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WO1996036595A1 - Phenylsulfamides disubstituees en positions 3,4 et leur utilisation therapeutique - Google Patents

Phenylsulfamides disubstituees en positions 3,4 et leur utilisation therapeutique Download PDF

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Publication number
WO1996036595A1
WO1996036595A1 PCT/GB1996/001204 GB9601204W WO9636595A1 WO 1996036595 A1 WO1996036595 A1 WO 1996036595A1 GB 9601204 W GB9601204 W GB 9601204W WO 9636595 A1 WO9636595 A1 WO 9636595A1
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WIPO (PCT)
Prior art keywords
dimethoxybenzenesulphonamide
benzyl
alkyl
ethyl acetate
optionally substituted
Prior art date
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Ceased
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PCT/GB1996/001204
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English (en)
Inventor
Hazel Joan Dyke
John Montana
Hannah Jayne Kendall
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Chirotech Technology Ltd
Original Assignee
Chiroscience Ltd
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Filing date
Publication date
Priority claimed from GBGB9510186.1A external-priority patent/GB9510186D0/en
Priority claimed from GBGB9523678.2A external-priority patent/GB9523678D0/en
Application filed by Chiroscience Ltd filed Critical Chiroscience Ltd
Priority to AU57722/96A priority Critical patent/AU5772296A/en
Publication of WO1996036595A1 publication Critical patent/WO1996036595A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C311/48—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 having nitrogen atoms of sulfonamide groups further bound to another hetero 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
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/18—Nitrogen atoms
    • 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
    • C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel sulphonamide compounds and pharmaceutically acceptable salts thereof, processes for their production and formulation and use as pharmaceuticals.
  • R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cyclothioalkyl, or cyclothioalkenyl ;
  • R is lower alkyl ;
  • R is aryl or heteroaryl;
  • Z and Z are independently oxygen or sulphur.
  • the only sulphonamide exemplified is N-(2- c h l o r o p h e n y l ) - 3 - c y c l o p e n t y l o x y - 4 - methoxybenzenesulphonamide.
  • European Patent Application 306 846 discloses sulphonamides of formula:-
  • R 3 may be sulphonamide, as catechol-O-methyl transferase inhibitors.
  • Phosphodiesterases regulate cyclic AMP concentrations.
  • Phosphodiesterase IV has been demonstrated to be a principal regulator of cyclic AMP in respiratory smooth muscle and inflammatory cells. [See Torphy and Creslinski, Molecular Pharmacology 37, 206, (1990); Dent et al British Journal of Pharmacology, 90 163p (1990)].
  • Inhibitors of phosphodiesterase IV have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and the function of eosinophils [See for example Giembycz and Dent, Clinical and Experimental Allergy 22 337 (1992)] and for treating other diseases and conditions characterised by, or having an etiology including, morbid eosinophil accumulation.
  • Inhibitors of phosphodiesterase IV are also implicated in treating inflammatory diseases, proliferative 5 skin disease and conditions associated with cerebral metabolic inhibition.
  • Tumour Necrosis Factor a serum glycoprotein
  • AIDS human acquired immune deficiency syndrome
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis
  • pyresis a number of autoimmune diseases, such as
  • HIV Human Immunodeficiency Virus
  • HIV-1 30 strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3.
  • T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte
  • Viruses such as HIV-1 or HIV-2 infect T lymphocytes after T cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication.
  • Cytokines are implicated in activated T- cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with cytokine activity such as by inhibition of cytokine production, notably TNF, in an HIV- infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection.
  • Monocytes, macrophages, and related cells, such as Kupffer and glial cells have also been implicated in maintenance of the HIV infection. These cells, like T cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells.
  • TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV) , influenza virus, adenovirus, and the herpes virus for similar reasons as those noted.
  • CMV cytomegalovirus
  • influenza virus influenza virus
  • adenovirus adenovirus
  • herpes virus herpes virus
  • TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells.
  • Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells.
  • US-A-4948809 discloses thromboxane antagonists including inter alia, arylsulphonamides. They are proposed for the treatment of cardiovascular diseases and asthma. There is no specific disclosure therein of one possible combination of substituents, comprising phenylsulphonamides in which the phenyl group is di(alkoxy)-substituted, and the N substituents are (i) phenyl(C,.
  • alkyl 4 alkyl
  • the phenyl group is 4-substituted by alkyl/alkenyl, for ylalkyl, hydroxyalkyl/ or -D-R 3 where D is -CO- or -CHOH- and R 3 is H, alkyl, hydroxyalkyl or alkylcarboxylic acid, and (ii) H, alkyl, acyl, aralkyl or aralkenyl, any aryl moiety being optionally substituted by halogen, alkyl, alkoxy, OH, CF 3 , CN, N0 2 , NH 2 , alkylamino, dialkylamino, acylamino, acyl or azido.
  • novel compounds of formula (i) have utility to treat disease states, for example disease states associated with proteins that mediate cellular activity, for example by inhibiting tumour necrosis factor and/or by inhibiting phosphodiesterase IV.
  • the novel compounds are of formula (i) :
  • R represents C ⁇ alkyl (optionally substituted with one or more substituents chosen from amongst halogen, C ⁇ alkoxy, aryloxy, arylalkyloxy, C, ⁇ alkylamino, arylalkylamino or arylamino) or cycloalkyl (optionally substituted with one or more substituents chosen from amongst halogen, C ⁇ alkoxy, aryloxy, arylalkyloxy, C 6 alkylamino, arylalkylamino or arylamino) ;
  • R 2 represents Cl-3 alkyl optionally substituted with halogen
  • R 3 represents arylalkyl, heteroarylalkyl, heterocycloalkyl, C0R 7 , S(0) m R 7 , C ⁇ alkyl optionally substituted with one or more substituents chosen from amongst hydroxy, C, ⁇ alkoxy, -C0 2 H, C0 2 R 8 , SO 2 NR 9 R 10 , CONR 9 R 10 , -CN, carbonyl oxygen, N sR 6 , COR-, S(0) n R 7 ;
  • R 4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl
  • R 3 and/or R 4 represents arylalkyl, heteroarylalkyl or heterocycloalkyl
  • the alkyl portion may be optionally substituted with one or more substituents chosen from amongst C0 2 H, C0 2 R g , sO j NR ⁇ ,,, CONR j R ⁇ , hydroxy, C,_ 6 alkoxy, NR 5 6 , COR 7 , S(0) n R 7 , -CN or carbonyl oxygen and/or the aryl/heteroaryl/heterocyclo portion may be optionally substituted with one or more substituents C0-6 alkyl-R n ;
  • R g and R 6 which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C 1 . 6 alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, C,. 6 alkylcarbonyl, C 1 . 6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, arylcarbonyl heteroarylcarbonyl, heterocyclocarbonyl or C,_ 6 alkylsulphonyl, provided that when R j is C ⁇ .
  • R 6 is not C ⁇ alkylcarbonyl, C 1 . 6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C 6 alkylsulphonyl, R 6 is not C ⁇ alkylcarbonyl, C 1 . 6 alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, heteroarylcarbonyl, heterocyclocarbonyl, arylcarbonyl or C,_ 6 alkylsulphonyl ;
  • R 7 represents aryl, heteroaryl, heterocyclo or C 1 . 6 alkyl, any of which may be optionally substituted with one or more substituents chosen from amongst halogen, aryl, heteroaryl, heterocyclo, C 6 alkoxy, hydroxy, C0 2 H, C0 2 R 8 , SO 2 NR-,R 10 , CON c ⁇ R,,,, NR g R g or carbonyl oxygen;
  • R 8 represents C 1 . 6 alkyl, arylalkyl, heteroarylalkyl or heterocycloalkyl;
  • R, and R 10 which may be the same or different, each represent H, aryl, heteroaryl, heterocyclo, C ⁇ alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl;
  • R represents H, aryl, heteroaryl, heterocyclo, hydroxy
  • n 0-2;
  • Preferred compounds of the invention include those in which, independently or in any combination:
  • R 1 is C,. 6 alkyl (optionally substituted with aryloxy) or cycloalkyl;
  • R 2 is methyl optionally substituted with halogen
  • R 3 is arylalkyl, heteroarylalkyl, C0R 7 , S0 2 R 7 or C 1 . 6 alkyl (optionally substituted with one or more substituents chosen from amongst hydroxy, C0 2 H, C0 2 R 8 , CONRpR,,., SO j Nl ⁇ R,, ) , CN, carbonyl oxygen, NR j R 6 , COR 7 or S0 2 R 7 ) ;
  • R 4 is arylalkyl or heteroarylalkyl
  • R 3 and/or R 4 represents arylalkyl or heteroarylalkyl
  • the aryl or heteroaryl portion may be optionally substituted with one or more substituents CO-6 alkyl-R ⁇ ;
  • R g and R 6 which may be the same or different , are H, C, ⁇ alkyl , C,_ 6 alkylcarbonyl , C 6 alkylsulphonyl , aryl , heteroaryl , arylsulphonyl , heteroarylsulphonyl , arylcarbonyl , heteroarylcarbonyl , arylalkyl or heteroarylalkyl ;
  • R 7 is C,. 6 alkyl (optionally substituted with CN , C0 2 H, C0 2 R g , CONR ⁇ o , SO 2 NR 9 R 10 , carbonyl oxygen or NR j R 6 ) , aryl or heteroaryl ;
  • R j5 is C,_ 6 alkyl
  • R o and R 10 which may be the same or different, are H, C 1-6 alkyl, arylalkyl or heteroarylalkyl;
  • R ⁇ is aryl, heteroaryl, hydroxy, C 1 . 6 alkoxy, CN, C0 2 H C0 2 R g , CONRoR 10 , SO 2 NRoR 10 , carbonyl oxygen, NR 5 R 6 , C0R 7 or S0 2 R 7 .
  • Suitable pharmaceutically acceptable salts are pharmaceutically acceptable base salts and pharmaceutically acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically acceptable base salts include metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine. Certain of the compounds of formula (i) which contain an amino group form acid addition salts.
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphate, ⁇ -ketoglutarate, ⁇ -glycerophosphate and glucose-1-phosphate.
  • the pharmaceutically acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
  • the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantio ers, and diastereoiso ers and mixtures including racemic mixtures thereof.
  • alkyl when used herein the term alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 atoms.
  • Alkyl-R ⁇ means that the R ⁇ substituent may be attached at any position on the alkyl group.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • Aryloxy means an aryl-O- group in which the aryl group is as defined below.
  • Arylalkyloxy means an aryl- alkyl-O- group.
  • Alkylamino means an alkyl-N- group in which the alkyl group is as previously defined, arylamino means aryl-N- and heteroarylamino means an heteroaryl-N- group (aryl and heteroaryl defined below) .
  • Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated.
  • Aryl indicates carbocyclic radicals containing about 6 to 10 carbon atoms.
  • Arylalkyl means an aryl-alkyl- group wherein the aryl and alkyl are as described herein.
  • Heteroarylalkyl means a heteroaryl-alkyl group.
  • Heterocycloalkyl means a heterocyclo-alkyl group.
  • Alkyl amide includes both monoalkyl and dialkyl amides, in which the alkyl groups (previously descirbed) may be the same or different.
  • Alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described.
  • Arylcarbonyl means an aryl-CO- group in which the aryl group is as previously described.
  • Arylsulphonyl means an aryl-S0 2 - group in which the aryl group is as previously described.
  • Heteroarylsulphonyl means a heteroaryl-S0 2 - group and heterocyclosulphonyl means a heterocyclo-S0 2 - group.
  • Heteroarylcarbonyl means a heteroaryl-co- group and heterocyclocarbonyl means a heterocyclo-CO- group.
  • Alkoxycarbonyl means an alkyloxy-CO- group in wich the alkoxy group is as previously desribed.
  • Alkylsulphonyl means an alkyl-S0 2 - group in which the alkyl group is as previously described.
  • Carbonyl oxygen means a -CO- group. It will be appreciated that carbonyl oxygen can not be a substituent on an aryl or heteroaryl ring.
  • Carbocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system which may be saturated or partially unsaturated.
  • Heterocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system (which may saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulphur atoms.
  • Heteroaryl means about a 5 to about a 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Heterocyclo means about a 5 to about a 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • TNF mediated disease or disease states means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6.
  • TNF-jS also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • This invention relates to a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof.
  • PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including: asthma, chronic bronchitis, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet's disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome.
  • allergic and inflammatory diseases including: asthma, chronic bronchitis
  • PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer's disease) , memory impairment associated with Parkinson's disease, depression and multi- infarct dementia. PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE IV inhibitors could have utility as gastroprotectants.
  • a special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
  • viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (i) .
  • viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex.
  • This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV) , which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (i) or a pharmaceutically acceptable salt thereof.
  • HAV human immunodeficiency virus
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, aedi virus and other lentiviruses.
  • the compounds of this invention are also useful in treating parasite, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • a preferred disease state for treatment is fungal meningitis.
  • the compounds of formula (i) are preferably in pharmaceutically acceptable form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a pharmaceutically acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
  • the invention further provides a process for the preparation of a compound of formula (i) , in which R ⁇ R ⁇ and m-n are as defined above.
  • functional groups such as amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, TW Greene.
  • the process for preparing compounds of formula (i) in which R 3 contains a -C0 2 H comprises deprotecting (for example by hydrolysis) a compound of formula (i) in which R 3 contains an appropriate -C0 2 R wherein R represents a suitable protecting group (eg methyl) .
  • a process for the preparation of a compound of formula (ia) comprises reaction of an appropriate sulphonyl chloride of formula (ii) with a suitable amine of formula (iii)
  • R 1a represents R 1 as defined in relation to formula (i) or a group convertable to R.
  • R 2a -R 4a similarly represent R 2 -R 4 or groups convertable to R 2 -R 4 respectively; and thereafter, if required, converting any group R 1a to R 1 and/or R 2a to R 2 and/or R 3a to R 3 and/or R 4a to R 4 .
  • the reaction of a sulphonyl chloride of formula (ii) with an amine of formula (iii) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
  • Sulphonyl chlorides of formula (ii) are either commercially available or are prepared using standard procedures known to those skilled in the art.
  • a sulphonyl chloride of formula (ii) may conveniently be prepared from the appropriate sulphonic acid (iv) by treatment with a suitable agent such as thionyl chloride or oxalyl chloride.
  • An appropriate sulphonic acid may be prepared from a compound of formula (v) by sulphonylation using an approriate sulphonylating agent, for example chlorosulphonic acid.
  • a sulphonyl chloride of formula (ii) may be prepared directly from a compound of formula (v) by using excess chlorosulphonic acid.
  • Compounds of formula (v) are either commercially available or may be prepared by standard procedures known to those skilled in the art.
  • Amines of formula (iii) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art. Some of the amines of formula (iii) are conveniently prepared by reductive amination of an appropriate carbonyl compound with a suitable amine. This amination may be carried out under any suitable standard conditions known to those skilled in the art.
  • a compound of formula (ia) may also be prepared by reaction of a sulphonyl chloride of formula (ii) with an amine of formula (x) to provide a compound of formula (ia) in which R 3 is H, followed by reaction with an appropriate agent of formula (xi) .
  • R 1a -R 4a are as defined earlier and X represents a suitable leaving group such as a halogen.
  • a sulphonyl chloride of formula (ii) with an amine of formula (x) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out in the presence of a suitable base, for example an amine such as triethylamine, preferably in an appropriate solvent such as dichloromethane.
  • Amines of formula (x) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
  • the reaction of a compound of formula (i) in which R 3 is H with an agent of formula (xi) may be carried out under any suitable conditions known to those skilled in the art. Favourably the reaction is carried out using an appropriate base, such as sodium hydride, preferably in an appropriate solvent such as dimethylformamide.
  • An agent of formula (xi) may be an alkylating agent such as propyl bromide, an acylating agent such as benzoyl bromide or a sulphonylating agent such as ethanesulphonyl chloride.
  • Agents of formula (xi) are either commercially available, previously described compounds or are prepared using standard procedures known to those skilled in the art.
  • a compound of formula (i) may also be prepared by interconversion of other compounds of formula (i) .
  • a compound in which R 4 contains an alkoxy group may be prepared by appropriate alkylation of a compound in which R 4 contains a hydroxy group.
  • a compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (i) or where appropriate a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier.
  • the active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tecniques.
  • warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc
  • the compounds of the invention are effective in the treatment of humans.
  • compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
  • composition of the invention is in the form of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stea
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non- aqueous vehicles (which may include edible oils) , for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl
  • compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of active compound suitably have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 10 microns, for example from 1 to 10 microns, 1 to 5 microns or from 2 to 5 microns.
  • small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
  • sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
  • corticosteroids such as prednisolone
  • adrenal stimulants such as ACTH
  • fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
  • Compounds of formula (i) may also be administered as a topical formulation in combination with conventional topical excipients.
  • Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, are conventional formulations well known in the art, for example, as described in standard text books such as Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British and US Pharmacopoeias.
  • the compound of formula (i) or if appropriate a pharmaceutically acceptable salt thereof, will compromise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
  • suitable unit doses may be 0.1 to lOOOmg, such as 0.5 to 200, 0.5 to 100 or 0.5 to lOmg, for example 0.5, 1, 2, 3, 4 or 5mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70kg adult is in the range of about 0.1 to lOOOmg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5mg/kg/day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for example 0.01, 0.02, 0.04, 0.05,
  • pharmaceutically acceptable encompasses materials suitable for both human and veterinary use.
  • the title compound was obtained as a white solid (lO.llg) .
  • N-Benzyl-3-methanesulphonyloxy-4-methoxybenzenesulphonamide (0.2g) in IM aqueous sodium hydroxide solution (5ml) was stirred at 45°C for 2 hours.
  • the clear solution was acidified with 6M aqueous hydrochloric acid (1ml) and extracted into ethyl acetate (3 x 15ml) .
  • the combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo. The residue crystallized upon standing to provide the title compound (0.17g) as a white crystalline solid.
  • the aqueous phase was further extracted with ethyl acetate (25ml) ; the combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo.
  • the crude product was recrystallized from ethyl acetate/hexane to yield the title compound (253mg) as an off-white solid.
  • Triethylamine (7.9ml) was added to a stirred solution of 3- hydroxybenzyl alcohol (2.0g) in dichloromethane (25ml) at 0°C under a nitrogen atmosphere and the solution stirred for 5 minutes.
  • a solution of methanesulphonyl chloride (3.9ml) in dichloromethane (20ml) was added dropwise over 20 minutes and stirring was continued for a further 10 minutes.
  • the reaction mixture was then washed with 5% aqueous sulfuric acid (50ml) , saturated aqueous sodium hydrogen carbonate solution (50ml) , water (50ml) and brine (50ml) .
  • the organic phase was dried (magnesium sulphate) , filtered and evaporated in vacuo. Crystallization from ethyl acetate/hexane afforded the title compound (3.7g) as an off-white solid.
  • 3-Cyclopentyloxy-4-methoxyaniline (15g) was diazotized in a mixture of concentrated hydrochloric acid (22ml) and water (7.5ml) using a solution of sodium nitrite (5.13g) in water (12.5ml), maintaining the temperature at 0°C.
  • the resulting solution was filtered through celite and the filtrate added to a solution of sulphur dioxide (14.5g) in glacial acetic acid (75ml) which contained copper(II) chloride (2.25g).
  • the mixture was stirred overnight at room temperature, diluted with water and extracted with dichloromethane. The extracts were washed with water, dried (magnesium sulphate) and evaporated in vacuo.
  • N-Furfuryl-3,4-dimethoxybenzenesulphonamide (1.0g) was added to a cooled (0°C) suspension of sodium hydride (60% dispersion in mineral oil, 0.16g) in DMF (6ml) with stirring. After 20 minutes, a solution of 2- phthalimidoethanesulphonyl chloride (0.9g) [J. Med. Chem. , 1977, 20, 1128-34] in dry DMF (6ml) was added dropwise over 10 minutes and the reaction mixture stirred at room temperature overnight. The mixture was poured into water (200ml) and extracted into ethyl acetate (2 x 50ml) .
  • a su s pens i on o f N- f urf ury l -N- ( 2 - phthalimidoethanesulphonyl) -3 , 4-dimethoxybenzene- sulphonamide (210mg) in 50% ethanol-THF (20ml) was heated to reflux to provide a complete solution. Hydrazine monohydrate (0.8ml) was added and after 30 minutes a white precipitate formed. The cooled reaction mixture was concentrated in vacuo. The residue was partitioned between water (60ml) and dichloromethane (50ml) . The aqueous phase was further extracted with dichloromethane (50ml) .
  • Example 2 N-Benzyl-N-(2-phenethyl) -3 ,4- dimethoxybenzenesulphonamide. Purification by column chromatography on silica, eluting with 25% ethyl acetate in hexane provided the title compound (0.77g) as a white solid.
  • Example 18 Methyl 2-[N-(3-cyanopropyl)-3,4- dimethoxybenzenesulphonamido]-3- phenylpropionate. Purification was achieved by column chromatography eluting with 50% ethyl acetate in hexane to afford the title compound (127mg) as an oil.
  • Example 26 N-Benzyl-N-(4-cyanobenzyl) -3,4- dimethoxybenzenesulphonamide. Purification was achieved by column chromatography on silica eluting with 33% ethyl acetate in hexane to afford the title compound (2.33g) as a white solid.
  • the crude product was partitioned between ethyl acetate and 2M HC1.
  • the aqueous phase was basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was dried over magnesium sulphate and concentated in vacuo to afford the title compund (40mg) as a clear gum.
  • Example 33 N-Benzyl-N-(3-methoxycarbonyl)benzyl-3,4- dimethoxybenzene-sulphonamide. Purification was achieved by column chromatography on silica eluting with 50% ethyl acetate in hexane to afford the title compound (1.76g) as a clear, viscous oil.
  • Lithium aluminium hydride (0.03g) was suspended in anhydrous tetrahydrofuran (10ml) under an atmosphere of nitrogen at room temperature. To this was added, over 15 minutes, a solution of the ethyl ester (0.20g) prepared as above, in anhydrous tetrahydrofuran (10ml) . The mixture was heated at 60°C for 5 hours then stirred at room temperature for a further 24 hours. After quenching with hydrochloric acid (4ml, 2M) the mixture was concentrated in vacuo.
  • the following compounds were prepared according to the above procedure from the appropriate sulphonamide and sulphonyl chloride.
  • IR (thin film) n ⁇ 1509, 1366, 1265, 1159 cm '1 .
  • Triethylamine 500 ⁇ l was added to a suspension of N-(2- Aminoethanesulphonyl) -N- (3 -pyridylmethyl) -3 , 4- dimethoxybenzenesulphonamide (1.22g) in dicloromethane (20ml) at 0°C under an inert atmosphere.
  • Benzenesulphonylchloride 340 ⁇ l was then added and the resultant solution was stirred at room temperature overnight.
  • the mixture was diluted with dichloromethane (20ml) and washed with 50% saturated sodium hydrogen carbonate solution (40ml) .
  • the solution was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography eluting with 5% methanol in ethyl acetate to provide the title compound as a pale yellow solid (630mg) .
  • Aqueous sodium hydroxide solution (IM, 25ml) was added to asolutionofN-benzyl-N-(3-methanesulphonyloxybenzyl)-3,4- dimethoxybenzenesulphonamide (2.0g) in 1,4-dioxane (25ml) and the mixture heated at 85°C for 3 hours.
  • the solvent was removed in vacuo and the residue partitioned between ethyl acetate (75ml) and 2M aqueous hydrochloric acid (75ml) .
  • the aqueous layer was further extracted with ethyl acetate (75ml) and the combined organic phases were dried (magnesium sulphate) , filtered and evaporated in vacuo. Crystallization from diethyl ether/hexane afforded an off- white solid (1.5g) .
  • Oxalyl chloride (0.09ml) was added to a stirred suspension of N-benzyl-N- ( 4 -carboxybenzyl ) -3 , 4 - dimethoxybenzenesulphonamide (0.43g) in dichloromethane (5ml) , under a nitrogen atmosphere. DMF (2 drops) was then added and stirring was continued at room temperature for a further 90 minutes. Ammonium hydroxide solution (8ml) was added to the reaction; the resulting precipitate was filtered off, washed with water and dried in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to afford the title compound (0.13g) as a white solid.
  • Oxalyl chloride (0.09ml) was added to a stirred suspension of N-benzyl-N- ( 4-carboxybenzyl) -3 , 4 - dimethoxybenzenesulphonamide (0.43g) in dichloromethane (5ml) , under a nitrogen atmosphere. DMF (2 drops) was then added and stirring was continued at room temperature for a further 90 minutes. The reaction mixture was then added to aqueous methylamine solution (40%, 10ml) . After stirring for a further 60 minutes, the layers were separated. The organic phase was washed with dilute hydrochloric acid (25ml) , water (20ml) , brine (20ml) , dried over magnesium sulphate and concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/hexane to afford the title compound (0.39g) as a white solid.
  • N- (2-Aminoethanesulphonyl) -N- (3-pyridylmethyl) -3,4- dimethoxybenzenesulphonamide (240mg) , nicotinic acid (71mg) , 1-hydroxybenzotriazole (172mg) and l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochoride (240mg) in dichloromethane (10ml) and tetrahydrofuran (5ml) were stirred at room temperature overnight under an inert atmosphere. The resulting solution was diluted with dichloromethane (20ml) and extracted with 50% saturated sodium hydrogen carbonate solution (40ml) .
  • Benzaldehyde (62 ⁇ l) was added to a stirred solution of N- (2-aminoethanesulphonyl)-N-(3-pyridylmethyl)-3,4- dimethoxybenzenesulphonamide (250mg) in dicloromethane (10ml) under an inert atmosphere.
  • Sodium triacetoxyborohydride (190mg) was then added and the reaction stirred at room temperature overnight.
  • the resulting solution was diluted with dichloromethane (40ml) and extracted with 50% saturated sodium hydrogen carbonate solution (50ml) .
  • the organic phase was dried over magnesium sulphate and concentrated in vacuo.
  • the residue was purified by column chromatography on silica eluting with 1% triethylamine/ 7.5% methanol in ethyl acetate providing the title compound as a clear oil (81mg) .
  • the assays used to confirm the phosphodiesterase IV inhibitory activity of compounds of formula (i) are standard assay procedures as disclosed by Schilling et al Anal. Biochem. 216 154 (1994), Thompson and Strada Adv. Cycl. Nucl. Res. 8 119 (1979) and Gristwood and Owen Br. J. Pharmacol. 87 91P (1986) .

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Abstract

L'invention concerne des benzénésulfamides disubstituées en positions 3,4 présentant la formule générale (i) dans laquelle R3 représente arylalkyle, hétéroarylalkyle, hétérocycloalkyle, COR7, S(O)mR7, alkyle C1-6 éventuellement substitué, R4 représente arylalkyle, hétéroarylalkyle ou hétérocycloalkyle et les autres substituents sont tels que définis dans la revendication 1, et peuvent être utilisés comme agents thérapeutiques par inhibition de la phosphodiestérase IV.
PCT/GB1996/001204 1995-05-19 1996-05-20 Phenylsulfamides disubstituees en positions 3,4 et leur utilisation therapeutique Ceased WO1996036595A1 (fr)

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GBGB9510186.1A GB9510186D0 (en) 1995-05-19 1995-05-19 Novel compounds
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US12433892B2 (en) 2018-12-22 2025-10-07 Gliapharm Sa Compositions and methods of treatment for neurological disorders comprising depression

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US11236055B2 (en) * 2016-07-01 2022-02-01 Venenum Biodesign, LLC Non-systemic TGR5 agonists
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