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(11) | EP 0 171 636 A1 |
| (12) | EUROPEAN PATENT APPLICATION |
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| (54) | Pharmacologically active piperazino derivatives and the process for their preparation |
| (57) New piperazino derivatives of formula
in which R is a phenyl radical substituted with at least one sulphonamido group or a substituted nitrogenated heterocyclit ring, and A is C0, CH2' SO2' possessing inhibiting activity towards carbonic anhydrase. The new products are prepared from compounds of formula R-A-X in which X is OH, SH, halogen, OR"" or SR"" in which R'''' is methyl, ethyl, phenyl, carbomethoxy, carboethoxy, and from a piperazino derivative of formula The R' group can also be introduced on termination of the reaction, by removing and substituting a protective group present at the nitrogen. |
[0001] This invention relates to a new class of pharmacologically active piperazino derivatives, and the process for their preparation.
[0002] More precisely, the invention relates to a new class of piperazino derivatives possessing inhibiting activity towards carbonic anhydrase. Carbonic anhydrase is known to be one of the most widespread enzymes in human tissues, and plays a determining role in many physiological and pathological processes.
[0003] Consequently its inhibition can be a factor in the solution of therapeutical problems of considerable importance.
[0004] The new compounds according to the present invention are those of general formula:
in which R is a phenyl radical containing at least one sulphonamido group and possibly various substituents chosen from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy; or a nitrogenated heterocyclic ring containing as substituent at least one amino, amido or sulphonamido group; A is CU, CH2, SO2; k' is H, alkyl, alkenyl, alkyl-aryl, alkyl-cycloalkyl, alkyl-acyl, alkyl-carboxyalkoxy, alkyl-carboxyamino, alkenyl-aryl, alkenyl- cycloalkyl, alkenyl-acyl, alkenyl-carboxyalkoxy, alkenyl-carboxyamino, acyl, aryl; R" is H or together with R' and with the nitrogen atom to which this latter is bonded forms a heterocyclic ring, provided that when R is a substituted phenyl radical and A is CO, R' is other than H, CI-C4 alkyl, benzyl.
[0005] Preferred meanings of the indicated radicals are as follows: R is 2-methoxy-5-sulphamoyl-phenyl, 2-sulphamoyl-imidazyl, 2-amino or 2-acetamido-1,3,4-thiadiazole; R' is H, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkenyl, alkyl-phenyl or alkenyl-phenyl in which the phenyl group is either simple or substituted with halogens, trihalomethyls, C1-C6 alkyls, C1-C6 alkoxys, C1-C6 alkylethers, sulphonamido groups; C2-C6 aliphatic acyl; alkyl-acyl radical in which the acyl is C1-C6aliphatic, aromatic or nitrogenated heterocyclic; C3-C6 alkyl-carboxyalkoxy; alkyl-carboxyamino in which the alkyl is C1-C3 and the amine is mono or disubstituted with linear or branched C1-C6 alkyl radicals; R" is H or together with R' forms a 5 or 6 term ring condensed with the piperazine, but again taking into account said limitation that when R is a substituted phenyl radical and A is CO, R' is other than H, C1-C4 alkyl, benzyl.
[0006] The new products according to the present invention are prepared essentially in accordance with the following reaction:
where R, R', R" are as heretofore defined, X is OH, SH, Cl, br, I, OR"", SR"" in which R"" is methyl, ethyl, phenyl, carbomethoxy, carboethoxy, in the presence of a base or a condensing agent.
[0007] The R' substituents can be introduced to the piperazino nitrogen either before or after reaction (II) is effected, using known methods comprising reacting the piperazino nitrogen bonded to the hydrogen with the required compound containing a reactive group.
[0008] Preferably, when the R' substituents are introduced to the piperazino ring as the final stage of the process, reaction (II) is effected beforehand using benzyl-piperazine
[0009] The benzyl derivative thus obtained is debenzylated by catalytic hydrogenation with Pd on C, and the compound obtained .
is reacted with a suitable compound YR', in which Y is a reactive group, preferably halogen.
[0010] It is in any case apparent that instead of the benzyl group, use can be made of any other suitable protective group of one of the piperazino nitrogens, which can be eliminated when reaction (II) is terminated.
[0012] Reaction (II) is preferably effected by reacting, with the compound R-A-OH and PCl3 or POC15 in a basic medium, the piperazino derivative containing the group R' or with one of the nitrogens suitably protected.
[0013] The amine:R-A-OH:PC13 ratio is generally stoichiometric, or has a slight deficiency (10-20X) of the compound R-A-OH relative to the stoichiometric.
[0014] The basic medium is preferably pyridine, or any organic basic solvent able to block the HC1 which forms during the reaction. The reaction takes place under hot conditions, preferably at the mixture reflux temperature.
[0016] In particular, it is purified by repeated crystallisations either as such or in the form of the hydrochloride. The compounds in which A is CH2 can be prepared by reducing the corresponding compounds in which A is C0, obtained by process (II).
[0017] Some practical examples are described hereinafter in order to better clarify the process according to the present invention and make it more easily reproducible, but these are to be considered as purely illustrative and in no case limitative of the process according to the present invention.
EXAMPLE 1
Preparation of the compound of formula
[0018]
A solution of N(2-methyl-l-butyl)piperazine in pyridine with an amine:pyridine weight ratio of 1:10 was fed into a suitable reactor, and a cold solution of PC13 in pyridine in a weight ratio of 1:10 was dripped in. The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added, and the mixture heated under reflux for 4 hours.
[0020] The cooled reaction mixture was evaporated under vacuum, taken up in dilute 10% sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0023] The product RV 12343 in the form of the hydrochloride was purified by repeated crystallisations from n.butanol. Yield 65X with respect to the acid.
EXAMPLE 2
Preparation of the compound of formula
[0025]
A solution of N-allyl-piperazine in pyridine with an amine:solvent weight ratio of 1:15 was fed into the reactor, and a cold solution of PC13 in pyridine in a weight ratio of 1:10 was dripped in. The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added, and the mixture heated under reflux for 4 hours.
[0027] The cooled reaction mixture was evaporated to dryness under vacuum, taken up in dilute 20% sodium hydroxide solution, washed with chloroform, acidified with acetic acid and filtered over carbon.
[0029] The precipitate was then filtered off, washed with water and recrystallised from ethyl acetate. Yield 35X.
EXAMPLE 3
Preparation of the compound of formula
[0031]
A solution of diazobicyclononane in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PC13 in pyridine in a weight ratio of 1:10 was dripped in.
[0032] The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added, and the mixture heated under reflux for 4 hours. Amine:PC13:acid ratio = 3:1:3.
[0033] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0034] The clear solution was alkalised with concentrated NH40H under agitation. The product does not precipitate, and it is therefore extracted with chloroform, washed with water, the organic phase evaporated to dryness, and crystallised from isopropyl alcohol. Yield 68X.
EXAMPLE 4
Preparation of the compound of formula
[0037]
A solution of piperonylpiperazine in pyridine with an amine:solvent weight ratio of 1:12 was fed into the reactor, and a cold solution of PCl3 in pyridine in a weight ratio of 1:10 was dripped in.
[0038] The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 4 hours. Amine:PC13:acid ratio - 3:1:2.7
[0039] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with CC14, acidified with dilute hydrochloric acid and filtered over carbon. The clear solution was alkalised with concentrated NH4OH under agitation.
[0040] The precipitate was filtered off, washed with water and recrystallised from ethyl alcohol. Yield 40X.
EXAMPLE 5
Preparation of the compound of formula
[0042]
A solution of 1-cyclohexyl-methyl-piperazine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PC13 in pyridine in a weight ratio of 1:10 was dripped in.
[0043] The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 4 hours. Amine:PCl3:acid ratio - 3:1:2.5
[0044] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0045] The clear solution was alkalised with concentrated Na2CO3 under agitation. The slightly tacky precipitate was filtered off, washed with water, dissolved in acidified water and reprecipitated with dilute ammonia. Yield 40%.
EXAMPLE 6
Preparation of the compound of formula
[0047]
A solution of 4-methoxy-benzylpiperazine in pyridine with an amine: solvent weight ratio of 1:15 was fed into the reactor, and a cold solution of PCI3 in pyridine in a weight ratio of 1:10 was dripped in.
[0048] The mixture was kept under agitation for 2 hours at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 3 hours. Amine:PCl3:acid ratio - 3:1:3
[0049] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with chloroform, acidified with acetic acid and filtered over carbon. The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off and washed with water. The acid-base treatment was repeated and the solid obtained was crystallised from isopropanol. Yield 65X.
EXAMPLE 7
Preparation of the compound of formula
[0052]
A solution of 3-methoxy-benzyl-piperazine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PC13 in pyridine in a weight ratio of 1:10 was dripped in.
[0053] The mixture was kept under agitation for 1.5 hours at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 4 hours. Amine:PC13:acid ratio - 3:1:3
[0054] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with CH2C12, acidified with acetic acid and filtered over carbon.
[0055] The clear solution was alkalised with IN KOH under agitation. The precipitate was filtered off, washed with water and recrystallised from isopropyl alcohol. Yield 67X.
EXAMPLE 8
Preparation of the compound of formula
[0057]
A solution of pyrrolidino-carbonyl-N-methyl-piperazine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PC13 in pyridine in a weight ratio of 1:10 was dripped in.
[0058] The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 5 hours. Amine:PCl3:acid ratio - 3:1:3.5
[0059] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon. The clear solution was alkalised with concentrated NH40H under agitation. The tacky precipitate was extracted with ethyl acetate, washed with water and evaporated to dryness. The residue was taken up in slightly alkaline water and solidified under agitation. It was filtered off and crystallised from aqueous ethyl alcohol. Yield 60X. M.P. - 205°-206°C.
EXAMPLE 9
[0061] benzyl-piperazine, PCl3 and 2-methoxy-5-sulphamoyl-benzoic acid were reacted in a reactor in accordance with the method described in Example 1. The product of formula
was separated, and debenzylated by catalytic reduction with 51 Pd on C in ethyl alcohol.
[0062] The 2-methoxy-5-sulphamoyl-benzoylpiperazine obtained in this manner was reacted with acetyl chloride in a molar ratio of 1:1, in benzene in the presence of pyridine, was filtered off, washed and crystallised from a mixture of methanol and ethyl acetate. Yield 70%.
EXAMPLE 10
[0065] A solution of ethoxycarbonyl-methyl-piperazine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PCl3 in pyridine in a weight ratio of 1:10 was dripped in.
[0066] The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 3 hours. Amine:PC13:acid ratio = 3:1:3.
[0067] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0068] The clear solution was alkalised with concentrated NH40H under agitation. The tacky precipitate was extracted with ethyl acetate, precipitated with alcoholic HC1, filtered off and crystallised from ethanol. Yield 40%.
EXAMPLE 11
[0071] A solution of cinnamyl-piperazine in pyridine with an amine:solvent weight ratio of 1:12 was fed into the reactor, and a cold solution of PCl3 in pyridine in a weight ratio of 1:10 was dripped in..
[0072] The mixture was kept under agitation for 2 hours at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 4 hours. Amine:PC13:acid ratio = 3:1:2.5
[0073] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0074] Tne clear solution was alkalised with concentrated NaOH under agitation. The precipitate was filtered off, washed with water and recrystallised from isopropyl alcohol. Yield 60%. M.P. = 110°C.
EXAMPLE 12
[0075] Preparation of the compound of formula
A solution of benzhydryl-piperazine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PC13 in pyridine in a weight ratio of 1:10 was dripped in.
[0076] The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 4 hours. Amine:PCl3:acid ratio = 3:1:3.
[0077] -The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with CC14, acidified with acetic acid and filtered over carbon.
[0078] The clear solution was alkalised with concentrated NH40H under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yield 61X.
EXAMPLE 13
[0081]
A solution of N(3Cl-phenyl)piperazine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PCl3 in pyridine in a weight ratio of 1:10 was dripped in.
[0082] The mixture was kept under agitation for 2 hours at ambient temperature, after which 2-methoxy-5-sulphnmoyl-henzoic acid was added and the mixture heated under reflux for 2 hours, Amine:PCl3:acid ratio = 3:1:2.7
[0083] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washad with other, acidified with acetic acid and filtered over carbon.
[0084] The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off and washed with water. The acid-base treatment was repeated, and the solid obtained was crystallised from aqueous methanol. Yield 60%.
EXAMPLE 14
[0087] A solution of N(4fluoro-phenyl)-piperazine in pyridine with an amine:solvent weight ratio of 1:12 was fed into the reactor, and a cold solution of PCl3 in pyridine in a weight ratio of 1:10 was dripped in.
[0088] The mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixtrue hheated under reflux for 3 hours, Anine:PCl3:acid ratio = 3:1:3
[0089] The reaction mixture was avaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with other, acidified with acetie acid and filtered over earbon.
[0090] The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yield 30%.
EXAMPLE 15
[0094] A solution of N(3-trifluoromethyl-phenyl)piperasine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a solution of PC13 in pyridine in a weight ratio of 1:10 was dripped in.
[0095] The mixture was kept under agitation for 1.5 hours at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 4 hours. Amine:PCl3:acid ratio = 3:1:2.5 The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with CHC13, acidified with acetic acid and filtered over carbon.
[0096] The clear solution was alkalised with concentrated NaOH under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yield 32X.
EXAMPLE 16
[0100] A solution of bis(4F-phenyl)-methyl-piperazine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PCl3 in pyridine in a weight ratio of 1:10 was dripped in.
[0101] The mixture was kept under agitation for 2 hours at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added, and the mixture heated under reflux for 4 hours. Amine:PCl3:acid ratio - 3:1:3 the reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0102] The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from n.butanol. Yield 56X.
EXAMPLE 17
[0106]
A solution of isopropyl-amino-carbonyl-methyl-piperazine in pyridine with an amine:solvent weight ratio of 1:10 was fed into the reactor, and a cold solution of PCl3 in pyridine in a weight ratio of 1:10 was dripped in.
[0107] Tne mixture was kept under agitation for one hour at ambient temperature, after which 2-methoxy-5-sulphamoyl-benzoic acid was added and the mixture heated under reflux for 2 hours. Amine:PCl3:acid ratio = 3:1:2.5
[0108] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0109] The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yleld 48%.
EXAMPLE 18
[0113]
A solution of benzyl-plperazine in pyridine with an amine:solvent weight ratio of 1:15 was fed into the reactor, and a cold solution of PCl3 in pyridine in a weight ratio of 1:10 was dripped in.
[0114] The mixture was kept under agitation for one hour at ambient temperature, after which 2-sulphamoyl-4-imidazole carboxylic acid was added and the mixture heated under reflux for 3 hours. Amine:PCl3:acid ratio - 3:1:3.
[0115] The reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0116] The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from n.butanol. Yield 30X.
EXAMPLE 19
[0120]
2-acetamido-1,3,4-thiadiazole 5-sulphochloride and piperonylpiperazine in stoichiometric ratio were fed in CHC13 solution into the reactor.
[0121] The mixture was kept under agitation for 4-5 hours, cooling it with ice, after which it was evaporated to dryness under vacuum and the residue was taken up in dilute sodium hydroxide solution, washed with ether, acidified with acetic acid and filtered over carbon.
[0122] The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yield 70%.
EXAMPLE 20
[0126] The compound obtained in Example 19 was hydrolysed in ethanol containing HC1 in a weight ratio of 20:3 by heating to a temperature of between 50° and 80°C for some hours.
[0127] The product obtained was isolated from the reaction mixture as described in the preceding examples, and recrystallised from ethanol. Yield 93%.
EXAMPLE 21
[0130] The N(2-methoxy-5-sulphamoyl)benzoyl-piperazine obtained as described in Example 9 was reacted with 4-sulphamido-benzyl chloride in a 1.1 N aqueous NaOH solution.
[0132] On cooling the aqueous solution, the desired compound precipitated and was purified by crystallisation from methanol. Yield 691.
EXAMPLE 22
[0135] The N-(2-methoxy-5-sulphamoyl)benzoyl-piperazine obtained as described in Example 9 was reacted under reflux for some hours with 3,4,5-trimethoxy-benzylchloride in stoichiometric ratio in a 1:1 chloroform: ethanol mixture in the presence of pyridine.
[0136] The reaction mixture was evaporated under vacuum, taken up in dilute sodium hydroxide solution, washed with chloroform, acidified with acetic acid and filtered over carbon.
[0137] The clear solution was alkalised with concentrated KOH under agitation. The precipitate was filtered off, washed with water and purified with silica gel. Yield 45X.
EXAMPLE 23
[0140] The N(2-methoxy-5-sulphamoyl)benzoyl-piperazine obtained as described in Example 9 was reacted with 3-methyl-benzylchloride in stoichiometric ratio in an aqueous dilute NaOH solution.
[0142] The desired product precipitated on cooling, and was recrystallised from isopropyl alcohol. Yield 50%.
EXAMPLE 24
[0145] The N-(2-methoxy-5-sulphamyl)benzoyl-piperazine obtained as described in Example 9 was reacted with 3F-benzylchloride in stoichiometric ratio in an aqueous alkal.ne solution at a temperature of 80°-100°C for 2 hours.
[0146] The desired product precipitated on cooling, and was recrystallised from isopropyl alcohol. Yield 35X.
EXAMPLE 25
[0149] Benzyl-piperazine and 2-methoxy-5-sulphamoyl-methylenechloride in stoichiometric ratio were fed in chloroform solution into a reactor.
1. Piperazino derivatives of formula
in which:
in which:
R is a phenyl radical containing at least one sulphonamido group and possibly other substituents chosen from the group consisting of halogen, C1-C4 alkyl, and C1-C4 alkoxy; or a nitrogenated heterocyclic ring containing as substituent at least one amino, amido or sulphonamido group;
A is CO, CH2, SO2;
R' is H, alkyl, alkenyl, alkyl-aryl, alkyl-cycloalkyl, alkyl-acyl, alkyl-carboxyalkoxy, alkyl-carboxyamino, alkenyl-aryl, alkenyl- cycloalkyl, alkenyl-acyl, alkenyl-carboxyalkoxy, alkenyl-carboxyamino, acyl, aryl;
R" is H or together with R' and with the nitrogen atom to which this latter is bonded forms a heterocyclic ring, provided that when R is a substituted phenyl radical and A is CO, R' is other than H, C1-C4 alkyl, or benzyl.
2. Piperazino derivatives as claimed in claim I, wherein
K is 2-methoxy-5-sulphamoyl-phenyl, 2-sulphamoyl-imidazyl, 2-amino or 2-acetamido-1,3,4-thiadiazole;
R' is H, linear or branched C1-C6 alkyl, linear or branched C1-C6 alkenyl, alkyl-phenyl or alkenyl-phenyl in which the phenyl group is either simple or substituted with halogens, trihalomethyls, C1-C6 alkyls, C1-C6 alkoxys, C1-C6 alkylethers, sulphonamido groups; C2-C6 aliphatic acyl; alkylacyl radical in which the acyl is C1-C6 aliphatic, aromatic or nitrogenated heterocyclic; C3-C6 alkylcarboxyalkoxy; alkyl-carboxyamino in which the alkyl is C1-C3 and the amine is mono or disubstituted with linear or branched C1-C6 alkyl radicals; R" is H or together with R' forms a 5 or 6 term ring condensed with the piperazine, provided that when R is a substituted phenyl radical and A is CO, R' is other than H, C1-C4 alkyl, or benzyl.
3. A process for preparing piperazino derivatives of formula
in which A, R, R', R" are as defined in claim 1, characterised by effecting the following reaction
in which X is OH, SH, Cl, Br, I, OR"", SR"" in which R"" is methyl, ethyl, phenyl, carbomethoxy, carboethoxy; AR, R, R" are as defined defined in claim 1, R"' is R' or. a protective group at the nitrogen, in the presence of a base or condensing agent, and the product obtained can be subjected to elimination of the protective group at the nitrogen and to introduction of a R' radical as defined in claim 1, or, when A is CO, can be subjected to reduction in order to obtain compounds in which A is CH2.
in which A, R, R', R" are as defined in claim 1, characterised by effecting the following reaction
in which X is OH, SH, Cl, Br, I, OR"", SR"" in which R"" is methyl, ethyl, phenyl, carbomethoxy, carboethoxy; AR, R, R" are as defined defined in claim 1, R"' is R' or. a protective group at the nitrogen, in the presence of a base or condensing agent, and the product obtained can be subjected to elimination of the protective group at the nitrogen and to introduction of a R' radical as defined in claim 1, or, when A is CO, can be subjected to reduction in order to obtain compounds in which A is CH2.
4. A process as claimed in claim 3, wherein the compound of formula R-A-OH is reacted
with the piperazino derivative in the presence of PC13 or POCl5 in a basic solvent, and the product obtained is isolated by conventional methods.
5. A process as claimed in claim 4, wherein the reaction is conducted with an amine:PCl3:acid ratio of 3:1:2.5-3, in pyridine.
6. A process as claimed in claim 3, wherein R"' is benzyl and is eliminated by reduction
with hydrogen using Pd on carbon as catalyst, before introducing the R' group by reaction
with a compound of formula YR', in which Y is halogen, in an organic solvent in the
presence of a strong inorganic or organic base.
7. A process as claimed in claim 3, wherein the reduction of the group A = CO to the
group CH2 is effected by hydrogenation.
Claims for the following Contracting State(s) : AT
Claims for Austria 1. A procese for preparing piperazino derivatives of formuls
in which A, R, R', R" are as defined in claim 1, characterised by effecting the following reaction
in which X is OH, SH, Cl, Br, I, OR'''', SR'''' in which R"" is methyl, ethyl, phenyl, carbomethoxy, carboethoxy; AR, R, R" are as defined defined in clain 1, R''' is R' or a protective group at the nitrogen, in the presence of a base or condensing agent, and the product obtained can be subjected to elimination of the protective group at the nitrogen and to introduction of a R' radical as defined in claim 1, or, when A is CO, can be subjected to reduction in order to obtain compounds in which A is CH2.
in which A, R, R', R" are as defined in claim 1, characterised by effecting the following reaction
in which X is OH, SH, Cl, Br, I, OR'''', SR'''' in which R"" is methyl, ethyl, phenyl, carbomethoxy, carboethoxy; AR, R, R" are as defined defined in clain 1, R''' is R' or a protective group at the nitrogen, in the presence of a base or condensing agent, and the product obtained can be subjected to elimination of the protective group at the nitrogen and to introduction of a R' radical as defined in claim 1, or, when A is CO, can be subjected to reduction in order to obtain compounds in which A is CH2.
2. A process as claimed in claim 3, wherein the compound of formula k-A-OH iF reacted with the piperazino derivative in the presence of PCl3 or POCl5 in a basic solvent, and the product obtained is isolated by conventional methods.
3. A process as claimed in claim 4, wherein the reaction is conducted with an amine:PCl3:acid ratio of 3:1:2.5-3, in pyridine.
4. A process as claimed in claim 3, wherein R"' is benzyl and is eliminated by reduction
with hydrogen using Pd on carbon as catalyst, before introducing the R' group by reaction
with a compound of formula YR', in which Y is halogen, in an organic solvent in the
presence.of a strong inorganic or organic base.
5. A process ac claimed in claim 3, wherein the reduction of the group A = CU to the
group CH2 is effected by hydrogenstion.