CA1069052A

CA1069052A - Composition containing bis-chromonyl compounds

Info

Publication number: CA1069052A
Application number: CA257,889A
Authority: CA
Inventors: John H. Bell; James E. Taylor; Clifford W.F. Clarke; Thomas J. Sullivan
Original assignee: Fisons Ltd
Current assignee: Fisons Ltd
Priority date: 1975-10-03
Filing date: 1976-07-27
Publication date: 1980-01-01
Also published as: JPS5244242A; GB1537047A; IT1076941B; BE845709R; NL7610057A; DK355076A; FR2326189A2; SE7608462L; NO762516L; FR2326189B2; FI762625A7

Abstract

ABSTRACT

Diseases of the skin and eye are combated by applying thereto compounds of formula

Description

- 2 1~69~15Z

The present invcntion relates to compositions for treating diseases of the skin and certain conditions of the eye.
Compounds of the general formula ~ O-X-O~
}~2 0 C02E

and therapeutically acceptable salts, esters and amides . ~hereof, rwherein Rl, R2, R3, R4, R5 and R6 are the sa~e or different and each is H or halogen, lower alkyl, hydroxy, lower al~oxy, lower alkenyl, benzyloxy, nitro9 substituted lower alkyl ; or substituted lol~er alkoxy, and X is a saturated or unsaturated, substituted or unsubstituted, straight or branched polymethylene chain which may be interrupted by one or more carbocyclic rings I or oxygen-containing heterocyclic rings, oxygen atoms or carbonylgroups~7, have been proposed for use in the treatment of the allergic disorders, notably allergic asthma, by administration by Inhalation of a powder formulation or o a nebulised aqueous formLlation.
Surprisingly, we have now found that the compounds o formula I have pharmacological activity when administered externally to the skin of a manmlal and are thus indicated for use 2~ in the treatment cf chronic skin disorders in n~n~als, e.g man, ca~s and dogs.

.

02/C/1~2 101~9~52 ~'e have also found that the compounds of formula I have pharmacological activity ~hen administered topically in the treatment of conditions of the eye in ~Yhich conditions allergic or immune reactions play a contributory part.
Accordingly, this invention provides a method for the treatment of chronic skin disorders, or condi~ions of the eye in l~hich conditions allergic or im~une reactions play a contributory part, which method comprises the topical application of an effective anount of a compound of general forn~la I or a pharmaceutically acceptable salt9 ester or amide thereof to the skin or eye ~issues of a mammal suffering therefrom.
~ Ye prefer to use those compounds of formula I in which Rl, R2, R3, R4, R5 and R6 are the s~me or different and each is a hydrogen or halogen atom ~e.g a chlorine, bromine, iodine or lS fluorine atom), a lower alkyl (e.g a methyl, ethyl, propyl, -isopropyl, butyl or tertiary butyl group), hydroxy, lower alkoxy (e.g a methoxy, ethoxy, propoxy, isopropoxyl butoxy or tertiary bu~oxy group) or substituted lower al~yl or lower alkoxy group, (for example a hydroxyloweralkoxy, lo~eralkoxyloweralkoxy, carboxyloweralkoxy, hydroxyloweralhyl or haloloweralkyl such as chloro-, bronLr, iodo- or fluoro-loweralkyl, a loweralkenyl, e.g allyl or methyi~allyl, benzyl or nitro, and X is a saturated or unsaturated, substituted or unsubstituted, straight or branched ~
polymethylene chain which may be in~errupted by one or more carbocyclic rings or oxygen containing heterocyclic rings, ~e.g

- 3 -- ' ~ ' .. ~ "

, '' - . . - . . ~: , , 03/C/~12 ` 3L(36 963S Z
- benzene, dioxan, tetrahydrofuran, or dihydropyran rings), oxygen atoms or carbonyl groups.
In general, it is preferred that no more than one of Rl, R2 and R3 and no more than one of R4, R5 and R6 is other than S ]IydTogen and are selected from a hydrogen or halogen atom or an alkyl, hydroxy, alkoxy or substituted alkoxy group, and X has the meaning defined above.
Particularly preferred compounds of formula I are those in ~i h 11 of Rl R2 R3 R4, R5 and R6 are hydrogen-The group X may be any of a wide variety of groups. Thus, for example, it`may be a straight or branched saturated or unsaturated hydrocarbon c~lain. Further, X may be such a chain interrupted by one or more oxygen atoms, carbonyl groups or carbocyclic or heterocyclic rings and may be substituted by one cr more halogen atoms (e.g chlorine, bromine, iodine or fluorine atoms~, or hydroxy or lo~er alkoxy (e.g methoxy, ethoxy, propoxy, isop~opoxy, butoxy, tert~ ~utoxy, etc) groups. Specific examples of the group X are groups of the formNlae:

.

.

04/C/1~2 '' ~06g~52 -(CH2)5--C~12 -C~'l=CH-C~12 - .
2CH2CH-(CH3)-CH2CH2--CH CH OCH CH -CH2 CH2 :
-c~ -cH(oc2l-ls) CH2 : .

CH

lS I 2~

.CH2Cl CH C~ICH :
-cH2c~x)Hc~I
; 20 etc.
~he group X is preferably a straight or branched hydrocarbon chain, ~hich may be interrupted by one or more oxygen atoms, and contains from 3 ~o 7 carbon atoms. Desirably such a chain is a - polymethylene chain substituted by one or more hydroxyl groups, a particularly prefert^ed chain being the 2-hydroxy-trimetllylene :
., ~ .

,, , ~ , ' `
~' ` ' ' ' ,: ' - 6 ~ ~ 6g~o 5 2 chain ~-C~12CI-10~1CH2-)-The cha m -0-X-0- may link differen~ or corresponding positions on the chromone molecules.
Thus, the preferred compounds of formula I for present use are those o-f the general ormula:

O

¦~ OCHzClla ICH20 _¢~e~L Il ~0 ~ ~0 Suitable pharmaceutically acceptable salts include, for example, amnonium salts, alkali-metal salts (e~g sodium, potassium and lithium), alkaline-earth metal salts (e.g magnesium and calcium), and salts with organic amines (e.g mono-, di- or tri-alkyl Cl_6 amines, piperidine, and trialkanol Cl 6 am~ne salts).Esters which may be mentioned include simple alkyl esters (e.g methyl, ethyl, propyl, isopropyl, butyl and tertiary butyl esters).
~mides which may be mentioned include simple amides (for example amides with ammonia and lo~Yer alkylamines such as meth~lamine, ethylamine etc) and more complex amides with amino acids, e.g glycine.
Specific compowlds of formula I and derivatives thereof ~or present use are:
bisodium salt of 1,3-bist2-carboxychromon-5-yloxy)prop~e~
Disodium salt of 1,3-bis(2-carbo~ychromon-5-yloxy)-2-- 7 - ~0691~52 hydroxypropane.
1,3-Bis(2-carboxychromon-S-yloxy)-2-hydroxypropane.
Calciwn salt o~ 1,3-bis~2-carboxychromon-5-yloxy)-2-hydroxypropane.
Magnesium salt of 1,3-bis(2-carboxychromon-5-yloxy)-2~
hydroxypropane.
Dipiperidine salt of 1,3-bis~2-carboxychromon-5-yloxy)-2-hydroxypropane.
1,12-Bis(2-carboxychromon-5-yloxy)-2,11-dihydroxy-4,9-dioxadodecane.
1,4-Bis~2-carboxychromon-5-yloxy)butane.
1,5-Bis(2-ca~boxychromon-S-yloxy)pentane.
1,6-Bis(2-carboxychromon-5-yloxy)hexane.
1,10-Ris(2-carboxychromon-S-yloxy)decane.
lS 1,7-Bis(2-carboxychromon-S-yloxy~-2,6-dihydroxy-4-oxaheptane.
1,S-Bis(2-carboxychromon-S-yloxy)-3-oxapentane.
1~4-Bis(2-carboxychromon-5-yloxy)-2,3-dihydroxybutane.
lJ4-Bis(2-carboxy~lromon-5-yloxy)-2-hydroxybutane.
l,5-Bis(2-carboxychromon-7-yloxy)pentane l~,10-Bis(2-carboxychromon~5-yloxy)-3,8-dioxa-4,7-dioxodecane.
1,5-Bis(2-carboxy-8-chlorocllromon-5-yloxy)pentane.
1 (2-Carboxychromon-5-yloxy)-3-(2-carboxychromon-7-yloxy)-2-hydroxypropane.

... ~.. .. , , ~ . , . . ~

: . . ' . , . :
, , . - . ~ .
:. ~. , , . ,:
.

- 8 - 1l3~ 5~

1-~2 Carboxychromon-S-yloxy)-5-~2-carboxyc}lromoll-7-yloxy)-pentane.
1,3-Bis(2-carboxy-7-me~lylchromon-5-yloxy)-2-hydro~y-propaneO
1,3-Bis~2-carboxy-8-ethylchromon-5-yloxy)-2-hydroxy-propane.
1-(2-CarboxychrGmon-5-yloxy)-3-~2-carboxy-8-etllyl-chro n-5-yloxy)-2-hydroxypropane.
1,5-Bis(2-carbox~chromon-8-yloxy)pentane.
1,5-Bis(2-carboxy-8-methylchromon-7-yloxy)pentane.
1,3-Bis(2-carboxy-8-methylchromon-7-yloxy)-2-hydroxyl)ropane.
1,5-Bis~2-carboxychromon-5-yloxy)-3-methylpentane.
1,3-Bis~2-carboxy-6-chiorochromon-7-ylox~)-2-hydroxypropane;
disodium salt.
1-~2-Carboxychromon-5-yloxy)-3-~2-carboxy-6-chlorochromon-7-yloxy-2-hydroxypropane; disodium salt.
1,S-Bis~2-carboxychromon-6-ylox~)pentane.
193-Bis~2-carboxychromone-7-yloxy~-2 hydroxypropane.
1,2-Bis(2-carboxychromon-5-yloxymethyl)benzene.
1,3-Bis(2-carboxychrom~n-6-yloxy)-2-hydroxypropane.
Disodium salt o~ 1-(2-carboxychromon-S-yloxy)-3-(2-carboxychromon-6-yloxy)-2-hydrox~propane.
Disodiu~. salt o~ -arboxychromon-5-yloxy)-3-(2-carboxychromon-8-yloxy)-2-hydroxypropane.
1,8-Bis(2-carboxychromon-5-yloxy)octane.

.~ .. ......... . . . . . .

. .

9 1~;116~CI52 Bis(2-carboxychromon-5 yloxy)nonane.
1~2-Bis(2-carboxychromon 5-yloxy)e~hane.
1,3-Bis~2-carboxychromon-5-yloxy)-2-chlorome~hyl-2-hydroxy-methylpropane; dipotassium salt tetrahydrate.
Disodium salt of 1~3-bis~2 carboxychromon 5-yloxy~-2-e~hoxypropan~.
Disodium salt of 133-bis(2-carboxychromon-5-yloxy) 2-oxopropane.
Diethyl ester of 2,5-bis(2-carboxychromon-5-yloxy-methyl)-diox~n.
1,3-Bis(2-carboxy-7-methoxychromon-5-yloxy)-prop~n-2-ol.
1,5-Bis~2-carboxy-7-methoxychromon-5-yloxy)-pentane.
1,3-Bis(2-carboxy-5(2-hydroxypropoxy)chromon-7-ylo.~y)-propan-2-ol.
1,3-Bis(2-carboxy-7-(2-hydroxypropoxy)chromon-5-yloxy)-propc~n-2-ol.
1j5-Bis(2~carbo~y-S-methoxychromon-7-yloxy)pentane.
1,5-Bis(2-carboxy-7-(2-~ydroxypropoxy)-chromon-6-yloxy)-pentane.
1,3-Bis(5-benzyloxy-2-carboxychromon-7-yloxy)propan-2-ol.
lJ3-Bis(2-carboxy-S-methoxychromon-7-ylox~)propan-2-ol.
1,3-Bis(2-carboxy-5~hydroxychromon~7-yloxy)propan-2-olO
1,3-Bis(8-allyl-2-carboxychromon-5-yloxy)propan-2-ol.
1J3-Bis(8-allyl-2-carboxychromon-7-yloxy)~ropan-2-ol.
1-(~-Allyl-2-carboxychromon-7-yloxy)-3-(2-carboxychro n-.. ..

- : . ' ............................................ .

.

09/C/~12 ~ - 10 - ~ 6169(;9~

7-yloxy)propan-2-ol.
1,3-Bis(2-carboxy-~-methallylchromon-7-yloxy)propan-2-ol.
1,3-Bis(8-allyl-6-bromo 2~carboxychromon-7-yloxy)propan-2-ol.
1-(8-Allyl-2-carboxychrom~on-7-yloxy)-3-~2-carboxycllron~,on-6-S yloxy)propan-2-ol.
1,5-Bis~8-allyl-2-carboxychromon-7-yloxy)pentane.
1,3-Bis(2-carboxy-8-nitrochromon-5-~loxy)propan-Z-ol.
The compound of formula I or a pharmaceutically acccptable salt; ester or amide thereo may be applied topically to the skin or eye tissues of the mammal, nota~ly man, ~t or do~ in any suitable ~ormLlation. We prefer the compound of ormula I to be ormulated as an ointment~ in which the finely ground compound o ol~Lla I
is dispersed in a wax~, fatty, protein or paraffin base, especially a soft paraffin base. Liquid paraffin, hard parafin, and wool ~at may be included in the ointment base.
~e prefer to use a composition containing a major proportion ~e.g 70-903 w/w) of a white or yellol~ sot paraffin and ~inor proportions of a liquid paraffin (5-lS~ w/w) and of a hard paraffin (0-12~ w/~). !
Z0 The ointment may also contain other liquid components e.g water or a polyethylene glycol to improve the consistency of the base, provide a solvent for the active i~gredient so that the active ingredient may be s~erilised by filtration and/or to alter the rate of release o the a~tive ingredient from the base.
The compound of formula I may alternatively be ~ormulated as ,, . ... , . . . . .

.

~69~52 .

a cream~ l~]liCh ~y be either an oil in water type, or a l~ater in oil type. Suitable e~ulsifying agents or the for3ner type include sodium, potassium, an nium and triethallolamine soaps;
polysorbates; and cationic, ~lionic, and non-ionic emulsifying S waxes. Suitable emulsify~ng agents ~or the latter type include calcium soaps, ~ol fat, ~ool alcohols, beeswax, and certain sorbitan esters.
The ointment ~nd cream com~ositions may if desired contain an effective proportion of a pharmaceutically acceptable preservative or sterilising agent suitable for an ointment or cream. Examples of preservatives which may be used are:
~ i) Chlorbutol (2,2,2-tric}~oro-1,1-dimethyl ethanol hemihydrate), which may be present in the co~lposition at about 0.5~ w/~,~, (ii) Chlorocresol, which may be present in the co~position from about 0.05~ to 0.2~ w/w and, ~ iii) methyl-p-hydroxybenzoate, eith~r alone or in combination with propy]-p-hydroxybenzoate.
The total concentration of hydroxybcnzoate esters in the composition may range from about 0.~8~ to 0.2~ W/l~
Other preservatives which may be employed include thiomersal.
The con~ound of formula I may alternatively be formulated as a lotion or liniment by dissolving or dispersing the compound in an aqueous or oily base. A suitable preservative may be included ~, , . , , ~
- : ' ' ~ ' ..
.
.. . ' ' .~ ' ll/C/112 in the formulation. Ethanol and/or glycerin may be included in the aqueous base. Examples of suitable oil bases include arachis oil, castor oil, and other vegetable oils. Where pastes or gels are desired, a thickening agent may be incorporated in an aqueous base. These ingredients may also serve as stabilising agents for emulsions. Suitable agents include Car~opol,* bentonite, soluble cellulose derivatives (e.g. sodium car~oxy methyl cellulose, hydroxypropyl methyl cellulose), Veegum* and polyvinyl alcohol.
Other ingredients e.g. humectants, antioxidants, perfumes and pigments may also be present if desired.
The compound of formula I may also be formulated as a dusting powder (although such formulations are not suitable for eye use) in which two or more ingredients are intimately mixed in fine powder form. Alternatively, the compound of formula I may be applied as a solution or suspension in a liquid carrier to the surface of a solid carrier and the coated particles dried.
Examples of solid carriers, which are normally sterilised, are talc, starch, lactose, zinc oxide, light kaolin, calcium carbonate.
A semi-solid base that has been found particularly suitable is based on a fatty alcohol/glycol mixture. Suitable fatty alcohols include saturated alkanols containing 16 to 24 carbon atoms and suitable glycols include 1,2-propylene glycol, 1,3-propylene glycol, polyethylene glycols of molecular weight 100 to 800, and dipropylene glycol. The fatty alcohol and glycol * Trade Marks A, i ~

9L(:1 6~052 are present in from 15 to 45:45 to 85 parts by weight, preferably 20 to 35 : 55 to 80 parts, respectively. If desired a plasticizer, e.g a polyethylene glycol of molccular l~eight 8CO to 20,000 or 1,2,6-hexanetriol, and~or a penetrant may also be present.
The compound of formula I or the salt, ester or amide thereof may be present in the compositions of this invention in an amount of from 0.5 to 20~ by ~Yeight.
Typical formulations of the compounds of formula I for application to the skin are illustrated by the following Examples:

Ointment Compound of formula I 10~ w/v Liquid paraffin BP 10~ w/v W~ol Fat BP 10~ w/v White Soft Paraffin BP 70~ w/v ample 2 ~ater ~scible Ointment Compound of formula I 10% w/v Polyethylene glycol 400 40~ w/v Polyethylene glycol 4,000 50~ w/v ' : . .

:

~6905Z

Example 3 Aqueous Cream Compound of fonmula I 5% w/v Emulsifying O m ~ment BP 30~ wjv Chlorocresol 1% w/v ~, Purified Water 64~ w/v , Oily Cream !
C~mpowld of forn~la I 10~ w/v ~ol alcohols BP 3~ w/v Hard paraffin BP 12~ W/V
Whit~ Soft Para~fin BP 10~ w/v Liquid Para.~fin BP 30~ w/v Purified l~ater 35~ w/v Exam1~1e 5 tion (Aqueous~
Compound of ~ormula I 10~ w/v Glycerol 20~ w/v Alcohol ~95~) 20~ w/v Sodium Carboxymethyl Cellulose 1~ w/v Puri.~ied ~ater 49~ w/v ~ .

.

l~/C/112 SZ

Example 6 tion (Oily) Compound of ~ormula I 15% w/v Arachis Oil 85% w/v 5 ~
_stîn~ Powder ~, .
Compound of formula I 10% w/v Zinc Oxide 25~ w/v Phrified Talc 10% w/v Sterilisable Maize S~arch 55~ w/v ~ .
Fatty alcohol/~lycol base Compound of ~ormula I 10% w/v Stearyl alcohol 27% w/v Propylene Glycol 63~ w/v The co~pound of fonmula I is typlcally present in the above formulations in from 5 to 20% by weîght, notably 10 to 15%.
Typîcal formulations of the compounds of formula I ~or topical application to the eye ~issues are illustrated by the following Examples.

.

.

..

69~SZ
. . .

Example 9 Disodium salt of 1,3-bis(2-carboxych.omon-S-yloxy)propan-2-ol 4.0~ w/w White soft paraffin BP 81.0~ w/w Liquid paraffin BP 10.0~ w/w Hard paraffin BP 5.0~ w/w a~ple 10 Disodium salt of l,3-bis(2-carboxychromon-S-yloxy)propan~2-ol 4.0~ w/w Purified water q.s.
Base to 100~ w/w Base:
Polyethylene glycol 400 5.0~ w/w White soft paraffin BP 80.0~ w/w Liquid paraffin BP 10.0~ w/w Hard paraffin BP S.0~ w/w The con~ound of formula I is typically present in ~ormulations for topical application to the eye in an amount of from 0.5 to 10~ by weight and pTeferably from 2 to 6~ by ~eight.
W~ere solid particles of the compound are present, e.g in a suspension or dispersion or in a po~der formulation, it is preferred that these have a mean particle size in the range 0.01 to 10 micrometres.
Thie com~ositions for present use may be made using any approp~iate technique, e.g by dry mixing the solid ingredients or by grinding the solid ingredients together, or by en~ulsifying an , . ' . ~
'' ':

1~36~()5~

aqueous solution of the compoun~ of ~ormula I ~ith an appropriate oil base.
The compound of formula I or the derivative thereof is preferably administered to the skin o a patient merely by smearing an ointment, cream or paste over the affected area of the skin. Alternatively, the con~ound may be impregnated into a gauze or similar pad and thîs pad then applied to the affected area; or a po~Yder containing the active ingredien~ may be puffed or dusted on to the afected area. For topical application to the eye tissues, ointments and creams are preerred.
T}le rate of application of the compound o ~onnula I will depend upon the severity and the surface area of the disorder to be treated and repeated applications may be made at intervals during the day, e.g from 1 to 6 times a day. For use in the eye a dosage of about 0.5 to 4.0 mg of active ingredient into the affected eye fn~m 1 to 4 times, and preferably twice, a day is fo~nd to be satisfactory l~ore frequent dosage may, of course, be usecl if desired.
The compounds of formula I or the pharmaceutically acceptable 2~ derivatives thereof ~ind use in the treatment of various disorders in mammals, notably man. Dermatoses which may be treated include those involving s~in mast cells and/or antibocly/antigen reactions and include eczemas, drug eruptions, psoriasis, dermatitis herpe~ifonnis, pemphigus and c}lronic skin ulcers~ notably those afecting man in tropical climates. The compounds of formula I

;'`' ' .
. .
.. . . . . .
- ~ ' , . ' ' . -.,.. , . - ' . : .
' .. ~ ' '' .

, ~ . , , - , , ` ~6~52 or derivatives therof are of particular usc in the treatment of atopic eczema in man.
Conditions of the outer eye in which the method of the ~Ivention is ~ndicated include vernal catarrh (Yernal ~.erato-conjunctivitis) and marginal corneal ulceration or infiltration.Other conditions ~hich may be trea*ed by the method of the invention include the occular effects of hay feverJ 'allergic eyes' where the allergen is kno~n or unkno~n and springsummer conjunctivitis. This latter term is used to mean allergic disorders of tlle eyes occurring in the spring cmd sl~nmer ~here ~n external allergen plays a part in the disorder. Further conditions of the eye which may be mentioned are 'irritable eye' or 'non-specific conjunctivitis', ~lerpes Simplex Kerati~is and Conjunctivitis, Herpes Zoster Keratitis an~ Conjuncti~itis, adenovirus infections, phlyctenular conj~mctivitis, corneal homograft rejection, Trachoma, anterioruveitis and drug sensitivity.
Example 11 Ointmen* formulations were prepared by mixing the disodium salt fo 1,3-bis~2-carboxychromon-5-yloxy)2-hydroxypropane ~th a vaseline base to give ointments containing 5 or 10~ by weight of the disodium salt. These ointments were applied to patients suffering from eczemas, notably atopic aczema, by smearing the ointmem s on to the affected areas of the skin from 2 to 4 times a day.

..

~69(1~i~

In 16 patients treated an improvement in pruritus ~as noted after 7 to 10 days and over the test period of 4 months the ointments continued to improve the skin. In some c.ases the improvement ~as at least as good as that which would have been S ~xpected with a steroid o7ntment.
In another aspect, there~.ore, the invention also pro~ides a composition for topical application to the s'~in or eye tissues of a mammal, notably man, which comprises a compound of formula I or a pharmaceutically acceptable salt9 ester or amide, notably a compound of formula II or the disodiuml salt thereof; in admixture ~ith a diluent suitable for topical application tc the s~in.
The term 'lower' is used herein ~1 respect of values for Rl to R6 to denote that that group contains ~rom 1 to 6 carbon atoms.
Some of the compounds of follmula I and their preparation are : 15 described in Rritish Patent No 1144905.

~0 : 25 . . . , '-' ' :

. . .
' . ' ' , ',

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A composition, in the form of an ointment, a cream, a lotion or a liniment, for the treatment of chronic skin disorders, or conditions of the eye in which conditions allergic or immune reactions play a contributory part, which composition comprises, as an active ingredient, a compound of the formula (1) or a pharmaceutically acceptable salt, ester or amide thereof, [wherein R1, R2, R3, R4, R5 and R are the same or different and each is H or halogen, lower alkyl, hydroxy, lower alkoxy, lower alkenyl, benzyloxy, nitro, substituted lower alkyl or substituted lower alkoxy, and X is a saturated or unsaturated, substituted or unsubstituted, straight or branched polymethylene chain which may be interrupted by one or more carbocyclic rings or oxygen-containing heterocyclic rings, oxygen atoms or carbonyl groups]
in admixture with a diluent suitable for topical application to the skin or eye tissues, the active ingredient being present in an amount of from 0.5 to 20% by weight.

2. A composition as claimed in claim 1, in the form of an ointment or cream.

3. A composition as claimed in claim 2 in the form of an oint-ment, wherein the diluent is a waxy, fatty, protein or paraffin base, and the compound of formula I or salt, ester or amide thereof is dispersed therein.

4. A composition as claimed in claim 3 wherein the diluent is a soft paraffin base.

5. A composition as claimed in claim 4 wherein the diluent comprises from 70 to 90% by weight of a white or yellow soft paraffin, from 5 to 15% by weight of a liquid paraffin and from 0 to 12% by weight of a hard paraffin.

6. A composition as claimed in claim 2 in the form of a cream wherein the diluent is an oil-in water emulsion.

7. A composition as claimed in claim 6 which contains an emulsifying agent selected from sodium, potassium, ammonium and triethanolamine soaps; polysorbates; and cationic, anionic and non-ionic emulsifying waxes.

8. A composition as claimed in claim 2 in the form of a cream wherein the diluent is a water-in-oil emulsion.

9. A composition as claimed in claim 8 which contains an emulsifying agent selected from calcium soaps, wool fat, wool alcohols, beeswax and sorbitan esters.

10. A composition as claimed in claim 1, 2 or 3 which contains one or more suitable preservative or sterilising agents.

11. A composition as claimed in claim 1, 2 or 3 for topical use on the skin, which contains from 5 to 20% by weight of active ingredient.

12. A composition as claimed in claim 1, 2 or 3, which contains from 10 to 15% by weight of active ingredient.

13. A composition as claimed in claim 1, 2 or 3 for topical application to eye tissues, which contains from 0.5 to 10 % by weight of active ingredient.

14. A composition as claimed in claim 1, 2 or 3 for topical application to eye tissues, which contains from 2 to 6% by weight of active ingredient.

15. A composition as claimed in claim 1 wherein the compound of formula I has the general formula (II) and is present in the form of a free acid or an alkali-metal, alkaline-earth metal, ammonium or amine salt thereof or in the form of an amide or alkyl ester thereof.

16. A composition as claimed in claim 15 wherein the active ingredient is an alkali-metal, alkaline-earth metal, ammonium or amine salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane.