HUE024552T2 - Helyettesített szulfonamidok, eljárás elõállításukra, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk glaucoma kezelésére - Google Patents

Helyettesített szulfonamidok, eljárás elõállításukra, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk glaucoma kezelésére Download PDF

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HUE024552T2
HUE024552T2 HUE08741979A HUE08741979A HUE024552T2 HU E024552 T2 HUE024552 T2 HU E024552T2 HU E08741979 A HUE08741979 A HU E08741979A HU E08741979 A HUE08741979 A HU E08741979A HU E024552 T2 HUE024552 T2 HU E024552T2
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bis
benzene
benzamide
sulfonamide
ethyl
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HUE08741979A
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Fridrich Gregan
Milan Remko
Elena Sluciakova
Jarmila Knapikova
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Unimed Pharma Spol Sro
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    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/18—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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Description

(19)
(11) EP 2 142 499 B1
(12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07C 311I16<200601> C07C 311I18<200S01> 10.12.2014 Bulletin 2014/50 C07D 207I12<2006 01> C07C 311l17<200e 01) C07D 2951096 (2006 01> C07D 2951125 <200e·01) (21) Application number: 08741979.2 C07D 295I13<200601> (22) Date of filing: 18.04.2008 (86) International application number: PCT/SK2008/050005 (87) International publication number: WO 2008/130332 (30.10.2008 Gazette 2008/44) (54) Substituted sulphonamides, process for their preparation, pharmaceutical composition comprising thereof and their use for treating glaucoma
Substituierte Sulfonamide, Herstellungsverfahren dafür, Pharmazeutische Zusammensetzungen damit und deren Verwendung zur Behandlung von Glaukom
Sulfamides substitués, leur procédé de préparation, composition pharmaceutique en contenant et leur utilisation pour le traitement de glaucome (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES Fl FR GB GR WO-A-2006/014134 WO-A-2008/071421 HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT US-A- 2 789 938 US-A- 3 502 652
RO SE SI SK TR
Designated Extension States: · FRANK A. GOMEZ ET AL: "Determination of AL BA MK RS Binding Constants of Ligands to Proteins by
Affinity Capillary Electrophoresis: (30) Priority: 20.04.2007 SK 542007 Compensation for Electroosmotic Flow" ANALYTICAL CHEMISTRY, vol. 66, no. 11,1994, (43) Date of publication of application: pages 1785-1791, XP002492063
13.01.2010 Bulletin 2010/02 · DATABASE CAPLUS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; (73) Proprietor: Unimed Pharma, Spol. S R.O. SATO, MASAO ET AL: "Photothermographic 821 05 Bratislava (SK) material containing diazonium, coupler, and
base" XP002492065 retrieved from STN Database (72) Inventors: accession no. 2001:444446 &amp; JP 2001 162950 A • GREGAN, Fridrich (FUJI PHOTO FILM CO., LTD., JAPAN) 19 June 821 05 Bratislava (SK) 2001 (2001-06-19)
• REMKO, Milan · DATABASE CAPLUS [Online] CHEMICAL 821 05 Bratislava (SK) ABSTRACTS SERVICE, COLUMBUS, OHIO, US; • SLUCIAKOVA, Elena COLOMBO, R. ET AL: "Effects of new 821 05 Bratislava (SK) sulfonamide molecules on rat gastric acid
• KNAPIKOVA, Jarmila secretion" XP002492066 retrieved from STN 821 05 Bratislava (SK) Database accession no. 1981:435276 &amp;
PHARMACOLOGICAL RESEARCH (74) Representative: Majlingova, Marta et al COMMUNICATIONS , 13(5), 525-34 CODEN: P.O. Box 56 PLRCAT; ISSN: 0031-6989, 1981, 850 07 Bratislava 57 (SK)
Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). • MILAN REMKO ET AL: "Theoretical study of gas-phase acidity, pKa, lipophilicity, and solubility of some biologically active sulfonamides" BIOORGANIC &amp; MEDICINAL CHEMISTRY, vol. 12, 2004, pages 5359-5403, XP002492064 cited in the application
Remarks:
The file contains technical information submitted after the application was filed and not included in this specification
Description
Field of the invention [0001] The present invention relates to the substituted sulphonamides, which are useful for use as medicaments. Background of the invention [0002] Sulphonamides represent an important group of drugs, the different chemical structures of which show antibacterial, diuretic, cancerostatic properties, they are effective carboanhydrase inhibitors, hypoglycaemics, protease inhibitors and cyclooxygenase inhibitors (C. T. Supuran, A. Casini, A. Scozzafava, Med. Res. Reviews 23 (2003) 535-558.
[0003] WO 2006014134 describes preparation of piperidine derivatives as well as salts and enantiomers thereof and pharmaceutical compositions containing the compounds. They are useful in therapy, in particular in the treatment of depression.
[0004] US 3 502 652 A describes a new basically substituted benzoic acid amides especially for treatment of hypertension.
[0005] US 2 789 938 A relates to diuretic compositions containing sulfonamides which serves to increase the elimination of cations.
[0006] The subject of the present invention relates to the novel compounds with the valuable properties, appropriate particularly in the manufacture of the pharmaceutical compositions. Proceeding from the fact, that the effective sulphona-mide type carboanhydrase inhibitors must have suitable spatial (3D) structure to be able to fill sufficiently active enzyme position on the basis of complementarity (M. Remko, J. Phys. Chem. A 107 (2003) 720-725). In addition to the 3D structure, for the high inhibition activity of the sulphonamides there is a certain balance needed between their water solubility and lipophilicity. These and other physic-chemical properties of sulphonamides fulfilling the conditions of Li-pinsky rules are highly effective pharmaceutical agents (M. Remko, C.-W. von der Lieth, Bioorg. Med. Chem. 12 (2004) 5395-5403). On the basis of the studies of the relationship between the structure and the activity of aromatic sulphonamides, there was a group of such compounds developed, which are effective carboanhydrase inhibitors and it shows to be effective as antiglaucomatics. It was established, these compounds decrease effectively intraocular pressure.
Summary of the invention [0007] The subject of the present invention relates to the novel use of the known substituted sulphonamides having general formula (I)
(I) wherein: if R1 is CO, then R2 is NH or O, and if R1 is S02, then R2 is NH; and R includes tertiary diC^alkylamine group, wherein alkyl moieties are the same or different, or amino group, alkyl moieties of which together form 5, 6 or 7-membered saturated ring, or the ends of the alkyl moieties are linked by heteroatom O, or R is 4-(N,N-diethylaminoethoxy)benzyl and then R1 is S02 and R2 is NH; or R is 4-[N-(morpholinopropyl)sulfamoyl]phenyl and then R1 is CO and R2 is NH. n is a number of linking aliphatic chain carbons, wherein n is 0, 2 or 3, and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a menidcament for the treatment of glaucoma.
[0008] According to the further embodiment, the subject of the invention relates to the use of compounds having general formula (I), wherein: R1 is CO and R, R2 and n are shown in the following Table:
and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a medicament for the treatment of glaucoma.
[0009] The subject of the present invention particularly relates to the use of the following compounds: N-(N,N-Diethylaminoethyl)benzene-1,4-bis(sulphonamide); (1-1), N-(N,N-Diethylaminopropyl)benzene-1,4-bis(sulphonamide); (I-2), N-(Pyrrolidinoethyl)benzene-1,4-bis(sulphonamide); (I-3), N-(Pyrrolidinopropyl)benzene-1,4-bis(sulphonamide); (I-4), N-(Morpholinoethyl)benzene-1,4-bis(sulphonamide); (I-5), N-(Morpholinopropyl)benzene-1,4-bis(sulphonamide); (I-6), N-(4-Diethylaminoethoxybenzyl)benzene-1,4-bis(sulphonamide); (I-7), N-(Dimethylaminoethyl)benzene-1,4-bis(sulphonamide); (I-8), N-(Dimethylaminopropyl)benzene-1,4-bis(sulphonamide); (I-9), N-(N,N-Dipropylaminoethyl)benzene-1,4-bis(sulphonamide); (1-10), N-(N,N-Dipropylaminopropyl)benzene-1,4-bis(sulphonamide); (1-11), N-(N,N-Diblutylaminoethyl)benzene-1,4-bis(sulphonamide); (1-12), N-(N,N-Dibutylaminopropyl)benzene-1,4-bis(sulphonamide); (1-13), N-(N-Methyl-N-ethylaminoethyl)benzene-1,4-bis(sulphonamide); (1-14), N-(N-Methyl-N-ethylaminopropyl)benzene-1,4-bis(sulphonamide); (1-15), N-(N-Ethyl-N-propylaminoethyl)benzene-1,4-bis(sulphonamide); (1-16), N-(N-Ethyl-N-propylaminopropyl)benzene-1,4-bis(sulphonamide); (1-17), N-(N-Ethyl-N-butylaminoethyl)benzene-1,4-bis(sulphonamide); (1-18), N-(N-Ethyl-N-butylaminopropyl)benzene-1,4-bis(sulphonamide); (1-19), N-(N-Propyl-N-butylaminoethyl)benzene-1,4-bis(sulphonamide); (I-20), N-(N-Propyl-N-butylaminopropyl)benzene-1,4-bis(sulphonamide); (1-21), N-(Piperidinoethyl)benzene-1,4-bis(sulphonamide); (I-22), N-(Piperidinopropyl)benzene-1,4-bis(sulphonamide); (I-23), 4-Sulfamoyl-N-(N,N-dimethylaminoethyl)benzamide; (11-1), 4-Sulfamoyl-N-(N,N-dimethylaminopropyl)benzamide; (II-2), 4-Sulfamoyl-N-(N,N-diethylaminoethyl)benzamide; (II-3), 4-Sulfamoyl-N-(N,N-diethylaminopropyl)benzamide; (II-4), 4-Sulfamoyl-N-(morpholinoethyl)benzamide; (II-5), 4-Sulfamoyl-N-(morpholinopropyl)benzamide; (II-6), 4-[N-(Morpholinopropyl)sulfamoyl]phenylsulfamoylbenzamide; (II-7), (N,N-Diethylaminoethyl)-4-sulfamoylbenzoate; (II-8), (N,N-Diethylaminopropyl)-4-sulfamoylbenzoate; (II-9), (N,N-Dipropylaminoethyl)-4-sulfamoylbenzoate; (11-10), (N,N-Dipropylaminopropyl)-4-sulfamoylbenzoate; (11-11), 4-Sulfamoyl-N-(N,N-dipropylaminoethyl)benzamide; (11-12), 4-Sulfamoyl-N-(N,N-dipropylaminopropyl)benzamide; (11-13), (N,N-Dibutylaminoethyl)-4-sulfamoylbenzoate; (11-14), (N,N-Dibutylaminopropyl)-4-sulfamoylbenzoate; (11-15), 4-Sulfamoyl-N-(N,N-dibutylaminoethyl)benzamide; (11-16), 4-Sulfamoyl-N-(N,N-dibutylaminopropyl)benzamide; (11-17), (N-Methyl-N-thylaminoethyl)-4-sulfamoylbenzoate; (11-18), (N-Methyl-N-ethylaminopropyl)-4-suffamoylbenzoate; (11-19), 4-Sulfamoyl-N-(N-methyl-N-ethylaminoethyl)benzamide; (II-20), 4-Sulfamoyl-N-(N-methyl-N-ethylaminopropyl)benzamide; (11-21), (N-Ethyl-N-propylaminoethyl)-4-sulfamoylbenzoate; (II-22), (N-Ethyl-N-propylaminopropyl)-4-sulfamoylbenzoate; (II-23), 4-Sulfamoyl-N-(N-ethyl-N-propylaminoethyl)benzamide; (II-24), 4-Sulfamoyl-N-(N-ethyl-N-propylaminopropyl)benzamide; (II-25), (N-Propyl-N-butylaminoethyl)-4-sulfamoylbenzoate; (II-26), (N-Propyl-N-butylaminopropyl)-4-sulfamoylbenzoate; (II-27), 4-Sulfamoyl-N-(N-propyl-N-butylaminoethyl)benzamide; (II-28), 4-sulfamoyl-N-(N-propyl-N-butylaminopropyl)benzamide; (II-29), (N-Ethyl-N-butylaminoethyl)-4-sulfamoylbenzoate; (II-30), (N-Ethyl-N-butylaminopropyl)-4-sulfamoylbenzoate; (11-31), 4-Suffamoyl-N-(N-ethyl-N-butylaminoethyl)benzamide; (II-32), 4-Sulfamoyl-N-(N-ethyl-N-butylaminopropyl)benzamide; (II-33), (Pyrrolidinoethyl)-4-sulfamoylbenzoate; (II-34), (Pyrrolidinopropyl)-4-sulfamoylbenzoate; (II-35), 4-Sulfamoyl-N-(pyrrolidinoethyl)benzamide; (II-36), 4-Sulfamoyl-N-(pyrrolidinopropyl)benzamide; (II-37), (Piperidinoethyl)-4-sulfamoylbenzoate; (II-38), (Piperidinopropyl)4-sulfamoylbenzoate; (II-39), 4-Sulfamoyl-N-(piperidinoethyl)benzamide; (II-40), 4-Sulfamoyl-N-(piperidinopropyl)benzamide; (11-41).
[0010] The subject of the present invention also relates to the novel compounds having general formula (I). wherein: R1 is S02 and R2 is NH, and R and n are shown in the following Table:
[0011] The subject of the present invention particularly provides these compounds: N-(N,N-Diethylaminoethyl)benzene-1,4-bis(sulphonamide); (1-1), N-(N,N-Diethylaminopropyl)benzene-1,4-bis(sulphonamide); (I-2), N-(Pyrrolidinoethyl)benzene-1,4-bis(sulphonamide); (I-3), N-(Pyrrolidinopropyl)benzene-1,4-bis(sulphonamide); (I-4), N-(Morpholinoethyl)benzene-1,4-bis(sulphonamide); (I-5), N-(Morpholinopropyl)benzene-1,4-bis(sulphonamide); (I-6), N-(4-Diethylaminoethoxybenzyl)benzene-1,4-bis(sulphonamide); (I-7), N-(Dimethylaminoethyl)benzene-1,4-bis(sulphonamide); (I-8), N-(Dimethylaminopropyl)benzene-1,4-bis(sulphonamide); (I-9), N-(N,N-Dipropylaminoethyl)benzene-1,4-bis(sulphonamide); (1-10), N-(N,N-Dipropylaminopropyl)benzene-1,4-bis(sulphonamide); (1-11), N-(N,N-Dibutylaminoethyl)benzene-1,4-bis(sulphonamide); (1-12), N-(N,N-Dibutylaminopropyl)benzene-1,4-bis(sulphonamide); (1-13), N-(N-Methyl-N-ethylaminoethyl)benzene-1,4-bis(sulphonamide); (1-14), N-(N-Methyl-N-ethylaminopropyl)benzene-1,4-bis(sulphonamide); (1-15), N-(N-Ethyl-N-propylaminoethyl)benzene-1,4-bis(sulphonamide); (1-16), N-(N-Ethyl-N-propylaminopropyl)benzene-1,4-bis(sulphonamide); (1-17), N-(N-Ethyl-N-butylaminoethyl)benzene-1,4-bis(sulphonamide); (1-18), N-(N-Ethyl-N-butylaminopropyl)benzene-1,4-bis(sulphonamide); (1-19), N-(N-Propyl-N-butylaminoethyl)benzene-1,4-bis(sulphonamide); (I-20), N-(N-Propyl-N-butylaminopropyl)benzene-1,4-bis(sulphonamide); (1-21), N-(Piperidinoethyl)benzene-1,4-bis(sulphonamide); (I-22), N-(Piperidinopropyl)benzene-1,4-bis(sulphonamide); (I-23).
[0012] Substituted benzene 1,4-bis(sulphonamides) can be prepared by the nucleophilic reaction of amines (IV) with 4-sulfamoylbenzenesulphonyl chloride (V) in the presence of triethylamine excess in tetrahydrofurane or in ether at the temperature 0 to 20 °C for 12 hours. In the preparation of the compounds (1-1) to (I-4), aliphatic amines IV were used in the reaction, wherein one amino group is primary and the other is tertiary. Carbon linking chain between the nitrogen atoms comprises 2 or 3 carbon atoms. Tertiary amino group contains two alkyl groups, 1-1 and I-2, or a nitrogen atom of this tertiary amino group is a part of the ring I-3, i-4,1-5 and I-6. In case of substituted 1,4-bis(sulphonamide) I-7, there was 4-diethylaminoethoxybenzylamine (XI) used as amine.
[0013] Substituted 4-sulfamoylbenzamides can be prepared by the nucleophilic reaction of amines having general formula (IV) with 4-sulfamoylbenzoyl chloride (VI) in tetrahydrofurane or in ether in the presence of triethylamine or N,N-diisopropylethylamine excess at the temperature 0 to 20 °C for 12 hours. In the preparation of the compounds 11-1 to II-6, there were aliphatic diamines used in the reaction, wherein one amino group is primary and the other is tertiary. Tertiary amino group comprises two alkyl groups or nitrogen atom of this tertiary amino group is a part of the ring. In case of substituted 4-sulfamoylbenzamide (Ii-7), 4-amino-N-(3-morpholinopropyl) benzene-sulphonamide (XIII) was used as an amine. For the preparation of the substituted benzoate II-8, 2-diethylaminoethanol was used as a compound with primary amino group.
[0014] The scheme for the preparation of the substituted benzene-1,4-bis(sulphonamides)
[0015] R = diethylamino, 1-pyrrolidino, 4-morpholino, 4-(diethylaminoethoxy)benzyl, n = 0, 2, 3
[0016] The scheme for the preparation of the substituted benzamides II
Χ=ΝΗ, Ο R = dimethylamino, diethylamino, 1 -pyrrolidino, 4-morpholino, 4-[N-(3-morpholinopropyl)aminosulphonyl]phenyl, n = 0, 2, 3
[0017] The scheme for the preparation of certain starting compounds set forth in detail in the examples of the embodiment.
[0018] In all cases, the ammonium salts were prepared by the acidobasic reaction of the amino group of the compounds I-7 and II-8 with the solution of hydrogen chloride in methanol.
[0019] Compounds of the general formula (I) were tested in the form of their salts with hydrogen chloride. The pH of aqueous solutions of these salts is close to the pH = 7 value. 1H-NMR were determined on the Mercury Plus 300 MHz spectrometer in the DMSO solution.
[0020] The invention also relates to the use of the compounds of the general formula (I) and physiologically and pharmaceutically acceptable salts, hydrates or solvates thereof in the manufacture of the pharmaceutical compositions. For this purpose they can be processed to the appropriate dosage form together with the auxiliaries, alternatively together with one or more other active agents, particularly with the active agents for the treatment of glaucoma.
[0021] These compositions according to the present invention can be used as the medicaments in the human and the veterinary medicine. Particular the auxiliaries are selected according to the pharmaceutical formulation and required way of administration.
[0022] In the pharmaceutical compositions according to the present invention for the oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal or intraocular administration, the active component of said general formula (I) or the acceptable salts, solvates or hydrates thereof can be administered as unit dosage forms as well as the mixtures with the conventional pharmaceutical véhiculés, to the animals and human for the prophylaxis or the treatment of the disorders or diseases associated with carboanhydrase enzyme. Appropriate dosage units include the formulations for oral way administration, such as tablets, gelatine capsules, powders, granules and oral solutions or suspensions, the formulations for sublingual, buccal, intratracheal or intranasal, subcutaneous administration, the formulations for intramuscular or intravenous administration and the formulation for rectal administration. For topical application the compounds of the present invention can be used in creams, ointments, solutions, emulsions, microemulsions, suspensions or in eyewash. If the topical composition is prepared in the form of the solution, specifically in the form of eye drops, main pharmaceutical component is mixed together with auxiliaries, i.e. : 0,001 to 2 % by weight, the auxiliaries maintaining the pH conditions (for example: boric acid, sodium borate, sodium phosphate, potassium phosphate and others) 0,001 to 2 % by weight, the auxiliaries adjusting isotonicity of the environs (for example: sodium chloride, potassium chloride, glucose, mannitol and others) 0,001 to 2 % by weight, the preservatives (for example: benzalconium chloride, chlorohexidine and others) 0,001 to 2 % by weight, the auxiliaries adjusting viscosity of the environs (for example: hydroxyethyl celulose, hydroxymethyl celulose, povidone, polyvinylalkohol and others) 0,001 to 2 % by weight, the antioxidants (for example: citric acid, mannitol, EDTA and other). These auxiliaries are given as examples, otherwise many other agents can be even used.
[0023] Compounds of the general formula (I) and physiologically acceptable salts, hydrates or solvates thereof can be used for prophylaxis and treatment of diseases, particularly for treatment of increased intraocular pressure, glaucoma.
[0024] On the basis of the above described assays and below described results of the assays, the synergic effect of our compound together with other antiglaucomatics selected from these groups can be expected: sympatomimetics (clonidine, brimonidine, epinephrine); parasympatomimetics (pilocarpine, carbachole); betablocators (timolol, betaxolol, levobunolol); prostaglandine analogues (latanoprost, bimatoprost, travoprost); and other antiglaucomatics (guanetidine, dapiprazole).
[0025] The invention is illustrated by following examples of the present invention embodiment, without limiting it in any way.
EXAMPLES
Preparation of the starting compounds Example 1
Preparation of 4-sulfamoylbenzenesulphonyl chloride (V) [Cross, P. E., Gatsby, B., J. Med. Chem. 21, 845 (1978); Holland, G. F., Funderburk, W. H., J. Med. Chem. 6, 307 (1963)].
[0026] To the 700 ml Erlenmeyer flask was taken up 54 ml of the distilled water and 72 ml of the concentrated hydrochloric acid. The solution was cooled to 0 °C and 24 g (0.139 mol) of sulfanilamide III was added successively portionwise under stirring. The mixture was stirred at this temperature another 1 hour. To this mixture, the solution of 9.6 g (0.139 mol) of sodium nitrite in 16 ml of the water was added dropwise for 30 minutes under stirring and cooling, so as the temperature of the mixture does not exceed 0 °C. The mixture was then stirred another 30 minutes at the 0 °C. In the meantime, the solution of 36 g (0.56 mol) of sulphurdioxid in 120 ml of 99% acetic acid was prepared. Sulphur dioxid was prepared by the successive addition of 100 g of sodium pyrosulphite to 250 ml 40% sulphuric acid. Prepared sulphur dioxid was taken up under cooling to the 120 ml of 99% acetic acid at +5 °C until the weight gain reaches 36 g. To this solution, 1.4 g of copper dichloride dihydrate was added and the mixture was stirred. To this mixture, the solution of prepared diazonium salt it is then added for 5 minutes under gentle stirring for 10 minutes in three portions so as the temperature of the mixture did not exceed +5 °C. After about 15 min evolution of forming nitrogen occurs. The mixture was stirred another 15 min, 200 ml of the mixture of the water and the grinded ice was added and the mixture was stirred another 20 min. Obtained solid was separated, washed 3 times with the ice water and dried. Crystallization from ethyl acetate. Colourless solid m.p. 156 - 157 °C. Afforded 14,9 g (42 %) of 4-sulfamoylbenzenesulphonyl chloride V.
Example 2
Preparation of sodium 4-sulfamoylbenzoate (VIII) [Gubert, S., Farmaco 45, 59 (1990); Rodionov, V. H., Javorskaja, E. V., Zh. Obsc. Chim. 18, 110 (1948)].
[0027] In the 500 ml Erlenmeyer flask the solution of 20.1 g (0.2 mol) potassium bicarbonate in 180 ml of the distilled water was prepared. To this solution, 40.2 g (0.2 mol) of 4-sulfamoylbenzoic acid VII was added portionwise for 30 minutes under stirring at 45 °C, each time until dissolution. The mixture was fizzing by leaking C02. Then the water was distilled off to the dryness from the solution on the vacuum rotatory evaporator (the temperature of the bath did not exceed 60 °C). Remaining humidity was removed by severalfold azeotropic distillation with toluene on the vacuum evaporator. The solid residue was shaken with dichloromethane, this was decanted and the solid product was dried under the infralamp. Colourless solid. Yield 43 g (98 %) of potassium 4-sulfamoylbenzoate VIII.
Example 3
Preparation of 4-sulfamoylbenzoyl chloride (VI) [Gubert, S., Farmaco 45, 59 (1990); Rodionov, V. H., Javorskaja, E. V., Zh. Obsc. Chim. 18, 110 (1948)].
[0028] To the 3-neck flask equipped with the stirrer and the thermometer, fresh distilled 55 ml of thionylchloride was taken up and 3 drops of dimethylformamide was added. The mixture was heated in the oil bath to 40 °C and at this temperature 35.8 g (0.149 mol) of potassium 4-sulfamoylbenzoate VIII was added portionwise for 30 minutes under stirring. Then the mixture was heated to 55 °C for another 40 min. On the vacuum rotatory evaporator, excess thionylchloride was distilled off and the product was extracted 3 times into 100 ml of hot (60 °C) anhydrous dioxane. The solution was diluted with adding 500 ml of petroleum ether. Obtained solid was separated, washed with petroleum ether or hexane and purified by crystallization from chloroform. Almost colourless solid, m.p 151-153 °C. Afforded 20 g (61 %) of 4-sulfamoylbenzoyl chloride VI.
Example 4
Preparation of 4-diethylaminoethoxybenzaldehyde X [Rodionov, V. H., Javorskaja, E. V., Zh. Obsc. Chim. 18,110(1948)].
[0029] To the solution of 18.4 g (0.15 mol) of 4-hydroxybenzaldehyde in 100 ml acetone, 27.5 g (0.16 mol) of N,N-diethyl-N-(2-chlorethyl)-amine IX and 22.1 g (0.16 mol) potassium carbonate was added at the room temperature under stirring. The mixture was then intensively stirred at the boiling temperature for 12 hours. The mixture was cooled, potassium chloride was separated, washed with acetone. The solvent was distilled off from the solution on the vacuum rotatory evaporator. Afforded 20 g (60.6 %) of 4-diethylaminoethoxybenzaldehyde X. Colourless fluid boiling point 120-123 °C / 0.5 torr, n20D = 1.536. Lit. [5] reports boiling point 123-125 °C / 0.8 torr, n20D =1.530.
Example 5
Preparation of 4-diethylaminoethoxybenzylamineXI [Cossey, H. D., Sharpe, C. J., J. Chem. Soc. 4322 (1963).Goldberg, M. W., Moutclair, U., Schw. Pat. 365387 (1962)] [0030] To the solution of 4-diethylaminoethoxybenzaldehyde X in 180 ml 10% solution of ammonia in anhydrous ethanol, 4.5 g RaNi was added and the mixture was heated to 80 °C at the pressure 68 atm in the autoclave under hydrogen input to the reaction mixture under stirring for 12 hours. The mixture was cooled, the catalyst was filtered off, washed with ethanol. The solvent was distilled off from the solution and the distillation residue was purified by distillation under the reduced pressure. Afforded 13 g (65 %) of 4-diethylaminoethoxybenzylamine XI. Colourless fluid 138-140 °C / 0.5 torr, n20D = 1.520. Lit [6,7] reports 130 °C / 0,3 torr, n20D = 1.5220.
Example 6
Preparation of 4-acetamido-N-(3-morpholinopropyl)benzenesulphonamideXIII [Goldberg, M.W., Moutclair, U., US. Pat. 2.879.293 (1959)] [0031] To the solution of 2.8 g (0.020 mol) of 3-morpholinopropylamine in 15 ml of acetone, the solution of 3.3 g (0.024 mol) of potassium carbonate in 3 ml of water was added under stirring. To this mixture, 5 g (0.021 mol) of 4-acetamido-benzenesulphonyl chloride XII was added portionwise at the room temperature for 15 min. The mixture was then stirred at the room temperature for another 2 hours. One half of the solvent volume was distilled off from the mixture, the mixture was cooled to 0 °C, Obtained solid was separated, washed 3 times with 5 ml of ice water and dried. Afforded 4,2 g (62 %) of 4-acetamido-N-(3-morpholinopropyl)benzenesulphonamide XIII, colourless solid, m.p. 97-98 °C.
Example 7
Preparation of 4-amino-N-(3-morpholinopropyl)benzenesulphonamide XIV [Goldberg, M. W., Moutclair, U., US. Pat. 2.879.293 (1959)].
[0032] The mixture of 3.4 g (0.001 mol) of 4-acetarnido-N-(3-morpholinopropyl)benzene sulphonamide XIII and 4 ml of 17% acid was heated for 3.5 hours until slight boiling under stirring. The mixture was cooled to the room temperature and neutralized to chloroform. The solvent was distilled off from the solution and the distillation residue - oil was macerated with ether. Afforded 2.1 g of (71 %) 4-amino-N-(3-morpholinopropyl)benzenesulphonamide XIV. Colourless solid, m.p. 96-97 °C. Lit. [8] reports 95 °C.
Example 8
Preparation of N-(N,N-diethylaminoethyl)benzene-1,4-bis(sulphonamide) (1-1) [0033] To the 250 ml 3 neck flask equipped with the thermometer, the add funnel, the magnetic stirrer, 50 ml of anhydrous tetrahydrofurane (0.0485 mol), Ν,Ν-diethylaminoethylamine IV and 24 g of (33 ml) (0.238 mol) triethylamine was taken up. The solution was cooled to 0 to 5 °C and the solution of 12 g (0.0469 mol) of 4-sulfamoylbenzenesulphonyl chloride V in 50 ml anhydrous tetrahydrofurane or ether was for 30 min added under cooling and stirring at 0 to 15 °C. The solid was separated. The mixture was then stirred for 12 hours at the room temperature. 100 ml of petroleum ether was added to the solution, the mixture was stirred, the semi-solid product was filtered off. This was triturated with 15 ml of saturated aqueous solution of sodium chloride. The solid product was separated, washed 2 times with 10 ml ice water and dried. Purification with crystallization from the watenethanol mixture (2:1). Afforded 7.4 g (47 %) of N-(N,N-diethyl-aminoethyl)benzene-1,4-bis(sulphonamide) 1-1. Colourless solid, m.p. 128-130 °C. Ammonium salt was prepared by acidification at pH = 4 of 5 g (0.015 mol) of this base solution in 50 ml of methanol with 10 to 20% hydrogen chloride solution in methanol. 50 ml ether was added to the mixture. Obtained solid was filtered off, washed with ether and purified with crystallization from the watenethanol mixture (3:1). Afforded 4.6 g (82 %) of ammonium salt of the agent 1-1. Colourless solid matter, m.p. 185 to 187 °C.
H-NMR of the compound 1-1.HCI 1-1 (salt) δ CHg 1.166, 1.177, 1.190, t (6 H), CH2 3.992, 3.112, 3.123, m (6 H) CH2 3.163, 3.169, 3.172 m (2 H) S02-NH2 7.653, s (H) Har. 8.036, (4 H) S02-NH 8.383, 8.395, 8.405, t (1 H) NH+ 10.173, s (1 H).
[0034] Instead of tetrahydrofurane, ether can be used (5,6 g) and instead of triethylamine, N,N’-diisopropylethylamine (DIPEA) can be used.
Example 9
Preparation of N-(N,N-diethylaminopropyl)benzene-1,4-bis(sulphonamide) (I-2) [0035] The procedure as in Example 8 (compound 1-1). 6.3 g (0.0485 mol) N.N-diethylamino-propylamine was used. Afforded 7.4 g (47 %) of N-(N,N-diethylaminopropyl)benzene-1 ,,4-bis(sulphonamide). Colourless solid, m.p. 133-135 °C. For the preparation of the ammonium salt 5.3 g (0.015 mol) of the base I-2 was used. Afforded 5.0 g (90.3 %) of the ammonium salt of compound i-2. Colourless solid, m.p. 198-200 °C. H-NMR: i-2 (salt) δ CH3 1.156, 1.180, 1.205, t (6 H) CH2 1.780- 1.800 m (2 H) CH2 2.864 - 2.884 m (2 (2 H) CH2 2.997, - 3.053 m (6 H) S02-NH2 1.648, s (2 H) Har 7.982, 8.011,8.027, 8.057 dd (4 H) S02-NH 8.068, 8.090, 8.0941 (1 H) NH+ 10.254, s (1 H).
Example 10
Preparation of N-(pyrrolidinopropyl)benzene-1,4-bis(sulphonamide) (I-4) [0036] The procedure as is Example 8. 6.2 g (0.0485 mol) of pyrrolidinopropylamine was used. Afforded 6.7 g (41.0 %) of N-(pyrrolidinopropyl)benzene-1,4-bis(sulphonamide). Colourless solid, m.p. 120-122 °C. For the preparation of the ammonium salt 5.5 g (0.0158 mol) of the base i-4 was used. According to the procedure as in Example 8, 5.2 g (85.8 %) of the ammonium salt of compound I-4 was afforded. Colourless solid, m.p. 180-183 °C. H-NMR: I-4 (salt) ÔCH2 1.835, 1.852, 1.875, 1.904, 1.943, 1.969 m (6 H) CH2 2.856 - 2.898 m (4 H) CH2 3.044-3.113 m (2 H) Har 7.987, 8.015, 8.026, 8.054 dd (4 H) S02-NH 8.079, 8.098, 8.118 t (1 H) NH+ 10.868 s (1 H).
Example 11
Preparation of N-(morpholinopropyl)benzene-1,4-bis(sulphonamide) (I-6) [0037] The procedure as is Example 8. 7 g (0.0485 mol) of morpholinopropylamine was used. Afforded 8.2 g (48,0 %) of N-(morpholinopropyl)-1,4-bis(sulphonamide) I-6. Colourless solid, m.p. 121-123 °C. H-NMR: I-6 (base) δ CH2-middle 1.533, 1.564, 1.574 t (3 H) CH2 2.377, m (4 H) CH2-N 2.806, 2.818, 2.829 t (2 H) CH2 3.557 m (6 H) S02-NH2 7.607 s (2H) S02-NH 7.865, s (1 H) Har 7.962, 7.975, 8.010, 8.023 dd (4 H).
[0038] For the preparation of the ammonium salt 6.0 g (0.0173 mol) of the base I-6 was used. The procedure as is Example 8. Afforded 4.9 g (86.0 %) of ammonium salt of compound I-6. Colourless solid, m.p. 232-234 °C. H-NMR: I-6 (salt) δ CH2 1.813-1.912 m (2 H) CH2 2.823 - 2.881 m (2 H) CH2 2.953 - 3.102 m (4 H) CH2 3.322 - 3.363 m (2 H) CH2 3.731 - 3.964 m (4 H) S02-NH2 7.642 s (2 H) Har 8.002, 8.011,8.022, 8.032 dd (4 H) S02-NH 8.053, 8.076, 8.096 t (1 H)NH+ 10.893 s (1 H).
Example 12
Preparation of N-(4-diethylaminoethoxybenzyl)benzene-1,4-bis(sulphonamide) (I-7) [0039] The procedure as in Example 8.10.8 g (0.0485 mol) of 4-diethylaminoethoxybenzylamine XI was used. Afforded 8.6 g (37.7% ) of N-(4-diethylaminoethoxybenzyl)benzene-1,4-bis(sulphonamide) I-7. Colourless solid, m.p. 72-74 °C.
[0040] For the preparation of the ammonium salt, the procedure as in Example 8 was used. For the preparation of the ammonium salt, 7.8 g (0.0176 mol) of the base i-7 was used. Afforded 6.4 g (76.2 % ) of the ammonium salt of compound i-7. Colourless solid, m.p. 92-94 °C. H-NMR: I- 7 (salt) δ CH3 1.217, 1.242, 1.265 t (6 H) CH2 3.166 - 3.217 m (4 H) CH2-N 3.960, 3.981 d (2 H) CH2-0 4.315, 4.318, 4.321 t (2 H) Har (O-phenyl) 6.87,380, 7, 6.906, 7.159, 7.188 dd (4 H) S02-NH2 7.635 s (2H) Har (S-phenyl) 7.961 -7.971 dd (4 H) S02-NH 8.380, 8.384, 8.387 t (1 H) NH+ 10.230 s (1 H).
Example 13
Preparation of 4-sulfamoyl-N-(N,N-dimethylaminoethyl)benzamide (11-1) [0041] To the 250 ml 3 neck flask equipped with the thermometer, the add funnel and the stirrer, 40 ml of tetrahydrofurane or ether, 4.3 g (0,0485 mol) of Ν,Ν-dimethylaminoethylamine and 24 g (33 ml) (0.238 mol) of triethylamine or DIPEA (diisopropylethylamine) was taken up. The solution was cooled to 0 °C and the solution of 10.3 g (0.0470 mol) of sulfamoylbenzoyl chloride IX in 60 ml tetrahydrofurane or ether was added dropwise for 30 min under cooling and stirring so as the temperature did not exceed 0 to 15 °C. The mixture was then stirred for 12 hours the at room temperature. 100 ml of petroleum ether or hexane was added to the mixture. The semi-solid product was filtered off and macerated with 20 ml of ice-cooled saturated aqueous sodium chloride solution. The solid product was separated, washed once with 10 ml saturated aqueous sodium chloride solution, 2 times with ice water and purified with crystallization from the watenethanol (2:1). Afforded 6.1 g (48.0 %) of 4-sulfamoyl-N-(2-dimethylaminoethyl)benzamide 11-1. Colourless solid, m.p. 150-151 °C. H-NMR: II- 1 (base) δ CH3 2.1821 (6 H) CH2-N+ 2.389, 2.412, 2.4351 (2 H) CH2-NCO 3.356 - 3.376 m (2 H) S02-NH2 7.472 s (2 H) S02-NH2 7.472 s (2 H) Har 7.871,7.899, 7.962, 7.991 dd (4 H), CO-NH 8.590, 8.594, 8.958 t (1 H).
[0042] Ammonium salt was prepared by acidification to pH=5 of 5 g (0.015 mol) of this compound 11-1 solution in 40 ml of methanol with 10 to 20% hydrogen chloride solution in methanol. 80 ml of ether was added to the mixture, the solid was filtered off and purified with crystallization from watenethanol (1:2). Afforded 4,5 g (80,4 %) of ammonium salt of compound 11-1.Colourless solid, m.p. 208-210 °C. H-NMR: 11-1 (salt) δ CH3 2.821 s (6 H) CH2-N+ 3.270, 3.270, 3.278, 3.297 t (2H) CH2-NCO 3.630, 3.649, 3.668 t (2 H) S02-NH2 7.524 s (2 H) Har 7.896, 7.924, 8.084, 8.113dd (4 H) CO-NH 9.087, 9.104, 9.123 t (1 H) NH+ 10.365 s (1 H).
Example 14
Preparation of 4-sulfamoyl-N-(N,N-diethylaminoethyl)benzamide (II-3) [0043] The procedure as in Example 13. 5.6 g (0.0485 mol) of Ν,Ν-diethylaminoethylamine was used. Afforded 6.2 g (44.0 %) of 4-sulfamoyl-N-(2-diethylaminoethyl)benzamide. Colourless solid, m.p. 174-176 °C. H-NMR: II-3 (base) δ CH3 0.945, 0.969, 0.993 t (6 H) CH2 2.501 - 2.584 m (8 H) S02-NH2 7.466 s (2 H) Har 7.873, 7.900, 7.957, 7.985 dd (4 H) CO-NH 8.568, 8.571, 8.574 t (1 H).
[0044] For the preparation of the ammonium salt 5.2 g (0.0184 mol) of base II-3 was used. According to the procedure as in Example 13, 5.1 g (85,4 %) of the ammonium salt of compound II-3 was used. Colourless solid, m.p. 201-202 °C. H-NMR: II-3 (salt) δ CH3 1.203, 1.233, 1.254 t (6 H) CH2 3.161 - 3.203 m (6 H) CH2-N+ 3.66 m (2 H) S02-NH27.51 s (2 H) Har 7.903, 7.932, 8.084, 8.101 dd (4 H) CO-NH 9.142, 9.173, 9.212 t (1 H) NH+ 10.383 s (1 H).
Example 15
Preparation of 4-sulfamoyl-N-(N,N-diethylaminopropyl)benzamide (II-4) [0045] The procedure as in Example 13. 6.2 g (0.0485 mol) of Ν,Ν-diethylaminopropylamine was used. Afforded 6.2 g (44.0 %) of 4-sulfamoyl-N-(N,N-diethylaminopropyl)benzamide II-4. Colourless solid, m.p. 122-123 °C. For the preparation of the ammonium salt, 5.2 g (0.0184 mol) of base was used. According to the procedure as in Example 13, 5.2 g (85.4 %) of the ammonium salt of compound II-4, was afforded. Colourless solid, m.p. 165-167 °C. H-NMR: II-4 (salt) δ CH3 1.173, 1.197, 1.221 t (6 H) CH2 middle 1.900 - 1.958 m (2 H) CH2 (3.350 - 3.358) m (2 H) S02-NH2 7.513 s (2 H) Har 7.887, 7.914, 8.018, 8.045 dd (4 H) CO-NH 8.936, 8.940, 8.944 t (1 H) NH+ 10.250 s (1 H).
Example 16
Preparation 4-sulfamoyl-N-(morpholinopropyl)benzamide (II-6) [0046] The procedure as in Example 13. 7.0 g (0.0485 mol) of morpholinopropylamine was used and 7.3 g (47.7 %) of 4-sulfamoyl-N-(morpholinopropyl)benzamide II-6 was afforded. Colourless solid, m.p. 196-198 °C. H-NMR: II-6 (base) δ CH2 (middle ) 1.643, 1.666, 1.689, 1.712, 1.736 quintet (2 H) CH2 2.306 - 2.353 m (6H) CH2 3.272 - 3.294 m (2 H) (CH2)2 O 3.548, 3.564, 3.580 t (4 H) S02-NH2 7.477 s (2 H) Har 7.874, 7.880, 7.897, 7.903, 7.971,7.987, 7.994 m (4 H) CO-NH 8.644, 8.662, 8.680 t (1 H).
[0047] For the preparation of the ammonium salt, 6.0 g (0.0183 mol) of base II-6 was used. According to the procedure as in Example 13, 5.9 g (88,0 %) of the ammonium salt of compound II-6 was used. Colourless solid, m.p. 196-198 °C. H-NMR: II-6 (salt) δ CH2 1.963-2.040 m (2 H) CH2 2.991 -3.152 m (4 H) S02-NH2 7.510 s (2 H) Har 7.892, 7.923, 8.021 8.053 dd (4 H) CO-NH 8.912, 8.933, 8.952 t (1 H) NH+ 10.992 s (1 H).
Example 17
Preparation of 4-[N-(morpholinopropyl)sulfamoyl]phenylsulfamoylbenzamide; (II-7) [0048] The procedure as in Example 13.14.6 g (0.0485 mol)of4-amino-N-(morpholinopropyl)-benzene-sulphonamide XIII was used and 10.1 g (44.5 %) of 4-sulfamoyl-N-[4-(morpholinopropyl) aminosulphonylphenyljbenzamide II-7 was afforded. Pale yellow oil. H-NMR: II-7 (base) δ CH2 1.493, 1.522, 1.543 t (2 H) CH2 3.510 - 3.542 m (6 H) S02-NH 7.502, 7.523, 7.541 t (1 H) S02-NH2 7.562 s (1 H) Har (CO-phenyl) 7.776, 1.805, 8.109, 8.137 dd (4 H) Har (N-phenyl) 7.961, 7.973, 7.990, 8.003 dd (4 H) CO-NH 10.763 s (1 H).
[0049] For the preparation of the ammonium salt, 8.0 g (0.0166 mol) of base II-7 was used. According to the procedure as in Example 13, 7.0 g (81.4 %) of the ammonium salt of compound II-7 was afforded. Colourless solid, m.p. 201-202 °C. H-NMR: II-7 (salt) CH2(middle) 1.815, 1.840, 1.865 t (2 H) CH2 2.780, 2.802, 2.823, 2.844 m (2 H) CH2 3.921, 3.960 d (2 H) S02-NH2 7.500 s (2 H), S02-NH 7.706, 7.7461 (1 H) Har (CO-phenyl) 7.796, 7.825,8.126, 8.154 dd (4 H) Har (N-phenyl) 7.962, 7.990, 8.005, 8.035 dd (4 H) NH+ 10.568 s (1 H) CO-NH 10.842 s (1 H).
Example 18
Preparation of N,N-diethylaminoethyl-(4-sulfamoylbenzoate) N-8 [0050] The procedure as in Example 13. 5.7 g (0.0485 mol) of Ν,Ν-diethylaminoethanol was used. Afforded 6.1 g (43.3 %) of N,N-diethylaminoethyl-(4-sulfamoylbenzoate) II-8. Colourless solid, m.p. 159-160 °C. For the preparation of the ammonium salt, 5.1 g (0.017 mol) of base II-8 was used. According to the procedure as in Example 13, 4.4 g (77.2 %) of the ammonium salt of compound II-8 was afforded. Colourless solid, m.p. 185-186 °C. H-NMR: II-8 (salt) δ CH3 1.242, 1.273, 1.291 t (3 H) CH2 3.203 - 3.242 m (4 H) CH2 3.522 - 3.541 m (2 H) CH2 4.653 - 4.702 m (2H) S02-NH2 7.621 s (1 H) Har 7.962, 7.993, 8.210, 8.243 dd (4 H) NH+ 10.633 s (1 H).
Example 19
The results of effectiveness assays [0051] Effectiveness of the compounds according to of the invention is supported with the results of the pharmacological assays.
[0052] The basic pharmacologic profile of the compounds of the general formula (I), which was focused on the determination of the intraocular pressure changes, was evaluated in in vivo conditions. In addition to the main potential therapeutic efFect, related side responses were also monitored. In the experiments the laboratory animals of chinchilla species were used, because the normotension eye of this animal species provides the best reactivity. Adult male Chinchilla (in the age of one to one and half year), of 2000-3500 g, examined by veterinarian, without disease symptoms, grown under the standard conditions was used as the animal model. The solutions of tested compounds of the general formula (I) were always freshly prepared. The distilled water was used as a control. Measurement apparatus Tono-Pen®XL from Medtronic XOMED was used for measurement of the intraocular pressure. The intraocular pressure values were expressed in Torr (mmHg). At the first day of the experiment the solutions of the tested compounds of the general formula (I) were applied twice a day, specifically at 8.00 a.m. and 2.00 p.m.. At the second day of the experiment the application was still in the 301h hour (i.e. at the second day at 2.00 p.m.).
[0053] The solution of each compound was always applied in an amount of 2 drops into the right conjunctiva sac. The left eye served as a control. Into the conjunctiva sac of this eye (left), the same number of drop (2 drops) of distilled water was applied. The distilled water served as placebo.
[0054] Into the conjunctiva sac of both eyes one drop of the local anesthetic (oxybuprocain) was administered and massaged by careful circular movement (1-2), before the measurement of the intraocular activity both of the compound solution or the distilled water.
[0055] Standard requirements were kept in all measurements. The measurements started in the morning at 7.00 a.m. The measurement was accomplished with Tono-Pen® XL apparatus by soft perpendicular touch of the probe to the cornea of the rabbit five times successively. The measurement was accomplished on the both cornea (right and left eyes) before administration of the sample. Thus the normal values of the intraocular pressure for both the right and left eyes were obtained. Then at 8.00 a.m. 2 drops of tested compound were applied in the right eye and 2 drops of the distilled water were applied in the left eye.
[0056] Further measurements were carried out after half an hour (at 8.30 a.m.), after one hour (at 9.00 a.m.), after four hours (at 12.00), after seven hours (at 3.00 p.m.), after 25 hours (on the second day at 9.00 a.m.) and after31 hours from the application in the right eye (on the second day at 3.00 p.m). The intraocular pressure changes in the left eye of the rabbit after placebo application, i.e. 2 drops of distilled water, were monitored in the same time intervals. Moreover, 2 drops of the tested compound in the right eye and 2 drops of distilled water in the left eye were applied again in the same group of the rabbits in the first day at 2.00 p.m. (i.e. 6 hours after application of the first dose of the compound) and in the second day of the experiment at 2.00 p.m. (i.e. in the 30th hour of the experiment). Thus the changes caused by the repeated administration of the compound can be monitored. For each compound and each concentration 10 independent assays were carried out.
[0057] No negative side effects were observed during the experiments.
[0058] Tables show a the absolute number values obtained by monitoring of compound I-4 at the concentration of 2% and 2,5 % and of compound II-4 at the concentration of 1% in determined time intervals.
(continued)
(continued)
Industrial utilization [0059] Substituted sulphonamides of the general formula I are useful as active compounds in the manufacture of the pharmaceutical compositions, drugs, in human and veterinary medicine, particularly as antiglaucomatics. They are effective carboanhydrase inhibitors and therefore they can have a wide use in the treatment of all diseases, where it is necessary to inhibit this enzyme.
Claims 1. Use of substituted sulphonamides having the general formula (I)
(I) wherein: if R1 is CO, then R2 is NH or O, and if R1 is S02, then R2 is NH; and R includes tertiary diC1_4alkylamino group, wherein alkyl moieties are the same or different, or amino group, alkyl moieties of which form together 5, 6 and 7-membered saturated ring, or their ends are linked by heteroatom O, or R is 4-(N,N-diethylaminoethoxy)benzyl when R1 is S02 and R2 is NH; or R is 4-[N-(morpholinopropyl)sulfamoyl]phenyl when R1 is CO and R2 is NH; and n is a number of carbons of linking aliphatic chain, wherein n is 0, 2 or 3, and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a medicament for the treatment of glaucoma. 2. Use of substituted sulphonamides having the general formula (I), according to claim 1, wherein when R1 is CO, R2, R and n are shown in the following Table:
(continued)
and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a medicament for the treatment of glaucoma. 3. Use of substituted sulphonamides having the general formula (I), according to claim 1,
wherein R1 is S02, R2 is NH, and R and n are shown in the following Table:
(continued)
and/or physiologically acceptable salts, hydrates or solvates thereof, in the manufacture of a medicament for the treatment of glaucoma. 4. Use of substituted sulphonamides according to one of preceding claims having the general formula (I) according to claim 1, selected from the group: N-(N,N-Diethylaminoethyl)benzene-1,4-bis(sulphonamide); (1-1), N-(N,N-Diethylaminopropyl)benzene-1,4-bis(sulphonamide); (I-2), N-(Pyrrolidinoethyl)benzene-1,4-bis(sulphonamide); (I-3), N-(Pyrrolidinopropyl)benzene-1,4-bis(sulphonamide); (I-4), N-(Morpholinoethyl)benzene-1,4-bis(sulphonamide); (I-5), N-(Morpholinopropyl)benzene-1,4-bis(sulphonamide); (I-6), N-(4-Diethylaminoethoxybenzyl)benzene-1,4-bis(sulphonamide); (I-7), N-(Dimethylaminoethyl)benzene-1,4-bis(sulphonamide); (I-8), N-(Dimethylaminopropyl)benzene-1,4-bis(sulphonamide); (I-9), N-(N,N-Dipropylaminoethyl)benzene-1,4-bis(sulphonamide); (1-10), N-(N,N-Dipropylaminopropyl)benzene-1,4-bis(sulphonamide); (1-11), N-(N,N-Dibutylaminoethyl)benzene-1,4-bis(sulphonamide); (1-12), N-(N,N-Dibutylaminopropyl)benzene-1,4-bis(sulphonamide); (1-13), N-(N-Methyl-N-ethylaminoethyl)benzene-1,4-bis(sulphonamide); (1-14), N-(N-Methyl-N-ethylaminopropyl)benzene-1,4-bis(sulphonamide); (1-15), N-(N-Ethyl-N-propylaminoethyl)benzene-1,4-bis(sulphonamide); (1-16), N-(N-Ethyl-N-propylaminopropyl)benzene-1,4-bis(sulphonamide); (1-17), N-(N-Ethyl-N-butylaminoethyl)benzene-1,4-bis(sulphonamide); (1-18), N-(N-Ethyl-N-butylaminopropyl)benzene-1,4-bis(sulphonamide); (1-19), N-(N-Propyl-N-butylaminoethyl)benzene-1,4-bis(sulphonamide); (I-20), N-(N-Propyl-N-butylaminopropyl)benzene-1,4-bis(sulphonamide); (1-21), N-(Piperidinoethyl)benzene-1,4-bis(sulphonamide); (I-22), N-(Piperidinopropyl)benzene-1,4-bis(sulphonamide); (I-23), 4-Sulfamoyl-N-(N,N-dimethylaminoethyl)benzamide; (11-1), 4-Sulfamoyl-N-(N,N-dimethylaminopropyl)benzamide; (II-2), 4-Sulfamoyl-N-(N,N-diethylaminoethyl)benzamide; (II-3), 4-Sulfamoyl-N-(N,N-diethylaminopropyl)benzamide; (II-4), 4-Sulfamoyl-N-(morpholinoethyl)benzamide; (II-5), 4-Sulfamoyl-N-(morpholinopropyl)benzamide; (II-6), 4-[N-(Morpholinopropyl)sulfamoyl]phenylsulfamoylbenzamide; (II-7), (N,N-Diethylaminoethyl)-4-sulfamoylbenzoate; (II-8), (N,N-Diethylaminopropyl)-4-sulfamoylbenzoate; (II-9), (N,N-Dipropylaminoethyl)-4-sulfamoylbenzoate; (11-10), (N,N-Dipropylaminopropyl)-4-sulfamoylbenzoate; (11-11), 4-Sulfamoyl-N-(N,N-dipropylaminoethyl)benzamide; (11-12), 4-Sulfamoyl-N-(N,N-dipropylaminopropyl)benzamide; (11-13), (N,N-Dibutylaminoethyl)-4-sulfamoylbenzoate; (11-14), (N,N-Dibutylaminopropyl)-4-sulfamoylbenzoate; (11-15), 4-Sulfamoyl-N-(N,N-dibutylaminoethyl)benzamide; (11-16), 4-Sulfamoyl-N-(N,N-dibutylaminopropyl)benzamide; (11-17), (N-Methyl-N-ethylaminoethyl)-4-sulfamoylbenzoate; (11-18), (N-Methyl-N-ethylaminopropyl)-4-sulfamoylbenzoate; (11-19), 4-Sulfamoyl-N-(N-methyl-N-ethylaminoethyl)benzamide; (II-20), 4-Sulfamoyl-N-(N-methyl-N-ethylaminopropyl)benzamide; (11-21), (N-Ethyl-N-propylaminoethyl)-4-sulfamoylbenzoate; (II-22), (N-Ethyl-N-propylaminopropyl)-4-sulfamoylbenzoate; (II-23), 4-Sulfamoyl-N-(N-ethyl-N-propylaminoethyl)benzamide; (II-24), 4-Sulfamoyl-N-(N-ethyl-N-propylaminopropyl)benzamide; (II-25), (N-Propyl-N-butylaminoethyl)-4-sulfamoylbenzoate; (II-26), (N-Propyl-N-butylaminopropyl)-4-sulfamoylbenzoate; (II-27), 4-Sulfamoyl-N-(N-propyl-N-butylaminoethyl)benzamide; (II-28), 4-sulfamoyl-N-(N-propyl-N-butylaminopropyl)benzamide; (II-29), (N-Ethyl-N-butylaminoethyl)-4-sulfamoylbenzoate; (II-30), (N-Ethyl-N-butylaminopropyl)-4-sulfamoylbenzoate; (11-31), 4-Sulfamoyl-N-(N-ethyl-N-butylaminoethyl)benzamide; (II-32), 4-Sulfamoyl-N-(N-ethyl-N-butylaminopropyl)benzamide; (II-33), (Pyrrolidinoethyl)-4-sulfamoylbenzoate; (II-34), (Pyrrolidinopropyl)-4-sulfamoylbenzoate; (II-35), 4-Sulfamoyl-N-(pyrrolidinoethyl)benzamide; (II-36), 4-Sulfamoyl-N-(pyrrolidinopropyl)benzamide; (II-37), (Piperidinoethyl)-4-sulfamoylbenzoate; (II-38), (Piperidinopropyl)4-sulfamoylbenzoate; (II-39), 4-Sulfamoyl-N-(piperidinoethyl)benzamide; (II-40), 4-Sulfamoyl-N-(piperidinopropyl)benzamide; (11-41). 5. Substituted sulphonamides having the general formula (I)
wherein R1 is S02, R2 is NH, and R and n are shown in the following Table:
and physiologically acceptable salts, hydrates or solvates thereof. 6. Substituted sulphonamides having the general formula (I), according to claim 5, which is: N-(N,N-Diethylaminoethyl)benzene-1,4-bis(sulphonamide); (1-1), N-(N,N-Diethylaminopropyl)benzene-1,4-bis(sulphonamide); (I-2), N-(Pyrrolidinoethyl)benzene-1,4-bis(sulphonamide); (I-3), N-(Pyrrolidinopropyl)benzene-1,4-bis(sulphonamide); (I-4), N-(Morpholinoethyl)benzene-1,4-bis(sulphonamide); (I-5), N-(Morpholinopropyl)benzene-1,4-bis(sulphonamide); (I-6), N-(4-Diethylaminoethoxybenzyl)benzene-1,4-bis(sulphonamide); (I-7), N-(Dimethylaminoethyl)benzene-1,4-bis(sulphonamide); (I-8), N-(Dimethylaminopropyl)benzene-1,4-bis(sulphonamide); (I-9), N-(N,N-Dipropylaminoethyl)benzene-1,4-bis(sulphonamide); (1-10), N-(N,N-Dipropylaminopropyl)benzene-1,4-bis(sulphonamide); (1-11), N-(N,N-Dibuthylaminoethyl)benzene-1,4-bis(sulphonamide); (1-12), N-(N,N-Dibuthylaminopropyl)benzene-1,4-bis(sulphonamide); (1-13), N-(N-Methyl-N-ethylaminoethyl)benzene-1,4-bis(sulphonamide); (1-14), N-(N-Methyl-N-ethylaminopropyl)benzene-1,4-bis(sulphonamide); (1-15), N-(N-Ethyl-N-propylaminoethyl)benzene-1,4-bis(sulphonamide); (1-16), N-(N-Ethyl-N-propylaminopropyl)benzene-1,4-bis(sulphonamide); (1-17), N-(N-Ethyl-N-butylaminoethyl)benzene-1,4-bis(sulphonamide); (1-18), N-(N-Ethyl-N-butylaminopropyl)benzene-1,4-bis(sulphonamide); (1-19), N-(N-Propyl-N-butylaminoethyl)benzene-1,4-bis(sulphonamide); (I-20), N-(N-Propyl-N-butylaminopropyl)benzene-1,4-bis(sulphonamide); (1-21), N-(Piperidinoethyl)benzene-1,4-bis(sulphonamide); (I-22), N-(Piperidinopropyl)benzene-1,4-bis(sulphonamide); (I-23). 7. Substituted sulphonamide of the general formula (I) according to claim 5 or 6, and/or physiologically acceptable salts, hydrates or solvates thereof, for use as carboanhydrase inhibitors, such as antiglaucomatics. 8. A pharmaceutical composition for use in the prophylaxis and the treatment of diseases, characterized in that it comprises substituted sulphonamide of the general formula (I) according to claim 5 or 6 and/or physiologic acceptable salts, hydrates or solvates thereof as the active compound and the pharmaceutical carrier. 9. A pharmaceutical composition according to claim 8, characterized in that it additionally comprises further active agent for the prophylaxis or the treatment of diseases, particularly for the treatment of eye diseases selected from the group consisting of sympatomimetics such as brimonidine, clonidine, apraclonidine; parasympatomimetics such as pilocarpine, carbachole; betablocators such as timolol, betaxolol, levobunolol; and prostagladine analougues such as latanoprost, bimaprost, travaprost; and other antiglaucomatics such as guanethidine or dapiprazole. 10. A process for preparing the compounds having the general formula (I) according to claim 5, characterized in that the amine of the general formula (IV)
(IV) wherein R is as defined in claim 5, is treated with 4-sulfamoylbenzenesulphonyl chloride of the formula (V)
(V) in organic solvent in the presence of base excess at the temperature 0 to 20 °C, wherein a nucleophilic reaction gives substituted 1,4-bis sulphonamide. 11. A process according to claim 10, characterized in that tetrahydrofurane or ether are used as organic solvents and triethylamine is used as base.
Patentansprüche 1. Verwendung substituierten Sulfonamide mit Allgemeinformel (I)
(I) wo wenn R1 ist CO, dann R2 ist NH oder O, und wenn R1 ist S02 dann R2 ist NH; und R beinhaltet tertiäre diC^Alkylaminogruppe, in welchen die Alkylteile sind gleich oder unterschiedlich, oder Aminogruppe, welcher Alkylteile bilden gemeinsam gesättigte Ringgerüste mit 5,6 und 7 Elementen, oderderen Enden sind über Heteroatom O verbunden oder, R ist 4-(N,N-Diäthylaminoethoxy)benzyl wenn R1 ist S02 und R2 ist NH; oder R ist 4-[N-(Morpholinopropyl)sulfamoyl]phenyl wenn R1 ist CO und R2 ist NH; und n ist Anzahl der Kohlenstoffe der aliphatische Verbindungskette, wo n ist 0, 2 oder 3, und/oder deren physiologisch geeignete Salze, Hydrate oder Solvate für Herstellung des Arzneimittel für Heilbehandlung des Glaukom. 2. Verwendung substituierten Sulfonamide mit Allgemeinformel (I), nach Anspruch 1, in welchen wenn R1 ist CO, R2, R und n sind in folgender Tabelle angegeben
(fortgesetzt)
und/oder deren physiologisch geeignete Salze, Hydrate oder Solvate für Herstellung des Arzneimittel für Heilbehandlung des Glaukom. 3. Verwendung substituierten Sulfonamide mit Allgemeinformel (I), nach Anspruch 1,
(I)
In welchen R1 ist S02, R2 ist NH, und R und n ist in folgender Tabelle angegeben:
(fortgesetzt)
und/oder deren physiologisch geeignete Salze, Hydrate oder Solvate für Herstellung des Arzneimittel für Heilbehandlung des Glaukom. 4. Verwendung substituierten Sulfonamide nach irgendeinem aus vorhergehenden Ansprüche, mit Allgemeinformel (I), nach Anspruch 1, ausgewählt aus der Gruppe: N-(N,N-Diethylaminoethyl)benzol-1,4-bis(sulfonamid); (1-1), N-(N,N-Diethylaminopropyl)benzol-1,4-bis(sulfonamid); (I-2), N-(Pyrolidinoethyl)benzol-1,4-bis(sulfonamid); (I-3), N-(Pyrolidinopropyl)benzol-1,4-bis(sulfonamid); (I-4), N-(Morpholinoethyl)benzol-1,4-bis(sulfonamid); (I-5), N-(Morpholinopropyl)benzol-1,4-bis(sulfonamid); (I-6), N-(4-Diethylaminoetoxybenzyl)benzol-1,4-bis(sulfonamid); (I-7), N-(Dimethylaminoethyl)benzol-1,4-bis(sulfonamid); (I-8), N-(Dimethylaminopropyl)benzol-1,4-bis(sulfonamid); (I-9), N-(N,N-Dipropylaminoethyl)benzol-1,4-bis(sulfonamid); (1-10), N-(N,N-Dipropylaminopropyl)benzol-1,4-bis(sulfonamid); (1-11), N-(N,N-Dibuthylaminoethyl)benzol-1,4-bis(sulfonamid); (1-12), N-(N,N-Dibuthylaminopropyl)benzol-1,4-bis(sulfonamid); (1-13), N-(N-Methyl-N-ethylaminoethyl)benzol-1,4-bis(sulfonamid); (1-14), N-(N-Methyl-N-ethylaminopropyl)benzol-1,4-bis(sulfonamid); (1-15), N-(N-Ethyl-N-propylaminoethyl)benzol-1,4-bis(sulfonamid); (1-16), N-(N-Ethyl-N-propylaminopropyl)benzol-1,4-bis(sulfonamid); (1-17), N-(N-Ethyl-N-buthylaminoethyl)benzol-1,4-bis(sulfonamid); (1-18), N-(N-Ethyl-N-buthylaminopropyl)benzol-1,4-bis(sulfonamid); (1-19), N-(N-Propyl-N-buthylaminoethyl)benzol-1,4-bis(sulfonamid); (I-20), N-(N-propyl-N-buthylaminopropyl)benzol-1,4-bis(sulfonamid); (1-21), N-(Piperidinoethyl)benzol-1,4-bis(sulfonamid); (I-22), N-(Piperidinopropyl)benzol-1,4-bis(sulfonamid); (I-23), 4-Sulfamoyl-N-(N,N-dimethylaminoethyl)benzamid; (11-1), 4-Sulfamoyl-N-(N,N-dimethylaminopropyl)benzamid; (II-2), 4-Sulfamoyl-N-(N,N-diethylaminoethyl)benzamid; (II-3), 4-Sulfamoyl-N-(N,N-diethylaminopropyl)benzamid; (II-4), 4-Sulfamoyl-N-(morpholinoethyl)benzamid; (II-5), 4-Sulfamoyl-N-(morpholinopropyl)benzamid; (II-6), 4-[N-(Morpholinopropyl)sulfamoyl]fenylsulfamoylbenzamid; (II-7), (N,N-Diethylaminoethyl)4-sulfamoylbenzoat; (II-8), (N,N-Diethylaminopropyl)4-sulfamoylbenzoat; (II-9), (N,N-Dipropylaminoethyl)4-sulfamoylbenzoat; (11-10), (N,N-Dipropylaminopropyl)4-sulfamoylbenzoat; (11-11), 4-Sulfamoyl-N-(N,N-dipropylaminoethyl)benzamid; (11-12), 4-Sulfamoyl-N-(N,N-dipropylaminopropyl)benzamid; (11-13), (N,N-Dibuthylaminoethyl)4-sulfamoylbenzoat; (11-14), (N,N-Dibuthylaminopropyl)4-sulfamoylbenzoat; (11-15), 4-sulfamoyl-N-(N,N-dibuthylaminoethyl)benzamid; (11-16), 4-Sulfamoyl-N-(N,N-dibuthylaminopropyl)benzamid; (11-17), (N-Methyl-N-ethylaminoethyl)4-sulfamoylbenzoat; (11-18), (N-Methyl-N-ethylaminopropyl)4-sulfamoylbenzoat; (11-19), 4-Sulfamoyl-N-(N-methyl-N-ethylaminoethyl)benzamid; (II-20), 4-Sulfamoyl-N-(N-methyl-N-ethylaminopropyl)benzamid; (11-21), (N-ethyl-N-propylaminoethyl)4-sulfamoylbenzoát; (II-22), (N-ethyl-N-propylaminopropyl)4-sulfamoylbenzoát; (II-23), 4-Sulfamoyl-N-(N-ethyl-N-propylaminoethyl)benzamid; (II-24), 4-Sulfamoyl-N-(N-ethyl-N-propylaminopropyl)benzamid; (II-25), (N-Propyl-N-buthylaminoethyl)4-sulfamoylbenzoat; (II-26), (N-Propyl-N-buthylaminopropyl)4-sulfamoylbenzoat; (II-27), 4-Sulfamoyl-N-(N-propyl-N-buthylaminoethyl)benzamid; (II-28), 4-Sulfamoyl-N-(N-propyl-N-buthylaminopropyl)benzamid; (II-29), (N-Ethyl-N-buthylaminoethyl)4-sulfamoylbenzoat; (II-30), (N-Ethyl-N-buthylaminopropyl)4-sulfamoylbenzoat; (11-31), 4-Sulfamoyl-N-(N-ethyl-N-buthylaminoethyl)benzamid; (II-32), 4-Sulfamoyl-N-(N-ethyl-N-buthylaminopropyl)benzamid; (II-33), (Pyrolidinoethyl)4-sulfamoylbenzoat; (II-34), (Pyrolidinopropyl)4-sulfamoylbenzoat; (II-35), 4-Sulfamoyl-N-(pyrolidinoethyl)benzamid; (II-36), 4-Sulfamoyl-N-(pyrolidinopropyl)benzamid; (II-37), (Piperidinoetyhl)4-sulfamoylbenzoat; (II-38), (Piperidinopropyl)4-sulfamoylbenzoat; (II-39), 4-sulfamoyl-N-(piperidinoethyl)benzamid; (II-40), 4-Sulfamoyl-N-(piperidinopropyl)benzamid; (11-41). 5. Substituierte Sulfonamide mit Allgemeinformel (I),
(I)
In welchen R1 ist S02, R2 ist NH und R und n ist in folgender Tabelle angegeben:
und/oder deren physiologisch geeignete Salze, Hydrate oder Solvate. 6. Substituierte Sulfonamide mit Allgemeinformel (I), nach Anschpruch 5, welche sind: N-(N,N-Diethylaminoethyl)benzol-1,4-bis(sulfonamid); (1-1) N-(N,N-Diethylaminopropyl)benzol-1,4-bis(sulfonamid); (I-2) N-(Pyrolidinoethyl)benzol-1,4-bis(sulfonamid); (I-3) N-(Pyrolidinopropyl)benzol-1,4-bis(sulfonamid); (I-4) N-(Morpholinoethyl)benzol-1,4-bis(sulfonamid); (I-5) N-(Morpholinopropyl)benzol-1,4-bis(sulfonamid); (I-6) N-(4-Diethylaminoetoxybenzyl)benzol-1,4-bis(sulfonamid); (I-7) N-(Dimethylaminoethyl)benzol-1,4-bis(sulfonamid); (I-8) N-(Dimethylaminopropyl)benzol-1,4-bis(sulfonamid); (I-9) N-(N,N-Dipropylaminoethyl)benzol-1,4-bis(sulfonamid); (1-10) N-(N,N-Dipropylaminopropyl)benzol-1,4-bis(sulfonamid); (1-11) N-(N,N-Dibuthylaminoethyl)benzol-1,4-bis(sulfonamid); (1-12) N-(N,N-Dibuthylaminopropyl)benzol-1,4-bis(sulfonamid); (1-13) N-(N-Methyl-N-ethylaminoethyl)benzol-1,4-bis(sulfonamid); (1-14) N-(N-Methyl-N-ethylaminopropyl)benzol-1,4-bis(sulfonamid); (1-15) N-(N-Ethyl-N-propylaminoethyl)benzol-1,4-bis(sulfonamid); (1-16) N-(N-Ethyl-N-propylaminopropyl)benzol-1,4-bis(sulfonamid); (1-17) N-(N-Ethyl-N-buthylaminoethyl)benzol-1,4-bis(sulfonamid); (1-18) N-(N-Ethyl-N-buthylaminopropyl)benzol-1,4-bis(sulfonamid); (1-19) N-(N-Propyl-N-buthylaminoethyl)benzol-1,4-bis(sulfonamid); (I-20) N-(N-Propyl-N-buthylaminopropyl)benzol-1,4-bis(sulfonamid); (1-21) N-(Piperidinoethyl)benzol-1,4-bis(sulfonamid); (I-22) N-(Piperidinopropyl)benzol-1,4-bis(sulfonamid); (I-23). 7. Substituiertes Sulfonamid mitAllgemeinformel(l), nachAnschpruch5oder6und/oderderen physiologisch geeignete Salze, Hydrate oder Solvate, für Verwendung als Inhibitoren von Karboanhydrase, als Antiglaukomika. 8. Pharmazeutisches Mittel für Verwendung für Verbeugung und Heilbehandlung von Krankheiten, dadurch geken-zeichnet, dass als wirksames Mittel Substituiertes Sulfonamid mit Allgemeinformel (I), nach Anschpruch 5 oder 6 und/oder deren physiologisch geeignete Salze, Hydrate oder Solvate und einen pharmazeutisch annehbaren Ex-zipienten, beinhaltet. 9. Pharmazeutisches Mittel nach Anschpruch 8, dadurch gekenzeichnet, dass zusätzlich weitere wirksame Substanz für Verbeugung und Heilbehandlung von Krankheiten beinhaltet, besonders für Heilbehandlung von Augenkrankheiten, ausgewählt aus der Gruppe umfassender Symphatomimetika wie Brimonidin, Klonidin, Apraklonidin; Para-symphatomimetika wie Pilokarpin, Karbachol; Betablokatoren.wie Thimolol, Betaxolol, Levobunolol; und Analoge von Prostagladine wie Latanoprost, Bimaprost, Travaprost und andere Antiglaukomika wie Guanetidin oder Dapi-prazol. 10. Verfahren für Herstellung der Verbindungen mit Allgemeinformel (I), nach Anschpruch 5, dadurch gekenzeichnet, dass ein Amin mit Allgemeinformel (IV),
(IV) wo R ist in Anschpruch 5 definiert, reagiert mit 4-sulfamoylbenzolsulfonylchlorid mit Formel (V)
(V) in Anwesenheit von Überschuss der Base in einem organischen Lösungsmittel bei der Temperatur 0 bis 20 °C, wobei durch eine nukleophile Reaktion substituiertes 1,4-bissulfonamid, entsteht. 11. Das Verfahren nach Anspruch 10, dadurch gekenzeichnet, dass, als organisches Lösungsmittel wird Tetrahydrofuran oder Ether benutzt und als Base wird Triethylamin benutzt.
Revendications 1. Utilisation des sulfonamides substitués répondant à la formule générale (I)
(I) dans laquelle : R2 représente un groupe NH ou O, si R1 est un group CO, et R2 représente un groupe NH, si R1 est un group S02; et R implique des groupes aminés tertiaries en di- Ολ_Α pour lesquels les parties alkyles peuvent être identiques ou différentes, ou des groupes amino dont les parties alkyles forment en commun un cycle saturé de 5, 6 et 7 chaînons, ou leurs extrémités sont raccordées par un atome hétéro O, ou R représente un groupe 4-(N,N-diéthylaminoéthoxy)benzyle, si R1 est un groupe S02 et R2 est un groupe NH ; ou R représente un groupe 4-[N-(morpholinopropyle)sulfamoyle]phényle, si R1 est un groupe CO et R2 est un groupe NH; et n est le nombre d’atomes de carbone de la chaîne de jonction aliphatique, où n est égal à 0, 2 ou 3, et/ou leurs sels, hydrates ou solvates physiologiquement convenables pour la fabrication du médicament pour le traitement du glaucome. 2. Utilisation des sulfonamides substitués représentés par la formule générale (I), selon la révendication 1, dans laquelle formule si R1 est CO, R2, R et n sont donnés dans le tableau suivant.
et/ou leurs sels, hydrates ou solvates physiologiquement convenables pour la fabrication du médicament pour le traitement du glaucome. 3. Utilisation des sulfonamides substitués répondant à la formule générale (I), selon la révendication 1,
(I) dans laquelle : R1 représente un group S02 R2 représente un group NH, et R et n sont donnés dans le tableau suivant.
et/ou leurs sels, hydrates ou solvates physiologiquement convenables pour la fabrication du médicament pour le traitement du glaucome. 4. Utilisation des sulfonamides substitués selon l’une des revendications précédentes, représentés par la formule générale (I) selon la révendication 1, sélectionnés dans le goupe constitué de N-(N,N-diéthylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-1), N-(N,N-diéthylaminopropyle)-benzène-1,4-bis(sulfonamide); (I-2), N-(pyrrolidinoéthyle)benzène-1,4-bis(sulfonamide); (I-3), N-(pyrrolidinopropyle)benzène-1,4-bis(sulfonamide); (I-4), N-(morpholinoéthyle)benzène-1,4-bis(sulfonamide); (I-5), N-(morpholinopropyle)benzène-1,4-bis(sulfonamide); (I-6), N-(4-diéthylaminoéthoxybenzyle)-benzène-1,4-bis(sulfonamide); (I-7), N-(diméthylaminoéthyle)-benzène-1,4-bis(sulfonamide); (I-8), N-(diméthylaminopropyle)-benzène-1,4-bis(sulfonamide); (I-9), N-(N,N-dipropylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-10), N-(N,N-dipropylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-11), N-(N,N-dibutylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-12), N-(N,N-dibutylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-13), N-(N-méthyle-N-éthylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-14), N-(N-méthyle-N-éthylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-15), N-(N-éthyle-N-propylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-16), N-(N-éthyle-N-propylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-17), N-(N-éthyle-N-butylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-18), N-(N-éthyle-N-butylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-19), N-(N-propyle-N-butylaminoéthyle)-benzène-1,4-bis(sulfonamide); (I-20), N-(N-propyle-N-butylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-21 ), N-(pipéridinoéthyle)-benzène-1,4-bis(sulfonamide); (I-22), N-(pipéridinopropyle)-benzène-1,4-bis(sulfonamide); (I-23), 4-sulfamoyle-N-(N,N-diméthylaminoéthyle)-benzamide; (11-1), 4-sulfamoyle-N-(N,N-diméthylaminopropyle)-benzamide; (II-2), 4-sulfamoyle-N-(N,N-diéthylaminoéthyle)-benzamide; (II-3), 4-sulfamoyle-N-(N,N-diéthylaminopropyle)-benzamide; (II-4), 4-sulfamoyle-N-(morpholinoéthyle)-benzamide; (II-5), 4-sulfamoyle-N-(morpholinopropyle)-benzamide; (II-6), 4-[N-(morpholinopropyle)-sulfamoyle]-phénylsulfamoylbenzamide; (II-7), (N,N-diéthylaminoéthyle)-4-sulfamoylbenzoate; (II-8), (N,N-diéthylaminopropyle-)4-sulfamoylbenzoate; (II-9), (N,N-dipropylaminoéthyle)-4-sulfamoylbenzoate; (11-10), (N,N-dipropylaminopropyle)-4-sulfamoylbenzoate; (11-11), 4-sulfamoyle-N-(N,N-dipropylaminoéthyle)-benzamide; (11-12), 4-sulfamoyle-N-(N,N-dipropylaminopropyle)-benzamide; (11-13), (N,N-dibutylaminoéthyle)-4-sulfamoylbenzoate; (11-14), (N,N-dibutylaminopropyle)-4-sulfamoylbenzoate; (11-15), 4-sulfamoyle-N-(N,N-dibutylaminoéthyle)-benzamide; (11-16), 4-sulfamoyle-N-(N,N-dibutylaminopropyle)-benzamide; (11-17), (N-méthyle-N-éthylaminoéthyle)-4-sulfamoylbenzoate; (11-18), (N-méthyle-N-éthylaminopropyle)-4-sulfamoylbenzoate; (11-19), 4-sulfamoyle-N-(N-méthyle-N-éthylaminoéthyle)-benzamide; (II-20), 4-sulfamoyle-N-(N-méthyle-N-éthylaminopropyle)-benzamide; (11-21), (N-éthyle-N-propylaminoéthyle)-4-sulfamoylbenzoate; (II-22), (N-éthyle-N-propylaminopropyle)-4-sulfamoylbenzoate; (II-23), 4-sulfamoyle-N-(N-éthyle-N-propylaminoéthyle)-benzamide; (II-24), 4-sulfamoyle-N-(N-éthyle-N-propylaminopropyle)-benzamide; (II-25), (N-propyle-N-butylaminoéthyle)-4-sulfamoylbenzoate; (II-26), (N-propyle-N-butylaminopropyle)-4-sulfamoylbenzoate; (II-27), 4-sulfamoyle-N-(N-propyle-N-butylaminoéthyle)-benzamide; (II-28), 4-sulfamoyle-N-(N-propyle-N-butylaminopropyle)-benzamide; (II-29), (N-éthyle-N-butylaminoéthyle)-4-sulfamoylbenzoate; (II-30), (N-éthyle-N-butylaminopropyle)-4-sulfamoylbenzoate; (11-31), 4-sulfamoyle-N-(N-éthyle-N-butylaminoéthyle)-benzamide; (II-32), 4-sulfamoyle-N-(N-éthyle-N-butylaminopropyle)-benzamide; (II-33), (pyrrolidinoéthyle)-4-sulfamoylbenzoate; (II-34), (pyrrolidinopropyle)-4-sulfamoylbenzoate; (II-35), 4-sulfamoyle-N-(pyrrolidinoéthyle)-benzamide; (II-36), 4-sulfamoyle-N-(pyrrolidinopropyle)-benzamide; (II-37), (pipéridinoéthyle)-4-sulfamoylbenzoate; (II-38), (pipéridinopropyle)-4-sulfamoylbenzoate; (II-39), 4-sulfamoyle-N-(pipéridinoéthyle)-benzamide; (II-40), 4-sulfamoyle-N-(pipéridinopropyle)-benzamide; (11-41). 5. Sulfonamides substitués répondant à la formule générale (I),
(I) dans laquelle : R1 représente un group S02 R2 représente un group NH, et R et n sont donnés dans le tableau suivant.
et leurs sels, hydrates ou solvates physiologiquement convenables. 6. Sulfonamides substitués représentés par la formule générale (I), selon la révendication 5, constitués par N-(N,N-diéthylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-1), N-(N,N-diéthylaminopropyle)-benzène-1,4-bis(sulfonamide); (I-2), N-(pyrrolidinoéthyle)benzène-1,4-bis(sulfonamide); (I-3), N-(pyrrolidinopropyle)benzène-1,4-bis(sulfonamide); (I-4), N-(morpholinoéthyle)benzène-1,4-bis(sulfonamide); (I-5), N-(morpholinopropyle)benzène-1,4-bis(sulfonamide); (I-6), N-(4-diéthylaminoéthoxybenzyle)-benzène-1,4-bis(sulfonamide); (I-7), N-(diméthylaminoéthyle)-benzène-1,4-bis(sulfonamide); (I-8), N-(diméthylaminopropyle)-benzène-1,4-bis(sulfonamide); (I-9), N-(N,N-dipropylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-10), N-(N,N-dipropylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-11), N-(N,N-dibutylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-12), N-(N,N-dibutylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-13), N-(N-méthyle-N-éthylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-14), N-(N-méthyle-N-éthylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-15), N-(N-éthyle-N-propylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-16), N-(N-éthyle-N-propylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-17), N-(N-éthyle-N-butylaminoéthyle)-benzène-1,4-bis(sulfonamide); (1-18), N-(N-éthyle-N-butylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-19), N-(N-propyle-N-butylaminoéthyle)-benzène-1,4-bis(sulfonamide); (I-20), N-(N-propyle-N-butylaminopropyle)-benzène-1,4-bis(sulfonamide); (1-21 ), N-(pipéridinoéthyle)-benzène-1,4-bis(sulfonamide); (I-22), N-(pipéridinopropyle)-benzène-1,4-bis(sulfonamide); (I-23), 7. Sulfonamide substitué représenté par la formule générale (I), selon la révendication 5 ou 6, et/ou ses sels, hydrates ou solvates physiologiquement convenables, pour l’utilisation comme inhibiteurs de la carboanhydrase, et comme agents antiglaucomiques. 8. Moyen pharmaceutique pour l’utilisation pour la prophylaxie et le traitement des maladies, caractérisé en ce qu’il comprend, comme matière active, un sulfonamide substitué représenté par la formule générale (I), selon la révendication 5 ou 6, et/ou ses sels, hydrates ou solvates physiologiquement convenables; et un véhicule pharmaceutique. 9. Moyen pharmaceutique selon la révendication 8, caractérisé en ce qu’il comprend, en plus, l’autre matière active pour la prophylaxie et le traitement des maladies, notamment pour le traitement des maladies d’oeil, sélectionnée dans le goupe impliquant les sympatomimetiques comme brimonidine, clonidine, apraclonidine; les parasympato-mimetiques comme pilocarpine, carbachol; les bêta-bloquants comme timolol, betaxolol, levobunolol; et les analogues de prostaglandines comme latanoprost, bimaprost, travaprost; et d’autres agents antiglaucomiques comme guanéthidine ou dapiprazole. 10. Méthode de fabrication des composés répondant à la formule générale (I), selon la révendication 5, caractérisé en ce qu’ on fait réagir sur un amine représenté par la formule générale (IV)
(IV) où R est donné dans la révendication 5, avec le chlorure de 4-sulfamoylbenzènesulfonyle de la formule (V)
(V) en présence de l’excès d’une base dans un solvant organique à une temperature comprise entre 0 et 20 °C, 1,4-bissulfonamide substitué étant formé par la réaction nucléophile. 11. Méthode selon la révendication 10, caractérisé en ce qu’ on utilise tetrahydrofurane ou éther comme solvant organique et triéthylamine comme base.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • WO 2006014134 A [0003] • US 3502652 A [0004]Non-patent literature cited in the description• C. T. SUPURAN ; A. CASINI ; A. SCOZZAFAVA. Med. Res. Reviews, 2003, vol. 23, 535-558 [0002] • M. REMKO. J. Phys. Chem. A, 2003, vol. 107, 720-725 [0006] US 2789938 A [0005] M. REMKO ; C.-W. VON DER LIETH. Bioorg. Med. Chem., 2004, vol. 12, 5395-5403 [0006]

Claims (4)

  1. ÍF2«24Siei Í244D Helyettesített «yIfeßamldsi'fc, eljárás előállításukra, ezeket tartalmazd gf égyszerkészitmények és alkalmazások glaucoma kezelésére Szattó^f W tgésiyponfek;· 1. (I) általános képlete helyettesített szalfenamrdok:
    » ahol: ha: f# jelentésé ö© esoporh akkpr R* jelentése NH osepert vagy ©, és he R* jelentésé 8©j> ósiport, akkor R'' jelentésé: MH céepoítzéé R maphao foglal larder diCiaB^itemlno-osoportot, ahol m atklynotelyferészék azonosak vagy küteniëzéek, vagy olyan amlnoesopoflpk amelynek afcik·· metekofarészafegyutt: :i-> vagy ?Ragá feltett gyyröí atkeinak, vagy az álkll-molekulafészek végek ö heteroatom kapcsolta össze, vagy : R jelentése OkNP'dietllaminoetoxOber^zil-csoport, amikor R' jelentésé SCO csopo rt, és R<; je Wise NH csoport: vagy ft jelentésé 4-{H-éröorföiinopropu)szulfamoihfenihosoport amikor R:1 jelentése QÜ és n a kapcsoló alifás Iá ne szér^atomptoak szama, ahol n jelentése 0,2 vagy 3, ésfmgf izlológiésan elfogadható silk, htdritjalk vagy szolváttalk alkalmazása glaucoma kezelésére alkalmas gyógyszer előállításéban,
  2. 2, Az t Igénypont szánni ff) általános képlető heiyeiestetf szuitónamldok, attól .. amikor............ ..... ...... ............. R1 jelentése OÛ csoporh R2, R és n a következő táilizafhan látható jelentésűi:
    és/cagy fiziológiását elfogadható sóik, hidrátjaik vagy szoiváíjaik alkalmazása glaucoma kezelésébe alkalmas gyógyszer előállításában..
  3. 3. Az 1. Igénypont szerinti (I) általános képtelő helyettesített szulfonámídok,
    ahol R’ jelentése 80s csoport, R2 jelentése NH csoport, és R és n a következő táblázatban látható jelentésű:
    és/vagy fiziológiásán elfogadható sóik, Ndrátjalk vagy szoiváfijalk alkalmazása glaucoma kezelésére alkalmas gyógyszer előállításában:.
    4. Az 1· igénypont szerinti í)} általános képlete helyettesített szulíonamkiok alkalmazása az előző igénypontok bármelyike szerint, amely szulfonamidot a következő csoportból választunk: NkM!N-dlóti!arnl:noefit)benzoim !4~bisz(szuifooaroiő); (1-1), .Ν”(ρΙίΓθΐ€ΐΙιιο:0ΐΙ))Ι>β:Π·ζοΙ*1ί4*01δζ(δζυΙΐ0ΠΜϊΐΐ£ί).; (1-3), Ν-(ρ(ΓΓθΐ!#^ορίορΰ)3^η^ο21:4-bls^(szu(föFiami^); (1-4), N-Cmorfoli^æCiiJtozpi-l^-bis^s^ulfobamiçl!}·; (1-% N-(morfoIinopropil)benzo!~1,4-blsz(szutfoyamid>; (1-6), N-(4-6felilami»oeteib€n2il)benzol~1,44>is^m#ßüafÄ): (47), N-(dimetiîamm:oeti:l)benzol-1,4-bisz(s2.ulfo«.amlci);; (1-8), H-ldimetiiamlnopï'opilIbenzol-l^-bijSzCszijioïiamid);; (1-3), N-CN^-^ipfôpilamliiô^tiObenzol-i^-foiszfszulloûamld!);' (1-10), N-iN,N'<lproplam!bopropy)ben^o!''1,4-blsziszutaami$); (1-11), :N-(Ns.N-dlbytilamiiioeílí)b@nzol-1..4-bisz(azyfonami<l); (1-12)., H~(N,N~dib:utfeminöp:ropíl)bfönzol-1;4-bíáz(szylfonamíö): (1-13),. N-(N-metli-N-etilamlaoetil:)benzol-14-b1sz(ezyfonamd); (1-14),. N-(N-meíií-N-etilami«op?opií)benzoM!4-bisz(szulíonamid); (1-1:5), N-(N-etil-N:-propilamlooetii:)b0nzol-1 ,.4~btez(szuífonamid): (M6),. N-CN-etil-^-pfopiíammapröpOlbanzöl-l^-bíszCszulfonamití); (1-17), N-(N~8lil-N-bytlaminoe!(l)benzo31,4~blsz(szy(fo:namid); (I-18), N^H-eW-N-feulilamlnopropyibabzol-l^-biszCszPlfonam^); (1-19), H-CN-pí^l-N-byÉaminoetillbenzol-l^-blsZ'Cszylfopamid).; (1-20), fsl-(N:-pmpH-N-bytilammoprDpil)l>en2öl-1,4~bisz(szylfDnaniid); ((-21 ), N“('plperidinoeiií)b«nzol-1,4-blszCszy|fonamld); (422), N-fpíp^rWinüpmpiíl)báyzöí-1,4-bisz(.szulfonamid); ÇI-23), 4-$zyllaiiiol4N-(N'!!N“dimetilam?noetil)beazamld': ((1-1), 4-szyteiol4NKN,N-dlmetilaminopmpl:l)benzamid;: (1(-2), 4-Bzidfamo((-N-(N,N^iief((ani(noet(()feenzamk1; (11-3), 4~$zulfamoil-N-(N>H~dieUlamiyo:propll)bapzamid';; (11-4), 4-szu(famoi(-N-(morfoiinoetil)benzami<J; (145), 4-szulfamy!l-H-(morf©linopropi{)benza;mM; (11-6), 4~fN-(morfolinoprop*!)szulfarnoil3fenitezuiamöí:íbenzarsi:id;: (147), (NsN'dleli(amsnoeti)'4-szy(famöí(benzoál; (11-8), {U,M-diet iiarmnopropil)-4-szyita-moilbanzoilt; (11-3), (fd,l4-dlpröpl(amlnoetll)-4-«zylfamol(b@nz0á4 (1410), {N:N-dipfopl(aminopropli)-4~szulfamollbenzoàt (11-11), 4-szuifamoii-N-(N.N-dipropflaminpetil)benzapiid.; (5-12), 4"Szyfamo?i-N"(N,N-dipropilaminopropil}benz8mid; (0-13), (KN-dlbuíOamlnoedlH-szulíanióslbenzoái, (11-14), íN,N-dibuíi!amlnQpropil)-4--szüífamoilbenzoát; (0-15), 4~$zuifamoil-N~(N,N“dibutilarninoetfl}b6n^amid; (0-16), 4-szu Ifamoli -·Ν-(Ν, N-«dibutilamsrmpfopif)benzamid, (Η-17), (H-nietii-N-eliiaminoetilH-sztiIfâmoIlbë^zoàt; (Η~1β), (N-metli-N-etiSamln-oprópilH-sziillámoltoenzoál; (11-19), 4>-szu|farnioil-NI~(lN-rnttil-N-eÔfa:m:|rKï@tî|ben2:am)d; (lf-2ö), 4rSZuiam0i-N>|^-matl}-N-ettemln.^fop^b6:nzamití;. (11-21), (N-etlí"N-propilaminoet:il)-4-szuífamoilben20át: (11-22), {M-etii-N-prqjMaminöpropilH-szu-llamoilbenzoát; (0-23), 4-szyJfamoiJ-N-(N~e!ll-N-propllami:n:ætil)benzamid; (0-24), 4-βζϋ1(3^οΙΙ-Ν-(Ν·-6ΐ10·Ν·-ρίορΙΐ3ίτ0ί]θρίορ!ΐ)0ΘπζΒπι1Ρ; (0-25), (N-propil-N-butiiamineetJlM-szulfamojlbenzoái; (11-26), (N“pfopií'H“but?laminopröpilH-szylfanioilbe«zoát; (0-27), 4~szüifamoi!-N-(N-propil-N-buiilaminoetií)benzamf:cl.; (0-28), 4-szulfamois-N-tN-propil-N-fculilaminopropil}benzamid; (0-29), (H-etil“N”buiiiarninoetil)«4-szulfamoilbenzoáf; (0-30), (N“etil“N-bufilaminopfopil)-4-s2u!famoi!benzoát; (0-31), 4-szulfamôii:“N-(N-etil>-M-buti!ammoeîii)ben2âmid; (0-32), 4-szulfamo!f-N-(N-etií-N-butilaminopropil)benzamid; (11-33), (plrrolld im>eil)-4-szuifamoilbenzoát; ( 8-34), (plrrohdinopropil)-4-szuifamoilbepzoát (0-35), 4-szu!famoi!-N-(pirrolidinoetiI)l5anzaniid; (11-36), ^-szulfarnoiON-íp-rralldinoproplllbenzamld; (0-37), Cpiperidinoefi]}-4-szulfamoiibenzoa.t; (11-38). ( p i p e rki 1 no p rop) I )-4-szu Ifamoíl ben zoá 0 ( 0 - 39), 4-szulfa:moll-N-(plperld)noeli))l>oozam)d: ( i 1-40), 4-szulfamol!-N-(p(peridinopropil)bonzaei)d: (lí -41),. S< (!) általános képletű helyettesített szoifonamldok;
    ahol R’ jelentése SO? csoport, Rx jelentése NH csoport, és R és n a következő táblázatban látható jelentésű:
    és feioloóglásan elfogadható sóik, Ndrátjaik vagy szolvátjalk. f:, Az §, igénypont szerinti (I) általános képlett* helyettesített szulfoaamid. amely á kővetkezők: N-(N;N~dieÖM ,4~bisz(szy1foaamid);; (1-1),: N^N^N-őletlerriínopropilbó^zDki.^feiszCszeltoeaíTiíő); p-2}, N-lpkroWiie^llbanzokl^blezIszyfeemicI); <í~3), 144pi;troiid:ineproptf)benz^ (M), hMmo#)!^ CMS), H-(moítőlíiiDprop|}|eezöl--l ,4-fefels^lföbÄi#;. (W)r N-(4H[J:l^tt|ipií^o^ő^ibep^pb«l"1 :,4-:blez|szy:Ífena:ré!Ő):; 0-·/), l^-{d:im#itimindi^íl)teziő!-1,44>fi§z(szulfonamid): (1-8)« M>-pmeliaPiÍnopropH)benzok:1:4-bisz(szulfonamd); Ci-9), N-(N,N-d*prop*taminoetil)benzol*1 ^^Ä^zyfohamid): 4-1 Οχ N-(N,N>d*propMaminoprop<})benzoi·· 1,4-bisz(szuiíonamíi)»',(;H 1 " N-CN.N-dibutiianiinoetiObenzoH^^iszCszuífonamkiíltCM^),. N-(N(N-dibutiiaminopropi})benZol-1f4-Pisz(szülîonamidK CM% N4N-metikN-eti!ae4noetH)benzel-1 J-fezIszylfoaamy): (1-1% N-(N-meti!-N-etií8minopropii)benzóM44~bisz(^utför#mldÍ; f-1% N4N'-etB''N'-propíiamlnoetk)benzol"1t4''b^z(szulfonamld); (1-16), •N4Ni«etiW^r©plami:»^r08)beozo^1 ;4~bisz(szuiionarmd); (117), !4-(N-etíuN-hytslamineetl!^^^ (1-18), M4f4-et)t-M-byiitamiaepreplt|beezö^ N^N-pr<$É#^b$a?^ ,:4ΦΜ^!α^Ρπ»% ((«§$). NdpipendineebOhenzoM ,4-b isz(szyífonemid) ; 0-22), N:4ppaddlaepropil)benzöi-1^^:.4>Őisz(szutÍ3eamid); (:1-23), f. Az 5. vagy 6. igénypont szedni, (!) általános képíetű helyettesített szolïonamîb és/vayy fiziológiásán elviselhető sói, hkírátjaí vagy szolvátlal karboanhidndáz gátlókként:, igy például gfaysoma ellepi szerként való alkalmazásra.
    8, Gyógyszerkészítmény betegségek megelőzésében és kezelésében vale alkalmazásra, azzal jellemezve, hegy tartalmaz hatóanyagként 5. vagy &amp; Igénypont szerinti 0) általános képiétől helyettesített szulfonamldot és/vagy annak fiziológiása?!"elfogadható sóit, hidrátjait vagy; szoívátjab és gyógyszerészeti :: hordozóanyagot &amp; A ®; Igénypotit szerinti gyógyszerkészítmény, azzal jettejm?«,. hogy tartalmaz: •még tovább! hatóanyagot betegségek megelőzésére vagy kezeléséin, különöse?! szembetegségek kezelésére, amelyet:: a következik; által etketoÉ; csoportból választunk: szIrapatoíBimetíkumök, így: például bhrnppldin, kfenjdtn, apraklonlóln:;: garaszií^atoniieielikuniok, így példáiul: plókárptp, karhaohgí:;; bétablokkolék, így például NmoioL betaxoioi, levobunoiol: és píosztáglandin analóigok, így például istanoproszt, bkoaproszi. bavaproszt; és· más glaucoma elleni szerek, így például guaneNdin vagy dapiprazoi. IO« Ellátás az 5. Igénypont szerint (I) általános képletű vegyültetek etőáiliására, azzal jellemezve:, hogy a (l¥) általános kiplelö amint: H2N"(CI-b):rE (IV), :: ahol R jelentése ez á, Igénypontlan meghatározói, (V) általános képlete..
  4. 4*szyfemoilÍeh^Íezy|o«ll4loridd«Í reagátetunk szerves oldószerben, feleslegben vett báz=s jelenlétében, 0 - 20 *C hőmérsékleten, atel a nuklpog 1! A íík Igénypont szerinti eljárás, azzal jellemezvé, bogy szerves oldószerként tetriblöröteánt vagy étert, és bázisként tnetilamlnt alkalmazunk.
HUE08741979A 2007-04-20 2008-04-18 Helyettesített szulfonamidok, eljárás elõállításukra, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk glaucoma kezelésére HUE024552T2 (hu)

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