GB2284153A - Therapeutic arylating agents - Google Patents

Therapeutic arylating agents Download PDF

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GB2284153A
GB2284153A GB9410420A GB9410420A GB2284153A GB 2284153 A GB2284153 A GB 2284153A GB 9410420 A GB9410420 A GB 9410420A GB 9410420 A GB9410420 A GB 9410420A GB 2284153 A GB2284153 A GB 2284153A
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acid
compound
nitro
chloro
hydrogen
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Washington Odur Ayuko
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RADOPATH Ltd
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RADOPATH Ltd
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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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    • 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
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    • 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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    • C07C205/57—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
    • 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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    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • 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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    • C07C237/28—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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    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/40—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitro or nitroso groups bound to the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/45—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
    • 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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    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
    • C07C63/70—Monocarboxylic acids

Abstract

Arylating agents active against cancer and viral infections e.g. aids have an aromatic ring having at least one labile leaving group and at least one electrophilic group. Typical agents are benzenesulphonic acids, dinitrobenzenes, nitroanilines, nitrophenols, halogenated and nitro benzoic acids, chloronitro benzamides.

Description

ARYLATING AGENTS The present 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.
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 aromatic ring is preferably carbocyclic and has in any event at least one labile substituent and at least one electrophilic substituent. The carbocyclic or other aromatic ring is preferably monocyclic and in any event the aromatic ring is conveniently one which bears one or more carboxylic acid or sulphonic acid moieties together with one or more nitro and/or amino groups and/or one or more halogen substituents. The substituents preferably do not include more than two nitro substituents. A combination of halogen (eg. chloro) and nitro substituents, especially in the context of a monocyclic arylating agent comprised of a ring carrying a carboxylic acid substituent, is a particularly efficacious structure. One example of such a structure is one based on a combination of mono-nitro- and mono-chloro- substitution (eg. 2-chloro-5-nitro benzoic acid and 2-chloro-4-nitro benzoic acid).
According to the invention there is provided a compound for use in the treatment of cancer or disease caused by viral infection, in particular AIDS, which compound comprises an aromatic ring structure having at least one labile leaving group substituent and at least one electrophilic group substituent provided that where there are two ortho nitro groups and a para sulphonic group or three symmetrical nitro groups and the labile group at position one is a group as defined in International Specification No.
W091/15200, use is at a concentration of more than 1 x 10 moles/litre.
Generally speaking the compound of the invention may be of the general formula:
wherein n is an integer and is at least 2 and each X is the same or different and is a labile group or an electrophilic group, provided that when there are at least two groups X which are other than nitro at least one is a labile group and at least one is an electrophilic group.
Moreover, since treatment is sought by what is believed to be an arylating mechanism use is typically at relatively high concentrations and consequently doses. Generally, such concentrations for use of the compounds of the invention will be at least about 1 x 10 2 moles/litre, which in dosage terms is generally at least about 5 mg/kg In selecting the substituent groupings for a compound according to the invention an essential feature is the provision within any particular aromatic ring context of at least one labile group substituent and at least one electrophilic group substituent. Moreover, a group which may be classified as labile within one particular ring context may be classifiable as electrophilic within another alternative ring context. Furthermore, where 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 - SO3H, SO3M (where M is a metal e.g.
potassium), halogen and NO2.
labile groups - halogen, SO3H, SO3M (where M is a metal), NH2, substituted NH2 e.g.
NHR1, NR1R2 (where R1, and R2 are the same or different and are each alkyl, alkyloxy or hydroxyalkyl), COOH, CONH2, substituted CONH2 e.g.
CONHR1, CONR1R2 (where R1 and R2 are as defined above) and COOR3 (where R3 is a metal or alkyl).
Thus, as general examples of compounds of the invention there may be mentioned the following, namely: chlorodinitrobenzenesulphonic acids chlorobenzenesulphonic acids dichlorobenzenesulphonic acids aminodinitrobenzenesulphonic acids nitromethylbenz enesulphonic acids glutathionyldinitrobenzenesulphonic acids nitrochlorobenzenesulphonic acids dinitrobenzenesulphonic acids dinitrochlorobenz enes dinitrofluorobenzenes dichlorodinitrobenzenes trinitrophenols e.g. picric acid trinitroanilines trinitrochlorobenzenes trinitrobenzenesulphonic acids chlorodinitrobenzoic acids dichlorobenzoic acids dinitrobenzoic acids nitrochloroanisoles aminodinitrobenzamides dinitroanilines dinitrochloroanilines chloronitroanilines dinitrofluoroanilines The above compounds may typically be summarised by compounds of the general formula:
wherein X' is SO3H, SO3M (where M is a metal), halogen e.g.
chloro, fluoro etc., COQ (where Q is hydroxy, amino or substituted amino, or the group OR3 in which R3 is a metal or alkyl), NH2, substituted NH2, NO2 or OH, X" is hydrogen, halogen, glutathione or nitro, each B is the same or different and is hydrogen, halogen or nitro and C is hydrogen, nitro, amino (including substituted amino), halogen, alkyl or glutathione.
In such compounds the following are preferred features: X' is SO3H, SO3M (where M is a metal), halogen e.g.
chloro, fluoro etc., amino, nitro or COOH, and C is hydrogen, alkyl e.g. methyl, amino or nitro.
The compounds which exhibit anti-cancer and anti-viral effects according to the invention may be sub-divided into a number of preferred groupings, for example, as follows: (i) A compound of the general formula:
wherein A is hydrogen, halogen e.g. chloro, fluoro etc., or glutathione, B is hydrogen, nitro or halogen e.g. chloro etc., C is hydrogen, nitro, amino (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 believed that the sulphonic grouping can contribute an emulsifying effect which is useful because it increases the solubility of the compounds, which in turn gives better bioavailability in cellular terms.
Amongst the above compounds of formula III, those more preferred'are: 4-chloro-3,5-dinitrobenzenesulphonic acid 4-chlorobenzenesulphonic acid 2,5-dichlorobenzenesulphonic acid 4-amino-3,5-dinitrobenzenesulphonic acid 3-nitro-4-methylbenzenesulphonic acid 2-chloro-3,5-dinitrobenzenesulphonic acid 2-glutathionyl-3, 5-dinitrobenzenesulphonic acid 4-glutathionyl-3 , 5-dinitrobenzenesulphonic acid 3-nitro-4-methylbenzenesulphonic acid 3-nitro-4-chlorobenzenesulphonic acid 2, 4-dinitrobenzenesulphonic acid.
Especially preferred are: 4-chloro-3, 5-dinitrobenzenesulphonic acid 4 -chlorobenzenesulphonic acid 2, 5-dichlorobenzenesulphonic acid 4-amino-3,5-dinitrobenzenesulphonic acid 3-nitro-4-methylbenzenesulphonic acid 2-chloro-3 , 5-dinitrobenzenesulphonic acid (ii) A compound of the general formula:
wherein halo is halogen e.g. chlorine, fluorine etc., and each B is the same or different and is as defined above.
Amongst the above compounds of formula IV, those more preferred are: l-chloro-2,4-dinitrobenzene l-chloro-3 , 4-dinitrobenzene 1-fluoro-2,4-dinitrobenzene 1, 2-chloro-4 , 5-dinitrobenzene 1,3-chloro-4,5-dinitrobenzene.
Especially preferred are: 1,3-chloro-4,5-dinitrobenzene l-chloro-2, 4-dinitrobenzene 1-f luoro-2, 4-dinitrobenzene (iii) A compound of the general formula:
wherein E is SO3H, SO3M (where M is a metal e.g.
potassium), NH2 or substituted NH2, halogen or hydroxy.
Amongst compounds of formula V, those more preferred are: 2,4,6-trinitrophenol (picric acid), 2,4,6-trinitroaniline, 2,4,6-trinitrochlorobenzene.
2,4,6-trinitrobenzenesulphonic acid.
Of the above preferred compounds the first and third are especially preferred.
(iv) A compound of the general formula:
wherein each B is the same or different and is as defined above, G is as defined above for group C except for alkyl and glutathione, J is hydrogen or halogen, and Q is hydroxy, amino or substituted amino, or the group OR3 in which R3 is a metal or alkyl.
Amongst compounds of formula VI, those more preferred are: 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, all but the last three are especially preferred.
(v) A compound of the qeneral formula:
wherein each B is the same or different and is as defined above, together with amino substituted derivatives thereof.
Amongst compounds of formula VII, those more preferred are: 2, 6-dinitroaniline 2, 4-dinitroaniline 3, 5-dinitroaniline 2,4-dinitro-6-chloroaniline 2,6-dinitro-4-chloroaniline 2-chloro-4-nitro aniline 2, 4-dinitro-5-fluoroaniline Especially preferred is: 2, 6-dinitroaniline As mentioned above, where there are at least two nitro substituents a ring hydrogen may provide a labile group.
Within that context there may be mentioned: (vi) A compound of the general formula:
that is to say: 1,2-dinitrobenzene 1, 3-dinitrobenzene 1,4-dinitrobenzene The compounds of the invention may be prepared by known process techniques for preparing benzene substituted compounds. Such techniques are described in various standard texts, for example, "Organic Syntheses 1963 Collective Volume 4, pages 364 to 366, by Harry P. Schultz and 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 sc administration) comprising at least one active compound and a diluent or carrier. Thus, the invention includes a pharmaceutical composition, which composition comprises a compound according to the invention and a pharmaceuticallyacceptable diluent or carrier (eg aqueous).
Such a composition may be in bulk form or, more preferably, unit dosage form. Thus, for example, the composition may be formulated as a tablet, 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 depend on the given context and the physician's choice.
Thus, for example, as illustrated below the compounds of the invention may be administered in solution in sterile deionised water. Also, if necessary, solution may be facilitated using dimethyl sulphoxide (DMSO) or alternatively an alcohol, a glycol or a vegetable oil. The compounds are most favourably administered in corn oil 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 preparation of a medicament 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 from animal studies such as that described below.
In such studies doses of from about 50 mg/kg typically up to about 200 mg/kg and even up to about 400 mg/kg and beyond have 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 40 mg/kg or higher. The concentration and dose are to be sufficient to bring an arylating mechanism into play.
As can be seen from the especially preferred compounds listed above, those compounds of the invention which are most efficacious are in believed descending order of activity as follows, namely: 4-chloro-3,5-dinitrobenzenesulphonic acid 4-chlorobenzenesulphonic acid 1,5-chloro-2,3-dinitrobenzene 2,4,6-trinitrophenol (picric acid) 2, 4-chloro-3 , 5-dinitrobenzoic acid 2,5-dichlorobenzenesulphonic acid 4-amino-3 , 5-dinitrobenzenesulphonic 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-dinitrobenzenesulphonic acid 2, 4-dinitrobenzoic acid Especially preferred compounds are those wherein at least one X is selected from: labile substituent group(s) - 1 or 2 halogen groups and/or NH2 or substituted NH2 and/or COOH or substituted COOH and/or alkyl and/or SO3H/SO3M electrophilic substituent group(s) - 1 or 2 nitro groups and/or S03H/SO3M and/or 1 or 2 halogen groups Moreover, while the compounds of the invention can be used within the dosage regimen exemplified above, where there are three symmetrical nitro substituents or the active agent is otherwise as disclosed in International Specification No WO 91/15200, as indicated above, the concentration of active agent in any formulation must be more than 1 X 10 3 moles/litre and preferably at least 1 X 10-2 moles/litre.
As shown by the results reported in Table 8 below, 2chloro-5-nitrobenzoic acid shows consideration anti-tumour activity in vivo. This could not be supported in vitro and it appears some compounds according to the invention require activation in the patient's liver. This and some other compounds may also be immunomodulators.
The following animal study illustrates the remarkable activity of compounds of the invention.
ANIMAL STUDIES The purpose of these studies was to evaluate the antitumour properties of a group of compounds with structural similarities that may act as arylating agents. Their in vivo anti-tumour responses were assessed against two ascitic tumours, the MAC15A murine colon adenocarcinoma and the P388 murine leukaemia and various solid tumour models.
The MAC1SA ascites tumour cells were transplanted into male NMR1 mice by ip inoculation at a cell density of 1 X 105 cells in 200p1 buffer (Table 1). The P388 were transplanted ip into male BDF1 mice at cell density of 1 X 106 cells in 200p1 buffer (Table 2). The solid tumour models included the MAC13 and MACING murine colon adenocarcinomas, the B16 F1 murine melanoma and the M5076 reticulum cell sarcoma.
Treatment commenced 3 days after ip transplant or, in the case of solid tumours such as MAC13 and MAC16, treatment commenced when average tumour volumes reached 40mm3.
The animals were located in both cases into groups of 5 to 8 animals.
The animals were sacrificed after 12 days or when tumours ulcerated, tumour volume exceeded 1000mm3 or loss of body weight exceeded 50%.
Except where otherwise stated, the compounds used were dissolved in DMSO and diluted in sterile distilled water, at appropriate concentrations before administration in a solvent volume of 200 y1. Anti-tumour responses were obtained by comparing the median survival times or tumour growth inhibition against solvent controls. The results obtained are as shown in Tables 1 to 8 below.
Preparation of dosage solutions is exemplified as follows: Subjects: No : 10 animals Weight: 22g Dosage: 50mg/kg body weight per animal per day thus 1.lug per mouse per day Total Mass Dosage: 55mg active ingredient (referred to 5 day treatment regime) Total Formulation: 10ml solvent plus 55mg for division into 50 doses of l.lmg dissolved in 20041 solvent T/C% is determined as follows: Animal Survival Test Control T days C days T/C% = T X 100 C Exam P1 e Animal Survival Test Control 443 days 100 days T/C% = 443 X 100 = 443 100 A figure of 158 or above indicates performance justifying clinical trial.
Conclusions The effect of a group of primarily halogenated arylating compounds on the growth rate of a number of experimental tumours has been evaluated in vivo and the following findings were noted: 1. Structure-activity relationships against the MAC15A murine colon adenocarcinoma, in the female NMRI mice showed maximal activity on a split-dose schedule and when the halogen was maximally activated for nucleophilic attack.
2. The most active compound was 4-chlorobenzenesulphonic acid (T/C% 443) administered at 100 mg/kg body weight in a daily schedule of 5 days.
3. Against the M5076 reticulum cell sarcoma, 2,4dichloro-3,5-dinitrobenzoic acid showed activity on a split-dose schedule down to 25 mg/kg body weight by both ip and sc routes. Both the amide and the methyl ester showed 10-fold increase in toxicity and were without antitumour activity. The acid also effectively inhibited growth of B16 murine melanoma and the MAC16 murine colon adenocarcinoma.
It is concluded that this group of compounds show a wide spectrum of activity against murine models.
TABLE 1 Anti-tumour activity against MACiSA (murine adenocarcinoma colon). Structure-Activity relationship. 5 animals per group. Dose 100 mg kg ip per day.
Compound Schedule T/C%a (days) 4-chlorobenzenesulfonic acid 1,2,3,4,5 443 4-chloro-3,5-dinitrobenzenesulfonic acid 1,2,3,4,5 414 l,5-dichloro-2,3-dinitrobenzene 1,2,3,4,5 386 2,4,6-trinitrophenol 1,2,3 300 4-amino-3,5-dinitrobenzenesulfonic acid 1,2,3,4,5 286 4-chloro-3 , 5-dinitrobenzoic acid 1,2,3,4,5 271 2 ,4-dichloro-3, 5-dinitrobenzoic acid 1,2 243 2-glutathionyl-3, 5-dinitrobenzenesulfonic acid 1,2,3,4,5 242 3-nitro-4-methylbenzenesulfonic acid 1,2,3,4,5 229 2,6-dinitroaniline 1,2,3,4,5 214 2,5-dichlorobenzenesulfonic acid 1,2,3,4,5 212 1,4-dinitrobenzene 1,2 200 1-chloro-3 , 4-dinitrobenzene 1,2,3,4,5 200 -1-chloro-2,4-dinitrobenzene 1,2,3,4,5 188 2,4,6-trinitrobenzenesulfonic acid 1,2,3,4,5 188 2-chloro-4-nitroaniline 1,2,3,4,5 171 2,5-dichlorobenzoic acid 1,2,3,4,5 171 2, 4-dinitrobenzenesulfonic acid 1,2,3,4,5 171 1,2-dichloro-4,5-dinitrobenzene 1,2,3,4,5 171 4-chloro-3-nitrobenzenesulfonic acid 1,2,3,4,5 140 2-chloro-3,5-dinitrobenzenesulfonic acid 1,2,3,4,5 137 1-chloro-2,4,6-trinitrobenzene 1,2,3 113 4-glutathionyl-3 , 5-dinitrobenzene 1,2,3,4 113 2,4-dinitroaniline 1,2 100 2,4-dinitrobenzoic acid 1,2,3,4,5 100 3,5-dinitrobenzoic acid 1,2,3,4,5 100 4-amino-3, 5-dinitrobenzamide 1 100 4-chloro-3-nitroanisole 1,2,3,4,5 100 4-chloro-2,6-dinitroaniline 1,2,3,4,5 87 6-chloro-2,4-dinitroaniline 1,2,3,4,5 87 1-fluoro-2,4-dinitroaniline 1 75 1-f louro-2 , 4-dinitrobenzene 1 62. 5b a=median, T-test group, C-solvent control; b-toxic death TABLE 2 Anti-tumour activity against P388 (murine leukaemia).
Eight animals per group. IP treatment on day 1 to 5.
Dosage is per day.
Compound Dose TC%a 4-chloro-3,5-dinitrobenzene sulphonic acid 100mg kg~l 203 4-chloro-3 , 5-dinitrobenzene- sulphonic acid 50 mg kg'l 259 a=mean, T=test group, C=solvent control.
TABLE 3 Anti-tumour activity against P388 (murine leukaemia) treated ip with 4-chloro-3,5-dinitrobenzenesulfonic acid (CDNSA). 8 animals per group. Dosage is per day.
Compound Dose (mg/kg) Schedule (days) T/C%a CDNSA 100 1,2,3,4,5 2 2 5 75 1,2,3,4,5 3 0 0 a=mean, T-test group, C-solvent control TABLE 4 Anti-tumour activity against M5076-reticulum cell sarcoma 16 days after im transplant. 7 animals per group. Drugs dissolved in corn oil. Dosage is per day.
Compound Dose Route Schedule % Tumour Weight (mg/kg) (days) Inhibition 2,4 BA 75a ip 1,4,6,9 79,88b 50 ip 1,4,6,9 57 25 ip 1,2,4,6,9 75 75 sc 1,4,5,7,9 66 50 sc 1,2,4,5,6,7,9 76 25 sc 1,2,4,5,6,7,9 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 34 2,4 BM 1.0a ip 1,2,3,4,5,6,7,8,9 41 0.5 ip 1,2,3,4,5,6,7,8,9 39 0.25 ip 1,2,3,4,5,6,7,8,9 42 a = Maximum tolerated dose b = two independent experiments; 4 animals had no tumour in the second experiment 2,4 BA = 2,4-dichloro-3,5-dinitrobenzoic acid 2,4 BZ = 2, 4-dichloro-3 , 5-dinitrobenzamide 2,4 BM = 2,4-dichloro-3,5-dinitrobenzoic acid methyl ester % Tumour Weight Inhibition: Treated Control Agm Bgm Tumour weight % inhibition = B - A X 100 B TABLE 5 Anti-tumour activity against B16Fl-murine melanoma 12 days after sc transplant. 6 animals per group. Drugs dissolved in corn oil. Dosage is per day.
Compound Dose Route Schedule % Tumour Weight (mg/kg) (days) Inhibition 2,4 BA 75a ip 1,5 71,81b 50 ip 1,5 45,56b 25 ip 1,5 13 75 sc 1,3,5 30 50 sc 1,3,5 9 25 sc 1,3,5 22 2,4 BZ 2.5a ip 1,2 39 1.25 ip 1,2 17 4 BA 100 ip 1,5 39 75 ip 1 1,5 41 50 ip 1,5 10 4 BZ 5a ip 1,3,5 18 2.5 ip 1,3,5 18 1.25 ip 1,3,5 27 4BM 2.5a ip 1,3 67 1.25 ip 1,2,3 43 a = Maximum tolerated dose b = Two independent experiments 2,4 BA = 2,4-dichloro-3,5-dinitrobenzoic acid 2,4 BZ = 2,4-dichloro-3,5-dinitrobenzamide 4 BA = 4-chloro-3,5-dinitrobenzoic acid 4 BZ = 4-chloro-3,5-dinitrobenzamide 4 BM = 4-chloro-3,5-dinitrobenzoic acid methyl ester TABLE 6 Anti-tumour activity against MAC13 murine colon adenocarcinoma 12 days after im transplant. Drugs dissolved in corn oil. Dosage is per day.
Compound Dose Route Schedule % Tumour Weight (mg/kg) (days) Inhibition 2,4 BA 75a ip 1,4,5 45 2,4 BA 50 ip 1,2,3g4,5,6,7,8,9 39 2,4 BA graph3 ip graph graph3 2,4 BZ 2.5a ip 1,2,3,4,5,6,7,8,9 51 2,4 BZ 1.25 ip 1,2,3,4,5,6,7,8,9 17 2 BA graph4 ip graph4 graph4 a = maximum tolerated dose 2,4 BA = 2,4-dichloro-3,5-dinitrobenzoic acid3 2,4 BZ = 2,4-dichloro-3,5-dinitrobenzamide 2 BA = 2-chloro-5-nitrobenzoic acid (3: see Figure 3 of the drawings; 4: see Figure 4 of the drawings) TABLE 7 Anti-tumour activity against MACl6, murine colon adenocarcinoma sc transplant on day 11 after the beginning of treatment with 2,4-dichloro-3,5-dinitrobenzoic acid (2,4 BA). Drug dissolved in corn oil. The tumour volumes were at least 40mm3 at the beginning of the treatment. 6 animals per group. Dosage is per day.
Compound Dose Route Schedule % Tumour Weight (mg/kg) (days) Inhibition 2,4 BA 75a ip 1,2,5,8 88 50 ip 1,2,4,5,8 91 a = maximum tolerated dose TABLE 8 Anti-tumour activity against B16 murine melanoma 12 days after sc transplant on female C57/black mice. 6 animals per group. Dosage is per day and is ip.
Compound Dose Schedule % Tumour Weight (mg/kg) (days) Inhibition 2-chloro-5- 700 1,2,3,4,5,6 62 nitrobenzoic acid In addition, the following primary assay was used to investigate the anti-viral activity of compounds in accordance with the invention, in particular 4-chloro-3,5dinitrobenzenesulphonic acid.
Anti-tumour activity and toxicity studies have additionally been completed for the following compounds with broadly satisfactory results: - C22 2,5-dichloro-4-nitrobenzoic acid C23 2,4-dichloro-5-nitrobenzoic acid C24 2,6-dichloro-4-nitrobenzoic acid C25 2-amino-5-nitrobenzoic acid C26 2-hydroxy-5-nitrobenzoic acid C27 3,5-dichloro-4-nitrobenzoic acid PRIMARY ASSAY (i) Acute Infection Assay. High titre virus stocks of the human immunodeficiency virus HIV-1RF were grown in H9 cells with RPMI 1640 (Flow laboratories) supplemented with 10% fetal calf serum, penicillin (lOOIU/ml). Cell debris was removed by low speed centrifugation, and the supernatant stored at -700C until required. In a typical assay C8166 T-lymphoblastoid CD4+ cells were incubated with l0xTCID50 HIV-lRF at 370C for 90 minutes and then washed three times with phosphate buffered saline (PBS). Cell aliquots (2 x 105) were resuspended in 1.5 ml growth medium in 6 ml tubes, and compounds in log dilutions [200 M to 0.2gM] were added immediately. 20 mM stock solutions of each compound were made up in 70% alcohol. The compounds were stored as a powder and made up freshly in distilled water before each experiment or were stored as a 20 mM stock solution in 70% alcohol. The final concentration of alcohol in the tissue culture medium was 1%. The cells were then incubated at 370C in 5% CO2. At 72 hours postinfection 200 yl of supernatant was taken from each culture and assayed for HIV (Kingchington et al, 1989, Robert et al 1990) using an antigen capture ELISA which recognizes all the core proteins equally (Coulter Electronics, Luton, UK).
The following controls were used: supernatants taken from uninfected and infected cells, infected cells treated with AZT (Roche Products UK, Ltd) and ddC (Roche) and R031-8959 (Roche) an inhibitor of HIV proteinase. The IC50 activities of 8959, AZT and ddC in infected cells were 1, 10, 20 nM and 200 nM respectively (accompanying Figure 2). 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 assesses the activity of compounds by measuring their inhibition of HIV core antigen levels.
(ii) Chronically Infected Cell Assay. Chronically infected cells (H9rf) were washed three times to remove extracellular virus and incubated with the active compounds (200-0.2 pM) for four days. HIV-1 antigen in the supernatant was then measured using an ELISA.
To test for compound toxicity uninfected H9 cells were incubated with the compounds for four days. Supernatants were discarded and the cells resuspended in 20041 pg growth medium containing 14C protein hydrolysate. After 6 hours the cells were harvested and the 14C incorporation measured.
(iii) Toxicity Assay. To test for compound toxicity, aliquots of 2 x 105 of uninfected cells were cultured with the compounds in the same dilutions for 72 hours. The cells were then washed with PBSA and resuspended in 20041 of growth medium containing 14C protein hydrolysate. After 12 hours the cells were harvested and the 14C incorporation measured. Uninfected, untreated cells were used as controls. Toxicity is expressed as inhibition of uptake of 14C protein hydrolysate.
The results of these assays for 4-chloro-3,5 dinitrobenzenesulphonic acid are shown in accompanying Figure 1 in which RC stands for Radopath compound C i.e.
4-chloro-3,5-dinitrobenzenesulphonic acid. The results are also summarised in Table 9 below: TABLE 9 Compound IC50 CD50 TI 4-chloro-3 , 5 -dinitrobenzenesulphonic acid 3yM 80 M 28.6 The IC50 is the drug concentration that causes a 50% reduction in HIV core antigen levels as detected by the Coulter P24 antigen assay and is determined by doubling dilutions of supernatant taken from tubes containing untreated acutely infected cells. The CD50 is the concentration of drug that causes a 50% inhibition of cells as measured by 14C protein hydrolysate uptake. The therapeutic index (TI) is determined by dividing the CD50 by the IC50.
Further results for other compounds in accordance with the invention are summarised in Table 10 below: TABLE 10 Compound IC50 CDso TI 2-chloro-3,5-dinitrobenzenesulphonic acid 25pm > 200ym > 8 4-amino-3,5-dinitrobenzenesulphonic acid 20ym lOO m 5 2,4,6-trinitrophenol < 0.2 m 95 m > 475 4-chloro-3,5-dinitrobenzoic acid 30ym 70ym 2.33 Initial tests performed approximately contemporaneously indicated 2-chloro-5-nitrobenzoic acid would demonstrate performance at least as efficaceous, if not more so, as any of the compounds whose tests are reported herein.
Following the methodology set forth earlier for performance assay against HIV, more extensive assays were performed as reported in Tables 11 below: TABLE 11.1 STRUCTURE-ACTIVITY RELATIONSHIP AGAINST HIV VIRUS CODE COMPOUNDS Ag1C50 TOXCCSO GROUP A P1 picryl chloride P2 picric acid P3 picrylsulfonic acid (sodium salt) GROUP B C1 2,4-dichloro-3,5-dinitrobenzoic acid C2 2,4-dichloro-3,5-dinitrobenzamide C3 2,4-dichloro-3,5-dinitrobenzoic acid methyl ester C4 4-chloro-3 , 5-dinitrobenzoic acid C5 4-chloro-3 , 5-dinitrobenzamide C6 4-chloro-3,5-dinitrobenzoic acid methyl ester C7 2-chloro-3 , 5-dinitrobenzoic acid C8 2-chloro-3,5-dinitrobenzoic acid methyl ester C9 4-chloro-3-nitrobenzoic acid C10 2-chloro-4-nitrobenzoic acid C11 3,4-dichlorobenzoic acid C12 2,5-dichlorobenzoic acid Cl3 4-chlorobenzoic acid GROUP C S1 4-chloro-3,5-dinitrobenzenesulfonic acid S2 2-chloro-3,5-dinitrobenzenesulfonic acid S3 4-amino-3,5-dinitrobenzenesulfonic acid S4 4-chloro-3-nitrobenzenesulfonic acid S5 4-chlorobenzenesulfonic acid S6 4-nitrotoilnenesulfonic acid S7 2,5-dichlorobenzenesulfonic acid S8 2, 4-dinitrobenzenesulfonic acid TABLE 11.1 (CONT/D) GROUP D El l-chloro-3 , 4-dinitrobenzene E2 l-chloro-2,4-dinitrobenzene E3 1,2-dichloro-4,5-dinitrobenzene E4 2,3-dichloronitrobenzene E5 2, 4-dichloronitrobenzene E6 2,5-dichloronitrobenzene E7 3,4-dichloronitrobenzene E8 3,5-dichloronitrobenzene E9 1,5-dichloro-2,3-dinitrobenzene E10 1,2,3-trichloro-4-nitrobenzene Ell 1,2,4-trichloro-5-nitrobenzene E12 2,4,6-trichlorobenzene E13 2,3,4,6-tetrachloronitrobenzene E14 pentachloronitrobenzene TABLE 11.2 P-Compounds IC50 CC50 SI (Antiviral) (Toxicity) (Selectivity Index) Against HIV-1RF P1 0.6 7 10 5 0.4 Average 0.5 6 12 P2 38 67 2 P3 > 200 > 200 Against HIV-1IIIB P1 0.6 7 11.6 1 7 7 Average 0.8 7 9 Against chronicallv infected cells P1 0.9 7 8 2 12 6 Average 1.5 9.5 6 TABLE 11.3 C-Compounds IC50 CC50 SI (Antiviral) (Toxicity) (Selectivity Index) Against HIV-IIIB C1 5 70 14 36 70 2 33 70 2 35 60 2 Average 27 70 3 Against HIV-1RF C1 7 60 8.5 56 16 56 3.5 Average 11.5 57 5 Against chronicallv infected cells C1 16 30 2 16 95 6 Average 16 63 4 Against HIV-1IIIB C2 2 70 35 C3 0.3 7 23 C4 40 100 2.5 30 70 2.3 Average 35 85 2.4 C5 5 50 10 C6 5 60 12 C7 23 150 6 5 > 200 > 10 Average 22 > 175 8 C8 10 60 5 C9 > 200 > 200 C-10 > 200 > 200 C-ll > 200 > 200 C-12 > 200 > 200 TABLE 11.4 S-Compounds IC50 CC50 SI (Antiviral) (Toxicity) (Selectivity Index) Against HIV-1RF S1 20 100 5 19 60 3 Average 20 80 4 S2 NR S3 NR S4 > 200 > 200 55 > 200 > 200 S6 > 200 > 200 57 > 200 > 200 S8 40 100 2.5 30 70 2 Average 35 75 2.4 TABLE 11.5 E-Compounds IC50 CC50 SI (Antiviral) (Toxicity) (Selectivity Index) Against HIV-1RF El 4 10 2.5 E2 4 13 3 E3 4 7 1.5 E4 80 > 200 1.5 E5 180 > 200 1 E6 110 > 200 2 E7 > 200 > 200 E8 120 > 200 1.5 E9 ND E10 > 200 90 Ell > 200 > 200 E12 > 200 > 200 E13 > 200 80 E14 > 200 > 200 While the invention has been described above in various specific details, it will be appreciated that numerous and various modifications may be made within the spirit and scope of the claims which follow. Thus, for example, the functional groups can be in various other positions, of which the above specifically recited are examples only.

Claims (33)

1. A compound for use as a pharmaceutical, the compound comprising an aromatic ring structure having at least one labile leaving moiety and at least one electrophilic moiety.
2. A compound as claimed in Claim 1 and having the general formula:
wherein one of X1 to X6 is a labile leaving moiety, one of the balance thereof is an electrophilic moiety and the remainder are the same or different and are hydrogen or a substituent.
3. A compound as claimed in Claim 2 wherein X1 is a labile leaving moiety, one of X to X6 is an electrophilic moiety and the remainder are, each independently, hydrogen or a substituent, provided that when X2 and X6 are nitro groups, X4 is neither a nitro group, a sulphonic acid group nor a sulphonate group or xl is not a labile group as defined below, namely a hydroxy group, an amino group, a sulfo group, a carboxy group, a methyloxy group, halogen or a hydrazyl group of the formula:
wherein A is hydrogen or an unpaired electron of the nitrogen atom, Y is hydrogen or an organic group and Z is an organic group, or Y and Z together with the adjacent nitrogen atom form a nitrogen-containing heterocycle.
4. A compound as claimed in Claim 2 wherein one of X1 to x6 is a labile leaving moiety, one of the balance thereof is an electrophilic moiety, and the remainder are the same or different and are hydrogen or an substituent with at least two thereof being other than nitro, at least one being a labile moiety and at least one being an electrophilic moiety.
5. A compound as claimed in any one of Claims 2 to 4, wherein at least one of X1 to X6is an electrophilic moiety or labile moiety selected from the following:electrophilic moieties - SO3H, S03M (where M is a metal), halogen and NO2 labile moieties - halogen, SO3H, S03M (where M is a metal), optionally substituted NH2, COOH, optionally substituted CONH2 and COOR3 (where R3 is a metal or alkyl).
6. A compound as claimed in any preceding claim which has the general formula:
wherein: - X7 is S03H, S03M (where M is a metal), halogen, COQ (where Q is hydroxy, amino or substituted amino, or the group OR3 in which R3 is a metal or alkyl), NH2, substituted NH2, NO2 or OH; X8 is hydrogen, halogen, glutathione or nitro; X9, X10 and X11 are, each independently, hydrogen, halogen or nitro; and X12 is hydrogen, nitro, optionally substituted amino, halogen, alkyl or glutathione.
7. A compound as claimed in Claim 6 wherein: X7 is SO3H; X8 is hydrogen, halogen or glutathione; X9 and X10 are, each independently, hydrogen, halogen or nitro; X11 is hydrogen; and X12 is hydrogen, nitro, optionally substituted amino, halogen, alkyl or glutathione.
8. A compound as claimed in Claim 7 and as set forth by name below:8.1 4-chloro-3, 5-dinitrobenzenesulphonic acid 8.2 4-chlorobenzenesulphonic acid 8.3 2, 5-dichlorobenzenesulphonic acid 8.4 4-amino-3,5-dinitrobenzenesulphonic acid 8.5 3-nitro-4-methylbenzenesulphonic acid 8.6 2-chloro-3,5-dinitrobenzenesulphonic acid 8.7 2-glutathionyl-3 , 5-dinitrobenzenesulphonic acid 8.8 4-glutathionyl-3 , 5-dinitrobenzenesulphonic acid 8.
9 3-nitro-4-methylbenzenesulphonic acid 8.10 3-nitro-4-chlorobenzenesulphonic acid 8.11 2, 4-dinitrobenzenesulphonic acid 8.12 4-chloro-3,5-dinitrobenzene sulfonic acid 8.13 a salt of any of the acids listed as 8.1 and 8.12 9. A compound as claimed in Claim 6 wherein: X7 is halogen; Xs, X9, X10 and X12 are, each independently, hydrogen, halogen or nitro; and X11 is hydrogen.
10. A compound as claimed in Claim 9 and as set forth by name below:10.1 2,4-dinitrochlorobenzene 10.2 3,4-dinitrochlorobenzene 10.3 2,4-dinitrofluorobenzene 10.4 1,2-dichloro-4,5-dinitrobenzene 10.5 1,3-dichloro-4,5-dinitrobenzene 10.6 1,5-dichloro-2,3-dinitrobenzene
11. A compound as claimed in Claim 6 wherein: X7 is SO3H, SO3N (where M is a metal), NH2 or substituted NH2, halogen or hydroxy; x8 is nitro; X9 is hydrogen; X10 is hydrgen; X11 is nitro; and X12 is nitro.
12. A compound as claimed in Claim 11 nd as set forth by name below:12.1 2,4,6-trinitrophenol (picric acid), 12.2 2,4,6-trinitroaniline, 12.3 2,4,6-trinitrochlorobenzene.
13. A compound as claimed in Claim 6 wherein: X7 is a group of formula-COQ in which Q is hydroxy, optionally substituted amino or has the formula -OR3 in which R3 is alkyl or metal; X8 is hydrogen or halogen; X9 and X10 are, each independently, hydrogen, halogen or nitro; xll is hydrogen; and X is hydrogen, nitro, optionally substituted amino or halogen.
14. A compound as claimed in Claim 13 and as set forth below by name: 14.1 2-chloro-5-nitrobenzoic acid 14.2 2,4-dichloro-3,5-dinitrobenzoic acid or its alkyl ester 14.3 4-chloro-3,5-dinitrobenzoic acid or its alkyl ester 14.4 2,5-dichlorobenzoic acid 14.5 2,4-dinitrobenzoic acid 14.6 3,5-dinitrobenzoic acid 14.7 3-nitro-4-chloroanisole 14.8 4-amino-3,5-dinitrobenzamide 14.9 4-chloro-3 , 5-dinitrobenzamide 14.10 2, 4-dichloro-3 , 5-dinitrobenzamide
15. A compound as claimed in Claim 6 wherein: X7 is optionally substituted amino; and R8 to R12 are, each independently, hydrogen, halogen or nitro.
16. A compound as claimed in Claim 15 and as set forth below by name:16.1 2, 6-dinitroaniline 16.2 2,4-dinitroaniline 16. 3 3 , 5-dinitroaniline 16.4 2,4-dinitro-6-chloroaniline 16.5 2,6-dinitro-4-chloroaniline 16.6 2-chloro-4-nitroaniline 16.7 2,4-dinitro-5-fluoroaniline
17. A compound as claimed in any one of Claims 1 to 5 wherein a ring hydrogen provides a labile moiety, the compound having the general formula:
18. A compound as claimed in Claim 17 and as set forth by name below:18.1 1,2-dinitrobenzene 18.2 1, 3-dinitrobenzene 18.3 1, 4-dinitrobenzene
19. A compound as claimed in any one of Claims 2 to 5, wherein at least one of xl to X6is selected from:labile moiety/moieties - 1 or 2 halo groups and/or NH2 or substituted NH2 and/or COOH or substituted COOH and/or alkyl and/or SO3H/SO3M electrophilic moiety/moieties - 1 or 2 nitro groups and/or S03H/S03M and/or 1 or 2 halo groups
20. A compound for use in the treatment or prevention of cancer, pre-cancer or disease caused by viral infection, which compound comprises an aromatic ring structure having at least one labile leaving moiety and at least one electrophilic moiety.
21. A compound for use in the treatment or prevention of cancer, pre-cancer or disease caused by viral infection, the compound being selected from the following classes of organic compounds: 21.1 chlorodinitrobenzenesulphonic acid 21.2 chlorobenzenesulphonic acid 21.3 dichlorobenzenesulphonic acid 21.4 aminodinitrobenzenesulphonic acid 21.5 nitromethylbenzenesulphonic acid 21.6 glutathionyldinitrobenzenesulphonic acid 21.7 nitrochlorobenzenesulphonic acid 21.8 dinitrobenzenesulphonic acid 21.9 dinitrochlorobenzene 21.10 dinitrofluorobenzene 21.11 dichlorodinitrobenzene 21.12 trinitrophenol e.g. picric acid 21.13 trinitroaniline 21.14 trinitrochlorobenzene 21.15 trinitrobenzenesulphonic acid 21.16 chloronitrobenzoic acid 21.17 chlorodinitrobenzoic acid 21.18 dichlorobenzoic acid 21.19 dichloronitrobenzoic acid 21.20 dichlorodinitrobenzoic acid 21.21 dinitrobenzoic acid 21.
22 nitrochloroanisole 21.
23 aminodinitrobenzamide 21.
24 dinitroaniline 21.
25 dinitrochloroaniline 21.26 chloronitroaniline 21.27 dinitrofluoroaniline 22. A compound for use in the treatment or prevention of cancer, pre-cancer or disease caused by viral infection, the compound being a compound as set forth below by name:22.1 2,4,6-trinitrophenol 22.2 2 ,4-dichloro-3, 5-dinitrobenzoic acid 22.3 4-chloro-3 , 5-dinitrobenzoic acid 23. A compound for use in the treatment or prevention of cancer or pre-cancer, the compound being a compound as set forth below by name:23.1 1,5-dichloro-2,3-dinitrobenzene 23.2 2-chloro-5-nitrobenzoic acid 23.3 4-chlorobenzenesulfonic acid 23.4 4-chloro-3,5-dinitrobenzene sulfonic acid 24. A compound for use in the treatment or prevention of disease caused by viral infection, the compound being a compound as set forth below by name:24.1 4-chloro-3, 5-dinitrobenzamide 24.2 2, 4-dichloro-3 , 5-dinitrobenzamide 25. A pharmaceutical composition, which composition comprises a compound according to any preceding claim and a pharmaceutically-acceptable diluent or carrier.
26. A composition as claimed in Claim 25, wherein the diluent or carrier is aqueous.
27. A composition as claimed in Claim 25 or Claim 26 which is in unit dosage form.
28. A composition as claimed in Claim 27 which is in the form of a tablet, capsule, powder, solution or suspension.
29. Use of a compound as claimed in any one of Claim 1 to 24 for the preparation of a medicament for the prophylaxis or therapy of cancer, pre-cancer or viral infection.
30. Use as claimed in Claim 29 wherein the compound is at a concentration and dose which enables an arylating mechanism to be brought into play.
31. A method of treating disease caused by viral infection, which method comprises administering an effective amount of a compound as claimed in any one of Claims 1 to 24 or a composition as claimed in any one of Claims 25 to 28.
32. A method of treating cancer or pre-cancer to reduce or eliminate cancerous growth, which method comprises administering an effective amount of a compound as claimed in any one of Claims 1 to 24 or a composition as claimed in any one of Claims 25 to 28.
33. A chloro or nitro-benzenesulfonic acid compound, a chloro- or nitro-benzoic acid compound or chloro or nitrobenzamide compound for use as a pharmaceutical.
GB9410420A 1993-05-21 1994-05-23 Substances for use in treatment of HIV-infection in HIV-infected patients Expired - Fee Related GB2284153B (en)

Priority Applications (2)

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GB9715492A GB2312375B (en) 1993-05-21 1994-05-23 Agents for treatment of cancer
GB9410420A GB2284153B (en) 1993-05-21 1994-05-23 Substances for use in treatment of HIV-infection in HIV-infected patients

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GB939310520A GB9310520D0 (en) 1993-05-21 1993-05-21 Arylating agents
GB9405292A GB9405292D0 (en) 1993-05-21 1994-03-17 Arylating agents
GB9410420A GB2284153B (en) 1993-05-21 1994-05-23 Substances for use in treatment of HIV-infection in HIV-infected patients

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GB2284153A true GB2284153A (en) 1995-05-31
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GB2311221A (en) * 1996-03-18 1997-09-24 Radopath Ltd Arylating agents for the treatment of viral infection
WO2004041256A3 (en) * 2002-11-08 2004-09-02 Novo Nordisk As Safe chemical uncouplers for the treatment of obesity
US7012100B1 (en) 2002-06-04 2006-03-14 Avolix Pharmaceuticals, Inc. Cell migration inhibiting compositions and methods and compositions for treating cancer

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GB866516A (en) * 1956-05-21 1961-04-26 Salsbury S Lab Substituted dinitrobenzamides and veterinary compositions containing them
GB1083001A (en) * 1963-10-29 1967-09-13 Merck & Co Inc Preparation and use of 2,6-dichloro-4-nitrobenzamide
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GB866516A (en) * 1956-05-21 1961-04-26 Salsbury S Lab Substituted dinitrobenzamides and veterinary compositions containing them
GB1083001A (en) * 1963-10-29 1967-09-13 Merck & Co Inc Preparation and use of 2,6-dichloro-4-nitrobenzamide
WO1991015200A2 (en) * 1990-04-03 1991-10-17 Radopath Limited Use of trinitrobenzenes or carminic acid in the treatment of cancer or viral diseases

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2311221A (en) * 1996-03-18 1997-09-24 Radopath Ltd Arylating agents for the treatment of viral infection
US7012100B1 (en) 2002-06-04 2006-03-14 Avolix Pharmaceuticals, Inc. Cell migration inhibiting compositions and methods and compositions for treating cancer
US7700615B2 (en) 2002-06-04 2010-04-20 Avolix Pharmaceuticals, Inc. Cell migration inhibiting compositions and methods and compositions for treating cancer
WO2004041256A3 (en) * 2002-11-08 2004-09-02 Novo Nordisk As Safe chemical uncouplers for the treatment of obesity

Also Published As

Publication number Publication date
GB2284153B (en) 1998-02-25
GB2312375A (en) 1997-10-29
GB9715492D0 (en) 1997-10-01
GB2312375B (en) 1998-02-25
GB9410420D0 (en) 1994-07-13

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