GB2119793A

GB2119793A - Azo compounds

Info

Publication number: GB2119793A
Application number: GB08311156A
Authority: GB
Inventors: Douglas Shortridge
Original assignee: Individual
Current assignee: Individual
Priority date: 1982-04-28
Filing date: 1983-04-25
Publication date: 1983-11-23
Also published as: GB2119793B; GB8311156D0

Abstract

A compound, useful as an anti- cancer drug or agent, having the formula R1-X-R2 where X represents a polynuclear aromatic or heteroaromatic hydrocarbon having between two and four fused rings which may be substituted by hydroxyl, amino, alkylamino, alkoxy or halogeno, R1 represents:- <IMAGE> where y represents one member selected from:- <IMAGE> or alkylated derivatives thereof, and R2 represents hydrogen or R1, an acid addition salt of said compound, a nitrogen oxide derivative of said compound in the case where it contains a ring nitrogen atom or atoms, and a quaternary salt of said compound in the case where it contains a ring nitrogen atom or atoms.

Description

SPECIFICATION Anti-tumour compounds This invention relates to chemical compounds useful for the purpose of cancer research and comprises a group of such compounds which exhibit activity against cancer in experimental animals.

In the field of anti-tumour compounds and compounds active against leukaemia, research is directed towards the discovery of compounds having a selective action against the tumour cell, and usually makes progress by the screening of large numbers of compounds which are chemically simiiar to compounds of known and established medical value. The present invention is the outcome of a theoretical approach to this subject based, inter alia, on considerations of selective bonding between the tumour cell and a compound of specific size, shape and electrical charge distribution, which can lead to the eventual destruction or control of the tumour cell.

This invention relates to materials of the general structure:

where R, represents hydrogen, hydroxy, amino or alkylamino. R2 represents between one and three aromatic ring structures annelated to one of the phenyl rings of azobenzene, or its azalogue. R3 represents a basic grouping

where R1 and R2 represent hydrogen or an alkyl group.

I have discovered that materials of this general type, which may be regarded as basic derivatives of azobenzene or its azalogue, possess anti-tumour properties.

It is also convenient to regard these materials as derivatives of aromatic or heteroaromatic polynulcear hydrocarbons of between two and four fused rings, possessing also as substituent one or more phenylazo groups of which the phenyl ring carries as substituent a basic amidine structure.

Where an alkyl group is or forms part of a substituent it preferably is C1-C4 alkyl, and more preferably is methyl or ethyl.

Any of the annelated rings that together form the condensed hydrocarbon portion of the structure may contain one or more ring nitrogen atoms, which may be present in N oxide form if desired.

This invention also includes compounds of the above mentioned general character in which nuclear substituents are present at one or more positions in any of the rings, e.g. halogeno, hydroxy, alkyl, alkoxy, amino, alkylamino substituents. Those compounds with a methyl group a to a ring nitrogen are especially preferred.

Further derivatives are obtained by quaternisation with suitable alkyl halides or esters.

The products are desirably prepared and used as the acid addition salts of any appropriate inorganic or organic acid. Materials carrying a second basic phenyl azo grouping as a substituent are especially preferred, as also are those compounds possessing a total of four or five aromatic or heteroaromatic ring structures.

The azo compounds are made by methods well known to those skilled in the art. It is most convenient to do so by coupling the diazonium salt of an aniline containing one of the desired basic groupings with a polynuclear aromatic or heteroaromatic hydrocarbon carrying one or more activating substituents to make coupling possible such as for example hydroxyl, amino or alkylamino. The nature of the activating grouping is not critical.

Compounds in accordance with the invention are active against the P388 leukaemia in mice and may be administered by injection, or orally, at a dose rate of, for example, 20 to 50 mg per kilogram of animal per day.

The survival time of mice treated with these substances has been extended typically by some 50% and much longer in some cases as compared with untreated mice after implantation of the leukaemia for the control mice.

The compounds are also active against solid tumours.

It will be appreciated that the invention also embraces pharmaceutical compositions containing any of the aforementioned compounds as the active constituent and methods for preparing such compounds in a form suitable for administration.

The invention will now be further described with detailed examples of the preparation of typical compounds in the form of hydrochloride salts but these examples do not limit the invention thereto.

Example I Preparation of the compound of the formula:-

2.0 grs. para amino benzamidine dihydrochloride is dissolved in 50 ml water and 1.0 ml concentrated hydrochloric acid and diazotised by addition of 0.7 gr sodium nitrite dissolved in 5 ml water desirably keeping all at under 100C. Excess nitrous acid is removed by careful addition of sulphamic acid, testing with starch iodide paper. The diazonium solution is then coupled with 1.0 gr 2.6 dihydroxy naphthalene dihydrate dissolved in 100 ml water with 0.4 gr sodium hydroxide and 10 ml pyridine, all at under 1 OOC., maintaining the pH value at approximately 8. When coupling is complete the resultant mixture is adjusted to a pH value of approximately 6 with hydrochloric acid, though this is not critical.The desired product is salted out with brine, washed well with ice cold water, and dried.

Example ll Preparation of the compound of the formula:-

2.0 grs. meta amino benzamidine dihydrochloride are diazotised and coupled with 1.6 grs. 8 hydroxy quinoline N oxide as in Example I.

Example Ill Preparation of the compound of the formula:-

1' aza 4' hydroxy 1.2 benzanthracene is made by allowing 2.9 grs 1-amino anthracene and 3.5 ml oxalacetic ester to stand for 48 hours over concentrated sulphuric acid in a vacuum desiccator.

The product is then added slowly to 50 ml light mineral oil heated to 2500C and kept at that temperature for about 30 minutes. The cooled product is filtered off and washed with benzene. The product is then hydrolysed by boiling with 5% caustic soda solution for two hours followed by neutralisation with hydrochloric acid. The product is then separated by filtration and dried. When heated slowly to above its melting point carbon dioxide is evolved and the desired product is obtained.

It is purified by dissolving in dilute caustic soda solution, filtering, neutralising with dilute hydrochloric acid, filtering, washing and drying. 1.25 grs of this material are dissolved in 40 ml pyridine and added to 200 ml water containing 0.75 gr sodium hydroxide all at under 500 C. This is coupled with 1.25 diazotised para amino benzamidine dihydrochloride, at under 50C, acidified and separated, all as in Example I.

Example IV Preparation of the compound of the formula:-

1.5 diaza 2.6 dimethyl 4.8 dihydroxy phenanthrene is made by reacting 1.5 grs meta phenylene diamine and 4.0 grs ethyl acetoacetate with 20 grs tetra phosphoric acid at 1 700C for 1 hour. The mixture is poured into water, neutralised with caustic soda, filtered, washed, and dried at a low temperature. 1.1 grs of this product are dissolved in 10 ml pyridine and diluted with 50 ml water and sodium hydroxide added to bring the pH value to approximately 8.

2.0 grs para amino benzamidine dihydrochloride in 20 ml water are diazotised and coupled with the above solution, keeping the pH value at approximately 8 and the temperature at under 5"C. When the reaction is complete the mixture is acidified to a pH value of approximately 6 with hydrochloric acid and the desired product salted out with brine. The precipitate is filtered off, washed well with ice cold water, and dried.

Example V Preparation of the compound of the formula:-

3.0 grs para acetylamino phenylguanidine are hydrolysed by heating for 1 hour on the steam bath with 20 ml water and 5 ml concentrated hydrochloric acid. After cooling to under 500C 0.4 gr sodium nitrate dissolved in 5 ml water at under 50C is added. After removal of excess nitrous acid with sulphamic acid the solution is coupled with 2.0 grs N,N-dimethyl-1-napthylamine dissolved in 25 ml dimethyl formamide and 50 ml water and acidifed with hydrochloric acid to bring to a pH value of about 4. After coupling the desired product is salted out with brine, filtered off, washed well with water and dried.

Example Preparation of the compound of the formula:-

2.0 grs para amino benzal amino guanidine in 20 ml water are diazotised and coupled with 2.0 grs 2-diethyl aminomethyl 1 -napthol in 100 ml water and 10 ml pyridine brought to a pH value of about 8, as in Example I.

Example VII Preparation of the compound of the formula:-

1.1 grs para amino benzamidine dihydrochloride in 15 ml water are diazotised in the standard manner and coupled with 1.0 gr 2-methyl 4-hydroxy 7.8 benzquinoline (Mallams a Israelstam J. Org.

Chem. 1964-3548) in 10 ml pyridine and 50 ml water at a pH value of about 8, all as in Example IV.

Example VIII Preparation of the compound of the formula:-

1.0 gr of 2-amino anthracene is dissolved in 20 ml dimethyl formamide. 100 ml water is added together with sufficient hydrochloric acid to bring the pH value to approximately 4 and cooled to under 50C.

1.2 grs para amino benzamidine dihydrochloride are diazotised in the standard manner and coupled with the amine.

When coupling is complete the pH value is adjusted to about 6 although this is not critical, and the desired product removed by filtration, washed well with water and dried.

Example IX Preparation of the compound of the formula:-

1.0 gr of the product of Example VIII is dissolved in 10 ml dimethyl formamide and 50 ml water and 1.5 ml concentrated hydrochloric acid. Diazotisation is effected by adding 0.4 gr sodium nitrite dissolved in 10 ml water all at under 50C. The solution is then mixed with a solution of 1.0 gr hydroquinone in 20 ml water and left for 24 hours at about 20-250C. The product is separated by filtration, washed well and dried.

Example X Preparation of the compound of the formula:-

2.2 grs para amino benzamidine dihydrochloride are diazotised and coupled with 0.8 gr 1.5 diamino napthalene as in Example VIII.

Claims

1. A compound of the formula R1-X-R2 where X represents a polynuclear aromatic or heteroaromatic hydrocarbon having between two and four fused rings which may be substituted by hydroxyl, amino, alkylamino, alkoxy or halogeno, R represents .

where y represents one member selected from:

or alkylated derivatives thereof, and R2 represents hydrogen or R1, an acid addition salt of said compound, a nitrogen oxide derivative of said compound in the case where it contains a ring nitrogen atom or atoms, and a quaternary salt of said compound in the case where it contains a ring nitrogen atom or atoms.

2. A compound according to claim 1 wherein an alkyl group being or forming part of a substituent is C1-C4 alkyl.

3. A compound according to claim 1 wherein an alkyl group being or forming part of a substituent is methyl or ethyl.

4. A compound according to claim 1 and substantially as described herein.

5. A compound according to claim 1 substantially as described in any of the specific Examples.

6. The use as an anti-cancer drug or agent of a compound as claimed in any of the preceding claims.

7. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 5 and an inert carrier or diluent therefor.