Classifications

• • 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.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=11194823

Family Applications (1)

Country Status (4)

Cited By (15)

Families Citing this family (40)

Citations (7)

Family Cites Families (5)

• 1984
  • 1984-08-14 IT IT22334/84A patent/IT1176613B/it active
• 1985
  • 1985-07-17 EP EP85108942A patent/EP0171636A1/fr not_active Withdrawn
  • 1985-07-18 US US06/756,257 patent/US4940793A/en not_active Expired - Fee Related
  • 1985-08-14 JP JP60177809A patent/JPS6156167A/ja active Pending

Patent Citations (7)

Also Published As

Similar Documents

Legal Events