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EP0171636A1 - Pharmacologically active piperazino derivatives and the process for their preparation - Google Patents

Pharmacologically active piperazino derivatives and the process for their preparation Download PDF

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Publication number
EP0171636A1
EP0171636A1 EP85108942A EP85108942A EP0171636A1 EP 0171636 A1 EP0171636 A1 EP 0171636A1 EP 85108942 A EP85108942 A EP 85108942A EP 85108942 A EP85108942 A EP 85108942A EP 0171636 A1 EP0171636 A1 EP 0171636A1
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Prior art keywords
alkyl
group
alkenyl
formula
phenyl
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German (de)
French (fr)
Inventor
Francesco Botre
Roberto Signorini
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Ravizza SpA
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Ravizza SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a new class of pharmacologically active piperazino derivatives, and the process for their preparation.
  • 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.
  • R is a phenyl radical containing at least one sulphonamido group and possibly various substituents chosen from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy; or a nitrogenated heterocyclic ring containing as substituent at least one amino, amido or sulphonamido group;
  • A is CU, CH 2 , SO 2 ;
  • 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
  • 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 C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkenyl, alkyl-phenyl or alkenyl-phenyl in which the phenyl group is either simple or substituted with halogens, trihalomethyls, C 1 -C 6 alkyls, C 1 -C 6 alkoxys, C 1 -C 6 alkylethers, sulphonamido groups; C 2 -C 6 aliphatic acyl; alkyl-acyl radical in which the acyl is C 1 -C 6 aliphatic, aromatic or nitrogenated heterocyclic; C 3 -C 6 alkyl-carboxyalkoxy; alkyl
  • 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.
  • 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.
  • reaction (II) is effected beforehand using benzyl-piperazine
  • 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.
  • the R'-R" cyclisation can also be effected before or after effecting reaction (II).
  • Reaction (II) is preferably effected by reacting, with the compound R-A-OH and PCl 3 or POC1 5 in a basic medium, the piperazino derivative containing the group R' or with one of the nitrogens suitably protected.
  • the amine:R-A-OH:PC1 3 ratio is generally stoichiometric, or has a slight deficiency (10-20X) of the compound R-A-OH relative to the stoichiometric.
  • 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.
  • the product obtained is separated and purified by normal methods.
  • 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 PC1 3 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.
  • 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.
  • the clear solution was alkalised with concentrated ammonia under agitation.
  • the precipitate was filtered off after some hours and washed with water.
  • 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.
  • 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 PC1 3 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.
  • 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.
  • the clear solution was alkalised with IN NaOH and left for some hours under agitation.
  • 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 PC1 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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.
  • 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 PCl 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with CC1 4 , acidified with dilute hydrochloric acid and filtered over carbon.
  • the clear solution was alkalised with concentrated NH 4 OH under agitation.
  • 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 PC1 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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.
  • 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 PCI 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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 NH 4 OH 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.
  • 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 PC1 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with CH 2 C1 2 , acidified with acetic acid and filtered over carbon.
  • 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 PC1 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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 NH 4 0H 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.
  • 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 PCl 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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 NH 4 0H under agitation.
  • the tacky precipitate was extracted with ethyl acetate, precipitated with alcoholic HC1, filtered off and crystallised from ethanol. Yield 40%.
  • 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 PCl 3 in pyridine in a weight ratio of 1:10 was dripped in..
  • 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.
  • reaction mixture was evaporated to dryness under vacuum, taken up in dilute sodium hydroxide solution, washed with CC1 4 , acidified with acetic acid and filtered over carbon.
  • 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 PCl 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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.
  • 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 PCl 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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.
  • 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 PC1 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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 PCl 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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 PCl 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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.
  • 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 PCl 3 in pyridine in a weight ratio of 1:10 was dripped in.
  • 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 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.
  • Example 19 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.
  • the mixture was kept under agitation for 3 hours at a temperature of 80°-100°C.
  • reaction mixture was evaporated under vacuum, taken up in dilute sodium hydroxide solution, washed with chloroform, acidified with acetic acid and filtered over carbon.
  • Tne mixture was heated to a temperature of 50°C for 2 hours.
  • 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.
  • the precipitated hydrochloride was purified by crystallisation from ethanol. It was dissolved in water and precipitated with ammonia. It was filtered off, washed with water and crystallised from ethanol. Yield 47X.

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Abstract

New piperazino derivatives of formula
Figure imga0001
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
Figure imga0002
The R' group can also be introduced on termination of the reaction, by removing and substituting a protective group present at the nitrogen.

Description

  • This invention relates to a new class of pharmacologically active piperazino derivatives, and the process for their preparation.
  • 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.
  • Consequently its inhibition can be a factor in the solution of therapeutical problems of considerable importance.
  • The new compounds according to the present invention are those of general formula:
    Figure imgb0001
    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.
  • 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.
  • The new products according to the present invention are prepared essentially in accordance with the following reaction:
    Figure imgb0002
    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.
  • 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.
  • 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
    Figure imgb0003
  • The benzyl derivative thus obtained is debenzylated by catalytic hydrogenation with Pd on C, and the compound obtained .
    Figure imgb0004
    is reacted with a suitable compound YR', in which Y is a reactive group, preferably halogen.
  • 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.
  • The R'-R" cyclisation can also be effected before or after effecting reaction (II).
  • 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.
  • 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.
  • 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.
  • The product obtained is separated and purified by normal methods.
  • 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).
  • 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
  • Figure imgb0005
    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.
  • Amine:PCl3:acid molar ratio = 3:1:2.5
  • 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.
  • The clear solution was alkalised with concentrated ammonia under agitation.
  • The precipitate was filtered off after some hours and washed with water.
  • 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.
  • M.P. = 184°-186°C n.c.
    Figure imgb0006
    • EXAMPLE 2 Preparation of the compound of formula
  • Figure imgb0007
    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.
  • Amine:PCl3:acid molar ratio - 3:1:3
  • 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.
  • The clear solution was alkalised with IN NaOH and left for some hours under agitation.
  • The precipitate was then filtered off, washed with water and recrystallised from ethyl acetate. Yield 35X.
  • The pure product had the following characteristics: M.P. = 104°-105°C n.c.
    Figure imgb0008
    • EXAMPLE 3 Preparation of the compound of formula
  • Figure imgb0009
    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.
  • 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.
  • 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 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.
  • M. P. = 123°-125°C
  • Figure imgb0010
    • EXAMPLE 4 Preparation of the compound of formula
  • Figure imgb0011
    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.
  • 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
  • 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.
  • The precipitate was filtered off, washed with water and recrystallised from ethyl alcohol. Yield 40X.
  • M.P. - 185°-186°C.
    Figure imgb0012
    • EXAMPLE 5 Preparation of the compound of formula
  • Figure imgb0013
    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.
  • 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
  • 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 Na2CO3 under agitation. The slightly tacky precipitate was filtered off, washed with water, dissolved in acidified water and reprecipitated with dilute ammonia. Yield 40%.
  • M.P. = 110°-112°C.
    Figure imgb0014
    • EXAMPLE 6 Preparation of the compound of formula
  • Figure imgb0015
    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.
  • 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
  • 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.
  • M.P. = 160°-162°C
  • Figure imgb0016
    • EXAMPLE 7 Preparation of the compound of formula
  • Figure imgb0017
    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.
  • 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
  • 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.
  • 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.
  • M.P. = 178°-179°C
    Figure imgb0018
    Figure imgb0019
    • EXAMPLE 8 Preparation of the compound of formula
  • Figure imgb0020
    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.
  • 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
  • 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.
    Figure imgb0021
    • EXAMPLE 9
  • Preparation of the compound of formula
    Figure imgb0022
  • 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
    Figure imgb0023
    was separated, and debenzylated by catalytic reduction with 51 Pd on C in ethyl alcohol.
  • 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%.
  • M.P. - 208°-210°C.
    Figure imgb0024
    • EXAMPLE 10
  • Preparation of the compound of formula
    Figure imgb0025
  • 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.
  • 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.
  • 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, precipitated with alcoholic HC1, filtered off and crystallised from ethanol. Yield 40%.
  • M.P. = 225°C (hydrochloride)
    Figure imgb0026
    • EXAMPLE 11
  • Preparation of the compound of formula
    Figure imgb0027
  • 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..
  • 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
  • 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.
  • 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.
    Figure imgb0028
    • EXAMPLE 12
  • Preparation of the compound of formula
    Figure imgb0029
     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.
  • 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.
  • -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.
  • The clear solution was alkalised with concentrated NH40H under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yield 61X.
  • M.P. - 255°-257°C.
    Figure imgb0030
    • EXAMPLE 13
  • Preparation of the compound of formula
  • Figure imgb0031
    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.
  • 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
  • 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.
  • 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%.
  • M.P. = 105°-107°C.
    Figure imgb0032
    • EXAMPLE 14
  • Preparation of the compound of formula
    Figure imgb0033
  • 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.
  • 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
  • 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.
  • The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yield 30%.
  • M.P. = 195°-197°C
  • Figure imgb0034
    • EXAMPLE 15
  • Preparation of the compound of formula
    Figure imgb0035
  • 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.
  • 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.
  • The clear solution was alkalised with concentrated NaOH under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yield 32X.
  • M.P. - 125°-127°C
  • Figure imgb0036
    • EXAMPLE 16
  • Preparation of the compound of formula
    Figure imgb0037
  • 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.
  • 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.
  • 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.
  • M.P. = 238°-240°C
  • Figure imgb0038
    • EXAMPLE 17
  • Preparation of the compound of formula
  • Figure imgb0039
    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.
  • 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
  • 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 NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yleld 48%.
  • M.P. - 228°-230°C
  • Figure imgb0040
    • EXAMPLE 18
  • Preparation of the compound of formula
  • Figure imgb0041
    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.
  • 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.
  • 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 NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from n.butanol. Yield 30X.
  • M.P. = 224°-225°C
  • Figure imgb0042
    • EXAMPLE 19
  • Preparation of the compound of formula
  • Figure imgb0043
    2-acetamido-1,3,4-thiadiazole 5-sulphochloride and piperonylpiperazine in stoichiometric ratio were fed in CHC13 solution into the reactor.
  • 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.
  • The clear solution was alkalised with concentrated NH4OH under agitation. The precipitate was filtered off, washed with water and recrystallised from ethanol. Yield 70%.
  • M.P. - 238°-240°C
  • Figure imgb0044
    • EXAMPLE 20
  • Preparation-of the compound of formula
    Figure imgb0045
  • 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.
  • The product obtained was isolated from the reaction mixture as described in the preceding examples, and recrystallised from ethanol. Yield 93%.
  • M.P. = 205°-208°C
    Figure imgb0046
    • EXAMPLE 21
  • Preparation of the compound of formula
    Figure imgb0047
  • 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.
  • The mixture was kept under agitation for 3 hours at a temperature of 80°-100°C.
  • On cooling the aqueous solution, the desired compound precipitated and was purified by crystallisation from methanol. Yield 691.
  • M.P. =182°-184°C
    Figure imgb0048
    • EXAMPLE 22
  • Preparation of the compound of formula
    Figure imgb0049
  • 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.
  • 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.
  • 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.
  • M.P. - 176°-178°C (hydrochloride)
    Figure imgb0050
    • EXAMPLE 23
  • Preparation of the compound of formula
    Figure imgb0051
  • 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.
  • Tne mixture was heated to a temperature of 50°C for 2 hours.
  • The desired product precipitated on cooling, and was recrystallised from isopropyl alcohol. Yield 50%.
  • K.P. - 180°-181°C
    Figure imgb0052
    • EXAMPLE 24
  • Preparation of the compound of ormula
    Figure imgb0053
  • 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.
  • The desired product precipitated on cooling, and was recrystallised from isopropyl alcohol. Yield 35X.
  • M.F. = 175°-176°C
    Figure imgb0054
    • EXAMPLE 25
  • Preparation of the compound of formula
    Figure imgb0055
  • Benzyl-piperazine and 2-methoxy-5-sulphamoyl-methylenechloride in stoichiometric ratio were fed in chloroform solution into a reactor.
  • The mixture was kept under reflux for 4 hours.
  • When the reaction terminated, the mixture was poured into ice and acidified with HCl.
  • The precipitated hydrochloride was purified by crystallisation from ethanol. It was dissolved in water and precipitated with ammonia. It was filtered off, washed with water and crystallised from ethanol. Yield 47X.
  • M.P. - 160°-164°C
    Figure imgb0056
    Figure imgb0057

Claims (7)

1. Piperazino derivatives of formula
Figure imgb0058
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
Figure imgb0059
in which A, R, R', R" are as defined in claim 1, characterised by effecting the following reaction
Figure imgb0060
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.
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US7375226B2 (en) 2004-12-15 2008-05-20 Hoffman-La Roche Inc. Bi- and tricyclic substituted phenyl methanones
US7485637B2 (en) 2005-01-04 2009-02-03 Hoffmann-La Roche Inc. Benzoyl-tetrahydropiperidine derivatives
US7220744B2 (en) 2005-01-07 2007-05-22 Hoffman-La Roche Inc. Monocyclic substituted phenyl methanones
US7790763B2 (en) 2005-01-18 2010-09-07 Hoffmann-La Roche Inc. Substituted phenyl methanone derivatives
US7442710B2 (en) 2005-01-26 2008-10-28 Hoffman-La Roche Inc. Substituted phenyl methanones
US7557114B2 (en) 2005-02-07 2009-07-07 Hoffman-La Roche Inc. Heterocyclic-substituted phenyl methanones
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