GB2288333A - Benzoic acid containing chloro and or nitro groups for cancer or viral therapy - Google Patents

Benzoic acid containing chloro and or nitro groups for cancer or viral therapy Download PDF

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GB2288333A
GB2288333A GB9505468A GB9505468A GB2288333A GB 2288333 A GB2288333 A GB 2288333A GB 9505468 A GB9505468 A GB 9505468A GB 9505468 A GB9505468 A GB 9505468A GB 2288333 A GB2288333 A GB 2288333A
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compound
chloro
dichloro
nitro
together represent
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GB9505468D0 (en
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Washington Odur Ayuko
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RADOPATH Ltd
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RADOPATH Ltd
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Priority claimed from GB9405292A external-priority patent/GB9405292D0/en
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Priority to GB9505468A priority Critical patent/GB2288333A/en
Priority to GB9614210A priority patent/GB2303790A/en
Publication of GB9505468D0 publication Critical patent/GB9505468D0/en
Publication of GB2288333A publication Critical patent/GB2288333A/en
Priority to PCT/GB1996/000650 priority patent/WO1996029067A1/en
Priority to AU51153/96A priority patent/AU5115396A/en
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    • 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
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Abstract

A compound of the general formula: wherein X 1 and X 2 are, independently chloro or hydrogen and X 3 and X 4 are, independently a nitro or hydrogen provided that at least two of X 1-4 is other than hydrogen. The compound may be administered in tablet or injectable solution form and is intended for prophylactic or therapeutic use in the treatment of neoplasia or viral infection. 2-chloro-5-nitro-benzoic acid is a preferred embodiment. Experimental data illustrating the anti-tumour and anti-HIV properties of these compounds is given.

Description

ANTI-VIRAL & ANTI-CANCER 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 infections (eg retrovirus infections such as HIV. As shown by studies reported herein, the compounds of the invention show marked anti-tumour activity and in AIDS and pre-AIDS therapy show the capacity to regress Kaposi's sarcoma, improve CD4 count in humans, increase the level of various blood parameters in murine patient models and to achieve weight gain and general patient condition by action against HIV and/or its effects (eg opportunistic disease).
According to the invention, there is provided a compound of the following general formula for use in the treatment of prophylaxis or therapy of neoplasm or viral infection such as HIV-infection:
wherein Xl and X2 are, each independently, hydrogen or chloro and wherein X3 and X4 are, each independently, hydrogen or nitro, provided that at least two of Xl, X2, X3 and X4 are other than hydrogen, or a salt or ester thereof (eg a salt wherein -COOH is substituted by -COOR in which R is optionally substituted amino).
Conveniently, X1 is chloro, X2 is chloro or hydrogen, X3 iS nitro and X4 is nitro or hydrogen. The following are preferred compounds:2, 4-dichloro-3, 5-dinitrobenzoic acid 4-chloro-3, 5-dinitrobenzoic acid 2-chloro-3, 5-dinitrobenzoic acid 2-chloro-5-nitrobenzoic acid 2, 5-dichlorobenzoic acid 2, 4-dinitrobenzoic acid 3, 5-dinitrobenzoic acid 2, 5-dichloro-4-nitrobenzoic acid 2, 4-dichloro-5-nitrobenzoic acid 2, 6-dichloro-4-nitrobenzoic acid 3, 5-dichloro-4-nitrobenzoic acid 4-chloro-3 -nitrobenzoic acid 2-chloro4-nitrobenzoic acid 3, 4-dichlorobenzoic acid Since treatment in accordance with the invention is by what is believed to be an arylating mechanism, use is typically at relatively high concentrations and, consequently, doses. Generally, the recommended dosage is lmg/kg body weight to 30mg/kg body weight per day for 5 days weekly.
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. Postpreparation sterilization may be required, at least following formulation of the compounds into pharmaceutical composition form.
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 pharmaceutically-acceptable 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 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. In the case of the use according to the invention of sodium salts of the active compounds, the active ingredient is preferably administered as an aqueous solution.
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 50mg/kg typically up to about 1000mg/kg (eg up to about 400mg/kg, conveniently about 200mg/kg or less). Thus it is to be expected that a typical dosage for humans will be from about Smg/kg upwards (eg up to about 20mg/kg). The concentration and dose are to be sufficient to bring an arylating mechanism into play. For intravenous administration the active compound will be dissolved or dispersed in an aqueous or other injectable liquid bearing in mind the aforementioned requirements of dosage.
Typically, concentration will be 250mg/ml or less. Patient tolerance was found to be of a higher order for concentrations below that threshold although concentrations of more than 250mg/ml may be used. Typically, a preferred concentration is less than 100mg/ml, with concentrations below 50mg/ml (eg 40mg/ml) being preferred. For oral administration, enteric coated tablets will often be preferred. Maximum strength will be less than 500mg and preferably 400mg or less. Thus, for example, a range of strengths for oral administration (whether in tablet or other solid form) will be 100mg, 200mg or 400mg. Patients who are subject to oral administration will generally fast for 8 hours prior to first dose with the fast continuing for 4 hours after first dose. Free access to fluid will generally be allowed during this fasting period. Intravenous treatment will generally take place by administration very slowly over a period, typically a period of approximately 20 minutes or more. Administration will typically be by catheter, for example a catheter left in situ after flashing with 2ml of saline. Of course, the catheter will in practice then be used for taking blood samples for pharmacokinetic measurements and removed prior to the patient's departure from the clinic.
As shown by the results reported in Table 6 below, 2-chloro-5-nitrobenzoic acid shows considerable 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 in vivo anti-tumour responses of various compounds according to the invention were assessed against the ascitic tumours, MAC1SA murine colon adenocarcinoma and various solid tumour models. The MAC1SA ascites tumour cells were transplanted into male NMRl mice by ip innoculation at a cell density of 1 x 105 cells in 200p1 buffer (Table 1). The solid tumour models included the MAC13 and MAC16 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 200C11. 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 6 below.
Preparation Preparation of dosage solutions is exemplified as follows: Subjects: No 10 animals Weight: 22g Dosage: 50mgAcg weight per animal per day thus 1. lmg 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 1 .lmg dissolves in 200C11 solvent T/C% T/C% is determined as follows: Animal Survival B Control T days C days T/C% = T X 100 C Example 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 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 MAC 15A 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. Against the M5076 reticulum cell sarcoma, 2, 4-dichloro-3, 5-dinitrobenzoic acid showed activity on a split-dose schedule down to 25mg/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 anti-tumour activity. The acid also effectively inhibited growth of B 16 murine melanoma and the MAC 16 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 MAC1SA (murine adenocarcinoma colon). 5 animals per group. Dose 100mg kg-l ip per day.
Code Compound Schedule T/C%a (days) C4 4-chloro-3, 5-dinitrobenzoic acid 1, 2, 3, 4, 5 271 C1 2, 4-dichloro-3, 5-dinotrobenzoic acid 1,2 243 C12 2, 5-dichlorobenzoic acid 1, 2, 3, 4, 5 171 C28 2, 4-dinitrobenzoic acid 1,2, 3, 4, 5 100 C29 3, 5-dinitrobenzoic acid 1, 2, 3, 4, 5 100 a = median, T-test group, C-solvent control TABLE 2 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 75" ip 1, 4, 6, 9 79, nub 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 2,4BM 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 (C1) 2,4 BM = 2, 4-dichloro-3, 5-dinitrobenzoic acid methyl ester (C3) % Tumour Weight Inhibition: Treated Control Agm Bgm Tumour weight % inhibition = B - A X 100 TABLE3 Anti-tumour activity against B16F1-murine melanoma 12 days after sc transplant. 6 animals per group. Drugs dissolves 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 4BA 100 ip 1, 5 39 75 ip 1,5 41 50 ip 1,5 10 4 BM 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 (Cl) 4BA = 4-chloro-3, 5-dinitrobenzoic acid (C4) 4 BM = 4-chloro-3, 5-dinitrobenzoic acid methyl ester (C6) TABLE4 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 2,4BA 50 ip 1,2,3,4,5,6,7,8,9 39 2, 4 BA graph1 ip graph1 graph1 2 BA graph2 ip graph2 graph2 a = Maximum tolerated dose 2, 4 BA = 2, 4-dichloro-3, 5-dinitrobenzoic acid' (C1) 2 BA = 2-chloro-5-nitrobenzoic acid (C17) (1: see Figure 2 ofthe drawings; 2: see figure 3 ofthe drawings) TABLE 5 Anti-tumour activity against MAC16, murine colon adenocarcinoma sc transplanted on day 11 after the beginning of treatment with 2, 4-dichloro-3, 5-dinitrobenzoic acid (2, 4 BA; Cl). 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 2,4BA 75a ip 1,2,5,8 88 50 ip 1,2,4,5,8 91 a = Maximum tolerated dose TABLE 6 Anti-tumour activity of C17 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.
Code Compound Dose Schedule % Tumour Weight (mg/kg) (days) Inhibition C17 2-chloro-5- 700 1, 2, 3, 4, 5, 6 62 nitrobenzoic 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 C26 2-hydroxy-5-nitrobenzoic acid C27 3, 5-dichloro-Pnitrobenzoic acid In addition, the following primary assay was used to investigate the anti-viral activity of compounds in accordance with the invention.
Primarv Assay (i) Acute Infection Assay. High titre virus stocks of the human immunodeficiency virus HIV-1RF were grown in H9 cells with RM1 1640 (Flow laboratories) supplemented with 10% fetal calf serum, penicillin (1 001U/ml). Cell debris was removed by low speed centrifugation, and the supernatant stored at -700C until required. In a typical assay C8 166 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 1.5my growth medium in 6ml tubes, and active compounds in log dilutions [200C1M to 0.2)1M] were added immediately. 20mM 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 90 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 post-infection 200p1 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 200nM 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 FM) 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 200,eL1 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 200jim of growth medium containing 14C protein hydrolysate. After 12, hours the cells were harvested and the '4C incorporation measured. Uninfected, untreated cells were used as controls.
Toxicity is expressed as inhibition of uptake of'4C protein hydrolysate.
The results of these assays are summarized in Table 7 below. 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 CDso 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 bythelC50.
TABLE 7 Code Compound 50 CDso TI C4 4-chloro-3, 5-dinitrobenzoic acid 30 m 70 m 2.33 Following the same methodology, more extensive assays were performed as reported in Tables 8 below.
TABLE 8.1 STRUCTURE ACTIVITY RELATIONSHIP AGAINST HIV VIRUS CODE COMPOUNDS C1 2, 4-dichloro-3, 5-dinitrobenzoic acid C3 2, 4-dichloro-3, 5-dinitrobenzoic acid methyl ester C4 4-chloro-3, 5-dinitrobenzoic acid 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 Cli 3, 4-dichlorobenzoic acid C12 2, 5-dichlorobenzoic acid C17 2-chloro-5-nitrobenzoic acid TABLE 8.2 IC50 CC50 SI (Antiviral) (Toxicity) (Selectivity Index) Against HIV-I IIIB C1 5 70 14 36 70 2 33 70 2 35 60 2 Average 27 70 3 C1 10 30 3 2.5 20 8 Against HIV-IRF C1 7 60 8.5 56 16 56 3.5 Average 11.5 57 5 Against Chronically infected cells C1 16 30 2 16 95 6 Average 16 63 4 Against HIV-1-IIIB 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 C7 > 1 35 > 35 10 30 3 C8 10 60 5 C9 > 200 > 200 C10 > 200 > 200 C11 > 200 > 200 C12 > 200 > 200 Against HIV-I IIIB 17 > 1 > 1000 > 1000 5 > 1000 > 200 Patient Tests A pilot study was conducted for safety, pharmacokinetics and preliminary activity of C17 in patients with HIV-1 infection and HIV-related Kaposi's sarcoma. In the pilot study, 10 patients were enrolled but only 6 were eligible for evaluation. These patients were positive for serum antibody to HIV-1 as determined by both enzymelinked immunosorbent assay (ELISA) and Western Blot. These patients had WHO Clinical Stage 2 to 3 for HIV infection and disease and fulfilled the inclusion and exclusion criteria as per the Clinical Trial Protocol. Their CD4 ranged from 0.072 to 0.812 x 103 cells/mm3 (normal range 1.0 x 1.3 x 103 cells/mm3). Patient 6 had AIDSrelated Kaposi's sarcoma confirmed on histology.
C17 was prepared for intravenous administration under GMP (good manufacturing practice) in strength of 40 mg/ml following the method set forth below for producing a 250mg/ml solution, additional water being added at Step 7: Method of Preparation 1. To 275ml water for injection add 266.4m1 4N sodium hydroxide solution and mix.
2. Add with stirring 182.5g of active compound.
3. Add additional 4N sodium hydroxide if needed to obtain solution.
4. Filter solution through a Sterivex GV 0.22clam filter.
5. Dilute to approximately 680ml with water for injection.
6. Adjust to pH 7.2-7.6 with hydrochloric acid.
7. Make-up to 730ml water for injection. Adjust pH if necessary.
8. Transfer solution to aseptic room and filter through Sterivex GV 0.22jim filter into injection vials. Seal with rubber stoppers and aluminium closures.
9. Effect terminal sterilization by autoclave.
The patients received 10mglkg body weight/day of C17 by deep intramuscular injection daily for 5 days weekly. The CD4 counts were estimated before and at about 2 weeks after the beginning of the therapy.
The CD4 counts in all 6 patients showed an increase which was associated with clinical improvements in patient general condition including weight gain and a marked decrease in opportunistic infections and diaorrhea. Patient observations are shown in Tables 9 below.
In the case of Patient 6, the sarcoma lesions disappeared.
Murine Haematologv Preliminary data on the administration of C17 in mice and rats showed increases in red blood cell count, haemoglobin concentration, macrophage count, white blood cell count (WBC), lymphocyte count and haematocrit (HTC) on day 7 when maximum tolerated dose (MTD) was given by 5 consecutive daily intravenous injections. These values returned to normal on day 14. The MTD values were 950mg and 900mg/kg body weight/day respectively in mouse and rat. The data are reported in Figures 4 to 11.
TABLE 9.0 (Summarizing Tables 9 1 to 9.6) PATIENTS 1 TO 6 IMMUNOLOGY: PATIENT 1 2 3 4 5 6 Before After Before After Before After Before After Before After Before After Lymphocytes x 103mm-3 2.1 2.0 2.0 1.9 0.9 1.1 1.8 2.0 2.8 3.1 2.1 1.9 CD4% 19 38 18 27 8 17 6 22 29 33 18 23 CD4 ABS/mm3 0.399 0.760 0.360 0.513 0.072 0.187 0.108 0.440 0.812 1.023 0.378 0.437 CD8 ABS/mm3 0.567 0.840 0.940 0.874 0.270 0.682 1.350 1.260 1.456 1.550 1.218 0.931 CD4/CD8 0.70 0.90 0.38 0.59 0.27 0.27 0.08 0.35 0.56 0.66 0.31 0.47 TABLE 9.1 PATIENT 1 IMMUNOLOGY: DAY 1 20 Lymphocytes x 103mm-3 2.1 2.0 CD4% 19 38 CD4 ABS/mm3 0.399 0.760 CD8 ABS/mm3 0.567 0.840 CD4/CD8 0.70 0.90 TABLE 9.2 PATIENT 2 IMMUNOLOGY: DAY 1 14 Lymphocytes x 103mm~3 2.0 1.9 CD4% 18 27 CD4 ABS/mm3 0.360 0.513 CD8 ABS/mm3 0.940 0.874 CD4/CD8 0.38 0.59 TABLE 9.3 PATIENT 3 IMMUNOLOGY: DAY 1 20 Lymphocytes x 103mum~3 0.9 1.1 CD4% 8 17 CD4 ABS/mm3 0.072 0.187 CD8 ABS/mm3 0.270 0.682 CD4/CD8 0.27 0.27 TABLE 9.4 PATIENT 4 IMMUNOLOGY: DAY 1 14 Lymphocytes x 103mm-3 1.8 2.0 CD4% 6 22 CD4 ABS/mm3 0.108 0.440 CD8 ABS/mm3 1.350 1.260 CD4/CD8 0.08 0.35 TABLE 9.5 PATIENT 5 IMMUNOLOGY: DAY 1 21 Lymphocytes x 103mm-3 2.8 3.1 CD4% 29 33 CD4ABS/mm3 0.812 1.023 CD8 ABS/mm3 1.456 1.550 CD4/CD8 0.56 0.66 TABLE 9.6 PATIENT 6 IMMUNOLOGY: DAY 1 34 Lymphocytes x 103mm~3 2.1 1.9 CD4% 18 23 CD4 ABS/mm3 0.378 0.437 CD8 ABS/mm3 1.218 0.931 CD4/CD8 0.31 0.47

Claims (21)

  1. Claims 1. A compound of the following general formula for use in the treatment of prophylaxis or therapy of neoplasm or viral infection:
    wherein X1 and X2 are, each independently, hydrogen or chloro and wherein X3 and X4 are, each independently, hydrogen or nitro, provided that at least two of X1, X2, X3 and X4 are other than hydrogen, or a salt or ester thereof.
  2. 2. A compound as claimed in Claim 1 wherein X1 is chloro, X2 is chloro or hydrogen, X3 iS nitro and X4 iS nitro or hydrogen.
  3. 3. A compound as claimed in Claim 2 wherein X1 and X2 are other than 4-chloro.
  4. 4. A compound as claimed in Claim 1 or Claim 2 wherein X1 and X2 together represent 2-chloro-, 4-chloro-, 2,5-dichloro-, 2, 4-dichloro-, 2, 6-dichloro-, 3, 5dichloro- or 3, 4-dichloro- and wherein X3 and X4 together represent two hydrogen atoms, 3-nitro-, 4-nitro-, 5-nitro-, 2, 4-dinitro- or 3, 5-dinitro-, provided that: (i) when X3 and X4 together represent 3, 5-dinitro-, Xl and X2 together represent 2-chloro-, (ii) when X3 and X4 together represent 5-nitro-, X1 and X2 together represent 2 chloro- or 2, 4-dichloro-, (iii) when X3 and X4 together represent two hydrogen atoms, X1 and X2 together represent 3, 4-dichloro-, (iv) when X3 and X4 together represent 4-nitro-, Xl and X2 together represent 2, 5 dichloro-, 3, 5-dichioro-2-chioro- or 2, 6-dichloro-, (v) when X3 and X4 together represent 3-nitro-, X1 and X2 together represent 4 chioro-.
  5. 5. A compound as claimed in Claim 4 wherein Xl X2, X3 and X4 are as there defined subject to provisos (I), (ii), (iv) and (v) and subject to the further proviso that when X3 and X4 together represent 5-nitro-, X1 and X2 together represent 2, 4 dichloro-.
  6. 6. 2-chloro-5-nitro-benzoic acid.
  7. 7. A compound as claimed in Claim 1 and as set forth by name below or an ester or salt thereof:7.1 2, 4-dichloro-3, 5-dinitrobenzoic acid 7.2 4-chloro-3, 5-dinitrobenzoic acid 7.3 2-chloro-3, 5-dinitrobenzoic acid 7.4 2, 5-dichlorobenzoic acid 7.5 2, 4-dinitrobenzoic acid 7.6 3, 5-dinitrobenzoic acid 7.7 2, 5-dichloro-4-nitrobenzoic acid 7.
  8. 8 2, 4-dichloro-5-nitrobenzoic acid 7.9 2, 6-dichloro-4-nitrobenzoic acid 7.10 3, 5-dichloro-4-nitrobenzoic acid 7.10 4-chloro-3-nitrobenzoic acid 7.12 2-chloro-4-nitrobenzoic acid 7.13 3, 4-dichlorobenzoic acid 8. A pharmaceutical composition for use in the treatment by prophylaxis or therapy of neoplasm or viral infection, the composition comprising a compound as claimed in any preceding claim together with a pharmaceutically-acceptable carrier or diluent.
  9. 9. A composition as claimed in Claim 8 wherein the carrier or diluent is aqueous.
  10. 10. A composition as claimed in Claim 8 wherein the carrier is a solid excipient.
  11. 11. A composition as claimed in Claim 8 which is in tablet, capsule, powder, solution or suspension form.
  12. 12. A composition as claimed in any one of Claims 8 to 11 which is in unit dosage form.
  13. 13. A composition as claimed in any one of Claims 8 to 12 and comprising 2chloro-5-nitrobenzoic acid, or a salt or ester thereof, encapsulated by a soft gel capsule or contained by a sustained release drug delivery system.
  14. 14. A method of preparing a pharmaceutical composition as claimed in any one of Claims 8 to 13 which method comprises combining a compound as claimed in any one of Claims 1 to 7 with aqueous sodium hydroxide solution to form a solution, adjusting the pH of the solution to an alkaline pH of not more than 8 by addition to the solution of an acidic material, optionally diluting the pH-adjusted solution with physiologically injectable water and sterilizing the solution.
  15. 15. A method of treatment by prophylaxis or therapy of neoplasm or viral injection in mammalian subjects, which method comprises administering to a mammalian subject an effective dose or dosage regime of a compound as claimed in any one of Claims 1 to 7.
  16. 16. Use of a compound as claimed in any one of Claims 1 to 7 for the preparation of a medicament for the treatment by prophylaxis or therapy of neoplasm or viral infection in mammalian subjects.
    ADDITIONAL CLAIMS
  17. 17. Use of a compound as claimed in any one of Claims 1 to 7 for the treatment of Kaposi's sarcoma
  18. 18. Use of a compound as claimed in any one of Claims 1 to 7 for the preparation of a medicament for the treatment of Kaposi's sarcoma.
  19. 19. A method of treatment of mammals for the prophylaxis of Kaposi's sarcoma which method comprises administering to the patient an effective dose of a compound as claimed in any one of Claims 1 to 7.
  20. 20. A pharmaceutical composition in the form of enteric coated tablets comprising a compound as claimed in any one of Claims 1 to 7 in strength 100 to 400mg, the compound being formulated as a mixture comprising the compound together with an inert pharmaceutically-acceptable solid tabletting carrier.
  21. 21. A pharmaceutical composition in the form of an injectable solution or dispersion of a compound as claimed in any one of Claims 1 to 7 in an aqueous or other injectable liquid carrier in a concentration of less than 250mg/ml.
GB9505468A 1994-03-17 1995-03-17 Benzoic acid containing chloro and or nitro groups for cancer or viral therapy Withdrawn GB2288333A (en)

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GB9505468A GB2288333A (en) 1994-03-17 1995-03-17 Benzoic acid containing chloro and or nitro groups for cancer or viral therapy
GB9614210A GB2303790A (en) 1994-03-17 1995-03-17 Benzoic acid containing chloro and or nitro groups for cancer or viral therapy
PCT/GB1996/000650 WO1996029067A1 (en) 1995-03-17 1996-03-18 Anti-viral and anti-cancer agents
AU51153/96A AU5115396A (en) 1995-03-17 1996-03-18 Anti-viral and anti-cancer agents

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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

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CN111116395B (en) * 2019-12-27 2023-04-07 湖北工业大学 Multi-iodo aromatic acid compound and application thereof in resisting adenovirus 7

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EP0098098A2 (en) * 1982-06-25 1984-01-11 Development Finance Corporation Of New Zealand Acridinecarboxamide compounds
JPS60258116A (en) * 1984-06-06 1985-12-20 Adeka Argus Chem Co Ltd Radiation sensitizer
WO1994027584A2 (en) * 1993-05-21 1994-12-08 Radopath Limited Arylating medicaments

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EP0098098A2 (en) * 1982-06-25 1984-01-11 Development Finance Corporation Of New Zealand Acridinecarboxamide compounds
JPS60258116A (en) * 1984-06-06 1985-12-20 Adeka Argus Chem Co Ltd Radiation sensitizer
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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

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