WO1998007742A1 - Sulfonamides - Google Patents

Sulfonamides Download PDF

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Publication number
WO1998007742A1
WO1998007742A1 PCT/GB1997/002222 GB9702222W WO9807742A1 WO 1998007742 A1 WO1998007742 A1 WO 1998007742A1 GB 9702222 W GB9702222 W GB 9702222W WO 9807742 A1 WO9807742 A1 WO 9807742A1
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WIPO (PCT)
Prior art keywords
tert
isobutyl
leucine
methylamide
sulfonylamino
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PCT/GB1997/002222
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English (en)
Inventor
Bernard Christophe Barlaam
Original Assignee
Zeneca Limited
Zeneca-Pharma S.A.
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Application filed by Zeneca Limited, Zeneca-Pharma S.A. filed Critical Zeneca Limited
Priority to AU40217/97A priority Critical patent/AU4021797A/en
Publication of WO1998007742A1 publication Critical patent/WO1998007742A1/fr

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    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur 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
    • C07C311/19—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 carboxyl groups
    • 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
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/42—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton 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 carboxyl groups
    • 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
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • 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
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to sulfonamides and in particular to sulfonamides wherein the sulfonamide group is located adjacent to a hydroxamate group. This invention further relates to processes for preparing such sulfonamides, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment.
  • the compounds of this invention are inhibitors of the production of TNF (Tumour Necrosis Factor) which is believed to be formed by the cleavage of a pro-form, or larger precursor, by the enzyme pro-TNF Convertase Applicants believe that the compounds of the present invention inhibit TNF production by mechanisms which include inhibition of pro- TNF Convertase.
  • TNF Tumour Necrosis Factor
  • 'TNF' is used herein to refer to Tumour Necrosis Factor in general but, in particular, to TNF .
  • the compounds of this invention will be useful in the treatment of disease or medical conditions in which excessive TNF production is known to give rise via a cascade of processes to a variety of physiological sequelae including the production of physiologically- active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferations and to angiogenesis. It is also known that, in certain cellular systems.
  • TNF production precedes and mediates the production of other cytokines such as interleukin-1 (IL-1 ) and interleukin-2 (IL-2) which are also believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity.
  • IL-1 interleukin-1
  • IL-2 interleukin-2
  • Excessive TNF production has also been implicated in mediating or exacerbating the development of various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular disorders such as myocardial infarction, angina and peripheral vascular disease.
  • various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinit
  • Excessive TNF production has also been implicated in mediating complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome. Excessive TNF production has also been implicated in mediating or exacerbating the development of adult respiratory distress syndrome, diseases involving cartilage or muscle resorption, Paget's disease and osteoporosis, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis.
  • AIDS malignant disease and acquired immune deficiency syndrome
  • the compounds of the invention may also be inhibitors of one or more matrix metal loproteinases such as collagenascs, stromelysins and gelatinascs. Thus they may also be of use in the therapeutic treatment of disease conditions mediated by such enzymes for example arthritis (rheumatoid and osteoarthritis). osteoporosis and tumour metastatis.
  • matrix metal loproteinases such as collagenascs, stromelysins and gelatinascs.
  • the present invention provides novel sulfonamides which have activity as inhibitors of TNF and/or are inhibitors of one or more matrix metalloproteinase enzymes.
  • R 1 is is aryl, heterocyclyl or heteroaryl
  • R 2 is is hydrogen, C,_ 8 a_kyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . g cycloalkyl, aryl, heteroaryl, heterocyclyl, arylC, .6 alkyl, heteroarylC,. 6 alkyl, heterocyclylC,. 6 alkyl or C,. 8 cycloalkylC
  • R 3 is C,. 6 alkyl, C 2 . 6 alkenyl, arylC,. 6 alkyl, heteroarylC,. ft alkyl or the side-chain of a naturally occurring amino acid;
  • R 4 is hydrogen, C, .6 alkyl, C ⁇ . 8 cycloalkyl, C 4 . 8 cycloalkenyl, arylC,. 6 alkyl, heteroarylC, .6 alkyl or heterocyclylC,. 6 alkyl;
  • R 5 is hydrogen or C h alky]; or R 4 or R 5 together with the nitrogen atom to which they are joined form a heterocychc ring; wherein any group or ring, in R'-R ⁇ is optionally substituted; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • Aryl in the terms “aryl” and “arylC ⁇ alkyl” typically means phenyl or naphthyl, preferably phenyl.
  • Heteroaryl in the terms “heteroaryl” and “heteroarylC,. ⁇ alkyl means an aromatic mono- or bicyclic 5-10 membered ring with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur. Examples of 'heteroaryl " include thienyl, pyrrolyl.
  • Heterocyclyl in the terms “heterocyclyl " and “heterocyclyl C,. 6 alkyr " means a non-aromatic mono- or bicyclic 5-10 membered ring with up to five ring hetero atoms selected from nitrogen, oxygen and sulphur.
  • heterocyclyF include pyrrolidinyl. morpholinyl, piperidinyl, dihydropyridinyl and dihydropyrimidinyl.
  • R'-R 5 may be optionally substituted, for example by up to five substituents, preferably up to three substituents which may be the same or different.
  • Typical substituents include: hydroxy, C,. 6 alkoxy for example methoxy, mercapto, C,. 6 alkylthio for example methylthio, amino, C,. 6 alkylamino for example methylamino, di-(C,. 6 alkyl)amino for example dimethylamino, carboxy, carbamoyl, C,. ft alkylcarbamoyl for example methylcarbamoyl, di-C,. 6 alkylcarbamoyl for example dimethylcarbamoyl, C,. 6 alkylsulphonyl for example methylsulphonyl, arylsulphonyl for example phenylsulphonyl,
  • C,. 6 alkylaminosulphonyl for example methylaminosulphonyl, di-(C
  • 6 alkanoyloxy for example acetoxy, C,. 6 alkyl for example methyl, ethyl, isopropyl or tert-butyl, halo for example fluoro, chloro or bromo, trifluoromethyl, aryl for example phenyl, arylC,. 6 alkyl for example benzyl, aryloxy for example phenoxy, arylC,. 6 alkoxy for example benzyloxy, heteroaryl, heteroarylC, .6 alkyl, heterocyclyl and heterocyclylC,. 6 alkyl.
  • a further typical substituent is trifluoromethoxy.
  • side chain of a naturally occurring amino acid means the side chain X of an amino acid NH 2 -CHX-COOH.
  • Suitable amino acids include alanine, arginine, aspartic acid, cysteine. asparagine, glutamine. histidine. homoserine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine. serine. threonine, tryptophan, tyrosine and valine.
  • the compounds of the present invention possess a number of chiral centres, at -CH(NHSO 2 R')-, at -CHRX at -CHR 2 - (when R 2 is not hydrogen) and possibly in the variables R'-R ⁇
  • the present invention covers all diastereoisomers and mixtures thereof that inhibit TNF Convertase and/or inhibit matrix metalloprotcinase enzymes.
  • R 1 is an optionally substituted phenyl group or optionally substituted naphthyl group.
  • R' is phenyl or naphthyl wherein either ring is unsubstituted or substituted by one or two groups selected from halogen for example chloro or fluoro, C h alky lcarbonyl for example acetyl, C, .f ,alkanoylam ⁇ no for example acetamido, trifluoromethyl, cyano, C,. 6 alkyl for example methyl, isopropyl or tert-butyl, trifluoromethoxy, carboxy, nitro. di-C
  • R' is phenyl or naphthyl wherein either ring is unsubstituted or substituted by one or two groups selected from halogen for example chloro or fluoro, C
  • R 1 is phenyl, 4-fluorophenyl. 4-trifluoromethylphenyl, 2-cyanophenyl,
  • R 1 is 2.4,6-trimethylphenyl, 3-trifluoromethyl, 4-carboxyphenyl, 4-bromophenyl, 3-chlorophenyl, 2-chloro-4- fluorophenyl, 4-isopropylphenyl, 3-nitrophenyl. 3-carboxyphenyl or 2,4,6-tri- isopropylphenyl. Most preferably R 1 is phenyl or 4-acetylphenyl.
  • R' may be naphth-1-yl or naphth-2-yl or naphthyl optionally substituted such as 5-dimethylaminonaphth-l -yl or 5-dimethylaminonaphth-2-yl.
  • R' is an optionally substituted heteroaryl group as hereinbefore defined. More particularly R 1 is an optionally substituted heteroaryl group wherein the heteroaryl group has 5 or 6 ring atoms, one to three of which are selected from nitrogen and sulphur or is a bicyclic derivative thereof wherein two adjacent carbon atoms arc fused to a benzene ring.
  • R 1 being a monocyclic heteroaromatic ring
  • examples of R 1 being a monocyclic heteroaromatic ring include pyridazinyl, pyrimidinyl, pyridinyl. triazolyl, imidazolyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl and isoxazolyl, any of which may be optionally substituted for example by such as methyl, halo such as chloro, fluoro or bromo, phenyl or pyridinyl.
  • R 1 is pyridazinyl, pyrimidinyl, pyridinyl, triazolyl, imidazolyl. thienyl, pyrrolyl or thiazolyl.
  • R> is a bicyclic heteroaromatic ring system wherein one or both rings may contain ring heteroatoms and wherein the sulfonamide link may be to either ring.
  • one ring is a benzene ring fused on two adjacent carbon atoms to a 5- or 6- membered nitrogen containing ring which ring may be saturated or unsaturatcd.
  • Examples of such favoured ring systems include quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, quinazolinyl. 3.4-dihydroquinazolinyl, indolyl.
  • Particular ring systems include quinolin-8-yl, quinolin-6-yl. l -methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl, oxindol-5-yl, isoquinolin-5-yl, l,2,3,4-tetrahydroquinolin-8-yl. 4-oxo-3.4-dihydroquinazolin-
  • R 1 may be an optionally substituted heterocyclyl group as hereinbefore defined. More particularly R 1 is an optionally substituted heterocyclyl group having 5 or 6 ring atoms, one to three of which are selected from nitrogen, oxygen or sulphur.
  • heterocyclyl groups include tetrahydropyran, tetrahydrofuran, piperidine and bicyclic derivatives thereof wherein two adjacent carbon atoms are fused to another ring.
  • a chiral centre at -CH(NHSO 2 R') it is preferred that this centre has the configuration indicated in formula (II) hereinafter. For most values of R 1 this centre will have the S-stereochemistry under the Cahn-Prelog-Ingold sequence rules.
  • R 2 Particular groups for R 2 include C,. 8 alkyl for example isopropyl, n-propyl, isobutyl, sec-butyl, n-butyl, tert-butyl, isopentyl, n-pentyl, hexyl, heptyl or octyl; C,. 8 alkyl interrupted by an oxygen or sulphur atom for example methoxypropyl, ethoxyethyl, propoxymethyl, ethylthioethyl, methylthiopropyl; phenylC,. 6 alkyl for example benzyl, phenethyl.
  • phenylpropyl or phenylbutyl phenylpropyl or phenylbutyl; phenylC ⁇ -6 alkyl wherein the alkyl chain is interrupted by oxygen or sulphur for example benzyloxypropyl and benzyloxybutyl; C .8 cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or C x cycloalkylC,. 6 alkyl for example cyclopropylmethyl, cyclopropylethyl. cyclobutylmethyl. cyclopentylmethyl or cyclohexylmethyl.
  • R2 may be C, .8 alkyl for example isopropyl, n-propyl, isobutyl, sec-butyl, n-butyl, tert-butyl, isopentyl. n-pentyl. hexyl, heptyl or octyl; C,. 8 alkyl interrupted by an oxygen or sulphur atom for example methoxypropyl, ethoxyethyl. propoxymethyl, ethylthioethyl or methylthiopropyl; phcnylC, .
  • alkyl for example benzyl, phenethyl, phenylpropyl or phenylbutyl; C 8 cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or C 3 . 8 cycloalkylC,_ ft alkyl for example cyclopropylmethyl, cyclopropylethyl. cyclobutylmethyl. cyclopentylmethyl or cyclohexylmethyl.
  • R 2 is isobutyl
  • R 3 Particular groups for R 3 include C, . alkyl for example methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, n-pentyl or hexyl; C,. 6 alkyl interrupted by an oxygen or sulphur atom for example methoxyethyl, methoxypropyl, methylthioethyl or 1,1 -dimethylmethylthiomethyl (MeSCMe 2 -); or phenylC,. alkyl for example benzyl or phenethyl.
  • R 3 is isobutyl, tert-butyl, 1,1-dimethylmethylthiomethyl or benzyl with tert-butyl being most preferred.
  • the chiral centre at -CHR 3 - preferably has the configuration indicated in formula (II) hereinafter. For most of R 3 this centre will have the S-stereochemistry.
  • R 4 include C,. 6 alkyl for example methyl, ethyl, n-propyl, isopropyl, tert-butyl or n-butyl; C,. 6 alkyl interrupted by an oxygen or sulphur atom for example hydroxyethyl, methoxyethyl, methylthioethyl or ethoxyethyl; phenylC,. 6 alkyl for example benzyl, phenethyl or phenylpropyl; or C 3 . 8 cycloalkylC
  • R 4 may be C
  • R 4 is methyl, ethyl, n-propyl. isobutyl, tert-butyl, dimethylaminoethyl, dimethylaminopropyl, morpholinoethyl or benzyl. Of these methyl is most preferred.
  • R" are hydrogen and C ,alkyl for example methyl or ethyl.
  • R 5 is hydrogen.
  • R 4 and R 5 together with the nitrogen atom to which they arc joined form a heterocychc ring, for example a 5 or 6 membered heterocychc ring such as morpholino, piperidino, piperazino or N-methylpiperazino. Of these morpholino is preferred.
  • a particularly suitable class of compounds of the present invention is that of formula (II):
  • R', R 2 , R 3 , R 4 and R 5 are as hereinbefore defined.
  • a preferred class of compounds of the formula (II) is that wherein R 1 is phenyl or naphthyl either being unsubstituted or substituted by one or two groups selected from halogen for example chloro or fluoro, C
  • R 2 is isobutyl:
  • R3 is isobutyl, tert-butyl, 1 ,1-dimethylmethylth ⁇ omethyl or benzyl;
  • R 4 is methyl, ethyl, n-propyl, isobutyl, tert-butyl, dimethylaminoethyl. dimethylaminopropyl, 2-morpholinoethyl or benzyl; and R 5 is hydrogen or methyl: or R 4 and R5 together with the nitrogen atom to which they are joined form a morpholine ring.
  • a preferred class of compounds of the formula (II) is that wherein R 1 is phenyl or naphthyl unsubstituted or substituted by one or two groups selected from halogen for example chloro or fluoro, C,. 6 alkylcarbonyl for example acetyl, C 1 ( ,alkanoylamino for example acetamido, trifluoromethyl, cyano.
  • C,. 6 alkyl for example methyl, isopropyl or tert- butyl or C
  • R 3 is isobutyl, 1 , 1 -dirnethylmethylthiomethyl, tert- butyl or benzyl
  • R 4 is methyl, ethyl, n-propyl, isobutyl, tert-butyl or benzyl
  • R s is hydrogen.
  • R 1 is quinolin-8-yl, quinolin-6-yl, l-methyl-2-oxo-l ,2,3,4-tetrahydroquinolin-6-yl.
  • oxindol-5-yl isoquinolin-5-yl, l,2,3,4-tetrahydroquinolin-8-yl, 4-oxo-3,4-dihydroquinazolin-8-yl or 4-oxo-3,4- dihydroquinazolin-6-yl;
  • R2 is isobutyl;
  • R3 is isobutyl, tert-butyl, 1 ,1-dimethylmethylthiornethyl or benzyl;
  • R 4 is methyl, ethyl, n-propyl, isobutyl, tert-butyl, dimethylaminoethyl, dimethylaminopropyl, 2-morpholinoethyl or benzyl; and R 5 is hydrogen or methyl; or R 4 and R5 together with the nitrogen atom to which they are joined form a morpholine ring.
  • Suitable pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine.
  • in vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animaFs body fluids.
  • Suitable m vivo hydrolysable esters for carboxy include methoxymcthyl and for hydroxy include acetyl.
  • a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester and pharmaceutically acceptable carrier.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
  • compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.5 to 75 mg/kg body weight (and preferably of 0.5 to 30 mg/kg body weight) is received.
  • This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. Therefore in a further aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use in a method of therapeutic treatment of the human or animal body.
  • the present invention provides a method of treating a disease condition mediated by TNF which comprises administering to a warm-blooded animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
  • the present invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof in the preparation of a medicament for use in a disease condition mediated by TNF.
  • the present invention provides a process for preparing a compound of the formula or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof which process comprises a) reacting a compound of the formula (III):
  • R'-R 5 are as hereinbefore defined, or an activated derivative thereof with hydroxylamine, O-protected hydroxylamine or a salt thereof; or b) coupling a compound of the formula (IV) with a compound of the formula (V):
  • any functional group is protected, if necessary, and: i. removing any protecting groups; ii. optionally forming a pharmaceutically acceptable salt or in vivo hydrolysable ester
  • Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods.
  • Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • Specific examples of protecting groups are given below for the sake of convenience, in which "lower” signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
  • a carboxyl protecting group may be the residue of an ester- forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (eg isopropyl, t ⁇ butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl, isobutoxymethyl): lower aliphatic acyloxy lower alkyl groups, (eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (eg 1-methoxycarbonyloxyethyl.
  • l-12C straight or branched chain alkyl groups
  • lower alkoxy lower alkyl groups eg methoxymethyl, ethoxymethyl, isobutoxymethyl
  • lower aliphatic acyloxy lower alkyl groups eg acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl
  • lower alkoxycarbonyloxy lower alkyl groups eg 1-methoxycarbon
  • aryl lower alkyl groups eg benzyl, p-methoxybenzyl, o-nitrobenzyl, r nitrobenzyl, benzhydryl and phthalidyl
  • tri(lower alkyl)silyl groups eg trimethylsilyl and t-butyldimethylsilyl
  • tri(lower alkyl)silyl lower alkyl groups eg trimethylsilyiethyl
  • (2-6C)alkenyl groups eg ally! and vinylethyl
  • carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.
  • hydroxyl protecting groups include lower alkyl groups
  • lower alkenyl groups eg allyl
  • lower alkanoyl groups eg acetyl
  • lower alkoxycarbonyl groups eg t-butoxycarbonyl
  • lower alkenyloxycarbonyl groups eg allyloxycarbonyl
  • aryl lower alkoxycarbonyl groups eg benzoyloxycarbonyl, D-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, r nitrobenzyloxycarbonyl
  • tri(lower alkyl)silyl eg trimethylsilyl, t-butyldimethylsilyl
  • aryl lower alkyl eg benzyl
  • amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2.4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (eg t-butoxycarbonyl); lower alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lower alkoxycarbonyl groups (eg benzyloxycarbonyl, -methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl): trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
  • aralkyl groups eg benzyl and substitute
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p_- nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photolytically.
  • Compounds of the formula (I) may be converted to other compounds of the formula (I) by standard chemical methodologies, for example hydrogenation of a quinoline to a 1 ,2,3,4-tetrahydroquinoline.
  • the hydroxylamine group (HONH-) in particular in process variants (b), (c) and (d), is typically O-protected for example with benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, t-butyl or a silyl (for example trimethylsilyl) group.
  • the compound of the formula (III) may be reacted in the form of the acid or an activated derivative thereof such as an acid halide.
  • acid anhydride or an 'activated" ester such as 1 H-benzof 1 ,2,3 Itriazol- 1 -y I. 1 -hydroxy-benzof 1 ,2,3Jtriazole. pentafluorophenyl or 2,4,5-trichlorophenyl in the presence of a carbodiimide.
  • the reaction of the compound of the formula (III) and hydroxylamine is performed under standard conditions.
  • an activated ester of a compound of the formula (III ) and hydroxylamine or O-protected hydroxylamine is performed in the presence of a base, for example 2,6-lutidine (optionally in the presence of dimethylaminopyridine) or N-methylmorpholine in an anhydrous aprotic solvent, for example dimethylformamide. at a non-extreme temperature, for example in the region -30° to +25°, preferably about 0°C.
  • the compound of the formula (III) may be prepared by reacting a compound of the formula (IX) with a compound of the formula (X):
  • the compounds of the formula (X), optionally with the carboxylic acid function protected, may be prepared by coupling a suitably protected compound of the formula (XI): NH-
  • R 2 is as hereinbefore defined, with a compound of the formula (V).
  • the compounds of the formula (XI) may be prepared in standard manner, for example by the alkylation of protected aspartic acid derivatives or by the reaction of a glycine nucleophilic equivalent with a compound of the formula: R--CI IX'-COOH (protected as necessary) wherein X 1 is a leaving group for example a triflate.
  • the compounds of the formula (IV) may be prepared by reacting a suitably protected compound of the formula (XIV):
  • the compounds the formula (XV) may be prepared by reacting a compound of the formula (XI) with hydroxylamine in a manner similar to that described hereinabove.
  • the compounds of the formula (V) may be prepared by reacting a compound of the formula (XIII) with a compound of the formula (VII) under standard coupling conditions.
  • the compounds of the formulae (VI) and (VII) are reacted under standard conditions for acylation of an amine with any functional groups protected as necessary.
  • the compounds of the formula (VI) may be prepared by reacting a compound of the formula (XVI):
  • the compounds of the formula (XVI) may be prepared by reacting compounds of the formulae (IX) and (XII) or by reacting compounds of the formulae (XIII) and (XIV) under conditions similar to those described above for similar reactions.
  • the compounds of the formula (VI) may also be prepared by reacting compounds of the formula (IV) and (XIII) or by reacting compounds of the formulae (IX) and (XVII):
  • the compounds of the formula (XVII) may be prepared by reacting compounds of the formula (XII) with hydroxylamine.
  • the compounds of the formula (VIII) and (IX) are reacted under standard conditions for sulphonylation of an amine with any functional groups protected as necessary.
  • X is a leaving group.
  • X is halo for example fluoro, chloro or bromo, or X is an anhydride-forming group or an ester- forming group. Most favourably X is chloro or bromo.
  • the compounds of the formula (VIII) may be prepared by reacting compounds of the formulae (V) and (XV), or by reacting compounds of the formulae (XVII) and (VII), or by reacting a compound of the formula (X) with hydroxylamine.
  • pro TNI ' convertase enzyme The ability of the compounds of this invention to inhibit pro TNI ' convertase enzyme is assessed in an isolated enzyme assay (termed “CON2").
  • Partially purified proTNF ⁇ convertase enzyme is obtained from the membranes of TUP- 1 cells as follows. 1.5-2.0x10" cells/ml THP-1 cells (initially cultured in RPMI 1640 medium + 10%(v/v) FCS, 10%(v/v) Ml . 2mM L-glutamine l OOIU/ml penicillin and l OO ⁇ g/ml streptomycin) are induced in RPMI 1640 containing l ⁇ g/ml LPS (E.
  • coli Ol 1 1 :B4 2mM Hydroxyurea, 50 ⁇ g/ml silica and l%(v/v) FCS at 37°C in a humidified (5%CO 2 /95%air) incubator. After 16 hours the cells are harvested from a 5L induction by centrifugation at 640xg for 1 minutes. The cell pellets are washed once in RPMI 1640 without additive (1 L per 2x10'° cells) and re-centrifuged at 640xg for 10 minutes. Cell pellets are resuspended in lOmM sodium phosphate buffer pH 7.4, containing ImM MgCl 2 , 30mM NaCl.
  • the pellet is then resuspended in Buffer A containing l%(w/v) Triton X-100 to a concentration of lmg/ml and mixed for 1 hour at 4°C.
  • the solubilised protein is recovered by centrifugation for 30 minutes at 100,000xg at 4°C
  • the supernatant is applied to a 25ml gelatin-sepharose 4B column equilibrated in lOmM Tris-HCl pH 8.0, lOOmM NaCl, 0.1 %(w/v) Triton X-100, 200 ⁇ M PMSF, 0.02%( /v) azide, l ⁇ M ZnCl 2 (Buffer B). After loading the column is washed with Buffer B.
  • the gelatin-sepharose flowthrough plus the first lOmls of the wash is then recycled overnight ( 1 ml/min) on a 30ml wheatgerm-sepharose column previously equilibrated in lOmM Tris-HCl pi I 8.0, 0.1%(w/v) Triton X-100, 200 ⁇ M PMSF, 0.02%(w/v) azide, l ⁇ M ZnCl 2 (Buffer C).
  • Buffer C Buffer C
  • the enzyme is eluted with Buffer C containing 300mM N-Acetyl Glucosamine.
  • the active enzyme fractions are applied to a 1 ml Mono Q column equilibrated in Buffer C.
  • enzyme After loading and washing with Buffer C, enzyme is eluted using a 0-500mM NaCl gradient in Buffer C. Active enzyme fractions are pooled and used as partially purified proTNF ⁇ convertase. In all cases the active fractions are assayed using the fluorogenic synthetic peptide substrate assay described below. This enzyme preparation cleaves 21kD soluble proTNF ⁇ at the correct cleavage site (Ala-Val) and enzyme activity is inhibited by matrix metal loprotease inhibitors (Gearing, A.J.H. et al., 1995, J Leukocyte Biol., 57,774-777).
  • the peptidic part of the substrate was assembled on Fmoc-NH-Rink- MBHA-polystyrene resin either manually or on an automated peptide synthesiser by standard methods involving the use of Fmoc-amino acids and O-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium hexafluorophosphate (HBTU) as coupling agent with at least a 4- or 5- fold excess of Fmoc-amino acid and FIBTU. Ser' and Pro 2 were double-coupled.
  • HBTU O-benzotriazol-l-yl-N,N,N',N'- tetramethyluronium hexafluorophosphate
  • the amino- peptidyl-resin so obtained was acylated by treatment for 1.5-2hr at 70°C with 1.5-2 equivalents of 4',5'-dimethoxy-fluorescein-4(5)-carboxylic acid (Khanna & Ullman, Anal Biochem, 108, 156-161, 1980) which had been preactivated with diisopropylcarbodiimide and 1 -hydroxybenzotriazole in DMF.
  • the dimethoxyfluoresceinyl-peptide was then simultaneously deprotected and cleaved from the resin by treatment with trifluoroacetic acid containing 5% each of water and triethylsilane.
  • the dimethoxyfluoresceinyl-peptide was isolated by evaporation, trituration with diethyl ether and filtration.
  • the isolated peptide was reacted with 4-(N-maleimido)-fluorescein in DMF containing diisopropylethylamine, the product purified by RP-HPLC and finally isolated by freeze-drying from aqueous acetic acid.
  • the product was characterised by MALD1-TOF MS and amino acid analysis.
  • Pro ' FNF ⁇ convertase enzyme 25 ⁇ l; 0.0144 units/ml in assay buffer) is added to all wells, except substrate alone controls which receive 25 ⁇ l assay buffer.
  • NB One unit of enzyme activity is defined as the convertase enzyme concentration which converts InMole substrate/hour).
  • TNF ⁇ production is assessed in TIIP-1 cells which are a human myelomonocytic cell line which synthesise and secrete TNF ⁇ when stimulated with lipopolysaccharide.
  • THP-1 cells (4x l 0 5 cells in 160 ⁇ l medium RPMI 1640 + bicarbonate, penicillin, streptomycin and glutamine) are incubated with 20 ⁇ l of test compounds (triplicates) in DMSO or appropriate vehicle, in a 96 well tissue culture (TC) plate, for 30 min at 37°C in a humidified (5%CO 2 /95%air) incubator, prior to addition of 20 ⁇ l lipopolysaccharide (LPS) (E. Coli.
  • LPS lipopolysaccharide
  • Each assay includes controls of THP-1 cells incubated with medium alone (six wells/plate) or with a standard TNF ⁇ inhibitor. The plates are then incubated for 6 hours at 37°C (humidified incubator) after which time lOO ⁇ l samples are removed from each well and transferred to a 96 well plate for storage at -70°C for subsequent analysis of TNF ⁇ concentration by ELISA. In this test, generally, compounds are of interest if they have activity below lO ⁇ M. Assessment in whole blood assay
  • HWBA human whole blood assay
  • Human whole blood secretes TNF ⁇ when stimulated with LPS.
  • This property of blood forms the basis of an assay which is used as a secondary test for compounds which profile as active in the THP-1 test.
  • Heparinized (lOUnits/ml) human blood obtained from volunteers is diluted 1 :5 with medium (RPMI 1640 + bicarbonate, penicillin, streptomycin and glutamine) and incubated (160 ⁇ l) with 20 ⁇ l of test compound (triplicates), in DMSO or appropriate vehicle, for 30 min at 37°C in a humidified (5%CO 2 /95%air) incubator, prior to addition of 20 ⁇ l LPS (E.
  • Each assay includes controls of diluted blood incubated with medium alone (6 wells/plate) or a known TNF ⁇ inhibitor as standard. The plates are then 5 incubated for 6 hours at 37°C (humidified incubator), centrifuged (2000rpm for 10 min; 4°C), plasma harvested (50-1 OO ⁇ l) and stored in 96 well plates at -70°C before subsequent analysis for TNF ⁇ concentration by ELISA. In this test, generally, compounds are of interest if they have activity below 50 ⁇ M.
  • In vivo assessment 10 The ability of the compounds of this invention as ex vivo TNF ⁇ inhibitors is assessed in the rat.
  • mice Male Wistar Alderley Park ( ⁇ P) rats (180-21 Og) are dosed with compound (6 rats) or drug vehicle (10 rats) by the appropriate route e.g. peroral (p.o.), intrapcritoneal (i.p.) . subcutaneous (s.c).
  • ⁇ P Wistar Alderley Park
  • rats drug vehicle
  • s.c subcutaneous
  • LPS 25 ⁇ l; final concentration l O ⁇ g/ml
  • Control wells are incubated with 25 ⁇ l of medium alone. Plates are then centrifuged for 10 min at 2000 m and 200 ⁇ l of the supernatants are transferred to a 96 well plate and frozen at -20°C for subsequent analysis of TNF concentration by ELISA.
  • the sediment is reconstituted in CON2 assay buffer and subsequently analysed for compound content using the TNF convertase assay (CON2). Briefly, a compound concentration- response curve is constructed for the compound undergoing evaluation. Serial dilutions of the reconstituted plasma extracts are assessed for activity and the amount of compound present in the original plasma sample is calculated using the concentration-response curve taking into account the total plasma dilution factor.
  • LDA lithium di-isopropylamide
  • THF means tetrahydrofuran
  • DMSO means dimethylsulphoxide
  • N 2 -[4-Hydroxy-2R-isobutyl-3S-bcnzenesulfonyIaminosuccinyl]-L-tert-leucine-N'- methylamide 600 mg, 1.32 mmol was dissolved in DMF (10 ml).
  • 1 -Hydroxybenzotriazole (231 mg, 1.7 mmol) was added, followed by N-ethyl-N'-(3- dimethylaminopropyl)carbodiimide hydrochloride (324 mg, 1.7 mmol) and 2,6-lutidine (181 ⁇ l, 1.6 mmol). The mixture was stirred at room temperature for one hour.
  • Trifluoroacetic acid (2 ml) was added dropwise to a solution of N 2 -[2R-isobutyl-3S- benzenesulfonylamino-4-tert-butyloxysuccinyl]-L-tert-leucine-N '-methylamide (780 mg, 1.52 mmol) in dry dichloromethane (4 ml). The solution was stirred at 0°C overnight. The solvents were evaporated in vacuo. The residue was taken up in toluene and the solvent was removed in vacuo (three times).
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) , from N -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leucine-N'- methylamide (600 mg, 1.6 mmol) and naphthalene-2-sulfonyl chloride (403 mg), there was 25 obtained N 2 -[2R-isobutyl-3S-(naphthalene-2-sulfonylamino)-4-tert-butyloxysuccinyl]-L-tert- leucine-N 1 -methylamide (690 mg, 77%) as a white foam; MS (ESI): 584 (M + Na * ).
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) , from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leucine-N'- methylamide (600 mg, 1.6 mmol) and 4-acetamidobenzenesulfonyl chloride (415 mg), there was obtained N 2 -[2R-isobutyl-3S-(4-acetamidobenzenesulfonylamino)-4-tert-butyloxy- succinyl]-L-tert-leucine-N' -methylamide (790 mg, 87%) as a white foam; MS (ESI): 591 (M + Na * ).
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) , from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leucine-N'- methylamide (600 mg, 1.6 mmol) and naphthalene- 1-sulfonyl chloride (403 mg), there was obtained N -f2R-isobutyl-3S-(naphthalene-l-sulfonylamino-4-tert-butyloxysuccinyl]-L-tert- leucine-N' -methylamide (620 mg, 69%) as a white foam; MS (ESI): 584 (M + Na ).
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) except that the crude reaction mixture after evaporation of the solvents was directly purified by flash chromatography on silica using dichloromethane-methanol (95:5) as eluant, from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leucine-N'- methylamide (700 mg, 1.88 mmol) and l-methyl-imidazole-4-sulfonyl chloride (375 mg), there was obtained N 2 -[2R-isobutyl-3S-(l -methylimidazole-4-sulfonylamino)-4-tert- butyloxysuccinyl]-L-tert-leucine-N '-methylamide (953 mg, 98%) as a white foam.
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v), from N 2 -[2R-isobutyl-3S-amino-4-tcrt-butyloxysuccinyI]-L-tert-leucine-N'- methylamide (500 mg, 1.34 mmol) and thiophene-2-sulfonyi chloride (295 mg), there was obtained N 2 -[2R-isobutyl 3S-(thiophene-2-sulfonylamino-4-.ert-butyloxysuccinyl]-L-tert- leucine-N'-methylamide (567 mg, 82%) as a white foam; MS (ESI): 540 (M + NaX This (600 mg, 1.06 mmol), in a manner analogous to that described in Example 1 (vi), was converted to N 2 -[4-hydroxy 2R-isobutyl 3S-(thiophene-2-sul
  • the starting material was prepared as follows In a manner analogous to that described in Example 1 (v) , from N ? -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leucine-N'- methylamide (500 mg, 1.34 mmol and 3,5-dichlorobenzenesulfonyl chloride (500 mg), there was obtained N 2 -[2R-isobutyl-3S-(3,5-dichlorobenzene- 1 -sulfonylamino-4-tert-butyloxy- succinyl]-L-tert-leucine-N'-methylamide (629 mg. 81%) as a white foam.
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v), from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinylJ-L-tert-leucine-N'- methylamide (500 mg, 1.34 mmol) and 4-fluorobenzenesulfonyl chloride (393 mg, 2 mmol). there was obtained N 2 -[2R-isobutyl-3S-(4-fluorobenzene-l -sulfonylamino-4-tert-butyloxy- succinylj-L-tert-leucine-N 1 -methylamide (522 mg.
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v), from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-te 1-leucine-N'- methylamide (500 mg, 1.34 mmol) and 8-quinolinesulfonyl chloride (460 mg, 2.02 mmol), there was obtained N 2 -[2R-isobutyI-3S-(quinoline-8-sulfonylamino)-4-tert-butyloxysuccinyl]- L-tert-leucine-N 1 -methylamide (375 mg, 50%) as a white foam.
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v), from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leucine-N'- methylamide (500 mg, 1.34 mmol) and 2-cyanobenzenesulfonyl chloride (407 mg, 2.02 mmol), there was obtained N 2 -[2R-isobutyl-3S-(2-cyanobenzene-l-sulfonylamino)-4-tert- butyloxysuccinylj-L-tert-leucine-N' -methylamide (507 mg, 71 %) as a white foam; MS (ESI): 559 (M + Na ).
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) , from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leucine-N'- methylamide (500 mg, 1.34 mmol) and 3-pyridinesulfonyl chloride (360 mg), there was obtained N 2 -[2R-isobutyl-3S-(3-pyridinesulfonylamino)-4-tert-butyloxysuccinyl]-L-tert- leucine-N 1 -methylamide (500 mg, 73%) as a white foam; MS (ESI): 513 (M + H'), 535 (M + Na + ).
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) , from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leucine-N'- methylamide (500 mg, 1.34 mmol) and l-methyl-2-oxo-l,2,3,4-tetrahydroquinoline-6-sulfonyl chloride'" 0 " 0 (524 mg), there was obtained N 2 -[2R-isobutyl-3S-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinoline-6-sulfonylamino)-4-tert-butyloxysuccinyl]-L-tert-leucine-N '-methylamide (679 mg, 85%) as a white foam; MS (ESI): 617 (M + Na ).
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) except that after completion of the reaction the mixture was diluted with ethyl acetate, washed with 5% sodium bicarbonate and purified by flash chromatography on silica gel, from N 2 -f2R-isobutyl-3S-amino-4-tert-butyloxysuccinylJ-L-tert-leuc ⁇ ne-N'-methylamide (500 mg, 1.34 mmol) and dansyl chloride (473 mg).
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) , from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxysuccinyl]-L-tert-leuc ⁇ ne-N'- methylamide (500 mg.
  • the starting material was prepared as follows;
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) except that the reaction mixture was directly purified by flash chromatography on silica gel after evaporation of the solvents, from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxy- succinyl]-L-tert-leucine-N' -methylamide (500 mg, 1.34 mmol) and quinoline-6-sulfonyl chloride (Nol ⁇ :) (400 mg), there was obtained N 2 -[2R-isobutyl-3S-(quinoline 6-sulfonylamino)-4- tert-butyloxysuccinyl]-L-tert-leucine-N' -methylamide (510 mg, 67%) as a white foam.
  • the starting material was prepared as follows: In a manner analogous to that described in Example 1 (v) except that the reaction mixture was directly purified by flash chromatography on silica gel after evaporation of the solvents, from N 2 -[2R-isobutyl-3S-amino-4-tert-butyloxy- succinyl]-L-tert-leucine-N'-methylamide (500 mg, 1.34 mmol) and isoquinoline-5-sulfonyl chloride (500 mg), there was obtained N 2 -[2R-isobutyl-3S-(isoquinoline-5-sulfonylamino)-4- tert-butyloxysuccinyl]-L-tert-leucine-N'-methylamide (580 mg, 77%) as a white foam.
  • the starting material was prepared as follows:
  • N-ethyl-N ' -(3-dimethylaminopropyI)- carbodiimide hydrochloride 118 mg, 0.62 mmol.
  • the mixture was stirred at room temperature for eighteen hours.
  • the solvents were evaporated in vacuo.
  • the residue was partitioned between water and ethyl acetate.
  • the organic layer was washed with saturated sodium bicarbonate, brine and dried over MgSO 4 .
  • L_tert-leucine dimethylaminoethylamide was prepared by the reaction of L-tert-Ieucine with triphosgene to give 3-(S)-tert-butyloxazolidine-l,4-dione which was then treated with N,N-dimethylethylenediamine.
  • the starting material was prepared as follows: (i) To a solution of 3S-(quinoline-8-sulfonylamino)-2R-isobutylbutan-1.4-dioic acid-4-tert- butyl ester (370 mg, 0.85 mmol) in DMF (2.5 ml) at 0°C was added successively 1 - hydroxybenzotriazole (137 mg, 1.02 mmol), L-tert-leucine morpholinoethylamide (No,e) (227 mg, 0.93 mmol), DMAP (103 mg, 0.85 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)- carbodiimide hydrochloride (194 mg, 1.02 mmol).
  • L_t er -ie ⁇ cine mo ⁇ holinoethylamide was prepared by the reaction of L-tert-leucine with triphosgene to give 3-(S)-tert-butyloxazolidine-1.4-dione which was then treated with mo ⁇ holinoethylamine.
  • the starting material was prepared as follows: (i) In a manner analogous to that described in Example 1 (v). from N 2 -[2R-isobutyl-3S-amino- 4-tert-butyloxysuccinyl]-L-tert-leucine-N !
  • the starting material was prepared as follows:
  • the starting material was prepared as follows:
  • L-tert-leucine dimethylaminopropylamide was prepared by the reaction of L-tert-leucine with triphosgene to give 3-(S)-tert-butyloxazoIidine-l ,4-dione which was then treated with N.N-dimethylpropylenediamine.
  • the starting material was prepared as follows:
  • L_tert-le cinc dimethylamide was prepared by the reaction of L-tert-leucine with triphosgene to give 3-(S)-tert-butyloxazolidine-l ,4-dione which was then treated with a saturated solution of dimethylamine.
  • a gas dispersion tube (with N 2 -[2R-isobutyl-3S-amino-4-(N-oxyamino)succinyl]-L- tert-leucine-N' -methylamide linked via the oxygen atom of the N-oxyamino group to SASRIN resin (100 mg, ca 0.05 mmol) inside) was placed in a test tube and 25% pyridine in dichloromethane (3 ml, v/v) was added, followed by a sulfonyl chloride (0.3 mmol) in dichloromethane (1 ml). The mixture was agitated in a sonicated bath for 2 hours. The gas dispersion tube was drained and sparged with nitrogen.
  • the standard protocol for washing the resin consisted in adding dichloromethane (2x6 ml), methanol (2x6 ml) and dichloromethane (2x6 ml) into the gas dispersion tube, followed by agitation by sonication for 5 minutes, and finally draining by gravity and sparging with nitrogen.
  • dichloromethane (2x6 ml) methanol (2x6 ml) and dichloromethane (2x6 ml) into the gas dispersion tube, followed by agitation by sonication for 5 minutes, and finally draining by gravity and sparging with nitrogen.
  • To the resin in a gas dispersion tube (itself placed in a test tube) was added 5% trifluoroacetic acid in dichloromethane (5 ml). The mixture was agitated in a sonicated bath for 15 minutes. The resin was drained, sparged with nitrogen, washed with methanol (3 ml), drained and sparged with nitrogen.
  • the filtrates were concentrated
  • SASRIN resin 4-(Hydroxymethyl)-2-methoxyphenoxymethyl-copoly(styrene- 1 %divinylbenzene)-resin (SASRIN resin) (No,e) (2.6 g. ca 0.7 mmol/g loading, 1.8 mmol) was suspended in dry chloroform (100 ml) and gently agitated for 30 minutes under a blanket of argon. N- hydroxyphthalimide (2.71 g, 16.6 mmol) and triphenylphosphine (4.36 g, 16.6 mmol) were added. The mixture was stirred for 15 minutes.
  • p re p arec j rom chloromethyl-copoly(styrene-l%divinylbenzene)-resin (Merrifield resin, supplied by Bachem, loading: 0.8-1 mmol/g) according to Mergler M. Tanner R, Gosteli J, Grogg P, Tetrahedron Lett., 1988. 29, 4005
  • N 2 -f2R-isobutyl-3S-(9- fluorenylmethoxycarbonylamino)-4-hydroxysuccinyl]-L-tert-leucine-N'-methylamide (2.62 g, 4.88 mmol)
  • N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.6 g, 18.8 mmol)
  • DMAP 600 mg
  • Typical tablet formulations for a compound of this invention or a pharmaceutical ly-acceptable salt thereof are:
  • the tablets may be prepared by conventional procedures well known in the pharmaceutical art and may be film coated with typical coating materials such as hydroxypropylmethylcellulose.

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Abstract

Cette invention concerne des composés de formule (I) ou leurs sels pharmaceutiquement acceptables ou leurs esters hydrolysables in vivo qui sont utiles en tant qu'inhibiteurs de la production du facteur de nécrose tumorale (TNF) et/ou d'une ou plusieurs métalloprotéases matricielles; ainsi que des compositions contenant ces composés et des procédés de préparation associés. Dans la formule (I), R1 représente aryle, hétérocyclyle ou héteroaryle; R2 représente hydrogène, alkyle C¿1-8?, alcényle C2-6, alcynyle C2-6, cycloalkyle C3-8, hétéroaryle, hétérocyclyle, aryle alkyle C1-6, hétéroaryle alkyle C1-6, hétérocyclyle alkyle C1-6 ou cycloalkyle C3-8 alkyle C1-6; R?3¿ représente alkyle C¿1-6?, alcényle C2-6, aryle, alkyle C1-6, hétéroaryle alkyle C1-6 ou la chaîne latérale d'un acide aminé d'origine naturelle; R?4¿ représente hydrogène, alkyle C¿1-6?, cycloalkyle C3-8, cycloalcényle C4-8, aryle aryle C1-6, hétéroaryle alkyle C1-6 ou hétérocyclyle alkyle C1-6; R?5¿ représente hydrogène ou alkyle C¿1-6?; ou bien R?4 et R5¿ forment un anneau hétérocyclique avec l'atome d'azote auquel ils sont liés; n'importe quel groupe ou anneau étant facultativement substitué dans R1-R5.
PCT/GB1997/002222 1996-08-23 1997-08-19 Sulfonamides WO1998007742A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998039329A1 (fr) * 1997-03-04 1998-09-11 Monsanto Company Composes d'acide hydroxamique sulfonamide a cycle amidoaromatique
WO1999006340A2 (fr) * 1997-07-31 1999-02-11 The Procter & Gamble Company Inhibiteurs de metalloprotease acycliques
US6197770B1 (en) 1999-03-03 2001-03-06 The Procter & Gamble Co. Alkenyl- and alkynl-containing metalloprotease inhibitors
WO2001077092A1 (fr) * 2000-04-07 2001-10-18 Samsung Electronics Co., Ltd. Derive sulfonamide utilise en tant qu'inhibiteur de metalloproteinase matricielle
WO2010007027A1 (fr) * 2008-07-14 2010-01-21 Novartis Ag Inhibiteurs sélectifs de mmp-12 et mmp-13 à base d’acide hydroxamique
US7892825B2 (en) 2003-08-08 2011-02-22 Arriva Pharmaceuticals, Inc. Method of protein production in yeast
US7914771B2 (en) 2004-03-09 2011-03-29 Arriva Pharmaceuticals, Inc. Treatment of chronic obstructive pulmonary disease by low dose inhalation of protease inhibitor
JP2013047236A (ja) * 2005-04-15 2013-03-07 Univ Of North Carolina At Chapel Hill ニューロトロフィン類似体を用いた細胞生存促進法
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10532988B2 (en) 2009-11-12 2020-01-14 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993020047A1 (fr) * 1992-04-07 1993-10-14 British Bio-Technology Limited Inhibiteurs de la collagenase et de la cytokine a base d'acide hydroxamique
WO1994010900A1 (fr) * 1992-11-06 1994-05-26 Research Development Foundation Systeme d'imagerie oculaire
WO1996000214A1 (fr) * 1994-06-24 1996-01-04 Ciba-Geigy Ag Acides hydroxamiques substitues par arylsulfonamino utilises comme inhibiteurs de metalloproteinases matricielles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993020047A1 (fr) * 1992-04-07 1993-10-14 British Bio-Technology Limited Inhibiteurs de la collagenase et de la cytokine a base d'acide hydroxamique
WO1994010900A1 (fr) * 1992-11-06 1994-05-26 Research Development Foundation Systeme d'imagerie oculaire
WO1996000214A1 (fr) * 1994-06-24 1996-01-04 Ciba-Geigy Ag Acides hydroxamiques substitues par arylsulfonamino utilises comme inhibiteurs de metalloproteinases matricielles

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6451791B1 (en) 1997-03-04 2002-09-17 Monsanto Company Amidoaromatic ring sulfonamide hydroxamic acid compounds
WO1998039329A1 (fr) * 1997-03-04 1998-09-11 Monsanto Company Composes d'acide hydroxamique sulfonamide a cycle amidoaromatique
WO1999006340A2 (fr) * 1997-07-31 1999-02-11 The Procter & Gamble Company Inhibiteurs de metalloprotease acycliques
WO1999006340A3 (fr) * 1997-07-31 1999-09-30 Procter & Gamble Inhibiteurs de metalloprotease acycliques
US6218389B1 (en) 1997-07-31 2001-04-17 The Procter & Gamble Co. Acyclic metalloprotease inhibitors
US6197770B1 (en) 1999-03-03 2001-03-06 The Procter & Gamble Co. Alkenyl- and alkynl-containing metalloprotease inhibitors
WO2001077092A1 (fr) * 2000-04-07 2001-10-18 Samsung Electronics Co., Ltd. Derive sulfonamide utilise en tant qu'inhibiteur de metalloproteinase matricielle
US6548667B2 (en) 2000-04-07 2003-04-15 Samsung Electronics Co. Ltd. Sulfonamide derivative as a matrix metalloproteinase inhibitor
US7892825B2 (en) 2003-08-08 2011-02-22 Arriva Pharmaceuticals, Inc. Method of protein production in yeast
US7914771B2 (en) 2004-03-09 2011-03-29 Arriva Pharmaceuticals, Inc. Treatment of chronic obstructive pulmonary disease by low dose inhalation of protease inhibitor
US8916556B2 (en) 2005-04-15 2014-12-23 The University Of North Carolina At Chapel Hill Pharmaceutical formulations comprising neurotrophin mimetics
JP2013047236A (ja) * 2005-04-15 2013-03-07 Univ Of North Carolina At Chapel Hill ニューロトロフィン類似体を用いた細胞生存促進法
WO2010007027A1 (fr) * 2008-07-14 2010-01-21 Novartis Ag Inhibiteurs sélectifs de mmp-12 et mmp-13 à base d’acide hydroxamique
US8841291B2 (en) 2008-07-14 2014-09-23 Novartis Ag Selective hydroxamic acid based MMP-12 and MMP-13 inhibitors
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10532988B2 (en) 2009-11-12 2020-01-14 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US11225467B2 (en) 2009-11-12 2022-01-18 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies

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AP9701079A0 (en) 1997-10-31
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