OA10196A - Arylating medicaments - Google Patents

Arylating medicaments Download PDF

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Publication number
OA10196A
OA10196A OA60743A OA60743A OA10196A OA 10196 A OA10196 A OA 10196A OA 60743 A OA60743 A OA 60743A OA 60743 A OA60743 A OA 60743A OA 10196 A OA10196 A OA 10196A
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OAPI
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acid
compound
nitro
hydrogen
halogen
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OA60743A
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Washington Odur Ayuko
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Radopath Ltd
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Priority claimed from GB939310520A external-priority patent/GB9310520D0/en
Application filed by Radopath Ltd filed Critical Radopath Ltd
Publication of OA10196A publication Critical patent/OA10196A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • 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
    • A61K31/04—Nitro compounds
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/06—Phenols the aromatic ring being substituted by nitro groups
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
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    • C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
    • C07C205/11—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings
    • C07C205/12—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms
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    • C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
    • C07C205/21—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C205/24—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring having three, and only three, nitro groups bound to the ring
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    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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    • C07C205/58—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by halogen atoms
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    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/39—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing halogen atoms bound to the carbon skeleton
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    • C07C309/46—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu

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Abstract

Various arylating agents having activity in the treatment of cancer and viral infection are disclosed. The active compounds include an aromatic ring having at least one labile leaving group and at least one electrophilic group. Preferred active compounds include chlorobenzenesulphonic acids and optionally halogenated nitrobenzene compounds. In an anti-viral context, the active compounds have efficacy against HIV infections.

Description

1
The présent invention relates to arylating agents. in particular phenylating agents, which are suitable as therapeutic compounds, especially in the treatment of cancer and disease caused by viral infection. 5
In its broadest sense, the invention relates to arylating agents for use in the treatment of neoplasm or of viral infection such as by HIV. The arylating agent will in particular be a compound having an aryl group whose 10 aromatic ring is preferably carbocyclic and has in any event at least one labile substituent and at least ona electrcphilic substituent. The carbocyclic or other aromatic ring is preferably tnonocyclic and ;.n any event the aromatic ring j.s conveniently one which bears one or 15 more carboxylic acid or sulphonic acid mo.ietîes together with one or more nitro and/or amino groups and/or cne or more halogcn substituents. The substituents preferably do 2 not include more than two ritro subst it.uents. combination of halogen (eg. chlore) and nitro substituants, especially -in the cor.text of a nonocyc’ic arylating agent comprised of a ring carrying a carbcxylic acid substituent, is a part;.culariy efficacious structure
One exemple of such a structure is one oased on u combination of mono-nitro- and rono-chloro- substitut ho (eg. 2--chloro-5-nitro benzoic acid and 2-chloro-4-nitro benzoic acid).
According to the invention, there is provided a compounô for use. in the treatment of cancer or disease causée by
viral infection, in particular AIDS, whuck uonpourU comprises an aromatic ring structure having ut leasr. ote labile leaving group substituent and at least or.e electrophilic group substituent provided that where there are two ortho nitro groups and a para sulphonic group or three symmetxical nitro groups and the labile group st position one is a group as defined m InternationalSpécification No. W091/1S200, use is at a concentration ofmore than 1 x 10'3 moles/litre. 01411 9 b 5 Gcneral’Ly speaking the compound of thc invention, may be of the general formula:
(I) 10 01019# 5 wherein n is an integer and is ait least 2. and each X i? the same or different and is a labile group or an electrophilic group, provided chat wr.en there are at Leasr. two groupe X which are other than nitro at leêist ont- ia a labile group and at least one is an electrophilic group. 10
Moreover, since treatment is sought by what. in believed t«_ be an arylating mechanism. use is typically ai: relatively high concentration» and conséquently doses. Generally, such concentrations for use of the corapounds of the 15 invention wïll be at. least abouo 1 z. 10"“ Toles/litre, which in dosage terrns is generally at least accut 5 mg/kg
In selecting the substituent, groupings for a compound according to the invention an e.ssential feature is· the 20 provision within any particular aromatic ring contezt or at least one labile group substituent and at least. one electrophilic group substituent. Moreover, a group tfhichmay be classified as labile within one particular ringcontext may be classifiable as electrophilic within 25 anot.her alternative ring context. Furthernore, whera 5 there are at least two nitro substituents the labile group substituent may be a ring hydrogen.
That having been understood preferred substituent groups may be defined as those wherein at least one X is selected from each of the following groups, namely: electrophilic groups - SOjH, S0:JM (where M is a métale.g. potassium), halogen and NO3. labile groups - halogen, SO3H, SO3M (where M is a métal), NH2, substituted NH2 e.g. NHRi, NF.yR2 (where R2, and K.2 are the sawe or different and are. each alkyl, alkyloxy or hydroxyalkyl) , cooh, conh;, ,substituted CONH3 e.g. CONHRj,CONRjR3 (where R_x and R2 are as defined above) and COOR3 (where R3 is a métal or alkyl) . 6 -010196 5 Thus, as general exemples of compounds of the .invention there may be mentioned the following, namely: ch'lorodinitrobenzenesulphonic acids chlorobenzeneaulphonic acids 10 dichLorobenzenesulphonic acids aminodinitrobenzene-sulphonic acids nitromethylbenzenesulpkonic acids glatâthionyldinitrobenzenesuLphonic acids nicrochlorobenzenesulphonic acids 15 dinitrobenzenssulphonic acida dimtrochlorobenzenes dinitrofluorobenzenes dichlorodinitrobenzenes·· trinitrophen.de e.g picric acid 2c trinitroanilines trinitrochlorobenzenes t r in i t robenz eue sulphoni c a c i d s chlorodinitrobenzoic acids dichlorobenzoic acids 25 dinitrobenzoic acids nitrochloroanisoles 01019* arr.inodinitrobenzamides dinitroanilines dinitrochloroanilines chloronitroanilines d.ini trof luoroanilines
The above compounds may typically be 3ummarised compounds of the general formula: 15
X a wherein X' is SO3H, SO3M (whare M ia a métal), halogen e.g. chloro, fluoro etc., COQ (where Q is hydroxy, amino or 20 substituted amino, or the group OR3 in. which R3 is a rnetsl oi- alkyl) , NH2, substituted NH2, NO2 or OH,. X" is hydrogen, halogen, glutathione or nitro, each B is the same or different and is hydrogen, 25 halogen or nitro and *oiou)e s 5 G is hydrogen, nitro, amino (including substituted amino), halogan, alkyl or glutathions.
Ir. such compounds the following are preferred faatures: l(i X' is SCjH, SO3M (where Misa métal) , nalogen a.g. chloro, fluoro etc., amine, nitro or COOK, and C is hydrogen, alkyl e.g. met.hyl, amino or nitro. 15 The compounds which exhibit anti-cancer and anti-viral effects according to the invention may be sub-dividec intc a number of preferred groupings, for exemple, as feliows·. (i) A compound of the general formula:
.111) 010196 wherein A is hydrogen, halogen. a.g. cbloio, fluoro etc., or glutathione, B is hydrogen, nitro or halogen e.g. chlore? etc. , C is hydrogen, nitro, smino (including substituted. amino) , halogen, alkyl or glutathione, and D is hydrogen, halogen or nitro.
The above compounds of formula III are preferred because it is balieved that the sulphortic grouping c:an contribute an emnlsifying effect which is .iseful because. it increases the solubility of the compounds, which in turn gives better bioavailability in cellular terras.
Amongst. the above compounds of formula III, those more oreferred are: ,b 4~chloro-3,5-dinitrotenzenesulphonic acid 10 5 4-chlorobenzenesulphonic acid 2, 5-dichlorobenzenesulphon.ic acid 4-amino-3,5-dinitrobenzenesulphonic acid 3-nitro-4-methylbenzenesulphonic acid 2- chloro-3,5-dinitrobenzenesuiphcnic acid. 10 2-glutathionyL-3,5-dinitrobenzeiiesulphonic 4 -ylutathionyl-3,5-dinitrobenzenesulphonic. 3- nitro-4-methylbenzenesulpho.nic acid 3- ni.tro-4-chlorobenzenesulphonic acid 2,4 -dinitrobcnzcncsulphonic ac id . 15
Especially preferred are: 4- chloro-3,5-dinitrobenzenesulphonic acid 4-chlorobenzenesulphonic acid 20 2,5-dichlorobanzenesulphonic acid 4-amino-3,5-dinitrobenzenesuiphcnic acid 3-nicro-4-methylbenzenesulphonic acid 2-chloro-3,5-dinitrobenzenesuiphcnic acid a c i d acid 25 A compound of the general formula: Ί) 1 0 1 9 6 HîxLo
wherein halo is halogen e.g. chlorine, fluorine etc., and each B is the saine or different and u: as defined above.
Arnongst the above compounds of formula IV, t.hose more preferred are: 1-chloro-2,4 -diriitrobenzene 1-chloro-3,4-dinitrobenzene 1-fluoro-2,4-dinitrobenzene 1.2- chloro-4,5-dinitrobenzene 1, 3-chloro-4,5-dinitrobenzene.
Especiêilly preferred are: 1.3- chloro-4,5-dinitrobenzene 1 "Chloro-2,4 -dinitrobenzene 1-fluoro-2,4-dinitrobenzene (iii)A compound of the general formula: £ 12 010190
whereïn S is SO^H, SOjM (where M is a métal e.g. potassium), KH2 or substituted KH-, halogen or hyd roxy.
Amongst compounds of formula V, those more preferred are: 2.4, δ-trinitraphenol (picric acid), 2.4.5- trinitroaniline, 2.4, δ-trinitrochlorobenzene, 2.4.5- trinitrdbenzenesulphon.ïc acid.
Of the above preferred compounds the first and third are especially preferred. 5 (iv) A compound of the general formula:
COQ 13
wherein. each B is the same or different and i as definad above. 15 G is as defined above for group C except fo alkyl and glutathione, J is hydrogen or halogen, and 20 Q is hydroxy, amino or substituted amino, or th group 0R3 in which R3 is a métal or alkyl.
Amongst compounds of formula VI, those more preferred are: 14 010196 2.4- chloro-3,5-dinitrobenzoic acid 4-chloro-3,5-dinitrobenzoic acid 2, 5-dichlorobenzoic acid 2.4- dinitrobenzoic acid 3.5- dinitrobenzoic acid 3- nitro-4-chloroanisole 4- amino-3,5 dinitrobenzamide
Of the above preferred compounds, ail but the last three are especiallv preferred. (x·) A compound of the général formula: (VII) wherein each B is the same or different and is as defined above, together wit.h amino substituted dérivatives thereof. 15
Amongst compounds of formula VII, those more preferred ai*e : 010196 2,6-dinitroaniline 2.4- dinitroaniline 3.5- dinitroaniline 2,4-dinitro-6-chloroan.iline 2.6- dinitro-4-chloroaniline 2-chloro-4-nitro aniline 2, 4-dinitro-5-fluoroaniline EEjpecially preferred ίε: 2.6- dinitroaniline
As rnentioned. above, where there are at least two nitro substituants a ring hydrogexi may provide a labile grouo.
Within that context there may be rnentioned: (vi) A compound of the general formula: 16
010196 that is ta say: — 1.2- dinitrobenzene 1.3- dinitrobenzene 1.4- dinitrobenzene
The cotnpounds of the invention xay be prepared by known procegs techniques for preparing benzene substituted ccmpounds. Such techniques are described in various standard texts, for example, Organic Synthèses" 1963
Collective Volume 4, pages 364 te 366, by Harry P. Sehultz ard published by John Wiley and Sons Inc.
The compounds of the invention may be formulated for use as pharmaceutical compositions (eg for iv, ip, oral or scadministration) comprising at least one active compound and a diluent or carrier. Thus, the invention includes a pharmaceutical composition, which composition comprises acompound according to the invention and a 17 pharmaceutically-acceptable diluent. or carrier (eg aqueous).
Such a composition may be in bulk forn or, more preferably, unit dosage form. Thus, for example, the composition may be formulated as a tabler,· capsule, powder, solution or suspension. Soft gel capsules may be especially convenient. The composition may be a liposomal formulation or administered in a slow sustained release delivery system.
Compositions in accordance with. the invention may be prepared using the active compounds defined herein in accordance with conventional pharmaceutical practice. The diluents, excipients or carriers, etc. which may be used are well known in the formulation art and the form chosen for any particular regimen will dépend on the given context and the physician's choies.
Thus, for example, as illustrated below the compounds of the invention may be administered in solution in stérile
Also, if necessary, solution may be deionised water. 18
01019 H facilitated using dimethyl sulphoxide (DMSO) or alternatively an alcohol, a. glycol or a vegetable oil.
The compounds are most favourably adniniatered in corn oii or as a solution in DMSO/sterile water.
The invention further includes within the above use context the use of a compound as defined herein in the préparation of a médicament for the prophylaxis or therapy of cancer or viral infection, eg to reduce or eliminate cancerous growth.
In using a compound of the invention dosage guidance can be taken frcm animal studiea such as that described below. ïn such étudiés doses of from about; 50 mg/kg typically up te about 200 mg/kg and even up to about 400 mg/kg and beyond hâve proved effective. Thus it is to be expected that a typical dosage for humans will be from about 5 mg/kg typically to about 20 mg/kg and perhaps generally to about 4 0 mg/kg or higher. The concentration and dose are to be sufficient to bring an arylating mechanism into play. 19 010196
As can be seen from the especially preferred listed above, those compounds of the invention most efficacious are in believed descending activity as followa, namely: 4-chloro-3, 5-dinitrobenzenesulphoni C cLCJ-d 4-chlorobenzenesulphonic acid 1,5-chloro-2, 3-dinitrobenzene 2,4,6-trinitrophenol (picric acid) 2.4- chloro-3,5-dinitrobcnzoic acid 2.5- dichlorobenzenesulphonic acid 4- amino-3,5-dinitrobenzenesu.Lphonic acid 3-nitro-4-methylbenzenesulphonic acid. 4 -chloro-3,5-dinitrobenzoic acid 2.6- dinitroaniline 2.4- dinitrochlorobenzene 2,4 -dinitrofluorobenzene 2.4.6- trinitrochlorobenzene 2.5- dichlorobenzoic acid 2--chloro-3,5-dinitrobenzenesalphonic acid compounds which are order of 2. 4-dinitrobenzoic acid 20
Olfllâh
Especially preferred compounds on a X iis selected from: labile substituent group(s) electrophilic substituent group(si thoee where. in at Least I or ; 2 halogen gcoups and/or NH2 or substi: ruted NK2 and/or COOH or substituted COOH and/or a 1 ky 1 and/or SO3H/SO5M 1 or 2 nitro groupa and/or SO^H/SO-jM and/or 1 or 2 halogen groupa
Mcreover, while the compounds cf the invention can be used within the dosage regimen exemplified abcve, where there are three symmetrical nitro substituents or the active agent is otherwise as disclosed in InternationalSpécification No WO 51/15200, as indicated above, the concentration of active agent ir any formulation muât bemore than 1 X 10’3 moles/litre and preferably at least 1 XIC’2 moles/litre. 21 010196
As shovn by the résulta reported in Table 8 belovz, 2- chlore-5-nitrobenzoic acid shows considération anti-tumour activity in vivo. This could not be supported in vitro and it appears some compounds accordina to the invention 10 require activation in the patient's liver. This and some other compounds may also be immunoniodulators.
The following animal 3tudy illustrâtes the remarkable activity of compounds of the invention. 15
ANIMAL STUDTES
The purpose of t’nese studies was to évaluaie the anti- tumour properties of a group of compounds with structural 20 similarities that may act as arylating agents!. Their in vivo anti-tumour responses were assessed against two ascitic tumours, the MAC15A murine colon adanocarcinoma and the P3 88 murine leukaemia and varions solid humour models. The MAC15A ascites tumour cells were transplanted 25 into male NMRl mice by ip inoculation ar. a cel 1 density of 1 X. lû’ cells in 200μ1 buffer {Table 1) . The P388 were 22 010196 transplanted ip into male BDF1 mice at cell density ot 1 X10s cells in 200μ1 buffer (Table 2} . The oolid turaour modela included the MAC13 and MAC16 murine colon adenocarcinomas, the B16 Fl murine melanotna and the M5076 réticulum cell sarcoma.
Treatment commenced 3 days after ip transplant or, lu the case of solid tumours such as MAC13 and MACIS, treatment commenced when average tumour volumes reached 4. OmmJ.
The animais were located in both cases into groups of 5 to 8 animais.
The animais were sacrificed after 12 days or when tumours ulcerated, tumour volume exceeded lOûOmm'' or .Loss of body weight exceeded 50%.
Except where otherwise stated, the compounds used were dissolved in DMSO and diluted in stérile distilled water, at appropriate concentrations before administration in a solvent volume of 200 μΐ. Ant.i-tumour respcnses were obtained by comparing the médian survïval t-imes or tumour 23
01019 K growth inhibition against solvent Controls. The résulta obtained are a3 shown in Tables 1 to S below. follows: -
Subj ects: of dosage solutions is exemplifiec! a.t NO :
Weight: 10 animais 22c
Dosage: 50mg/kg body weight per animal per day thus 1. Img per tnouse per day
Total Mass Dosage: 55mg active ingrédient (referred to 5 day treatment régime)
Total Formulation: 10ml solvent plus 55mg for division into 50 doses of 1. Img dissolved in 200μ1 solvent T/C% is determined as follows
Animal SurvivalTesfc Cantrol T days C dsys T/'C% - T X 100 24 01019 8
5 C F.xajnpl e
O
Animal ,3urvival Test Control 443 days 100 days 5 T/C% = 44 3, X 100 = 4431 00 A figure of 158 or above indicates performance justifying clinical trial. 0 Conclusions
The effect of a group of primarily halogenated arÿlatir.g compounds on the growth rate of a number of experimental tumours has been evaluatei in vivo and the following 5 finding3 were noted:
1. 3tructu.re-activi.ty relationships against the MAC15A murine coion adenocarcinoma, in. the female NMRI tnice showed maximal activity on a split-dose schedule and when 0 the halogen was maximally activated for nucleophilic attack. 25 5 2. The most active compound wa:> 4-chloroben2:ere.sulpbon. i c acid (T/C% 443) adtiinistered at. 100 mg/kg body weight in ·?.daily schedule of 5 days. 3. Against the M5076 réticulum call sarcoma, 2,4- 10 dichloro-3,5-dinitrobenzoic acid showed activity on o split-dose schedule down to 25 mg/kg body weight by boL.n ip and sc routes. Both the amide and the methyl ester showed 10-fold increaae in toxicity and wsre without antitumour activity. The cicid also effectively inhibited 15 growth of B16 murine melanoma and the MACIS murine colon adenocarcinoma,
It is concluded that this group of compounds show a wide spectrum of activity against murine models.
An tï - tcniour activity against MAC15A (mûrir,e adenocarcinéma colon), Structure-Activity relazionship. .5 animais par group. Dose 100 mg kg'1 ip par day. T-ftBLE 1 010196
Compour.d
Schedule ‘T/C%a;days)
Π) (N r-t Γ-Ι i-t CJ Cl Cû (N r-f '1' (N r-t >.? <M 4 -chlorobenzene3ulfonic acid 1,2,2,4,5 ! / 7' r -J -, 4-chloro-3,5-dinitrobenzenesulfortic acid 1,2,3,4,5 414 1,5-dichloro-2,3-dinitrobenzene 1,2,3,4,5 186 2,4,6- Lrini Lrophenoi 1,2, 3 3 0 0 4-amino-3,5-dinitrcbenzenesulfonic acid 1,2,3 4,5 286 4 -chlciro-·3,5 -dinitrobenzoic acid 1,2,3,4,5 171 2,4-dichioro-3,5-dinitrobenzoic acid 1,2 24 3 2-yluLai2iionyl-3 ,S-di2îicrohsJi2enest;lfonic acid 1, -, 3 .< c, 42 3 - ni t r o - 4 - methylben z ene su 1 f. on .1 c ci c i d 1,2 ·' , 4 , 5 22 5 2 , S -dinitroan.il ins 1,2.. 3,4,5 214 2,5-dichlorobenzenesulfonic acid 1,2,3,4,5 212 1,4-dinitrobenzene 1,2 2 0 0 1-chloro-3,4-dinitrobenzene 1,2,5,4, t» 200 l-chloro-2,4-dinitrobenzene 1,2,3,4,5 138 2,4,6-trinitrobenzenesulfonic acid 1,2,3,4,5 1Θ8 2-chloro-4-nitroaniline 1,2,3,4,5 1.71 2,5-dichlorobenzoic acid 1,2,3,4,5 171 2,4-dinitrobenzenssulfonic acid 1,2,3,4,5 171 1,2-dich.loro-4,5-dinitrobenzene 1.2.,.-,s 171 4-chloro-3-nitrobenzenesulfonic acid 1,2,3,4,5 14 0 2-chloro-3,5-dinitrcbenzenesulfonic acid 1,2,3.4,5 137 l-chloro-2,4,6-trinitrobenzene 1,2, "J, Ί ]_ 4 -çjlutathionyl-3,5-dinitrobenzene 1,2,3,4 i 3 2,4-dinitroaniline 1,2 100 2,4-dinitrobenzoic acid 1,2,3,4,5 100 3,5-din.itrobenzoic acid 1,2,3,4,5 1 00 4 -atnino-3,5-dinitrobenzamide ') 100 4-chloro-3-nitroanisole 1,2,3,4,5 10 0 4-chloro- 2,6-dinitroaniline 1,2,3,4,5 8 7 0101 9 27 5 6-chloro-2,4-dinitïtoaniline l-fluoro-2,4-dinitj?oaniline 1-flouro-2,4-dinitrobenzene 1,2,3,4,5 87 1 75 1 62. a=median, T-test grouu, C-sclvent control; b-toxic deeith 10 01019 6 28
Anti-tuxiour activity against P388 (murine leukaemia) .
Bight animale per group. IP tzeazmsnt on day 1 te 5,
De3âge ia per day. TABLE 2
Compound
Pose
TGV 4 -chl.oro-3,5-dinitrobenzene-· sulphonic acid lOOmg kg 20: 4-chloro--3,5-diniLroben2ene- sulphonic acid 5 0 mg kg" 259 a=nean, T=test group, C=solvent ccntrol. TABLE 3.
Anti-tuwur activity against 8388 (murine leuk&amp;emia.)treated. ip wïth 4-chloro-3,5-dinitrobenzenesuîfonic acid.(CDDSA). 8 animais per group. Dosage is per day.
Compound
Dose (mg/kg) Schedule (davs) T/C%a
CDNSA 100 7 5 1,2,3,4,5 1,2,3,4 01019( 29 a=mean, T-test group, C-solvent ccntrol 30 01019‘i TABLE 4
Anti-tuwur activity against K5076-,reciculuin cell sarccmaΙό days after im transplant. 7 animais per group. Drugsd.issolved in corn oïl. Dosage is per day..
Compound Dose Route Scheduie Tumeur Weight (mg/kg) (days t Inhibition 2,4 BA 75a ipl,4,6,9 79 , 88b 50 ipi,4,6,9 57 25 ipl,2,4,6,9 75 75 sel,4,5,7,S 56 50 SCI,2,4,5,6,7,9 76 25 sel,2,4,5,6,7,9 63 2,4 BZ 2.5a ip 1,2,3,4,5,6,7,8,9 51 1.25 ip 1,2,3.4,5,6,7,8,9 3 4 2,4 BM 1. oa ip 2. ,2,3,4,5,5,7,8,9 41 0.5 ip 1,2,3,4,5,6,7,8,9 3 9 0,25 ip 1,2,3,4,5,6,7,8,9 42 a = Maximum tolerated dose b = two independent expérimente; 4 animais had no turcourin. the second experitnent 2,4 BA 2,4-dichloro-3,5-dinitrobenzoic acid 2,4 ΏΖ = 2,4-dichloro-3,5-dinitroben::amide 2,4 BÎ4 - 2,4 -dichloro-3,5-dinitroberzoic acid methyl ester 01019^ 31 %· Tumour Weicrht Inhibition
Treateri Control 10 Agm Bgm inhibition = B - A Z 100 *b ïumour weight 32 01019( 5 TABLE 5
Anti-tuniour activity against. B J.6P1-murine melanoma10 ajfter sc transplant. 6 animais per group. dissolved in corn oil. Dosage is per dey. 12 deysDru g s 15
Compcund Dose (ir.g/kg)
RouteSchedule 1 Tumour Wsight(days) Inhibition 2 0 25 2,4 KA 75a 50 25 75 50 25 ip ip ip SC SC SC 1,5 1,5 1.5 1,3,530 1.3.5 91,3,522 71,8145,55 13 2,4 BZ 2.5° ip 9 .3 9 1.25 ip 1, 2 17 3 0 4 BA 100 i? :., .5 39 7 5 ip 1,5 41 50 ip 1,5 10 3 5 4 BZ _ë. □ i? 1,3,518 2.5 ip 1,3,518 1.. 25 ip 1,3,527 4EM 2.5 ip 1,3 67 4-0 1.25 ip 1,2,343 — a « Maximum tolerated dose 45 b =* Two independent expe.ri.ment s 2,4 BA - 2,4-dichloro-3,5-dinitrobcnzoic acid 01019e 33 2,4 BZ = 2,4-dichloro-3,5-dinitrobenzamide4 BA - 4 chloro-3,5-dinitrobenzoic acid4 BZ = 4-chloro-3,5-dinitrobenzamide4 BM - 4-chloro-3,5-dinitrobenzoic acid methyl ester 34
Ariti -tumour activity against MAC13 murine colon adenccarcinoma 12 days after im transplant, Drugs 01019ο dissclved ïz3 corn oil - Dosage is per day. Ccmpound Dose Fou ce Schedu'le Weight 'j Tumo: (ng/kg) (days) Inhibition 2,4 B.A 75a ipl,4,5 45 2,4 BA 50 ipl,2,3,4,5,5,7,3,0 3 9 2,4 BA graph3 ip graph3 graph" 2,4 BZ 2.5a ipl,2,3,4,5,5,7,3,3 51 2,4 BZ 1.2 5 ipl,2,3,4,5,6,7,3,9 17 2 BA graph4 ip graph4 graph4 a = maximum tolerateo. dose 2,4 BA = 2,4-dichloro-3,5-dinitroben2oic acid5 2,4 BZ ~ 2z4-dichloro-3,5-dinitX'obenzamide 2 EA = 2-chloro-5-nitrobenzoic acid (3: sse Fi<gure 3 of the drawings; 4: see Figure 4 of thedrawings) TABLE 7
Anti-tumeur activity against MAC16, murine colon adenocarcinoma sc transplant en day 1.7. ai'ter the beginning oi‘ treatmenb with 2,4-dichloro-3,5-dinitrcbenzoic acid (2,4 BA) . Drug dissolved in corn oii. The tumour volumes 010196 35 wer<; ai: least 40mm al, the beginning of the trestxenc.animal.?· per group. Dosage i.s per day.
Compound Dcse Soute Schedule
Waight (tr.g/kg) (days) lumou r
Inhibition 2,4 3A 75a50 i.p 1,2,5,8 ip 1,2,4,5,8 88 91 a = maximum tolsrated dose TABLE 8
Anti--tumour activity against Bl€ murine melanoma 12 daysaftei: 5C transplant: on female C57/b.lack mice. 6 animais 10 per group. Dosage is per day and is ip. 15 Cotnpound Dose (mg/kg) Schedule % (days) Tu'mour WeightInhibition 2 0 2-ohloro-5-nitrobenzoic acid 700 1,2.3,4,5,6 62 25 In addition, the follcwing primary î. :ssay was used to investxgats the anti-viral activrty of compounde in accordance with Lire invention, in parti' eu lar 4-chloro-3,5- di n i t roben z enesulphoni c acid. 30 Ar-ti-tumour activity and toxicity étudiés hâveac.dit îonally been completed for the following compcundswith broadly satisfactory résulté:- C22 2,5-d,ichloro-4-nitrobenzoic acid 35 C23 2,4-dichloro-5-nitrobenzoic acid C24 2,6-dichloro-4-nitrobenzoic acid 37 5 C2S 2-amino-5-nitrobenzoic acid C26 2-hydroxy-5-nitrobenzoic acid C27 3,5-dichloro-4-nitrobenzoic acid
PRIMARY ASSAY 10 (:.) Acute Infection Aësay. High titre vii'us stocks of the human immunodeficiency virus HIV-lRr were grown in H9 cells with RPMI 1640 (Plow laboratoires) supplemented with 10% fêtai calf sérum, penicillin (lOOIU/ml). Cell débris 15 was removed by low speed centrifugation, and the supernatant stored at -70°C until required. In a. typi.cal assay C816 6 T-lymphoblastoid CD4 + cells ware incubated with 10xTCID50 HIV-lpj at 37°C for 90 minutes and then wasbed three times with phosphate buffered saline (PE3) .
Cell aliquots (2 x 10s) were resuspended in 1.5 ml growth medium in 6 ml tubes, and compounds in log dilutions [200μΜ to 0.2μΜ] were added immedfately. 20 mM. stock solutions of each compound were made up in 70% alcohol
The compouncls were stored as a powder and made up frcshly25 in distilled water before each experiment or were stored as a 20 irM stock solution in 70% alcohol . The fine" 0 1 0 ί 9 fi concentration of alcohol in the tissue culture medium was 1¾ . The tells were then incubated at 37°C in 5S CO-; . .At 7 2 hours post-infection 200 pi of supernatant was taken f:roin each culture and assayed for HIV (Kingchinctor et al„ 1989, Robert et al i I.99U) using an antigen capture ELISA which recognizes ail the core protsins equally (Coulter Electronics, Luton, UK; . The following Controls were used: supernatants 1 taken from uninfecced and infected cells, infected cells treated with AZT (Roche Products CK,
Ltd) and ddC (Roche) and R031-8959 (Roche) an inh.ibitor of
HIV protéinase. The 1C5O activâties of 3 959, AZT and ddC in infected cells were 1, 10, 20 nM and 200 nl< respectively (accompanying Figure 2J . The ELISA plates were read with a spectrophotometer. Compounds were tested in duplicate at each concentration, and the data shown is the average of at least two assays. This assay aeeesses the activity of compounds by measuring their inhibition of
Hiv core antigen levels. (ii) Ckronically Infected Cell Ases.y. Chronical ly infected cells (H9rf; were washed three times to remove cxtracellular virus and incubated with the actim 010196 35' 5' compounds (200-0.2 μΜ) for four days. Hiv-i antiger. inthe supernatant was then measured using an ELISA.
To test for compound toxicity uninfected H9 colis were incubated with the compounds for four days. Supernatants 10 were discarded and the celle resuspended in 200μ1 pggrowth medium containing i4C proteir hydrolysate. After 6hours the cells were harvested and the l4C incorporation measured. 15 (iii) Toxicicy Aseay. To test for compound ooxicity,aliquots cf 2 x 10s of uninfected cells were cultured withthe compounds in the same dilutions for 72 hours. The cells were then washed with PESA and resuspended in 200μ1of growth medium containing 14C protein hydrolysate. After 2 0 12 hours the cells were harvested and the 14c incorporation measured. Uninfected, untreated cells were used as
Controls. Toxicity is expreseed as inhibition of uptakeof 14C protein hydrolyaate. 25 The results of these assays for 4-chloro-3,5-dinitrobenzenesulphonic acid are shown in accompanying 010196 40 5 Figure 1 in which RC stands for Radopath cempound C i.e. 4 chloro-3,5-dinitrobenzenesulphonic acid. The resu.Lts are al3o suramarised in Table 9 below-, TABLE 9
IC
Compaund IC.^ TI 4--chloro-3,5 15 -dinitrobenzene- sulphonic acid 3μΜ 80μΜ 28.6
The IC50 is the drug concentration that causes a '50% réduction in Hiv core antigen levels as detected by the 2C Coulter P24 antigen assay and is determined by doubling dilutions of supernatant taken from tubes containing· untreated acutely infected cells. The CDS0 is the concentration of drug that causes a 50% inhibition ofcells as measured by 14C protein hydrolysate uptake. The' 2 5 therapeutic index (TI) is determined by dividing the CD60 by the IC50. 010196 41 5 Further resuit s for other compounds in accordance with t'.he invention are summarised in Table 10 below.· 42 TABLE 1Q. 010196
Compound 2-chlox'0-3,5-dinitro- benzenesulphonic acid
XC50 I.I 25gm >20Cgm >8 4 - amine-3,5-dinitro- 15 benzenesulphonic acid 20μιη ΙΟΟμτη 5 2,4,6-trinitrophenol <0.2μιιι
95μΐη >4 7S 4-chloro-3,5-dinitro- 20 benzoic acid 3 0μτη 70μτ! 2.3 3 ίΠ
Initial tests performed approximately contemporaneoualy indicated 2-chloro-5-nitrobenzoic acid would damonstrate performance at least as efficaceous, if non more so, as any of the compounds whese tests are reported herein. 010196 43
Pollowing the methodology set forth earlier performance assay again3t I-IIV, more extensive assays performed as reported in Tables 11 below: for were 44 oiom
STRUCTURE-ACTIVITY RELATIONSHIP AGAINST HIV VIRUS CODE COMPOUNDS isIC50 Tc"CC5O GROUP A PI picryl chloride P2 picric acid PB picrylsulfonic acid (sodium sait)
GROUP B
Cl 2,4-dichloro-3,5-dinitrobenzcic acid C2 2, 4-dichloro-3, 5-dinitrobenzamide C3 2,4-dichloro-3,5-dinitrobenzcic acid methy] ester C4 4-chloro-3,5-dinitrobenzoïc acid CB 4-chloro-3,5-dinitrobenzarnide C6 4-chloro-.3 , δ-dinitrobenzoïc acid methyl ester C7 2-chloro-3,5-dinitrobcnzoic acid C8 2-chloro-3,5-dinitrcbenzoic acid methyl ester C9 4-chloro-3-nitrobenzoic acid CTO 2-chloro-4-nitrobenzoic acid CTI 3,4-dichlorobenzoic acid Cl 2 2,5-dichlorobenzoic acid CT 3 4-eblorobenzoic acid
GROUP C 010196 45
IC 51 52 53S 4SSSGS 7S8 4-chloro-3,5-dinitrobenzenesulfonic acid 2-ehloro-3,5-dinitrobenzenesulfonic acid4-amino-3/5-dinitrobenzenesulfonic acid4-chloro-3-nitrobenzeriesulfonic acid4-chlorobenzenesulfonic acid 4-nitrotoilnenesulfonic acid 2,5-dichlorobenzenesulfonic acid2,4-dinitrobenzeneaulfonic acid 15 46
S TABLE 11.1 (CQNT/D IC GROUP Ώ 15 El 1-chloro-3,4-dinitrcbenzene E2 l-chloro-2,4-dinitrcbenzene E3 E4 1.2- dicblorc-45-dinitrobenzene 2.3- dichloronitrobenzene ES 2,4-dichloronitrobenzene 20 Eb* 2,5-dichloronitrobenzene E7 3,4-dichloronitrobenzene B 8 3,5-dichloronitrobenzene E9 1,5-dichlorc-2,3-dinitrobenzene E10 1,2,3 -trichloro-4-nitrobenzene 2:5. Eli 1,2,4-trichloro-5-nitrobenzene E12 2,4,6-trichlorobenzene E13 2,3,4,ζ-tetrachloronitrobenzene Ε14 pentachloronitrobenzene 3 =
Γ-Ccmpounds IC50 CC5C SI (Antiviral) (Tozicity)
Index)
Fl 0.6 7 5 0.4 4Ξ Average 0.5 6 F2 38 67 2 E3 (Seïectivity 10 >200 >20 0 12 010196 47
Acramsl PI 0.6 7 1 7 K) Average 0.8 7
Against c'nronically jnferre.d relis 15
PI 0.9 7 2 12
Average 1.5 9.5 6 46
SI (Selectivity IASL£_il_rJ. 010196 C-Compounds index) IC50 (Antiviral) CC50 (Toxicity)
Cl 5 36 70 7 0 14 2 33 73 2 35 6 0 2 Average 27 70 3
Cl 7 60 55 3.5 56 3 - 5 57 5 Average 16 11.5 Agi ajLnst chrc nicallv infect ed cells Cl 16 30 à 16 9.5 ç, Average 16 63 4:
Against Hl'V-lIIIB C2 2 70 35 C3 0.3 7 23 C4 4 0 130 2.5 30 7 0 2.3 Average 35 35 2.4 C5 5 50 10 C6 5 60 12 C7 23 150 6 49 10
Average 5 22 >200 >175 >10 8 CS 10 60 c; C9 >200 >200 - C-10 >200 >200 - C-ll >200 >200 - C-12 >200 >200 15 50 010196 TABLE._ 11 .,.4
IC S-Compounds
Index) IC50 (Antiviral) CC50 (Toxicity)
SI (Selectivity
Ag.ainst HIV-IRF SI 20 100 19 60 Average 20 30 S 2 NR S 2 NR S 4 >200 >200 S5 >200 >200 S 6 >200 >200 S 7 >200 >200 S 8
Average 40 100 2.5 30 70 2 35 75 2.4 35 51 010196 TABLE 11.5 10 E-Ccmpounds Index) IC50 CC5O {Antiviral) SI (Toxicity) Acrainst HIV -1RF 15 El 4 10 2.5 E2 4 13 O E3 4 7 1.5 2 0 E4 80 >200 1.5 E5 180 >200 1 2 Ei Eb 110 >200 2 E7 >200 >200 - ES 120 >200 1.5 3 0 E9 ND E10 >200 90 - 3 Ξ- Eli >200 >200 - El 2 >200 >200 El 3 >200 80 4 0 E14 >200 >200 (Selectivity 45 While the invention has been described above in various spécifie details, it will be éippreciated that nunerous and 010196 52 various modifications may be made within the spirit and scope of the daims which follow. Thus, for example, the functional· groupa car), be in various other positions, of which the above specifically recited are examples only.

Claims (15)

  1. 53
    1. A compound for use as a pharmaceuticai, the compound ccmprising an aromatic ring structure having at least one labile leaving moiety and at least one electrophilic 10 moiety. 010196 CIAIMS 15
  2. 2. A compound as claimed in daim 1 and having the general formula: x' _ ..Χ* ! o x3 * * I X wherein one cf X1 to X6 is a. labile leaving moiety, cne of20 the balance thereof is an electrophilic moiety and theremaindsr are the same or different and are hydrogen or a substituent.
  3. 3. A compound as claimed in daim 2 vherein. X1 is a25 labile leaving moiety, one of X2 to X6 is an electrophilicmoiety and the remainder are, each independently, hydrogen or a substituent, provided t'nat vhen X2 and Χε are nitro groups, X'] is neither a nitro group, a sulphonic acid group nor a sulphonata group or X1 is not a labile group as 3 4 «10196 defined fcelow, r.amely a hydroxy group, an amine group, asulfo group, a carboxy group, a methyloxy group, halogen ora hydratyl group of the formula : 2 - N - N - I Iy a wherein A is hydrogen or ë-ri unpaired électron of thenitrogen atom, Y is hydrogen or an orgsnic group and ?. isan organrc group, or Y and 2 together with the adjacentnitrogen atom fora a nitrogen-containing heterocycle.
  4. 4. A com.pound as claim.ed in Claim 2 wherein. one of X1 toX® is a labile leaving moiety, one of the balance thereof isan electrophilic moiety, and the remainder are the ssmc ordifferent and are hydrogen or an substituent witn at leasttwo thereof being other than nitro, at least one being a l.abile moiety and at least one being an. electrophilicmoiety.
  5. 5. A compound as claimed in any one of Claim.s 2 to 4,wherein at least one of X1 to X£ is an electrophilic moietycr labile moiety selected from the follcwing : - electrophilic moieties - SO3H, SOjlI (where >i is a métal) . halc-gen and NO^ 55 halogen, SOîH, SO3X (where M is a métal), optionally sübstituted NH2, COOH, optionally sübstituted CONHs and COOR, (where R3 is a métal cr alkyl). labile moieties 10 010196
  6. 6. A compound as claimed in any preceding claim which has 15
    2C wherein: X7 * is SO3H, SOjM (where M is a métal), halogen, COQ(where Q is hydroxy, amino or substituted amino, or thegroup OR3 in which Rj is a métal or alkyl) , NH2, substitutedNHa, NO2 cr OH; x’ is hydrogen, halogen, glutathions ornitro; X9, X10 and X11 are, each independently, hydrogen, halogen or nitro; and Xu is hydrogen, nitro, optionallysubstituted amino, halogen, alkyl or glutathione.
  7. 7. A compound as claimed in Claim 6 wherein the substituent définitions are as set forth below:- 25 56 J) 1 01 9 6 {a] X7 is SO3H; X5 is hydrogen, halogen or glutathions; x3and Xl° are, each independently, hyclrogen, halogen or nitro;X1’ is hydrogen; and X12 is hydrogen, nitro, optionallysubstituted amino, halogen, alkyl or gïutathione; {bl· X7 is halogen; Xe, X9, X10 and X12 are, each indépendant ly, hydrogen, halogen or nitro; and Xu ishydrogen; (cl· X7 is SOjH, SOîM (where M is a métal) , NH.2 orsubstitvted NH2, halogen or hydroxy; Xe is nitro; X? ishydrogen; X*° is hydrogen; X11 is nitro; and X12 is nitro. (d) X7 is optionally substituted éunino; and R* to are,each independently, hydrogen, halogen or nitro.
    6. A compound as clairoed in Cïsira 6 wherein:- X7:. is a group of formula-COQ in which Q is hydroxy,optionally substituted ar.ino or has the formula -ORS inwhich R’ is alkyl or métal; X3 is; hydrogen or halogen; X9and X10 are, each independently, hydrogen, halogen or nitro;X11 is hydrogen; and X12 is hydrogen, nitro, optionallysubstituted amino or halogen. 57 010196
  8. 9. A compound as claimed in Claira. 1 and as set forthbelow by name:- 5.1 2-chloro-5-nitrobenzoic acid 5.2 2,4-dichloro-3, S-dinitroben.2oic acid or its alkyl ester 9.3 4-ch.loro-3, 5-dinitrobenzoic acid or its alkyl ester 5.4 2,5-dichlcrobenzoic acid 9.5 7., 4-dinitrobenzoic acid 9.6 3,5-dinitroben2oic acid 9.'? 3-nitro-4~chIoroanisole 9.3 4-araino-3,5-dinitrobenzamide 9.9 4-chloro-3,5-dinitrobenzamide 9.10 2,4-dichloro-3,5-dinitrobenzaînide 9.11 4-chloro-3,S-dinitrobenzenesulphonic acid 9.12 4-chlorobenzenasulphonic acid 9.13 2,5-dichlorobenzanesulphonic acid 9.14 4-araino-3,5-dinitrobenzenesulphonic acid 9.15 3-r,itro-4-methylbenzenesulphonic acid 9.1 S 2-chloro-3,5-dinitrobenzen35u.lphonic acid 9.17 2-glutathionyl-J,5-dinitrobenzenesulphonic acid 9.13 4’-çflutathionyi-3/5-dinitrobenzenesulphonic acid 9.19 3-riitro-4-methylbenzene5ulphonic acid 9.20 3-nitrO“4-chlorobenzenesulphonic acid 9.21 2, 4-dinitrobenzenesulphonic acid 9.22 4-chloro-3,5-dinitrobenzene solfonic acid 58 010196 9.23 2, 4-dinitrochlorobenzene 9.24 3,4-dinitrochlorobenzene 9.25 2, 4-dinitrofluorobenzene 9.26 1,2-di.chi].oro-4,5-dinitrobenzene 9.2“ 1, 3-dichloro-4,5-dinitrobenzene 9.28 1,5-dichloro-2,3-dinitrobenzene 9.29 2, 4,6-trinitrophenol (picric acid), 9.30 2,4,6-trinitroaniline, 9.31 2,4,6-trinitrochIcrobenzene. 9.32 2, 6-dinitroaniline 9.33 2,4-dinitroaniline 9.34 3, 5-dir.itroaniline 9.35 2, 4--dinitro-6-chloroaniline 9.36 2,6-dinitro-4-chloroaniline 9.37 2-chloro-4-nitroaniline 9.38 2, 4-dinitro-5-fluoroaniline 9.39 1, 2-dinitrobenzene 9.40 1,3-dinitrobenzene 9.41 1, 4~dinitrobenzene
  9. 10. A compound as claimed in any one of Claims 1 to 5 wherein a ring hydrogen provides a labile mciety, thecompound having the general formula: 59 010196
  10. 11. A compound for use in the treatment or prévention ofcancer, pre-cancer or disease caused by viral infection,which compound comprises an aromatic ring structure havingat least one labile leaving moiety and at least oneelectrophilic moiety.
  11. 12. A compound for use in the treatment or prévention ofcancer, pre-cancer or diseasa caused by viral infection,the compound being a compound as set forth below by naaie:- 12.1 2,4,6-trinitrophenol 12.. 2 2, 4-dichloro-3,5-dinitrobenzoic acid 12.. 3 4-chlorc-3,5-dinitrobenzoic acid 12.. 4 I, 5-dichloro-2, 3-dinitrobenzer.e 12.. 5 2-chloro-5-nitrobenzoic acid 12.6 4-chlorobenzenesulfonic acid 12.7 4-chloro-3,5-dinitrobenzene sulfonic acid 12.3 4-chloro-3,S-dinitrobenzamide 12.9 2,4-dichloro-3,5-dinitrobenz3mice 60 010191 5
  12. 13.. A pharmaceutical composition, which compositioncomprises a compound as claimed in any preceding daim anda pharmaceutically-acceptable diluent or carrier.
  13. 14.. Use of a compound as claimed in any one of Claim 1 to 12 for the préparation of a médicament for the prophylaxisor therapy of cancer, pre-cancer cr viral infection.
  14. 15.. A method of treating (a) disease caused. by viral 15 infection or (b) cancer or pre-cancer to reduce or eliminate cancerous growth, which method comprisesadministering an effective amount of a compound as claimedin any one of Clairns 1 to 12 or a composition as claimed in Claim 13. 20
  15. 16. A chlore- or nitzo-benzenesulfcnic acid compound, achloro- or nitro-benzoic acid compound or chloro- cr nitro-benzamice compound for use as a pharmaceutical - 25
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