IL42319A - Anti-allergic pharmaceutical compositions containing indane derivatives certain such compounds and their preparatio - Google Patents

Description

pharmaceutical compositions containing indane derivatives f certain such novel compounds and their preparation GROUP LIMITED 40498 This invention relates to pharmaceutical composition which are useful in the inhibition of the effects of certain types of and are therefore useful in the prophylaxis and treatment of diseases associated with allergic or immunological certain types of asthma and and also in the treatment of We have discovered that certain derivatives of have useful activity in mammals they effects of In they appear to inhibit the release of mediator such as which are normally released after antibody combinations and which normally mediate the allergic The class of derivatives which we have found to be active in this way has formula and the salts of compounds are also In formula hydrogen or alkox phenyl or halogen groups or any two adjacent groups and R2 and or taken together may be joined to form with the carbon atoms to which they are attached a carbocyclic ring which ring may be substituted by one or more lower lower phenyl or halogen this definition or and R4 being subject to the proviso that and are not simultaneously a search of are novel we list those compounds of formula which are mentioned in the literatur together with the appropriate literature I H 1961 I H Chem 8 68 I H 11379b I H 37507 s I H 1 I H La Zinat H ibid 1971 In the above no reference has been given fo the first itself which of a laboratory Although the above compounds are reported in the no form of useful biological activity has been ascribed to Likewise there has been in the literature no suggestion that such compounds are likely to possess any form of useful biological and in particular the discovery that they have activity has not been predicted in any the present invention provides in its broadest a pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt together with one or more pharmaceutically acceptable in which formula and represent hydrogen or lower lower phenyl or halogen and any two adjacent groups and and or and may be joined to form with the carbon atoms to which they are attached a carbocyclic ring which ring may be substituted by one or more lower lower phenyl or halogen this definition of and being subject to the proviso that and are not simultaneously It will be noted that the above definition of the compositions of this invention specifically excludes compositions This exclusion is necessary since such compositions ar2 claimed in a different pending patent application in our compositions of this invention may be presented as a microfine powder for as a snuff or in capsules of hard They may also be presented together with a liquid carrier for Some of the compounds of formula appear to be active when given by the oral route and thus the compositions of this invention may be in the form of pills or Preferably the compositions of this invention are presented in unit dosage or in a form in which the patient can administer to himself a single If a small amount of bronchodilator compound may be incorporated in the compositions of the both to inhibit the cough response if the composition is insufflated and to provide iate relief during an asthmatic The effective dose of compound depends on the particular compound but is generally in the range of from to 100 The precise nature of the pharmaceutical carrier in the composition of this invention is not Standard pharmaceutical practice may be but it is perhaps worth noting that if the composition is to be administered by a microfine powder where substantially all the particles have diameters of less than microns is The present invention also in another of its aspects compounds of formula and salts wherein and are each hydrogen or lower lower phenyl or halogen or any two adjacent and R2 R2 and and 4 may be joined to form with the carbon atoms to which they are attached a carbocyclic ring which ring may be substituted by one or more lower lower phenyl or halogen with the exception of the following compounds and salts 42319 Hereafter in this speci ication when the phrase compounds of this is it is to understood that we mean compounds of and salts thereof excluding the eight compounds specifically listed and their Examples of groups and which be present in the of this invention include methyl and and butyl and and or In addition and or and and taken together may represent the residue of a or which may carry one or more of the substituents listed Compounds of the present invention which are especially preferred for their high activity include the following compounds and their pharmaceutically acceptable f In the preceeding we have referred to pharmaceutically acceptable salts of the of formula Such salts include the alkali salts sodium or and salts with organic bases such as amines or amino These compounds on be capable of existing in an anhydrous form or one or more The invention includes all of these The compounds of this invention may be prepared by a process which comprises nitrating the parent of formula wherein and are as hereinbefore The nitration step may be carried out at various temperatures although usually below In general temperature range of from to will be with being The starting materials of formula above may be prepared by known the choice of method being dependent on the nature of the uents With a single relatively chemically inert substituent such as a or phenyl the method of choice is the Claisen condensation wherein a compound formula 0 wherein R is the inert substituent and X is an alkyl group is reacted with ethyl With alkyl or alkoxy in both the and position of the Claisen condensation may sometimes afford only low yields of the required diones and the same is true for the In such the preferred method involves the reaction of a compound formula formed from the appropriate anhydride and acetic anhydride wherein both and are or alkyl or alkoxy groups or is a thylenedioxy with a strong base such as sodium Neither of the above procedures is advisable the presence of halogen here the reaction is best This involves the reaction of an active compound with compound o formula wherein and are the same or different and each is hydrogen or a halogen The use of ethyl acetoacetate as the active methylene compound is most convenient but has led to difficulties with both the and tetrachloro in which the carbethoxy intermediates are isolated and For this ethyl acetoacetate has been replaced by the more easily removable butyl acetoacetate with complete The Examples illustrate the preparation of some of the compounds of this invention also a few of the previously known compounds listed and illustrate the biological activity of such EXAMPLE 1 To a of sodium hydride in mineral oil mole of was added a solution of diethyl phthalate in ethyl acetate and the mixture refluxed with occasional swirling on a steam bath for 4 After the bright yellow sodium salt was filtered and washed with a little cold ethyl To the dried sodium salt was added rapidly a hot solution of hydrochloric acid in water and the product kept at until decarboxylation ceased cooled to and the pale yello solid filtered and washed with Recrystallisation from benzene afforded a pale yellow crystalline To a stirred suspension of dlone in anhydrous ether at 10 C was added dropwise and with fuming nitric acid After 10 a dark solution formed followed by precipitation of a bright yellow The mass was filtered and washed with 5N hydrochloric Recrystallisation from hydrochloric acid afforded the title EXAMPLE 2 This was prepared as in Example from diethyl 7 ione Nitration as in Example yielded the nitro hydrochloric 0 EXAMPLE 3 thoxy phthalate in ethyl acetate was added to a of hydride in mineral oil of and the mixture re fluxed for 4 in a water After cooling the red oil was treated with water and the yellow solid filtered and washed well with cold The sodium salt was carboxylated with hydrochloric acid at Nitration of as in Example afforded the title hydrochloric EXAMPLE 4 ione Dimethyl phthalate was converted into according to Example Direct nitration of with fuming nitric acid as in Example gave the hydrochloric 2H20 EXAMPLE This was prepared by an analagous procedure to that described in Example Nitration of with fuming nitric acid in ether at afforded the title hydrochloric 0 6 phthalalyl acetic acid phthalic anhydride Si was treated with freshly fused potassium acetate and acetic anhydride The resulting mixture was heated for 1 at and then for a further 4 at A ter cooling water was added and the dark precipitate filtered and washed well with cold water and methanol until the filtrate was the solid was extracted with aqueous sodium onate and the filtered extract A pale yellow precipitate of the phthalalylacetic acid o separated in quantitative C 61 Sodium hoxide sodium methanol was added with vigorous shaking to a solution of l phthalalyl acetic acid in methanol and the mixture stood at ambient for 2 The resulting orange gel was heated for 5 at cooled and then On addition of hot hydrochloric acid spontaneous decarboxylation ensued and an solid Filtration and crystallisation afforded the as a buff c Treatment of with fuming nitric acid as in Example gave the derivative as a yellow hydrochloric omo ione A solution of phthalic anhydride Si in acetic anhydride containing triethylamine was treated at room temperature with ethyl acetoacetate After 24 with crushed ice and trated hydrochloric acid were added and the precipitated red solid Addition of a hot solution of hydrochloric acid in water to this solid resulted in lation and generation of as red 02 Nitration as described in Example converted to its hydrochloric EXAMPLE 8 A of the procedure used in in which ethyl was replaced by butyl acetoacetate afforded from the decomposes above This was prepared as for the isomer hydrochloric EXAMPLE Q Using the procedure outlined in Example gave from phthalic The title compound was formed by nitration of at chloric EXAMPLE 10 Tetrachloro phthalic anhydride was converted to the indane by the method described in Example decomposes on rachloro Nitration of at afforded the hydrochloric 18 EXAMPLE 11 Dimethyl phthalate butadiene and dimethyl acetylene dicarboxylate were heated to in an autoclave and maintained at the temperature for 4 After cooling ether was added and the solution Evaporation of the filtrate afforded the title compound which was recrystallised from light petroleum Dimethyl phthalate The above dihydro aromatic was added to palladium on charcoal and the mixture aerated at for 3 After cooling ether was added and the mixture Evaporation and distillation afforded dimethyl alate light petroleum ione Dimethyl phthalate in ethyl acetate was added to a dispersion of sodium hydride in mineral oil mole of and the mixture re fluxed for 4 on a steam After cooling the yellow solid was filtered and washed with a little cold ethyl Treatment with a hot solution of concentrated hydrochloric acid in water for 7 gave the title suspended in anhydrous ether was stirred at during the addition of fuming nitric acid After the addition complete the mixture was stirred at ambient temperature for 1 and the precipitated yellow solid hydrochloric EXAMPLE 12 Dimethyl phthalate in ethyl acetate was cautiously added to a dispersion of sodium hydride in mineral oil mole of and the mixture fluxed for 4 hours on a steam A yellow solid separated after was filtered and washed with a little ethyl Addition of this solid to IN hydrochloric acid at caused immediate decarboxylation which was complete within After cooling and recrystallisation petroleum afforded the title ione suspended in dry ether was treated dropwise and with stirring with fuming nitric acid at The resulting solution was treated with hydrochloric acid and evaporated to a crystalline hydrochloric EXAMPLE 13 6 Dimethyl Dimethyl phthalate in ethyl acetate was treated with a dispersion of sodium hydride in mineral oil mole of and the mixture re fluxed for 4 at filtration the resulting yellow sodium salt was treated for 7 at with hydrochloric acid in water and the dione product filtered and 4 h l suspended in anhydrous ether was nitrated to the title product as described in 12 hydrochloric EXAMPLE 14 a Benz To a dispersion of sodium hydride in mineral oil added to a solution of diethyl naphthalene in ethyl acetate and the mixture refluxed for on a steam After cooling the precipitated orange solid was filtered and decarboxylated with hydrochloric acid in water at over 7 to yield indan Nitration of as described in Example 12 afforded the derivative as an orange crystalline hydrochloric 13 EXAMPLE acid anhydride g was treated with freshly fused potassium acetate and acetic anhydride o and heated at 100 C for 1 The mixture was then heated to which temperature it was maintained for 4 After water was added and rown solid filtered off and washed well with water and cold After extraction of the residue with sodium bicarbonate followed by acidification of the the title compound was isolated as a yellow Sodium sodium S methanol was added with vigorous stirring to a solution of phthalalyl acetic acid in methanol and the gel allowed to stand for 2 The red suspension was then re luxed for 5 hours on a steam cooled and Addition of the solid to hot hydrochloric acid caused immediate decarboxylation and ation of the After cooling the indane dione was c in dry ether was nitrated with fuming nitric acid as described in Example 12 to give chloric EXAMPLE 16 phthalate Dimethyl acetylene dicarboxylate was added to a solution of in dry benzene and the mixture stirred in an autoclave at for 24 oration and distillation then afforded the dihydro aromatic adduct as a colourless Aeration of this at in the presence of palladinised charcoal over 3 hours then after spinning bend the title compound as a colourless oil 2 A solution of dimethyl phthalate in ethyl acetate was added to a dispersion of sodium hydride in mineral oil and the mixture reluxed for 4 hours on a steam After cooling the yellow sodium salt was washed well with dry ether and Treatment with a hot solution of hydrochloric acid in water over 10 then gave the requisite dione A suspension of in dry ether was treated dropwise at with fuming nitric acid and the precipitated product filtered after 40 at room hydrochloric requires EXAMPLE 17 l Dimethyl phthalate in ethyl acetate was added to a dispersion of sodium hydride in oil and the mixture refluxed for 4 hours at Addition of ethyl acetate to the residual cooled oil afforded a yellow solid which was Treatment of this solid with 5N hydrochloric acid at during 7 afforded the title product A suspension of dione in dry ether was nitrated as in Example to yield the chloric 05 EXAMPLE 18 Claisen condensation of dimethyl phthalate as given in Example l6 afforded the title product petroleum Nitration of a suspension of hoxy in dry ether as described in Example gave the EXAMPLE 19 A solution of dimethyl henyl phthalate in ethyl acetate was cyclised to the indane dione as described in Example petroleum Nitration of with fuming nitric acid as described Example l6 gave hydrochloric 6 2 EXAMPLE 20 ione A solution of phthalate 1 mm in ethyl acetate 34 was treated with a dispersion of sodium hydride in mineral oil and the solution refluxed for 4 hours on a steam The bright yellow solid which separated was filtered and cleaned by trituration with ether 1 Decarboxylat on with hydrochloric acid at over 10 gave the title petroleum suspended in dry ether 5 was treated dropwise with fuming nitric acid at and the clear dark red solution left to stir at room temperature for 1 Evaporation in the presence of hydrochloric acid gave the derivative as a yellow chloric a ipne Claisen condensation of phthalate with ethyl acetate as described in Example l6 afforded the title petroleum Nitration of ione as described in Example afforded the hydrochloric EXAMPLE 22 Claisen condensation of dimethyl phthalate with ethyl acetate as described Example 20 afforded Nitration of ione as described in Example 16 the hydrochloric EXAMPLE 23 a Dimethyl phthalate in ethyl acetate was added to a dispersion of sodium hydride in mineral oil and the mixture for 4 on a steam Separation of the bright yellow solid followed by decarboxylation with a hot solution of hydrochloric acid in water over 7 gave the title Nitration of as described in Example 16 afforded the hydrochloric 119 2 EXAMPLE 24 All of the prepared in the preceding were for biological The test system was the Rat Passive eous Anaphylaxis test described below in Serum containing heat labile totropic antibody was raised in rats by a method similar to that used by Mota Immunology Male rats of were injected intraperitoneally with of Bordatella pertussis vaccine 4x dead organism per and subcutaneously with ml of an emulaion of 100 of ovalbumin in 2 ml of saline and incomplete Rats were bled by cardiac puncture on day the blood was pooled and separated and serum stored at and thawed only once before The test was similar to that described by Ovary and Bier Ovary and and Goose and Blair Goose and N Immunolgy r of each of six old serial dilutions of the serum in saline were injected intradermally into separate sites on the shaved dorsal surface of 72 hours later the animals were challenged by injection of of ovalbumin mixed with ml of a solution of pontarnine sky blue dye both in isotonic saline buffered with Sorenson buffer The rats were killed after 20 minutes and the diameter of of the blue wheals at the antibody injection sites were The starting dilution of the serum was adjusted so that there was no after at the site of injection of the highest dilution and a maximum response at the lowest six twofold serial dilutions of the serum from to were Compounds were tested for their ability to reduce the diameter of the wheels at the injection sites of dilutions of antibody which on all the controls have less than maximum Amounts of the compounds were administered to rats each amount to a test group of six animals at a specified time prior to intravenous challenge with The diameters of the blue wheals which developed on the tests group of animals were compared with those on a control group of six animals treated in the same way as the test but which had not received the compound under Inhibition of 100 a The mean of the sum of the diameters of the wheals produced in the test group of animals at those antibody sites where all the control group of animals gave less than maximum respon b The mean of the sum of diameters of the wheals produced in control group of animals at those antibody sites where all the animals in the group gave less than maximum The preferred method of administration was solution of the test compound dissolved in pH buffer and neutralised with sodium For those compounds having insoluble sodium the salts were isolated by reaction of the free nitro compound with sodium hydroxide and the filtered sodium salt washed free of alkali with The dried salts were then administered as suspension in methyl The Claisen condensation of dimethyl tetralxn 5 late wi h ethyl acetate as described in afforded a yellow crystalline To a stirred suspension of in anhydrous ether at was added acid drop stirring at for 1 and then at room temperature for a further 1 water was the ether removed under vacuo and the solution Addition of concentrated hydrochloric acid to the yellow filtrate afforded the title compound on hydrochloric 26 Condensation of dimethyl indane ethyl acetate as in example b gave the dione as a yellow petroleum Fuming nitric acid added dropvdse to a stirred suspension of i in dry ether at the mixture stirred at this temperature 45 stirring a temperature for 1 by addition of water evaporation of filtration a Addition of of hydrochloric acid to the latter yielded the as a crystalline hydrochloric A solution of dimethyl in ethyl acetate added to a dispersion of hydride in oil of and the mixture for The salt separated with filtered and dried in Addition of the dried solid to hot 5 hydrochloric acid followed by for 7 the title dicne as a yellow titration of ne as outlined in example 1b gave the derivative as an initially yellov solid which turned orange on C C for insufficientOCRQuality

Claims (35)

CLAIMS;

1. l) A pharmaceutical composition comprising a compound of formula (i) or a pharmaceutically acceptable salt thereof: together with one or more pharmaceutically acceptable carriers, in formula R R , R and R represent hydrogen or lower alkyl, lower alkoxy, 1 » <- 4 phenyl or halogen groups and any two adjacent groups ^ and ^» R2 an< ^5 or R_ and R. may be joined to form with the carbon atoms to which they are 3 4 attached a carbocyclic ring which ring may be substituted by one or more lower alkyl, lower alkoxy, phenyl or halogen groups, this definition of ^, 2» ^ and ^ being subject to the proviso that R^, R^» a d R^ are not all hydrogen.

2. ) A pharmaceutical composition as claimed in claim I wherein a sodium salt of a compound of formula (i) is present.

3. ) A pharmaceutical composition as claimed in claim 1 or claim 2 wherein the groups R^, ^, ~ and R^ in the compound of formula (i) or salt thereof represent hydrogen or methyl, ethyl, n- or isq- propyl, ri-, sec- or tert-butyl, methoxy, ethoxy, n or iso-propoxy, n-, sec- or tert-butoxy, phenyl, fliioro, chloro, bro oror iodo groups, with the proviso that ^, R^, ^ and R^ are not all hydrogen.

4. ) A pharmaceutical composition as claimed in claim 1 or claim 2, wherein -4i - the groups R^ and R^* or ^ anc* ^ in the compound of formula (i) or a Ξ'Ί(~ thereof are joined to form with the carbon atoms to which they are attached a fused benzene ring, or are joined to form a butenylene j tetramethylene or trimethylene moiety.

5. ) A pharmaceutical composition as claimed in claim 1 or claim 2, wherein the groups and R^ in the compound of formula (i) or a salt thereof are joined to form with the carbon atoms to which they are attached a fused benzene ring, or are joined to form a butenylene, tetramethylene or trimethylene moiety.

6. ) A pharmaceutical composition as claimed in claim 4 or claim 5, wherein the fused benzene ring or the butenylene, tetramethylene or trimethylene moiety carries one or more of the substituent groups listed in claim 3·

7. ) A pharmaceutical composition as claimed in claim 5» wherein the groups ^ and R_, in the compound of the formula (i) or a salt thereof are joined to formatetramethylene or trimethylene moiety.

8. ) A pharmaceutical composition as claimed in any one of the preceding claims, wherein two of the groups R, , R„, R, and R. in the compound of 1 4 formula (i) or salt thereof are hydrogen.

9. ) A pharmaceutical composition as claimed in claim 1 which comprises 5,6-dimethyl-2-nitroindane-l,3-dione or a pharmaceutically acceptable salt thereof. -

10. ) A pharmaceutical composition as claimedin claim 1, which comprises one of the following compounds or a pharmaceutically acceptable salt thereof; 2-nitrobenz f Jindane-1,3-dione; 4-methoxy-6-ethyl-2-nitroindane-l, -dione 4-n-butoxy-2-nitroindane-l,3-dione ; 4,6-dimethyl-2-nitroindane-l , 3-dione; -42 - 5-methyl-2-nitroindane-1 , 3-dione; 4-fluoro-2-nitroindane-1 , 3-dione ;

11. ) A pharmaceutical composition as claimed in any one of the preceding claims which is in the form. of a microfine powder for insufflation,

12. ) A pharmaceutical composition as claimed in claim 11 wherein the microfi powder is such that substantially all the particles have diameters of less than 50 microns.

13. ) A pharmaceutical composition as claimed in claim 11 or claim 12 which additionally comprises a bronchodilator compound.

14. ) A pharnaceutical composition as claimed in claim 13 wherein the bronchodilator compound is isoprenaline .

15. J A pharmaceutical composition as claimed in any one of claims 1 to 10 which include a sterile liquid carrier suitable for injection.

16. ) A pharmaceutical composition as claimed in any one of claims 1 to 10 in the form of a pill, tablet, capsule, syrup or powder suitable for mixing wit water to form a syrup.

17. ) A compound of formula (i) as defined in claim 1 and pharmaceutically acceptable salts thereof, with the exception of the following compounds and .salts thereof: 2-nitroindane-l, 3-dione; 5-methoxy-2-nitroindane-1 , 3-dione ; 4, 5-dimethoxy-2-nitroindane-l, 3-dione; 5-bromo-2-nitroindane-1 , 3-dione ; 4-chloro-2-nitroindane-l, 3-dione ; 5-chloro-2-nitroindane-1 , 3-dione ; 4-methyl-2-nitroindane-l , 3-dione ; 5-iodo-2-nitroindane-1, 3-dione ; 4-bromo-2-nitroindane-l , 3-dione; 42319-2 tetrafluoro-2-nitroindane-l,3-dione.

18. ) The sodium salt of a compound of the formula (l) as c med in claim 17.

19. ) compound as claimed in claim 17: or 18» wherein the groups R^, R,,, R„ and R, in formula (i) are as defined in claim 3· 3 4

20. ) A compound as claimed in claim 17 or 18, wherein the groups R^ and ^» o ^ and ^ in formula (i) are as defined in claim 4.

21. ) A compound as claimed in claim 17 or 18, wherein the groups R^ and in formula (i) are as defined in claim 5·

22. ) A compound as claimed in claim 20 or 21, wherein the fused benzene ring or the butenj^lene , tetramethylene or trimethylene moiety carries one or more of the substituent..-groups listed in claim 3.

23. ) A compound as claimed in claim 17 or 18, wherein the groups R^ and R^ are as defined in claim 7.

24. ) A compound as claimed in any one of the claims 17 to 23, wherein two of the groups R^, ^2*^ an< ^ ^n ^orinu^-a (^ are hydrogen.

25. ) 5,6-dimethyl-2-nitroindane-l,3-dione and pharmaceutically acceptable salts thereof. ■

26. ) 2-nitrobenz fj indane-l,3-dione and pharmaceutically acceptable salts thereof.

27. ) 4-methoxy-6-ethyl-2-nitroindane-l,3-dione and pharmaceutically acceptabl salts thereof. -

28. ) 4-n -Butoxy-2-nitroindane- >3-dione and pharmaceutically accep salts thereof.

29. ) 4,6-Dimethyl-2-nitroindane-l,3-dione and pharmaceutically acceptable salts thereof.

30. ) 5-IIethyl-2-nitroindane-l,3-dione and pharmaceutically acceptable s lts thereof.

31. ) 4-Fluoro-2-nitroindane-l,3-dione and pharmaceutically acceptable salts thereof.

32. ) The substituted 2-nitroindane -1,3-diones named in examples 3»4,6,10, 12,14rl7,19»20f22 and 23 and pharmaceutically acceptable salts thereof.

33. ) A process for the preparation of a compound as claimed in claim 17 which process reacting the parent indane-rl>3-dione of formula (III)

34. R. wherein R^, R2> ^, and R are as defined in claim 17 v/ith a nitrating agent. 34) A process as claimed in claim 3'3 wherein the nitrating agent is f ming nitric acid.

35. ) A process as claimed in claim 33 -or claim 34 wherein the reaction is o o carried out at a temperature of from - 20 C + 20 C.