IL31079A - N,n'-disubstituted diazacycloalkanes alkylated at carbon atoms of the heterocyclus and pharmacologically acceptable acid addition salts thereof - Google Patents

Description

31079/2 n* p'*»i enn nyati»'f»'v*aana¾ *·ρ*κ mama ' Q'Vapn on w ο»·»η3-Βΐππ ηΐώ'οπ 'Π^Β,Υ .n'XV'jl KBIB Π3'Π3Β N^N'-dlsubstituted diazacycloalkahee alkylated at carbon atoms of the heterocyclic ring and pharmacologically acceptable acid addition salts thereof.

ASTA-WERKE AKTIENGE3ELLSCHAFT C: 29279 SPECIFICATION There are already open chained and cyclic N, ' -disub-stituted diamines producing coronary dilatation. For instance, German patent specification No. 1,182,239 describes compounds of the general formula I A being a lower alkylene group.

None of . these compounds have been so satisfactory to a satisfactory market the medical profession to yield /i«-^---t-?ade product. A trade product is for instance the compound Ν,Ν' -dimethyl- Ν,Ν' -bis- ¾3' ,4' ,5' -trimethoxy-benzoyloxy) -propyl7~ ethylene-diamine-dihydrochloride disclosed in Austrian patent specification No. 231,432. However, further research works aims to new compounds which are improved as to their chemotherapeutical, pharmacological and other properties.

It is therefore an object of the present invention to provide new compounds with improved coronary dilatatory Another object of the present invention is to provide an improved method in the treatmant of conditions of coronary and cerebral vascular insufficiency such as angina pectoris and the like.

Still other objects of the present invention and advantages thereof will become apparent as the description proceeds. · new Ν,Ν' -disubstituted diazacycloalkanes alkylated ic ring carbon atoms of the heterocycli*s-/have the following ' general formula II wherein , R2, R^ and R^, which may be the same or different, represent hydrogen atoms or lower alkyl groups having from 1 to 4 carbon atoms, at least one of these groups ^ , 2, ^ and R^ being such an alkyl group, m is 0 or 1 and n is 2 or 3· The invention furthermore embraces the pharmacologically acceptable acid addition salts of the compounds of formula II .

The new compounds according to the present invention are characterized b that the roduce a hi h dilatation of coronary blood vessels. Thus, they. are regarded as the most powerful coronary dilatators.

In view of their particular properties those compounds of formula II and their pharmacologically acceptable . acid addition salts are preferred wherein R;j , R2, R^ or R^ represent hydrogen, the methyl or' the ethyl group and one or two of these groups being a methyl or ethyl group, m is 0 or 1 and n is 2 or 3· Among .these compounds those are most preferred wherein n is 3,. -j and R2 represent hydrogen, m is 0, ^ is methyl or ethyl and ^ is hydrogen, methyl or ethyl, or wherein n is 3, R-j and R2 are hydrogen, m is 1 , ^ is methyl and ^ is hydrogen or methyl.

The most preferred pharmacologically acceptable acid . addition salts of the compounds of formula II are those malreic" of the hydrochloric, sulphoric', malea-i-e, embonic, citric and tartaric acids.

Among the above compounds the most preferred compound is that of the following formula III and its pharmacologically acceptable acid addition salts, in particular those of the above named preferred acids. ' Pharmacological tests showed that in particular the than 2.5 times as effective in relation of the increase in the blood circulation in the myocard of dogs, than the trade -compound Ν,ΚΓ' -dimethyl-Ν,ΚΓ' -bis- 3-( 3' ,4' ,5'-trimethoxy-benzoyloxy)-propyl7-ethylene-diamine-dihydro-chloride (Hexobendine) .

The myocardic blood circulation has been determined by means of thermoelements in dogs narcotized' with morphine-chloralose-urethane (method of BETZ, BRAASCH and HENSEL, Arzneimittelforschung vol. 11, (1961) pages 333 to 336).

In order to quantitatively determine the relation between the dose and the effectiveness, the effect produced by the test compounds are compared, with the effect of a predetermined dose (1 mg./kg.) of the known coronary dilatator Prenylamine (see Lindner, Arzneimitteldorschung, vol. 10, (1960) pages 569 to 573). From the reported dose versus effectiveness diagrams, the dose DE 1.00 is extrapolated which produces the same effectiveness as 1 mg./k . of Prenylamine, i.e. N- 3' -phenyl-propyl-( » -diphenyl propyl-( 3) -amine . In these tests, the compounds of the present invention have been compared with the' trade product Hexobendine (N,N* -dimethyl-Ν,Ν* -bis- 3-( 3' , 4' , 5 ' -trimethoxy-benzoyloxy) -propyls-ethylene diamine, which is the most related compound of the prior art. The results of these tests are given in the following Table 1.

Table 1 Effectiveness to the blood circulation in the myocard of dogs 1 ) g. 2 ) dose which produces the sameeffectiveness as j 1 mg./kg. ! ■ of prenylamine. J The process for the production of the compounds of the above formula II is characterized in that A) a 3 , 4 , 5-trimethoxy benzoic acid halogenoalkyl ester of the general formula IV" wherein n has the same meaning as in formula 'II and Hal is a halogen atom, preferably a. chlorine !or bromine atom, i is subject to reaction with a diazacycloalkane compound of the wherein -j , g, R^ and R^ and m have the same; meaning as in formula II, or a 3, , 5-trimethoxy benzoic acid halide, preferably the chloride or bromide, an ester preferably a lower alkyl ester or the anhydride of this acid is subjected to reaction with a Ν,Ν' -bis-(hydroxyalkyl)-diazacyclo-alkane compound of the general. formula VI wherein aning as in f or - C) a salt, preferably an alkali metal or alkaline; earth metal salt of 3, 4, 5-trimethoxy benzoic acid is; subjected to reaction with a Ν,ϋί' -bis-(halogenoalkyl)-diazacly- cloalkane compound of the general formula VII , Hal-(CH2)n - 'CH !■ R1 wherein R-j , Rg» R^> ^» m and n have the same reaning as in formula II and Hal is a halogen atom, preferably a chlorine or bromine atom. ; The reaction A most preferably is carried out in the presence of a suitable inert organic solvent such.ias an alcohol or in particular dimethyl formamide, and in the presence of an anhydrous acid binding agent such as anhydrous potassium carbonate, and at an elevated temperature in the range of about 100° C to about 180° C. The' best results in the reaction B have been obtained with 'the acid halides, preferably the chloride or bromide. Preferably, this reaction too is carried out in the presence of an inert organic solvent and of an acid binding agent and at an elevated temperature, preferably at the boilingj point of the reaction mixture. Preferred acid binding agents are the tertiary amines such as triethyl amine. Suitable dioxane or the aromatic hydrocarbons like benzene, toluene or xylene. The reaction C also preferably is' carried out in an inert organic solvent and at j an elevated temperature, in particular at the boiling point of the reaction mixture. Where a salt of the above' formula VII is used, the reaction C is carried iout in caustic the presence of an acid binding agent such as/.potash or i a tertiary amine. ! I The starting products preferably are used in equivalent amounts. In the reactions A and C an excess of the diazacycloalkane of the general formula V or, respectively, of the salt of the 3,4, 5-trimethoxy benzoic acid may i be used, the excess serving as acid binding agent. ·■% i ■ be The thus obtained basic compounds may, if desired ¾on-verted into the acid addition salts or obtained; salts may be converted into the free basic compounds.'. wherein R^,. Rg and n have the same meaning as in'iformula II, s with an alkylene dihalogeniade of the general fdrmula IX Hal - CH - (0H )m - CH - Hal 1 2 m I IX R3 R4 wherein R^, ^ and m have the same meaning as in formula II and Hal are halogen atoms, preferably chlorine or bromine atoms.

! The first mentioned method is described for instance • i by Pyman,'Soc. 1908, p. 1802, and by Gardner et al. Am. Soc. vol. 55, (1933), p. 3823· The diaminodihalide of formula VII may be produced in manners known per se such as by reacting a compound of the above formula VI with for instance thionyl chloride or, respectively, bromide.

The production of the compounds of formula V is described for instance in L.J. Kitchen and E.S. Hanson, Am.; Soc.j vol. 73, pharm.

Soc. Japa 51 (ref. C.A. et al., J. pharm. 8) page 229 (ref. C.A. vol. 52 (1958) 11862 a); as well as by P. Poppelsdorf and R. Myerly, J. org. Chem./ vol. 26 (196 ) page 131.

The following examples serve to further illustrate the. present invention and the production of the compounds according thereto. ί i Example 1 : ;' ' y ' ϋΓ,-Ν' -Bis-^-C 3' , 4' , 5 ' -trimethoxy-benzo oxy)-prppyl7--2-methyl-piperazine-dihydrochloride I . _ ( 40.4 g. (0.14 mol) of 3, 4, 5-trimethoxy benzoic; acid (3*-chloropropyl)-ester, 7 g. (0.07 mol) of methyl piperazine, 7 g. (0.07 mol)- of KgCO^ and 70 cc. of dimethyl formamide are heated with stirring at .120° C. for a period of 25 hours. The reaction mixture 'is poured into water and the resulting mixture is extracted twice with methylene chloride. The combined extracts- ;are washed with water and the organic layer thereof is dried over anhydrous sodium sulfate. The solvent is distilled off in a vacuum. Thus, the raw base is obtained in a yield of 34 g^ (801° of the theoretical). 25 g. (0.04; mol); * of the raw base are dissolved in 100 cc. of acetone. The resulting solution is mixed with the same volume of anhydrous ether and the raw base is precipitated as dihydrochloride by the addition of an anhydrous ! ethereal solution of hydrochloric acid with stirring. The resulting dihydrochloride is re crystallized from isopropariol with the addition of animal charcoal. j Mp: 1S5 to- 190° C. I Example 2; ■ Ν,ΪΤ' -Bis~^-( 31 ,4* , 5 ' -trimethoxy-benzoyloxy) -propyl7-cis- 2 , 5-dimethyl-piperazine-dihydrochloride Admixture of 40.4 g. (0.14 mol) of 3, 4, 5-trimethoxy- benzoic acid ( 3' -chloropropyl) -ester, 8.0 g. (0.07 mol) of cis-2, 5-dimethyl-piperazine, 9·7 g. (0.07 mol) of KgOO^ and 70 cc. of dimethyl formamide are heated to 120° C. with stirring for a period of 25 hours. The cooled reaction mixture is poured into water and the separated oil is extracted with ether. The combined ether extracts are washed with water twice and the ethereal layer is thoroughly shaken with 2 H hydrochloric acid. The hydrochloric acid layer is separated immediate.ly. After a short period of time, the dihydrochloride crystallizes therefrom. The dihydrochloride is filtered off with suction and recrystallized from e'thanol.

Mp: 207 to 209° C.

Example 3: Ν,Ν' ' ,4' , ' -trimethoxy-benzoyloxy) -propyl7- trans-2 , 5-dimethyl-piperazine-dihydrochloride A mixture of 40.4 g. .(Ό.14 mol) of 3 , 4, 5-trimethoxy benzoic acid ( 3' -chloropr.opyl) -ester, 8,0 g. (0.07 mol) of ,trans-2, 5-dimethyl-piperazine, 9·7 g. (0.07 mol) of KgCO^ and 70· cc. of dimethyl formamide are heated to 120° C. with stirring for a period of 25 hours. The cooled re product is extracted several times with methylene chloride. The combined extracts are washed with water twice. and the resulting methylene chloride layer is shaken with 2 Ϊ hydrochloric acid. After a short period of time the dihydrochloride crystallizes from this layer. The salt is filtered off with suction and recrystallized from dimethyl formamide.

Mp: 220 - .221° C.

Example 4: 2-ethyl-piperazine-dihydrochloride 40.4 g. (0.1 '4 mol) of 3, 4, 5-trimethoxy benzoic acid (3' -chloropropyl)-ester, 8.0 g. (0;.07 mol) of 2-ethyl-piperazine, 9·7 g. (0.07 mol) of gCO^ and 70 cc. of dimethyl formamide are heated to 120° C. with stirring for a period of 22 hours. The cooled reaction mixture is poured into water, extracted twice with ether and the combined ether extracts are washed several times A«/ith water. The ethereal solution then is thoroughly shaken with 2 N hydrochloric acid and the acidic organic layer is separated at once. After a short period of time the dihydrochloride crystallizes from this layer. The salt is filtered off with suction and recrystallized from isopropanol.

Mp: 202 - 207° C.

Example 5 - N,N'-Bis- I-(3' ,4' , 5 ' -trimethoxy-benzoyloxy) -ethyl/- .. 2 , 5-dimethyl-piperazine-dihydrochloride 2.7.7 g. (Ο.23 mol) of 3, 4, 5-trimethoxy benzoic acid chloride dissolved in 50 cc. of anhydrous benzene are added dropwise with stirring to a warmed solution of .1 g. (0.05 mol) of -bis-( S-hydroxy-ethyl)-2, 5- dimethyl-piperazine and 12.1 g. (0.12 mol) of triethyl- amine in 150 cc. of anhydrous benzene. After the addition is completed, the reaction mixture is refluxed for 1 1/2 hours. After cooling, the separated triethyl amine hydrochloride is filtered off and the filtrate is washed three times with water and is dried over anhydrous sodium sulfate. The benzene is distilled off in a vacuum and the resulting base is dissolved in methylene chloride. This solution is diluted with the same volume of ether. An ethereal solution of hydrochloric acid is. added to this solution with cooling until a weak acidic reaction. The thus precipitated dihydrochloride is filtered off , washed .with ether and dried.

Mp: 223 - 226° C. Yield: 33 g. (99·4 σ/° of the theoretical).

Example 6; ■Έ, ' -Bis-^-( 3' ,4' , 51 -trimethoxy-benzoyloxy) -propyl/- 2 , 5-dimethyl-piperazine-dihydrochloride 27.7 g. (0.12 mol) of 3, 4, -trimethoxy benzoic acid chloride dissolved in 50 cc. of anhydrous benzene are added dropweise and with stirring to a warmed solution of 11.5 g. (0.05 mol) of Ν,Ν' -bis-( B-hydroxy-propyl)- 2 , 5-dimethyl-piperazine and 12.1 g. (0.12 mol) of triethylamine in 150 cc. of anhydrous "benzene. Thereafter, the reaction mixture is refluxed for 1 1/2 hours. After cooling, the precipitated triethylamine hydrochloride is filtered off and the filtrate is washed three times with water and dried over anhydrous sodium sulfate. The benzene is distilled off in a vacuum. The thus resulting base is dissolved in acetone and the solution is diluted with the same volume of ether. An ethereal solution of 'hydrochloric acid is added to this solution with cooling until a weakly acid reaction thereof. The thus preci-_ pitated dihydrochloride is filtered off with suction, washed with ether and dried.

Mp: 207 - 215° C. Yield: 28 g. (80.91° of the theoretical).

Example 7: N, 5f' -Bis-^-i 3' , 4' , ' -tri.methoxy-benzoyloxy)-propyl7- cis-2 , 3-dimethyl-piperazine-dihydrochloride 40.4 g. (0.14 mol) of 5, 4, 5-trimethoxy benzoic acid (V -chloropropyl)-ester, 8.0 g. (0.07 mol) of cis-2,3- ■ dimethyl-piperazine, 9*7 g. (0.07 mol) of ^COT. and 70 cc. of dimethyl formamide are heated with stirring at 1 0° C. for a period of 20 hours. The cooled reaction · mixture is poured into water and the resulting mixture is extracted three times with ether. The combined ethereal extracts are washed twice with dilute hydrochloric acid. The resulting acidic extracts are then rendered alkaline by the addition of soda lye and the mixture is then extracted again three times with ether. The combined ether extracts are dried over anhydrous sodium sulfate and the ether is distilled off in a vacuum.' The t.hus crude ^ obtained 11 g. of saw base (25-4 of the theoretical) are dissolved in anhydrous ether and an equivalent amount of an ethereal, solution of hydrochloric acid is added thereto with cooling. The precipitated salt is recrysta-11- ized once from water and another time from isopropanol.

• Mp: 18o - 187° C.

Example 8 : , 7-dimethyl-homopiperazine-dihydrochloride g. (0.075 mol) of 3, 4, -trimethoxy benzoic acid (3'- bromopropyl)-ester, 10 g. (0.075 mol) of.5,7-dimethyl- homopiperazine and 75 cc. of dimethyl formamide are heated to 100° C. for- a period of 24 hours. The' solvent is distilled off in a vacuum, the residue is taken up in water and extracted with ethyl acetate. The organic layer is washed with water and extracted twice with dilute hydrochloric ' acid. The acidic solution is saturated with potas ium carbonate and the separated oil is extracted with ether. After drying and evaporation of the solvent, converted into the dihydrochloride by the addition of ethereal hydrochloric acid.

Yield: 8 g. (29 # of the ' theoretical) .

Colourless crystals.

Mp: 195 - 200°· C.

Example 9» N,N' -Bis- B-( 31 ,4' , 5 ' -trimethoxy-benzoyloxy) -ethyl7-5 , 7-dimethyl-homopiperazine-maleate g. (0.10 mol) of 3» , -trimethoxy benzoic acid (2'-chloroethyl)-ester, 12.8 g. (0.10 mol) of , 7-dimethyl-homopiperazine and 100 cc. of anhydrous alcohol are refluxed for 55 hours. The solvent is distilled off and the base is isolated as described, in Example- 8.

The base then is converted into the maleate by the addition of maleic acid in an ethereal alcoholic solution. The colourless crystals have a melting point of 120 - 124° Example 10: N,W 3 ' ,4' ,5' -trimethoxy-benzoyloxy) -propyl/-5-methyl-homopiperazine-dihydrochloride 27.6 g. (0.12 mol) of 3, 4, 5-trimethoxy benzoic acid chloride, 11.5 g. (0.05 mol) of Ν,Ν' -(^-hydroxy-propyl) -5-methyl-homopiperazine and 10.1 g. (0.10 mol) of triethyl amine are dissolved in 100 cc. of- benzene.,During this procedure there is observed an increase in temperature. The mixture then is refluxed for 2 hours and cooled and the separated triethylamine hydrochloride is -filtered off with suction. The benzene solution is extracted with dilute hydrochloric acid, the acidic extracts are rendered alkaline and the resulting mixture containing the base is extracted with ether. The' ether is distilled off and the residue is dissolved in ethanol. The di-hydrochloride of the base is obtained by the addition of an ethereal solution of hydrochloric acid to the ethanolic solution. The resulting dihydrochloride is recrystallized twice from ethanol. Thus, 1 7 g. of the desired salt ( 55 i° of the theoretical) are obtained.

Mp: 1 95 - 200° C.

The active compounds according to the present invention may be converted into usual pharmaceutical compositions such' as injection solutions, tablets, dragees or suppo- raethods sitories by *aim©*s- known per se.

Example 1 : Injection solution Active ingredient according to Example 1 .5 mg. aqua bidest,. ' filled up to 5 cc. per ampoule or active ingredient according to Example 1 0 5 mg. aqua bidest. filled up to 2 cc. per ampoule.

Example 12 : Dragees containing 25 or respectively 50 mg. of active ingredient 1 kernel contains: 25 mg. ' 50 mg« active ingredient according to Example 1 25.0 mg. 50.0 mg. ollidon 25 (polyvinylpyrrolidone)' 0.7 mg. 1.4 mg. lactose 50.0 mg. 60.0 mg. granulated anhydrous secondary calcium . phosphate 30.0 mg. 40.0 mg. potatoe starch 16.3 mg. 20.0 mg. talcum ' 17.0 mg. 17.0 mg. magnesium stearate 1.0 mg. 1.6 mg. 1 0.0 mg. 200.0 mg.

The dragee kernels containing 25 mg. of the active ingredient have a diameter of 7 mm. and a curvature radial of 5 mm. They are coated with a usual coating to weigh 240 mg. each. The dragee kernels containing 50 mg. of the active compound have a diameter of 8 mm. and a curvature radial of 6 mm. They are coated with a usual coating to weigh 370 mg. The coating is carried out according to the conventional sugar coating method in manners known per se. - -

Claims (1)

1. γ . WHAT WE CLAIM IS: 1. New Ν,ϋί' alkylated at the carb having the general formula II wherein ^ , R2, R^ and R^, which may be the same or · different, represent hydrogen atoms or lower alkyl groups having from 1 to 4 carbon atoms, at least one of the groups R-j, Rg, ^ and R^ representing such an alkyl group, m is 0 or 1 and n is 2 or 3, and the pharmacologically ac- ■ ceptable acid addition salts thereof. .iCompounds as claimed in claim 1 wherein R^ , R2, ^ and ^ are hydrogen, the methyl or the ethyl group, one- or tv/o groups of R^ , Rg, R^ and R^ being a methyl or ethyl group and the other being hydrogen, m is 0 or 1 , n is 2 or 3· · Compounds as claimed in claim 1 wherein n is 3, -R-j and R2 are hydrogen, m is 0, ^ is methyl or e hyl aid R^_ is hydrogen, methyl or ethyl, or n is 3, R^ and 2 are hydrogen, m is 1 , R^ is the methyl group and R^ is hydrogen or the 'methyl group. 4. Ν,Ν' -Bis-^-( 3' ,4' , 5 ' -trimethoxy-benzoyloxy) -propyl/- 2-methyl-piperazine and the pharmacologically acceptable addition salts thereof. 5. Ν,Ν' -Bis-^-( 3 ' ,4' , 5 ' -trimethoxy-benzoyloxy) -propyl/- 5-methyl-homopiperazine and the pharmacologically acceptable- addition salts thereof. 6. A compound as claimed in any of the preceeding claims whenever' produced substantially as described with reference to Examples 1 to 10. 7. Pharmaceutical compositions comprising as active ingredient a compound as claimed in claims 1 to 6 and a pharmaceutically acceptable carrier. 8. Pharmaceutical compositions as claimed in claim 7 containing a compound of formula II as active ingredient wherein , Rg, R^ or ^ represe t hydrogen, the methyl or ethyl groups, one or two of these groups R-j , Rg, ^ and R^ being a methyl or ethyl group and the other group being hydrogen, m is 0 or 1. and n is 2 or 3· 9· Pharmaceutical compositions as claimed in claim 7 containing compounds of formula II as active ingredients wherei,n n is 3, R-| and R2 are hydrogen and m 13 0, R^ is the methyl or ethyl group and R. is hydrogen, the methyl or ethyl group, or n is 3, and are hydrogen and m is 1 , R^ is ^ke methyl group and R^ is hydrogen. or the methyl group. 10. Pharmaceutical compositions as claimed in claims 7 to 9 ■wherein the active ingredient is Ν,Ν' ( 3' , 4' , 5 ' - trimethoxy-benzoyloxy) -propyl7-2-methyl-piperazine or a pharmacologically acceptable acid addition salt thereof. 1.1.' Pharmaceutical compositions as claimed in claims. 7 to 9 wherein the active ingredient is ΪΓ,Ν' -bis-^-( 3 ' , 4' , 5 ' - trimethoxy-benzoyloxy)-propy 7-5-methyl-homopiperazine or a pharmacologically acceptable acid addition salt thereof. 12. Pharmaceutical compositions as claimed in any of the preceeding claims 7 to 11 whenever produced substantially as described in Examples 11 or 12. 13. Process for the production of i*ew- Ν,-Ν' -disubstituted diazacycloalkane compounds alkylated at the carbon atom ic rin of the heterocyclus/as claimed in claims 1 to 5, com-' prising subjecting to reaction A) a 3, , 5-trimethoxy benzoic acid halogenoalkyl ester of the general formula IV CH,0 CH COO - (CH ) - Hal in Claim 1 wherein n has the same meaning as in formula II/ and Hal is a halogen atom, preferably a chlorine or bromine atom, with a diazacycloalkane compound of the general formula V wherein R«j, Rg, R^ and R^ and m have the same meaning as in formula II, or a 3, , 5-trimethoxy benzoic acid halide, preferably, the chloride or bromide, an ester preferably a lower alkyl ester or the anhydride of this acid with a -bis-(hydroxyalkyl) -diazacycloalkane compound of the general formula VI wherein R^ , R2, R^, ^» m and n have the same meaning as in formula II, in claim 1 or C) a salt, preferably an alkali metal or alkaline' earth metal salt of 3, 4, 5-trimethoxy benzoic acid with a • Ν,ΪΓ' -bis-(halogenoalkyl)-diazacycloalkane compound of the general formula VII Hal - (CH2)n - al wherein R^ , R2, ^, R^, .m and h have the same meaning in claim 1 · as in formula Il/and Hal is a halogen atom, preferably a .chlorine or bromine atom, and, if disired, converting obtained basic compounds in claim 1 ■ of the formula II .into pharmacologically acceptable acid addition salts or obtained salts of compounds of formula II into the free bases. 14. Process as claimed in claim 13 wherein. -j , R2, R-^ and R^ are hydrogen, the methyl or the ethyl group, one or two groups of R-| , R2, R^ and R^ being a methyl or ethyl group and the other being hydrogen, m is 0 or 1 and n is 2 or 3. 15· Process as claimed in claim 13 wherein n is 3, † and R, are hydrogen, m is 0, R^ is methyl or ethyl and R^ is hydrogen, methyl or ethyl, or n is 3, R^ and R2 are hydrogen, m is 1, R^ is the methyl group and ^ 'is hydrogen or the methyl group. Process as claimed in any of claims 1 3 to 1 5 wherein the reaction is carried out in the presence of an inert solvent and/or at an elevated temperature and/or in the presence of an acid "binding agent. Process as claimed in any of claims 1 3 to 16 substantially as described in any of the Examples 1 to 1 0.