645 13
The structure identification was carried out by centesimal analysis, UV spectrum (see figure 2) spectrum (se e figure 3) identification are : CIO, H7, N3, i 04, SI ; 258 Calculated C 46.51 % H 2, 45.58% 2. = 3 50 nm I :CD = 0.605) .
c’T
The results of this N 16.40 %16.71 % 12.40 %12.67 %
Preparation of Composition C A composition according to the invention hasbeen prepared by mixing PH 5776 and the compoundprepared hereabove, the weight content of said compoundwith respect to the weight of the said compound andFH 5776 being 4 %.
9 9 8 0 0 / 9 6 /d/dV 20 Composition A1 100 g nttazoxanide (PH 5776) was mixed in 100ml water with 10 g of polyvinylpyrrolidone (wettingagent) and 5 g carboxymethyl starch. The mixture has 25 been dried under vaccum.
Said composition can then be used for makinggranules, sachets, tablets or capsule for buccal or oraladministration. 30 Compositions El, Cl, DI,Ξ1, FI,G1
Compositions similar to composition A1 wereprepared, except that only 5 g and 2 g of polyvinyl-pyrroiydone, and 2 g and 1 g carbcxymethyl starch wereused. 14
The following table gives the content (g) ofnitazoxanide "N", polyvinylpyrrolidone "PVP" andcarboxymethyl starch "CS" of the compositions.
Composition N (g) PVP (g) CS (g) SI 100 5 5 Cl 100 2 2 DI 100 5 2 El 100 5 1 FI 100 2 1 G1 100 5 0
Compositions Hl, II, J1 15 Compositions containing nitazoxanide, as well as another active agent have been prepared by preparingan aeneous medium containing PVP and carboxymethylstarch and by adding to said medium nitazoxanide andanother active agent. The medium was then dried to 23 obtain a water content lower to 5 V. AP 00645 15
Compo- sition N c PVP σ cs σ Other active agent g Water con- tent V Hl 50 5 2 Prazi- quantel 50 2 — 7 c r- 3 2 Prazi- quantel 50 1 Jl 75 5 2 Prazi- quantel 50 2
Compositions A2 to J2 10 ·, c
Compositions similar to compositions A1 to Jlhave been prepared.
The compositions A2 to J2 differ fromcompositions A1 - Jl only by the fact that they containa mixture of nitazcxanide (PH 5776 - compound B) andcompound A of formula : AP/P/ 9 6 / 0 0 8 66
(instead of nitazcxanide only in compositions A1 - Jl) .
The following table gives the amount ofcompounds A and 5 which have been used for the 25 preparation of the composition A2 - J2 . 20 16
Composition Compound A (g) Compound B (g) A2 - G2 4 96 H2 2 48 X X 2 72 3 72
Preparation of Galenic formulations 1C Formulation K1 500 g Nitazoxanide in powder has been mixedwith 10 g polyvinylpyrrolidone, 20 g carboxymethylstarch, 25 g com starch, 5 g magnesium stearate and 15 50 g water, and the so obtained mixture was then formed into granules of 560 mg (i.e. granules containing 500 mgof active agent). The granules which had a diameter ofabout 1 cm were then dried at about 50° C.
The so obtained microgranules were then 2 0 provided with a coating obtained by spraying a hot sugarsolution. The sugar coating formed a membrane.
Formulation K2 25 A powder mixture of 480g Nitazoxanide (PH5776) and 20g of compound A has been mixed with 10 gpolyvinylpyrrolidone, 20 g carboxymethyl starch, 25 gcorn starch, 5 g magnesium stearate and 50 g water, andthe so obtained mixture was then formed into granules of 30 560 mg (i.e. granules containing 500 mg of active aoentl . The granules which had a diameter of about 1 cmwere then dried at about 50° C. AP 00645 ο; 17
The so obtained microgranules were thenprovided with a coating obtained by spraying a hot sugarsolution. The sugar coating formed a membrane.
It is obvious that the microgranules may also= contain one or several excipients or other activeagents, such as microcristalline cellulose (Avicel ®EMC,' , mechylceilulose, ethylcellulose, carboxymethyl-cellulose, hydrcxyethylcellulose, hydroxypropyl- cellulose, starch, etc. 11 In the same way, the membrane may also comprise : * a pharmacological acceptable excipient such as aplastifiant, a pigment, a filler, a wetting agent,a lubricant,.... or a mixture thereof, and 15 * a film forming composition which comprises a substance insoluble in the gastric acid but enterosoluble (polymeric substance or not, for examplecellulose acetophthalate, polyvinyl acetophthalate,hydrcxypropylmethylcellulose, . . .) . 20
TESTS ) TESTS 1 35 AP/P/ 9 6 / 0 0 8 66 25 During phase 1. pharmacokinetics study was carried out on € volunteers who received a single 500 mgoral dose of the composition 0. Approximately 3 mcg/mlof 2-(hydroxy)-N-(5-nitro-2-thiazolyl) benzamide couldbe assayed in the blood by High Pressure Liquid 3 0 Chromatography. This product was also · excretedunchanged in urine during the first 24 hours followingtreatment. There is no trace of-2-(acetolyloxy)-N-(5-nitro 2-thiazclyl) benzamide in blood and urine.
During Phase II clinical studies conducted ina total of SO patients, post-treatment repeated fecal 18 20 25 examinations and/or vaginal smears revealed that 500 mgof the composition A1 given twice a day for 3 to 7consecutive days was highly effective (60-95 %) againstTrichomonas vaginalis, Entamoeba histolytica, Gardialamblia, Entercbius vermicularis, Ascaris lumbricoides,Necatcr americanus, Ancvlostcma duodenale, Trichuristrichiura, Strcngyloides stercoralis, Taenia saginata,Taenia solium, Diphylobottrium latum and Kymenolepisnana. Tolerance was gccd and only a few epigastricpains, nausea, vomiting and diarrhea were observed inabout 10 % of patients depending on the duration oftreatment. Blood chemistry and hematology carried outbefore and after treatment remained unafected by thecomposition.
In vitro studies against Trichomonas vaginalishas shown that while 2-(acetolyloxy)-N-(5-nitro-2-thiazolyi) benzamide had a Minimum InhibitoryConcentration of 0.5 to 1.25 mcg/ml, 2-(hydroxy)-N-(5-nitro-2-thiazolyl) benzamide in the same experimentalconditions showed 1 to 1.25 mcg/ml. This is demonstrating that 2-(hydroxy)-N-(5-nitro-2-thiazolyl)benzamide has an antiparasitic activity equivalent to2-(acetolyloxy)-N-(5-nitro-2-thiazolyl)However, these studies showed that 2(hydroxy)-N-(5-nitro 2-thiazolyl) had a substantiallyimmediate action, which was not the case for 2-(acetolylcxy)-N-(5-nitro 2-thiazolyl) benzamide).
Finally in vitro studies have shown that thecomposition was effective against gram positive and gram•negative aerobic bacteria such as Staphylococcus aureus,Escherichia ccii, Shigella sonei, Helicobacter pylori ;anaerobic bacteria such as Eactercides fragilis,Fusobacterium ulcerans, Veillonella alcadescens,Gardnerella vaginalis, dermatophytes of such as Trichophyton mentcgraphvtes, that orbenzamide . yeasts fungiMicrcsDcrum 30 AP 00645 • •-’ίΐ 19
audcvini, Epidermcpkvtcn Flocosum and Candida albicans.By using a compound of formula I
- Λ* in which cne cf the symbols R,,R;,R3,R4 and Rj represent OK, whereas the remaining symbolsrepresent H, preferably a compound A, even in very low amount, it was1= possible to increase the efficiency of compounds offormula I, especially of compound PH 5776, or compound B. TESTS 2 AND 2 20 In order to show the effectiveness of the composition according to the invention, two groups of 5mices (4-8 weeks old; 18-20 g weight each) were tested,both groups being infected with Cryptosporidium parvum.
The infected mices suffered of chronic 25 diarrhea.
Before the treatment, it was easy to determinethe mices suffering of chronic diarrhea by fecalanalysis .
The treatment takes place by using the3 0 . compositicn Cl cf nitazcxanide disclosed herebefore.The mices suffering cf chronic diarrhea received by oralgavage during one week, each day about 0.01 g of nitazoxamde (i.e. about 0.6 g/kg mice). AP/P/' S 6 t 0 0 8 6 6 35 20
After one week of treatment, it was no morepossible to determine by fecal analysis which group ofmices suffered firstly of diarrhea.
Infected mices were also treated by using theΞ composition D2. Said mices received by oral gavageduring one week, each day about 0.0096 g nitazoxan-ί rip and about 0.0004 g of compound A of formula III.
Before the end of one week of treatment, itwas no mere possible to determine by fecal analysis 10 which group of mices suffered firstly of diarrhea. TESTS 4 AND 5
Aqueous compositions (100 g) containing 10 gof an active agent have been prepared. IS For the composition containing nitazoxanide or a mixture of nitazoxanide (9.6 g) and compound A asactive agent, the composition contained furthermore0.5 g 'saccharose distearate.
The compositions have been used for treating 20 various parasites, helminths, bacteria and fungus.
The activity of the compositions is given in the following table : 25 AP 00645 <««'·
1 J·
Protozoa
Trichomonas vagi-nalis
Trichomonas intes-tinalis
Entamoeba histo-lytica
Entamoeba discarEntamoeba coliEndclimax nanaBalantidium coliDientamoeba fragilisGiarda lambliaIsospora belliCryptosporidiumparvum
Bladtocvstis hcminis
Enterocytozocn bieneusi
Septata intestinalis
EnterobiusvemicularisAscaris lumbricoidesNecator amerrcanusAnvcyloslomaduodenale
Trichuris trichiuraStrongyloidesstercoralisTaenia sagtnataTaenia soliumHvmenoleois nana
ACTIVITY OF
Pl I P2 P3 P4 P5 4- No No + 4- + No No + * No No + 4- No No + * - No No + 4- 4- No No + + 4- No No + 4- No No + + 4“ No No 4» 4- + +/- No + + + No No No + No No No No No No * + No No No + 4- No No No + + + + No + + No 4- + + No 4- + + No + + + + No + + No No No + No No No + + No No No + 4* No No No AP/P/ 9 6 / 0 0 8 66
Pl = Nitazcxanide-· saccharose distearate ?2 = Nitazoxanide - Compound A * saccharose distearateP3 = Albendazole P4 = Mebendazole P5 - Metronidazole 22 ACTIVITY OF Pl P2 P3 P4 P5 Bacteria aerobic Staphylococcus aureus - No No No Escnerichia cell - + No No No Prccens vulgaris •r No No No Bactsri3 anaerobic Clcstridum species - + No No + Bacteroides species 4- No No + Peptococcus speciesPepcostrepto-coccus SPP + + No No + Fusobacterium SPP 4 No No + Fungus + + No No + Candida AlbicansTrychophyton + 4- No No No Mentagrophyt es 4- + No No Microsporum audcviuiEpidermophyton 4 No No floccsum 4- + No No
Pl => Nitazoxanide + saccharose distearate P2 = Nitazoxanide + Compound A + saccharose distearateP3 = Albendazole P4 = Mebendazole PS = Metronidazole AP u ο 6 4 5 23 'T’TTCT c*
General procedures for determining AntiviralEfficiency and Tcxixitv are given hereafter. c
Laboratory Procedures for Determining Antiviral Efficacyand Toxicity A. Preparation of Human Foreskin Fibroblast Cells 10
Newborn human foreskins were obtained as soon aspossible after circumcisions were performed and placedin minimal essential medium (MEM) containing vancomycin,fungizone, penicillin, and gentamycin, at the usual
IS concentrations, for four hours. The medium was thenremoved, the foreskins minced into small pieces andwashed repeatedly until red cells were no longerpresent. The tissue was then trypsinized using trypsinat 0.25% with continuous stirring for 15 minutes at 37®C
20 in a CO, incubator. At the end of each 15 minutes periodthe tissue was allowed to settle to the bottom of theflask. The supernatant containing cells was pouredthrough sterile cheesecloth into a flask containing MEM X,·"· and 10 % fetal bovine serum. The flask containing the 25 medium was kept on ice throughout the trypsinizingprocedure. After each addition of cells, the cheesecloth was washed with a small amount of MEM containingserum. Fresh trypsin was added each time to theforeskin pieces and the procedure repeated until no more 3 0 cells became available. The cell containing medium was then centrifuged at 1000 RPM at 4°C for ten minutes. Thesupernatant liquid was discarded and the cellsresuspended' in a small amount of MEM with 10 % FBS(Fetal Bovine Serum) . The cells were then placed in an 35 aopropriate number of 25 cm: tissue culture flasks. As AP/P/ 9 6 / 0 0 8 66 24 cells became confluent and needed trypsinization, theywere gradually expanded into larger flasks. The cellswere kept cn vancomycin and fungizone to nassage four.
5 B. Cytcpathic Effect Inhibition Assay - HSV, HCMV, VZV
Low passage human foreskin fibroblast cellswere seeded into 96 well tissue culture plates 24 hoursprior to use at a cell concentration of 2.5 x 104 cells 13 per ml in 0.1 ml of minimal essential medium (MEM)supplemented with 10 % fetal bovine serum (FBS). Thecells were then incubated for 24h at 3 7°C in a CO,incubator. After incubation, the medium was removed and100 μΐ of MEM containing 2 % FBS was added to all but 15 the first row. In the first row, 125 μΐ of experimentaldrug was added in triplicate wells. Medium alone wasadded to both cell and virus control wells . The drug inthe first row of wells was then diluted serially 1:5throughout the remaining wells by transferring 25 μΐ 20 using the Cetus Liquid Handling Machine. After dilutionof drug, 100 μΐ of the appropriate virus concentrationwas added to each well, excluding cell control wellswhich received 10 0 μΐ of MEM. For HSV-1 and HSV-2assays, the virus concentration utilized can be 25 1000 PFU's per well. For CMZ and VZV assays, the virus concentration added can be 2500 PFU's per well. Theplates were then incubated at 37°C in a CO, incubatorfor three days for HSV-1 and HSV-2, or 10 days for VZV,or 14 days for CMV. After the incubation period, media 30 was aspirated and the cells stained with a’0.1% crystalviolet solution for 3 0 minutes. The stain was thenremoved and the plates rinsed using tap water until allexcess stain was removed. The plates were allowed todry for 24h and then read on a Skatron Plate Reader at 35 620 nm. AP 00645 25 C. Plaque Reduction Assay for HSV-1 and HSV-2 usingSemi-Solid Overlay
Two days prior to use, HFF (Human Foreskin5 Fibro blast) cells are plated into six well plates andincubated at 37eC with 5% CC; and 90V humidity. On thedate of assay, the drug is made up at twice the desiredconcentration in 2x MEM and then serially diluted 1 : 5in 2x MEM and then serially diluted 1:5 in 2x MEM usingic six concentrations of drug. The initial startingconcentration is usually 200 μσ/ml down to O.Ofi μg/ml.The virus to be used is diluted in MEM containing 10 VFBS to a desired concentration which will give 20-30plaques per well. The media is then aspirated from the 15 wells and 0.2 mi of virus' is added to each well induplicate with 0.2 ml of media being added to drugtoxicity wells. The plates are then incubated for onehour with shaking every fifteen minutes. After theincubation period, an equal amount of 1 % agarose was 20 added to a equal volume of each drug dilution. Thiswill give final drug concentrations beginning with100 gg/ml and ending with 0.03 gg/ml and a final agaroseoverlay concentration of 0.5 %. The drug agarosemixture is applied to each well in 2 ml volume and the 25 plates then incubated for three days, after which thecells were stained with a 1.5 % solution of neutral red.At the end of 4-6hr incubation period, the stain isaspirated, and plaques counted using a stereomicroscopeat lOx magnification. 30 · EC» (50 % effective, concentration) is the concentrationrequired to inhibit viral cytopathogenicity by 50 V.ICjo (50 V inhibitory concentration) is the concentrationrequired to inhibit cell proliferation by 50 %.Selective Index (S.I.) = IC;0/EC;0. AP/P/ 9 6 / 0 0 8 6 6 35 26 D. VZV Plaque Reduction Assay - Semi-Solid Overlay
The procedure is essentially the same as forthe HSV plaque assay described above with two excep- 5 tions : 1. After addition of the drug, the plates areincubated for ten days. 2. On days three and six an additional 1 ml overlaywith equal amounts of 2x MEM and 1 % agarose are 12 added. Ξ. CMV Plaque Assay - Semi-Solid Overlay
The procedure again is nearly the same as for 15 HSV with a few minor changes. The agarose used for boththe initial overlay and the two subsequent overlays is0. S % rather than 1 %. The assay is incubated for 14days with the additional 1 ml overlays being applied ondays four and eight. 20 F. Plaque Reduction Assays Using Liquid Medium Overlay
The procedure for the liquid overlay plaqueassay is similar to that using the agarose overlay. The 25 procedure for adding the virus is the same as for theregular plaque assay. The drugs area concentration tobe used in MEM with 2 % FBS. The drugs are not made upat 2x concentration as in the previous assays but aremade up at the desired concentration. For HSV-1 and 50 HSV-2 assays, an antibody preparation obtained fromBaxter Health Care Corporation is diluted 1:500 andadded to the media that the drug is diluted in. For CMVand VZV, no antibody in the overlay is utilized. For theCMV assay, additional medium without new drug is added 55 on day five and allowed to incubate for a total of 10 AP 00645 27 days. For VZV, additional media is added on day fiveand incubated for a total of 10 days. At the end of theincubation period for all of the assays, 2 ml of a 1:10dilution of stock neutral is added to each well and 5 incubated for six hours. The liquid is then aspiratedoff and plaques enumerated using a stereomicroscope.
G. Screening and Confirmation Assays for EBV 1. Virus 13 There are two prototypes of infectious EBV.
One is exemplified by the virus derived fromsupernatant fluids of the P3KR-1 cell line. Thiscell line produces nontransforming virus thatcauses the production of early antigen (EA) after 15 primary infection or suiperinfection of B cell lines. The other prototype is exemplified by theB-95-8 virus. This virus immortalized cord bloodlymphocytes and induced tumors in marmosets. It does not, however, induce an abortive productive « 20 infection even in cell lines harboring EBV genome copies. The virus used in our assays is P3HR-1. 2. Cell Lines 3 Ramos is an exceptional 3 cell line derived from Burkitt' s lymphoma tumor but containing no 25 detectable EBV genome copies and is EBNA negative.
Ramos/AW was obtained by in vitro infection ofRamos with the P3KR-1 virus and contains oneresident EBV genome ccpy/ce.I. Raji is a Burkitt'slymphoma cell line containing 60 EBV genomes/cell, 3 0 and will be the primary cell used for screening antiviral activity against EBV EA expression. Daudiis a low level producer that contains 152 EBVgenome copies/cell. It spontaneously expresses EBVEA in 0.25%-0.5 % of the cells. It will be used in 35 follow-up studies to confirm activity. These cell AP/P/ 9 6 / 00 8 66 X» 28 lines respond co superinfection by EBV byexpressing EA(D), EA(R), and VCA. All cell linesare maintained in RPMI-1640 medium supplemented by10% PCS, l-giutamine and 100 Mg/ml gentamicin. Thecultures are fed twice weekly and the cellconcentration adjusted to 3 x 10i/ml. The cellsare kept at 37°C in an humidified atmosphere with5% CC,. 10 3. Immunofluorescence Assays witr. Monoclonal
Antibodies
Cells are infected with the F3KR-1 strain of EBVand the drugs to be tested are added afteradsorption (45 minutes at 37°C) and washing of the 15 cell cultures. The cultures are incubated for two days in complete medium to allow viral geneexpression. Following the 48 hours incubationperiod, the number of cells of each sample arecounted and smears made. Monoclonal antibodies to 20 the different EA components and VCA are then added to the cells incubated and washed. This isfollowed by a fluorescein conjugated rabbit anti-mousse Ig antibody ; and, the number of fluorescence positive cells in the smears are 25 counted. The total number of cells in the cultures positive for EA or VCA are then calculated andcompared. H. Cell Proliferation Assay - Toxicity 30
Twenty four hours prior to assay, HFF cellsare seeded in 6-well plates at a concentration of 2.5 x104 ceils per well in MEM containing 10 % FBS. On theday of the assay, drugs are diluted serially in MEM 3 5 containing 10 % FBS at increments of 1:5 covering a AP 00645 - > 29 range from 100 μσ/ml to 0.03 gg/ml. For drugs that haveto be solubilised in DMSO, control well receive MEMcontaining 10 % DMSO. The media from the wells is thenaspirated and 2 ml of each drug concentration is then 5 added to each well. The ceils are then incubated in aCO, incubator at 27°C for 72 hours. At the end of thistime, the media-drug solution is removed and the cellswashed. One ml of 0.25% trypsin is added to each welland incubated until the cells start to come off of the 10 plate. The cell-media mixture is then pipetted up andj down vigorously to break up the cell suspension and 0.2 ml of the mixture is added to 9.8 ml of Isoton IIIand counted using a Coulter Counter. Each sample iscounted three times with three replicate wells per 15 sample. I. MTT Assay for Cell Cytotoxicity
Twenty-four hours prior to essay, HFF cells 2 0 are plated into 96 well plates at a concentration of 2.5 x 104, cells per well. After 24 hours, the media isaspirated and 125 microliters of drug is added to thefirst row of wells and then diluted serially 1:5 usingthe automated Cetus Liquid Handling System in a manner 25 similar to that used in the CPE assay. The plates arethen incubated in a CC, incubator at 37°C for sevendays. At this time, each well receives 50 micrcliters of1 gg/ml solution of MTT in Dulbecco's Phosphate Suffered 'Saline. The plates are then incubated for an additional 3 0 four hours. At this time, the media is removed, and replaced with 100 μΐ of 0.04N hydrochloric acid inisoprcpanol. After shaking briefly, the plates are thenread on a plate reader at 550 nm. APZP/ 36 / 00866 35 30 J. Neutral Red Uptake Assay - Toxicity
The procedure for plating cells and addingdrug is the same as for MTT Assay. 5 After drug addition, the plates are incubated for seven days in a CO, incubator at 37eC. At this timethe media/drug is aspirated and 200 μΐ/well of 0.01 %neutral red in DFBS is added. This is incubated in theCO, incubator for one hour. The dye is aspirated and the 10 cells are washed using a Nunc Plate Washer. Afterremoving the DPBS wash, '200 gg/well of 50 % ΞΤΟΗ(ethanol)/1% glacial acetic acid (in Η,Ο) is added. Theplates are rotated for 15 minutes and the opticaldensities are read at 550 nm on a plate reader. t_5
TestS a : Antiviral activity against H3V replication incultures (Hepatites B)
The protocol for essaying anti-HBV compounds 20 in cultures of 2.2.15 cells can be briefly summarized asfollows (Korba and Milman, 1991, Antiviral Res.217:217) : * Chronically HBV-producing human liver cells (Acs, 25 et al. 1987, PNAS 84.:4641) are seeded into 24 well tissue culture plates and grown to confluence. * Test compounds are then added daily for acontinuous 9 day period. Culture medium (changed 30 daily during the treatment period) is collected and stored for analysis of extracellular (virion)H3V DNA after 0,3,6 and 9 days of treatment. AP u ΰ 6 4 5 31 * Treated cells are lysed 24 hours following day 9 oftreatment for the analysis of intracellular H3Vgenomic forms. = * K3V DNA is then analyzed in a quantitative and qualitative manner for overall levels of HBV DNA(both extracellular and intracellular DNA) and therelative rate of HBV replication (intracellularDNA) . 10
The protocol for determining toxicity of compounds incultures of 2.2.15 cells can be briefly summarized asfollows (Kcrba and Gerin, submited for publication) : 15 * 2.2.15 ceils were grown to confluence in 96 well fat-bottomed tissue culture plates and treated withcompounds (in 0.2 ml culture medium/well) asd_escribed above. Four concentrations of eachcompound were assayed, each in triplicate cultures, 20 3 to 10-fcid steps. * Untreated control cultures were maintained on each96 well plate. On each 96 well plate, wellscontaining no cells were used to correct for light 25 scattering. * Toxicity was determined by the inhibition of theuptake of neutral red dye, determined by absorbanceat 510 nanometers relative to the absorbance for 30 untreated ceils (Finter et al., 1969, J. Med. Chem. 5.:419), 24 hours following day 9 of treatment. AP/P/ 9 6 / 0 0 8 66 32 15 20 was
The antiviral activity of compound A has beencompared with that of zaicitabine.
It was found that when using compound A, theeffective concentration (EC 50) was 1.8 ± 0.1 microgram/ml (μσ/l) for having a 50% inhibit of viralcytopathogenicity, while the cytotoxic concentration(fcr having a 50 % inhibit of cell proliferation) wasgreater than 1000 gg/mi. The selective index SI forcompound A was thus equal to >1000/1.8, i.e. a indexhigher than 500.
For Zaicitabine, the tests showed thefollowing results : EC 50 : 1.8 ± 0.2 gg/ml CC 50 : 261 ± 24 /ig/mi i.e. a selective index SI of 261/1.8 about 145.
As it can be seen from this text, Compound Aless toxic than Zaicitabine, whereby a more appropriate treatment with less secondary effects can beobtained against H3V replication. i.e,
TEST 5b : Antiviral activity aoainst VZV A mixture of Nitazoxanide (96%) and compound25 A (4%) was also used in order to determine its activityagainst a Varicella Zoster Virus (a standard laboratory strain).
It was found a EC50 of 4 gg/ml and a CC50 of34 μρ/τηΐ, for the said mixture against said Varicella 30 Zoster Virus, i.e. a S.I. index of about 8.5.
In view cf the low toxicity and the efficiencyof the mixture, the mixture was particularly suitablefor the treatment of Varicella Zoster Virus known asresistant to antiviral agent such as Acyclovir. AP 0 0 6 4 5 33
Compound A and the composition according tothe invention can be administrated orally, for exampleby means of tablets.
The compositions of the invention, especiallythose containing PH 5776 and/or a further antiviralagent are compositions having a broad spectrum of actionon Herpes viruses such as : HERPES SIMPLEX VIRUS TYPE 1 (KSV-I, KSV-1 resistant toacyclovir) ; HERPES SIMPLEX VIRUS TYPE 2 (HSV-S, HSV-2 resistantacyclovir) ; HUMAN CYTOMEGALOVIRUS (HCMV, HCMV resistant to ganciclovir) ; VARICELLA ZOSTER VIRUS (VZV, VZV resistant to * c acyclovir) ; EPSTEIN BARR BIRUSS (EBV) ; 20 wet MURINE CYTOMEGALOVIRUS (MCMV).
The compositions can contain excipients known as such for the purpose of preparing' forms suitable fororal administration.
The compositions contain advantageously ating agent and possibly a starch derivative. AP/P/ 9 6 / 0 0 8 66

Claims (20)

  1. AP 00645 34 WEA' ft,.tog «"« P"*»'”*^•crrained s“’d *r!ut η»»*'·<*Μ tHC i rtcvribeB w®ir)vrn«i«o ami Hl,s ,·, V* 1/ wc 4**“® * Comccur.d of formula
    with /one or/the symbol^ —«τ,—π, and representing OH, whereas the remaining symbols represent H.
  2. 2. Pharmaceutical composition comprising asactive agent, a compound of formula :
    20 with jono of/ the symbol^ Rt / R-r?—Sr?—7¾ and-R;/ representingOK, whereas the remaining symbols represent K. < ( c c < c c c <
  3. 3. Pharmaceutical composition of claim 2, whichcomprises, as active agent, a mixture of a compound A offormula
    mended sweet AP 00645 with Rj = OK and R; = R3 =' R4 = Rj = Hand ccmccund S of formula
  4. 4. Pharmaceutical composition of claim 2 or 3, for oral administration, said composition furthercontaining a wetting agent.
  5. 5. Pharmaceutical composition of claim 4, in 15 which at least one wetting agent is selected among thecrcuo consisting of the anionic surfactants. 20 25
  6. 6. Pharmaceutical composition of claim 4, inwhich the wetting agent is selected among the groupconsisting of sugar esters, polyoxyethylene,polyoxvpropylene, anhydrohexitol derivatives, fattyalkanol amides, fatty amine oxides, sucrose, mannitol,sorbitol, lecithins, polyvinylpyrrolidones, fatty acidesters, glycerides of sucrose, esters of xylose,polyoxyethylene glycerides, esters of fatty acids andof fatty alcohols andacids esters of sorbitan,esters of fatty acids of sorbitan,of alcohol polyglvcides ether catty polyoxyethylenepolyoxyethylenepolyoxyethyleneglyceride-polyglycides esters and mixture thereof . 30 comocsiticn of anyone of the :s a starch derivative. AP/P/ 96/00866 AMENDE? SHEET AP 00645 10 36
  7. 8. Pharmaceutical composition of claim 7, whichcontains carhcxymethyl starch cr a salt thereof.
  8. 9. The composition of claim 4, which contains upto 2 0 % by weight of surfactant with respect to theweight of active agent (s) and up to 20 % by weight ofstarch derivative with respect to the weight of activeagent or agents .
  9. 10. Galenic formulation for oral administration,said galenic formulation comprising a core containing acomposition containing : * an effective amount of a ccmoound of formula I 15
    ‘ 3 20 with jbne cd the symbol# R, I RrR3, R, ana Rr/ reoresenting OH, whereas the remaining symbols representH, possibly mixed with a compound B of formula fto/o/ QR/nnsfifi 25 30 .NO.
    * a wetting agent, and * a starch derivative, the water content of said composition being less than25 % by weight. AMENDED SHEET AP 00645 37
  10. 11. The formulation of claim 10, containingcarboxymethyl starch or a salt thereof.
  11. 12. Ointment for the treatment for combatting ·affections of the lower abdomen, containing : * an effective amount of active agent of formula I
    15 with [ono off the symbol^ R,aaa It/ representing CH, whereas the remaining symbols representH, possibly mixed with a compound B of formula :
    AP/P/ 9 6 / 0 0 8 66 and * a wetting agent.
  12. 13. Ointment of claim 12, which contains a starch derivative. sheet AP 00645 14; Use of a compound of formula I 33
    with jgiic jff the symbol^ R, /- R;, R;1—*4 ^and representingOH, whereas the remaining symbols represent E, as anti-parasitic agent.
  13. 15. Use of a mixture of a compound A of formula 15 20
    with Ri = OH and R, = R, = R4 = R< = Hand a compound B of formula CC C£ a c c u d C c < 25
    30 as antiparasrccc agent. AMENDED SHEET AP 00645
  14. 16. Use of a compound of formula I 39
    with |one mg the symbol^ R| —Rm—Ry ar.s ?/ representingOH, whereas the remaining symbols represent H, as anti-bacterial agent.
  15. 17. Use of a mixture of a compound A of formula15
    AP/P/ 96/00866 with R, = OK and R2 = R3 = R4 = Ri = Hand of a compound B of formula 25 30
    as ante-cacterta. acent. ;HEET AP 00645
  16. 18. Use of a compound of formula I 40
    with fcr.e ef/ the symbol^ RJ R;, On, Ry-ar.d IW representing10 OH, whereas the remaining symbols represent H, as anti- fungal agent. 19 . Use of a mixture of a mixture of a compound A 20 of formula
    6 o G C c (J c 4UI/U v with Rj = OH and Ri = R3 = R4 = Ri = H and of a compound B of formula 25
    as an gat agent. AMENDED SHEE' AP 00645
  17. 20. Use of a compound of formula : 41 NC.
    with bne of/ the symbol $ Rtj. R.r,—?gj, R< ana representingOE, whereas the remaining symbols represent H, asantiviral acent.
  18. 21. Use of the ccmncund of formul. NC.
    AP/P/ 9 6 / 0 0 8 66 25 with/one oef the symbol^ R, R3,— and -Rj/ representingOH, whereas the remaining symbols represent H, asantiviral aoent. 30
  19. 22 . Use of a mixture of a ccmpond A of formulaR „ R, AP 00645 42 with R[ = OH and R, = R3 = R4=Rj = H and of a coirroound of formula 10 15 20 NO.
    as antiviral agent.
  20. 23. Food composition- comprising, as preservingagent, * an effective amount of an active aoent of formula I, NO.
    < c c c c (J c a r>/n/ with lane off the symboljfe R, / R,, R3,—R, and 1¾^ representingOH, whereas the remaining symbols respect H, 25 * possibly a compound B of formula 30 NO.
    35 possibly a starch derivative. amended sheet
APAP/P/1996/000866A 1994-04-13 1995-04-11 Benzamine derivative, compositions containing said derivative and use thereof. AP645A (en)

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US08/227,033 US5387598A (en) 1994-04-13 1994-04-13 Composition and galenic formulation suitable for combatting affections of the lower abdomen
US08/301,407 US5578621A (en) 1994-09-08 1994-09-08 Benzamide derivatives
US38385595A 1995-02-06 1995-02-06
PCT/EP1995/001334 WO1995028393A1 (en) 1994-04-13 1995-04-11 Benzamide derivative, compositions containing said derivative and use thereof

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PT755386E (en) 2002-11-29
SK130796A3 (en) 1997-06-04
AU689582B2 (en) 1998-04-02
BG100884A (en) 1997-07-31
AU2344095A (en) 1995-11-10
HU9602798D0 (en) 1996-12-30
WO1995028393A1 (en) 1995-10-26
BG62932B1 (en) 2000-11-30
DE69526936T2 (en) 2003-02-20
KR100373081B1 (en) 2003-02-25
PL186504B1 (en) 2004-01-30
CZ287002B6 (en) 2000-08-16
CA2187110C (en) 2002-03-19
DK0755386T3 (en) 2002-08-26
ES2161201T1 (en) 2001-12-01
JPH09511997A (en) 1997-12-02
CZ295996A3 (en) 1997-03-12
CA2187110A1 (en) 1995-10-26
DE69526936D1 (en) 2002-07-11
ATE218557T1 (en) 2002-06-15

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