IE51990B1 - Anti-inflammatory compositions and their use - Google Patents

Abstract

1. Anti-inflammatory compositions for local topical administration containing an effective amount of a compound of the general formula see diagramm : EP0039059,P10,F2 wherein X signifies a sulphur or oxygen atom, Y signifies the group -CH=, -CH2 - or -N=, R signifies lower alkyl or hydroxy-lower alkyl, R' signifies lower alkyl, halogen, cyano, lower alkylthio, carboxy or lower alkylcarboxy and Z signifies the number 0 or 1, with the proviso that R' signifies bromine and X signifies a sulphur atom when Y signifies the group -CH2 -, and X signifies an oxygen atom when Y signifies the group -N=, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier material which is designed for local topical application.

Description

This invention relates to topical pharmaceutical compositions . Among the more common conditions whioh can be treated as described herein one can mention psoriasis, eczema, dermatitis of varying etiology and keratosis. The foregoing list is only intended to be illustrative.

In particular, the invention relates to pharmaceutical compositions for topical application to the inflamed area. Heretofore, the most widely used agents for topical antiinflammatory use have been the corticosteroids, i.e. steroi10 dal substances secreted by the adrenal cortex, and their synthetic analogs, particularly hydrocortisone. While the corticosteroids are effective in reducing the inflammation and associated symptoms, they have undesirable side effects, especially when their use is prolonged. Among the effects associated with prolonged use of corticosteroids are thinning and striations of the skin and interference with the body's immune system. Because of these undesirable side effects, the art has been searching for a non-steroidal pharmaceutical agent having topical anti-inflammatory activity compa20 rable to the corticosteroids but without the concomitant undesirable side effects.

A number of non-steroidal agents have been found to have systemic anti-inflammatory activity. For example, phenylbutazone, naproxen, and ibuprofen are all compounds which have systemic anti-inflammatory activity. Generally, however, the non-steroidal compounds which have exhibited systemic anti-inflammatory activity have not been useful as 51980 topical drugs for treatment of inflammatory skin disease. While the etiology of inflammations of the skin is not completely understood, it is generally recognized that it differs substantially from the etiology of systemic inflammations. Further, absorption of compounds through the multifold dermal layers involves quite a different set of physiochemical requirements than absorption/distribution processes on a systemic basis. For these reasons, it can be appreciated that it is not expected that systemieally effective anti-inflammatory agents will also be topically effective, especially in the case of non-steroids.

In accordance with this invention, it has been disttxmd that inflammation of dermal tissues can be treated by topically administering an effective amount of a compound of the general formula wherein X is -S- or -O-; Y is -CH=, -CHg- or -N=; R is lower alkyl or hydroxy-lower alkyl; R' is lower alkyl, haloger^ cyano, lower alkylthio, carboxy or lower alkylcarboxy; and z is zero or 1; provided that when Y is -CHg-, R' is bromine and X is -S-; and when Y is -N=, X is -0-; or a pharmaceutically acceptable salt thereof.

The invention thus provides topical pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier material for topical application.

In accordance with another aspect of this invention, it has been discovered that the effectiveness of compounds of formula I as topical anti-inflammatory agents is significantly enhanced by employing in conjunction therewith compounds of the general formula wherein is halogen, hydrogen, lower alkyl or lower alkoxy; R^, R^ and R^ taken independently of each other are hydrogen, lower alkoxy or hydroxy-lower alkoxy and provided that R2, R3 and R4 taken independently of each other represent at least one oxygenated substituent; or R^, R2< R3 and R4 taken as an adjacent pair is methylenedioxy.

Accordingly, one or more compounds of formula II can optionally be present in the topical pharmaceutical compositions of this invention.

Pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof and a compound of formula II are novel per se, i.e. without regard to the nature of the pharmaceutical formulations containing same, and also form part of the present invention.

The invention is furthermore concerned with the use of compounds of the general formula I or of pharmaceutically acceptable salts thereof, optionally in conjunction with compounds of the general formula II, in the manufacture of medicaments for the topical treatment of inflammation of dermal tissues, sucn as psoriasis quite generally, eczema, dermatitis of varying etiology, keratosis and the like.

As used herein the term lower alkyl is meant to include straight and branched chain saturated hydrocarbon radicals having from 1 to 7, preferably 1 to 4, carbon atoms. Exemplary lower alkyl radicals include methyl, ethyl, n-propyl, i-propyl, n-propyl, n-butvl, n-hexyl, and n-heptyl. The term halogen" is meant to include chlorine, fluorine, bromine and iodine.

One can mention as exemplary of the compounds of formula I, 8-chloro-10-(4-methylpiperazino)dibenzo[b,f]thiepin; 8-brom-10-(4-methylpiperazino)dibenzo[b,f]thiepin; 8-methylthio-10-(4-methylpiperazino)dibenzo[b,f]thiepin; 8-cyano10-(4-methylpiperazino)dibenzo[b,f]thiepin; 8-methylthio-104 (4-methylpiperazino)dibenzo[b,f]thiepin N -oxide; 8-cyano4 - (4-methylpiperazino)dibenzo[b,f]thiepin N -oxide; 4-(8chlorodibenzo[b,f]thiepin-10-yl)-1-piperazine-propanol; the corresponding oxepin compounds; 8-bromo-10-(4-methylpiperazino)-10,ll-dihydro-dibenzo[b,f]thiepin; and 2-chloro11- (4-methyl-1-piperazinyl)dibenzoCb,f][4,ljoxazepin. Preferred compounds of formula I are those in which X is —S—, Y is -CH=, R is methyl, and z is zero. The most preferred compound of formula X is 8-chloro-10-(4-methylpiper azino )dibenzo[b,f]thiepin.

The compounds of formula I are known or they can be prepared according to known procedures. For example, they can be prepared by methods taught in U.S. Patent 3,681,354; German Offenlegungsschrift 22 52 806; Collect. Czech. Chem. Comm., 35 3721-3723 (1970); and U.S. Patent 3,546,226.

U.S. Patent 3,681,354 teaches the preparation of compounds of formula I in which R' is lower alkyl or halogen, Y is -CH= and z is zero. While the patent discloses that the compounds have, among other things, anti-inflammatory activity the disclosure teaches anti-inflammatory activity 51980 only when the compounds are administered orally, i.e. systemic anti-inflammatory activity. It was quite unexpected and surprising that the compounds exhibited topical anti-inflammatory activity.

German Offenlegungsschrift 22 52 806 teaches the preparation of compounds of formula I in which R' is cyano, halo or alkylthio, X is -S- and Y is -01^=. The corresponding compounds in which X is -0- are prepared in an analogous manner. The N-oxide compounds of formula I, i.e. compounds in which z is 1 , can also be prepared by methods described in German Offenlegungsschrift 22 52 806. The compounds described in the Offenlegungsschrift are disclosed as psychodepressants.

Collect. Czech. Chem. Comm., 15, 3721-3723 (1970), teaches the preparation of compounds of formula I in which R' is lower alkylthio. The compounds are disclosed therein as neuroleptics.

U.S. Patent 3,546,226 teaches the preparation of compounds of formula I in which X is -O- and Y is -N=, i.e. 2o oxazepin compounds. The compounds are disclosed therein as neuroleptics.

The compounds of formula I form acid addition salts with conventional pharmaceutically acceptable acids, i.e. inorganic acids such as, e.g., hydrochloric acia, sulfuric acid, phosphoric acid and hydrobromic acid, or organic acids such as, e.g., citric acia, acetic acia, succinic acid, meleic acid, methanesulfonic acid and £-toluenesulfonic acid.

In accordance with the teachings of this invention, the compounds of formula I or pharmaceutically acceptable 3q salts thereof are applied topically to the inflamed dermal tissues to be treated. The compounds or salts can be conveniently applied in the form of a composition comprising S1990 an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for topical administration. Topical dosage forms of the present invention will typically contain from 0.01 to 10 weight percent, preferably from 0.1 to 1.0 weight percent of the compounds of formula I or pharmaceutically acceptable salts thereof, based on the total weight of the composition. The minimum amount of the compounds of formula I or pharmaceutically acceptable salts thereof which is effective may vary somewhat among individuals and depending on which compounds of formula I or pharmaceutically acceptable salts thereof are employed. However, it is well within the skill of the practitioner to determine the effective amount in any particular circumstance. By effective amount is meant an amount which is sufficient to reduce the symptoms of the inflammation, e.g. to lessen redness, scaling, itching and pain or to reduce thickening of the skin at the site of the inflammation. Typically, the topical compositions will be applied in a thin layer to the inflamed area from one to six times daily, depending on factors such as the severity and type of condition being treated, the location of the inflamed area being treated and the concentration of active ingredients in the topical composition.

As mentioned above, the topical pharmaceutical compositions of this invention optionally can, in addition to the compounds of formula I or pharmaceutically acceptable salts thereof contain one or more compounds of the formula II.

Such combination preparations will typically contain from 0.1 to 10 weight percent, preferably from 0.5 to 5 weight percent of a compound of the general formula II, based on the total weight of the composition. A suitable ratio of a compound of the general formula II to a compound of the general formula I ranges from about 2:1 to about 100:1, preferably from 10:1 to 50:1.

The compounds of formula II are known in the art, as are methods of their preparation. While there is no strict upper limit on the amount of the compounds of formula II which can be present in the topical pharmaceutical compositions of this invention, no particular advantage is obtained by having more than 10% weight, based on the total weight of the composition, present therein. A pre51990 ferred compound of formula IX for use in the compositions of this invention is 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone.

By employing compounds of formula II in a topical pharmaceutical composition of this invention, the amount of the compounds of formula I or pharmaceutically acceptable salts thereof present therein can be reduced without loss of effectiveness as anti-inflammatory agents. It was quite an unexpected finding that compounds of formula II enhanced the effectiveness of the topical anti-inflammatory agents of formula I or pharmaceutically acceptable salts thereof, since 4-(3-butoxy-4-methoxy-benzyl)-2-imidazolidinone, i.e. a compound of formula II, displayed little or no antiinflammatory effect of its own at a concentration of 5%.

The term topical as employed herein relates to the use of the active ingredient, incorporated in a suitable pharmaceutical carrier, and applied externally at the site of the inflammation for the exertion of local action. Accordingly, the topical compsitions include those pharmaceutical forms in which the compound is applied externally by direct contact with the skin. The topical dosage forms comprise gels, creams, lotions, ointments, powders, aerosols and other conventional forms for applying medication to the skin obtained by admixing the compounds of formula I or pharmaceutically acceptable salts thereof and optionally the compounds of formula II with known pharmaceutical topical carrier materials.

Ointments and creams encompass formulations having oleaginous, absorption, water-soluble and emulsion-type bases such as, e.g., petrolatum, lanolin and polyethylene glycols.

Lotions are Liquid preparations and can be aqueous or hydroalcoholic preparations containing finely divided substances. The compositions contain suspending or dispersing agents such as cellulose derivatives (e.g. ethyl cellulose or methyl, cellulose), gela10 tin or gums, which incorporate the active ingredient in a vehicle made up of e.g., water, alcohol or glycerin.

Gels are semi-solid preparations made by gelling a solution or suspension of the active ingredient (s) in a carrier vehicle. The vehicles, which can be hydrous or anhydrous, are gelled using a gelling agent such as carboxy polymethylene and neutralized to a proper gel consistency with the use of alkalis such as sodium hydroxide and amines such as polyethylenecocoamine.

Aerosols are made up of solutions or suspensions of active ingredients in an inert carrier which are dispensed with the use of a special spraying device. Some of the carriers commonly used are trichloromonofluoromethane and dichlorodifluoromethane. 1990 The pharmaceutical compositions of the invention cah be submitted to conventional pharmaceutical expedients such as sterilization and/or can contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for adjusting the osmotic pressure, buffers and the like. If desired, they can also contain other therapeutically useful materials including ingredients known to have topical antiinflammatory activity, in conjunction with the compounds of formula I or pharmaceutically acceptable salts thereof and, if present, the compounds of formula II. These ingredients are employed in the known effective concentrations.

The following experiments and examples are intended to further illustrate the invention. Unless otherwise indicated, all parts and percents are by weight and all temperatures are in degrees Centigrade.

In the experiments, the following test procedures were used to demonstrate the topical anti-inflammatory activity of the compounds tested. 1. Cantharidin Inflammation in the Rat A solution of 1 part ethanol, 1.5 parts collodion, parts acetone, and 3 parts diethylether by volume which contains 400 ug cantharidin per 0.1 ml and the test compound at the desired dose was applied topically to the outer surface of the ears of Charles River CD 21-day-old « male rats in a volume of 0.1 ml. Separate groups of rats were treated with vehicle alone, cantharidin alone, and cantharidin plus test compound. Where indicated in the examples, the test compound was applied separately 24 hours after the application of the cantharidin irritant. Autopsy was carried out 72 hours after cantharidin administration. Uniform punches were obtained through the site of application and weighed. Weight changes reflect effects on both the fluid and tissue components of the inflammatory pro1O cess. A reduction in weight of the skin punch taken from rats treated with irritant plus test compound, compared with those of rats treated with irritant alone, indicates anti-inflammatory activity. (J. Invest. Dermatol. 68: 161-164, 1977) 2. Croton Oil Inflammation in the Mouse A solution of 0.1 part croton oil, 1 part distilled water, 4 parts pyridine and 4.9 parts diethylether by volume containing the test compound was applied topically to the ears of Charles River CD-I 21-day-old male mice in a volume of 25 yl. Separate groups of mice were employed as vehicle controls and croton oil alone group. Ear punch weights are determined at 6 hours and measure primarily the edema component of inflammation. Reduction in punch weight in mice receiving test compound and irritant compared with those receiving irritant alone, was indicative of antiinflammatory activity. (Endocrinology 77: 625-634, 1965; Clin. Pharm. Exp. Therap. 16: 900-904, 1974). 3. Oxazolone Inflammation in Pre-Sensitized Mice Charles River CD-I 21-day-old male mice were sensi30 tized with oxazolone, 400 yg in 20 yl acetone, applied topically to the scrotum. One week later 10 yl of acetone or 200 ug of oxazolone was applied topically to the inner surface of the ear while test compound in 10 yl acetone was applied to the outer surface of the ear. Separate groups of mice served as vehicle controls and oxazolone-alone groups. Ear punch weights were measured 24 hours later. Reduction in ear punch weights of the mice receiving the test compound and oxazolone, compared with those of mice receiving the oxazolone alone, was indicative of anti-inflammatory activity. (Br. J. Pharmacol. 43: 403-408, 1971). 4. Cotton Pellet Granuloma Procedure in the Rat Test compounds were dissolved in a suitable solvent and 0.1 ml was applied to uniform, pre-weighed cotton pellets cut from dental cotton rolls. The pellets were permitted to dry at room temperature. Two compound-instilled pellets were implanted subcutaneously on the dorsum of Charles River CD, 5 week old, male rats. Pellets were removed 72 hours later. Wet and dry weights were determined and correc15 ted for tare weight of the pellet. A decrease in granuloma weight of the pellet treated with test compound, relative to vehicle-treated pellets, was indicative of anti-inflammatory activity. (Endocrinology BO: 153-160, 1957) In the experiments, the following designations are used 2o to identify the compounds of formula I employed.

Compound A Compound B Compound C Compound D Compound E Compound F Compound G Compound H Compound I Compound J 8-methylthio-10-(4-methylpiperazino)dibenzo[b,f] thiepin 4-(8-chlorodibenzolb,f] thiepin-10-yl)-l-piperazine-propanol 8-methylthio-10-(4-methylpiperazino)dibenzo[b,f] thiepin N4-oxife 8-chloro-10-(4-methylpiperazino)dibenzo[b,f] thiepin N4-oxide 8-chloro-10-{4-methylpiperazino)dibenzo(b,fl thiepin 8-bromo-10-(4-methylpiperazino)-10,Il-dihydro-dibenzo[b,f]ttiepin 8-eyano-10-(4-methylpiperazino)dibenzo[b,f] thiepin N4 oxide 8-cyano-10-{4-methylpiperazino)dibenzo[b,f] thiepin 8-bromo-10-(4-methyIpiperazino)dibenzo[b,f] thiepin 8-fluoro-10-(4-methylpiperazino)dibenzo[b,i] thiepin Compound K Compound L 2-ehloro-ll-(4-methyl-l-piperazinyl)dibenz[b,f] [1,4] oxazepin 8-ehloro-10-(4-methylpiperazino)dibenzo[b,f] oxepin 51890 Experiment 1 A series of compounds of formula I were tested for to pical anti-inflammatory activity by the cantharidin inflam mation test in the rat. Each compound was tested at each of five doses. Results of the rest, given as percent inhibition, i.e. percent reduction of the increase in punch weight due to cantharidin, are given in the table below.

J < e w Ξ e ca s o < 2 >4 RAT Cc Z z r4 Z »—« Pl IDI I—i s tf < a < X cc t* o o z ¢4 Z < «C ϋ o Cc z O TY I ION v1 £ IBIT ϋ X < z o >< tf 5 o w O e- MM < td fo z 3 NTI- © to < ϋ S o o tn ο o w tn o a m Si 81990 I rfj ω o G •d Tj Φ G •d $4 ω Φ Ό G Φ Φ Λ υι φ rt ω 43 3 TJ rd G rt 3 G 0 M Λ Φ g -P Ο X υ φ Ul ri ♦d rt 43 0 •P 0 r—I 4-1 P 0 G 44 0 •d Φ -Ρ H 3 Λ r-j nJ 0 -P W -d rt ui G 4-1 3 0 Ul tn-d G •d G •P 0 tfl -d •d P w 3 G H 0 0 υ to M rt Φ N 43 •d ϋ

Claims (17)

CLAIMS:

1. A pharmaceutical anti-inflammatory composition for local external application containing -an effective amount of a compound of the general formula wherein X is -S- or -0-; Y is -CH=, -CHj- or -N=; R is lower alkyl or hydroxy-lower alkyl; R' is lower alkyl, halogen, cyano, lower alkylthio, carboxy or lower alkylcarboxy; and z is zero or 1; provided that when Y is -CH 2 -, R 1 is bromine and X is -S-; and when Y is -N=, X is -O-; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for topical application.

2. Λ composition as claimed in claim 1 in the form of a gel, cream, lotion, salve, powder or aerosol.

3. A composition as claimed in claim 1 or 2, wherein X is -S-, Y is -CH=, R is methyl and z is zero.

4. A composition as claimed in claim 1 or 2, wherein said compound of formula I is 8-chloro-10-(4-methylpiperazino)dibenzo[b,f]thiepin.

5. A composition as claimed in any one of claims 1 to 4, wherein said compound of formula I is present in an amount from 0.01 to 10 weight percent, based on the total weight of the composition.

6. A composition as claimed in claim 5, wherein said compound of formula I is present in an amount of from 0.1 to 1.0 weight percent, based on the total weight of the composition.

7. A pharmaceutical composition containing a compound wherein X is -S- or -0-; Y is -CH=, -CHg- or -N=; R is lower alkyl or hydroxy-lower alkyl; R' is lower alkyl, halogen, cyano, lower alkylthio, carboxy or lower alkylcarboxy; and z is zero or 1; provided that 10 when Y is -CHg-, R' is bromine and X is -S-; and when Y is -N=, X is -O-; or a pharmaceutically acceptable salt thereof and a compound of the general formula 15 wherein is halogen, hydrogen, lower alkyl or lower alkoxy; Rg, Rg and R 4 taken independently of each other are hydrogen, lower alkoxy or hydroxy-lower alkoxy and provided that Rg, Rg and R 4 taken independently of each other represent at least one oxygenated 20 substituent; or R^, Rg, Rg and R 4 taken as an adjacent pair is methylenedioxy.

8. A composition as claimed in claim 7, wherein X is -S-, Y is -CH=, R is methyl and z is zero.

9. A composition as claimed in claim 7, wherein said compound of formula I is 8-chloro-10-{4-methylpiperazino)5 dibenzofb.f]thiepin.

10. A composition as claimed in any one of claims 7 to 9, wherein said compound of formula I is present in an amount from 0.01 to 10 weight percent, based on the total weight of the composition. 10

11. A composition as claimed in claim 10, wherein said compound of formula .I is present in an amount from 0.1 to 1.0 weight percent, based on the total weight of the composition.

12. A composition as claimed in any one of claims 15 7 to 11, wherein said compound of formula II is present in an amount up to 10 weight percent, based on the total weight of the composition.

13. A composition as claimed in any one of claims 7 to 12, wherein said compound of formula II is 4-ΟΣΟ butoxy-4-methoxybenzyl)-2-imidazolidinone.

14. Use of a compound of the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, optionally in conjunction with a compound of the general formula II as defined in claim 7 in the manufacture 25 of a medicament for the local external topical treatment of inflammation of dermal tissues. as

15. Use according to claim 14, wherein the compound of the general formula I is 8-chloro-10-(4-methylpiperazino)dibenzo[b,f]thiepin.

16. A pharmaceutical anti-inflammatory composition 5 according to claim 1, substantially as hereinbefore described with particular reference to Examples A and C of the accompanying Examples.

17. A pharmaceutical composition according to claim 7, substantially as hereinbefore described with particular 10 reference to Example B of the accompanying Examples.