WO2002083112A2 - Method for the treatment of polycystic kidney disease - Google Patents

Method for the treatment of polycystic kidney disease Download PDF

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WO2002083112A2
WO2002083112A2 PCT/US2002/010751 US0210751W WO02083112A2 WO 2002083112 A2 WO2002083112 A2 WO 2002083112A2 US 0210751 W US0210751 W US 0210751W WO 02083112 A2 WO02083112 A2 WO 02083112A2
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phenyl
sulfonyl
ynyloxy
hydroxy
amino
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PCT/US2002/010751
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French (fr)
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WO2002083112A3 (en
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Philip Frost
Jeremy Ian Levin
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Wyeth Holdings Corporation
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Priority to BR0208784-7A priority Critical patent/BR0208784A/en
Priority to US10/473,857 priority patent/US7488754B2/en
Priority to AU2002256095A priority patent/AU2002256095A1/en
Publication of WO2002083112A2 publication Critical patent/WO2002083112A2/en
Publication of WO2002083112A3 publication Critical patent/WO2002083112A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

  • the present invention relates to a method of treating polycystic kidney disease.
  • TACE tumor necrosis factors-alpha converting enzyme
  • ARPKD Autosomal recessive polycystic kidney disease
  • EGFR epidermal growth factor receptor
  • TGF- ⁇ transforming growth factor-
  • the present invention provides a method for treating, inhibiting the progression of, or eradicating polycystic kidney disease of in a patient in need thereof which comprises providing to said patient an effective amount of a TACE inhibitor compound alone or in combination with an effective amount of an EGF receptor kinase inhibitor.
  • the present invention provides a method for treating, inhibiting the progression of, or eradicating polycystic kidney disease of in a mammal in need thereof which comprises providing an effective amount of a TACE inhibitor compound.
  • TACE inhibitor compounds are described in WO 00/44730, WO 00/44749, WO 00/44709, WO 00/44711, WO 00/44710, WO 00/44716, WO 00/44740, WO 00/44713, and WO 00/44723 each of which is hereby incorporated by reference thereto.
  • Especially preferred TACE inhibitor compounds include those of formula I:
  • X is SO 2 or -P(O)-R 10 ;
  • Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;
  • Z is O, NH, CH 2 or S
  • R-l is hydrogen, aryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms;
  • R2 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 3-6 carbon atoms, C4-C8 cycloheteroalkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms; or Ri and R 2 , together with the atom to which they are attached, may form a ring wherein R and R 2 represent a divalent moiety of the formula:
  • Q a carbon-carbon single or double bond, O, S, SO, SO 2 , -N-Rn, or -CONR 14 ;
  • m 1-3;
  • r 1 or 2, with the proviso that when Q is a bond, r is equal to 2;
  • R 3 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, C4-C8 cycloheteroalkyl, aralkyl, or heteroaralkyl; or R 1 and R , together with the atoms to which they are attached, may form a 5 to
  • Q and m are as defined above;
  • A is aryl or heteroaryl;
  • s is 0-3;
  • u is 1-4;
  • R 4 and R 5 are each, independently, hydrogen or alkyl of 1-6 carbon atoms, -CN, or -CCH;
  • R 6 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -
  • R 8 and R 9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, or -C4-Cs-cycloheteroalkyl; Rio is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl;
  • Rn is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, -S(O) n R 8 , -COOR 8 , -CONR 8 R 9 , -SO 2 NR 8 R 9 or -COR 8 ;
  • R ⁇ 2 and R 13 are independently selected from H, -OR 8 , -NR 8 R 9 , alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, -COOR 8 ; -CONR 8 R 9 ; or
  • R 12 and R 13 together form a -C3-C6-cycloalkyl of 3-6 carbon atoms or a - C ⁇ -C ⁇ -cycloheteroalkyl ring; or R 12 and R 13, together with the carbon to which they are attached, form a carbonyl group; with the proviso that R 10 and R 12 or Rn and R 12 may form a cycloheteroalkyl ring when they are attached to adjacent atoms;
  • R 14 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; and n is 0-2; or a pharmaceutically acceptable salt thereof.
  • Heteroaryl as used throughout, is a 5-10 membered mono- or bicyclic ring having from 1-3 heteroatoms selected from N, NR 1 , S and O. Heteroaryl is preferably
  • K is O, S or -NR14 and R14 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms.
  • Preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole.
  • Heteroaryl groups may optionally be mono or di substituted.
  • C4-C8 cycloheteroalkyl refers to a 5 to 9 membered saturated or unsaturated mono or bi-cyclic ring having 1 or 2 heteroatoms selected from N, NR 14 , S or O.
  • Heterocycloalkyl rings of the present invention are preferably selected from;
  • K is NR ⁇ , O or S and R ⁇ 4 is a bond, hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms.
  • Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. Cycloheteroalkyl groups of the present invention may optionally be mono- or di- substituted.
  • Aryl, as used herein refers to a phenyl or napthyl rings which may, optionally be mono-, di- or tri-substituted.
  • Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chain as well as branched moieties.
  • Alkyl, alkenyl, alkynyl, and cycloalkyl groups may be unsubstituted
  • Lower alkyl moieties contain from 1 to 6 carbon atoms.
  • Aralkyl as used herein refers to a substituted alkyl group, -alkyl-aryl, wherein alkyl is lower alkyl and preferably from 1 to 3 carbon atoms, and aryl is as previously defined.
  • Heteroaralkyl as used herein refers to a substituted alkyl group, alkyl-heteroaryl wherein alkyl is lower alkyl and preferably from 1 to 3 carbon atoms, and heteroaryl is as previously defined.
  • Halogen means bromine, chlorine, fluorine, and iodine.
  • Suitable substituents of aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, alkenyl, alkynyl, and cycloalkyl include, but are not limited to hydrogen, halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms; alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -OR 8l -[[O(CH 2 ) p ] q ]-OCH3,
  • NR 8 C(O)CH CHaryl, -NR 8 C(O)(CH 2 ) n NR 8 R 9 ,
  • R 8 and R 18 may be further substituted with halogen, C
  • substituents R ⁇ in this case
  • TACE inhibitor compounds of the present invention include compounds of formula II, III and IV:
  • R 6 is as defined above with CH 3 and CH 2 OH being preferred;
  • R 7 is H or alkyl with H or methyl being preferred; and
  • R 15 is alkyl, with isopropyl and CH(CH 3 )OH being preferred.
  • R 6 is defined as above with methyl and CH 2 OH being preferred; R 16 and R 7 are alkyl preferably methyl.
  • R 6 is as defined above with methyi being preferred.
  • TACE inhibitor compounds which are especially useful in the present invention are 4-(4-but-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; (3S)-N-hydroxy-4-( ⁇ 4-[(4-hydroxy-2-butynyl)oxy]phenyl ⁇ sulfonyl)-2,2- dimethyl-3-thiomorpholinecarboxamide; (2R)-N-hydroxy-2-[( ⁇ 4-[(4-hydroxy-2- butynyl)oxy]phenyl ⁇ sulfonyl)(methyl)amino]-3-methylbutanamide; and (2R,3S)-2-( ⁇ [4-(2- butynyloxy)phenyl]sulfonyl ⁇ amino)-N,3-dihydroxybutanamide.
  • the present invention also encompasses a method for the treatment of PKD by using a TACE inhibitors compound in combination with an EGF receptor kinase inhibitor.
  • Preferred EGF receptor kinase inhibitor compounds are described in US Patent
  • TACE inhibitor compounds of the present invention are described in WO 00/44730, WO 00/44749, WO 00/44709, WO 00/44711 , WO 00/44710, WO
  • WO 00/44716 WO 00/44740, WO 00/44713, and WO 00/44723.
  • the following compounds are preferred compounds in the present invention: 4-(4-substituted- benzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-hydroxamic acids such as 1-Acetyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-
  • TACE inhibitor compounds include acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids such as
  • TACE inhibitor compounds include aryl sulfonamide hydroxamic acid MMP/TACE inhibitors in which the sulfonyl aryl group is para-substituted with a substituted butynyl moiety or a propargylic ether, amine or sulfide such as
  • Methyl 1 [2-( ⁇ 2-[ ⁇ [4-(2-butynyloxy)phenyl]sulfonyl ⁇ (methyl)]amino]-3-(hydroxyamino)-1 , 1 - dimethyl-3-oxopropyl ⁇ sulfanyl)ethyl]-2-pyrrolidine-carboxylate;
  • TACE inhibitor compounds of the present invention include acetylenic ⁇ - sulfonamido and phosphinic acid amide hydroxamic acids such as
  • TACE inhibitor compounds include acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acids such as
  • Still another preferred group of TACE inhibitor compounds of the present invention includes acetylenic aryl sulfonamide thiols such as 4-But-2-ynyloxy-N-((1 R)-2-mercapto-1-methyl-ethyl)-N-methylbenzene-sulfonamide; (2R)-2- ⁇ [4-(2-Butynyloxy)phenyl]sulfonyl ⁇ [2-(4-morpholinyl)ethyl]amino ⁇ -3- sulfanylpropanamide; and
  • TACE inhibitor compounds of the present invention includes acetylenic aryl and heteroaryl sulfonamide and phosphinic acid amide hydroxamic acids such as (3-[methyl-(4-but-2-ynyloxy-benzenesulfonyl-amino]-N- hydroxy-2,6-dimethoxy-isonicotinamide and 3-(4-But-2-ynyloxy-benzenesulfonylamino)- N-hydroxy-2,6-dimethoxy-isonicotinarnide.
  • TACE inhibitor compounds of the present invention include alkynyl containing hydroxamic acid compounds such as 2-(4-But-2-ynyloxy-benzenesulfonyl)-N-hydroxy-2-methyl-3-pyridin-3-yl- propionamide;
  • TACE inhibitor compounds of the present invention include carboxamides and hydroxamides such as
  • an effective amount of the EGF receptor kinase inhibitor compound will vary with inter alia the individual patient and the severity of the disease, however generally it will be at least about 5 mg/kg. A preferred range is about 10 to 50 mg/kg.
  • an effective amount of the TACE inhibitor compound will vary with a variety of factors including the individual patient and the severity of the disease. Typically the effective amount will be at least about 5 mg/kg. A preferred range is about 20 to 40 mg/kg.
  • the dosing schedule of the drug(s) may be from once to several times per day or may be less frequent. Preferably the dosing will be less frequent, for example dosing every other day, every third day or once a week.
  • TACE inhibitor TACE inhibitor compound
  • EGF receptor kinase inhibitor EGF receptor kinase inhibitor
  • EGF receptor kinase inhibitor compound include all optical isomers and diastereomers as well as pharmaceutically acceptable salts.
  • salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety.
  • Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains an acidic moiety.
  • the compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomericaliy pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. It is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other.
  • This model arose from a spontaneous mutation in a colony of BALB/C mice.
  • Affected animals have many similarities to the human disease including collecting tubule (CT) cysts and biliary ectasia and fibrosis.
  • CT tubule
  • the kidney disease has a consistent and severe phenotype.
  • Mice homozygous for the bpk mutation have microscopic evidence of cyst formation at birth.
  • Proximal tubule (PT) cysts are present at birth, which are gradually replaced by CT cysts as the disease progresses. Cyst expansion and kidney fibrosis result in death due to renal failure at 24-28 days.
  • Heterozygotes show no phenotypic abnormalities and are identified by their ability to breed affected offspring.
  • Unaffected (noncystic) littermates of cystic bpk mice are either wild-type or heterozygous at the bpk locus.
  • TGF- ⁇ expression in bpk mice are either wild-type or hetero
  • Kidneys were obtained from cystic bpk mice and noncystic littermates at postnatal days 7, 14 and 21. Immunohistology was performed formaldehyde-fixed specimens embedded in plastic [See Sweeney WE et al.: Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor, Kidney Int. 57:33-40, 2000.] Primary antibody was a polyclonal anti-TGF- ⁇ (Chemicon, Temecula, CA) directed against recombinant 6 kD human TGF- ⁇ and reactive to mouse. Tubular localization of antibody staining was assessed by staining of serial sections with segment-specific biotinylated lectins. Protein was isolated from whole kidneys by homogenization in RIPA buffer
  • Cystic bpk mice and phenotypically normal littermates were injected with a dose of 100 mg/kg/dose of 1 -acetyl-4-(4-but-2-ynyloxy-benzenesu!fonyl)-2,3,4,5-tetrahydro- 1 h-[1 ,4]benzodiazepine-3-carboxylic acid hydroxyamide given intraperitoneally once daily, in a vehicle containing 0.5% methocellulose (Fluka Biochemica, Ronkonkoma, NY) and 2% Tween 80 (JT Baker, Phillipsburg, NJ), beginning at postnatal day 7. Age- matched untreated cystic bpk mice and their noncystic littermates served as controls.
  • mice were sacrificed. Blood was obtained by orbital puncture prior to sacrifice. Kidney weight and body weight for treated and untreated cystic and noncystic mice were measured at sacrifice. Blood urea nitrogen (BUN) was assessed using a colorimetric assay. Serum creatinine was assessed using standard techniques in the hospital laboratory. Differences in clinical and laboratory parameters between treated and untreated cystic and noncystic mice were analyzed by two-tailed Student's t-test.
  • BUN Blood urea nitrogen
  • Kidneys were fixed in 4% paraformaldehyde and embedded in plastic. Segment- specific localization of cysts was assessed using lectins specific to proximal tubule (Lotus tetragonolobus, LTA), and collecting tubule (Dolichos biflorus agglutinin, DBA). Serial LTA and DBA stained sections were examined by light microscopy and assessed for severity of cystic dilatations in PTs and CTs, expressed on a scale of 0 to 5 using a modified cystic index:
  • TGF- ⁇ expression in 1 -acetyI-4-(4-but-2-ynyloxy- benzenesulfonyl)-2,3,4,5-tetrahydro-1 h-[1 ,4]benzodiazepine-3-carboxylic acid hydroxyamide-treated and untreated cystic and noncystic animals was assessed by Western analysis as described in Example 1.
  • A 1-acetyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid hydroxyamide ** p ⁇ 0.01 cystic treated compared to cystic untreated Table 3.
  • A 1-acetyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[1 ,4]benzodiazepine-3-carboxylic acid hydroxyamide
  • B 1-Be ⁇ zyI-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidi ⁇ e-4-carboxylic acid hydroxamide

Abstract

The present invention provides a method for treating, inhibiting the progression of, or eradicating polycystic kidney disease of in a patient in need thereof which comprises providing to said patient an effective amount of a TACE inhibitor compound alone or in combination with an effective amount of an EGF receptor kinase inhibitor.

Description

METHOD FOR THE TREATMENT OF POLYCYSTIC KIDNEY DISEASE FIELD OF INVENTION
The present invention relates to a method of treating polycystic kidney disease.
More particularly it involves the use of tumor necrosis factors-alpha converting enzyme (TACE) inhibitor, alone or in combination with other agent(s) such as EGF receptor kinase inhibitor, to treat the disease.
BACKGROUND
Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disorder that usually presents in the newborn period with massive kidney enlargement (due to rapidly expanding cysts) and hepatic fibrosis. ARPKD occurs in approximately 1 :10,000 to 1:40,000 births and produces significant morbidity and mortality. Data from experimental models of both recessive and dominant forms of PKD have identified three key pathophysiologic processes in cyst formation and enlargement: increased cell proliferation, increased fluid secretion and altered matrix biology. (Marcia NS, Sweeny WE Armer ED: New insights into the molecular pathophyscology of polycystic kidney disease, Kidney Int., 55: 1187-1197, 1999). A growing body of evidence has established the central role of the epidermal growth factor receptor (EGFR) in the pathogenesis of cell proliferation in PKD.
Published reports have also suggested that transforming growth factor- (TGF-α) a ligand of the EGFR, is abnormally expressed in PKD. Mice transgenic for TGF-α develop renal cysts. TGF-α is present in mitogenic quantities in cyst fluid from bpk mice (a murine model of ARPKD) and immunoprecipitation of TGF-α reduces this mitogenic effect (Abstract; J Am Soc Nephrol 7: 1610, 1996).
US Patent 6,002,008 discloses that certain EGF receptor kinase inhibitors are useful in the treatment of PKD; however no disclosure of the present invention is disclosed therein.
There is currently no completely effective therapy for polycystic kidney disease. A search for therapeutic agents useful for the treatment of PKD is ongoing. SUMMARY OF INVENTION
The present invention provides a method for treating, inhibiting the progression of, or eradicating polycystic kidney disease of in a patient in need thereof which comprises providing to said patient an effective amount of a TACE inhibitor compound alone or in combination with an effective amount of an EGF receptor kinase inhibitor.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a method for treating, inhibiting the progression of, or eradicating polycystic kidney disease of in a mammal in need thereof which comprises providing an effective amount of a TACE inhibitor compound.
Preferred TACE inhibitor compounds are described in WO 00/44730, WO 00/44749, WO 00/44709, WO 00/44711, WO 00/44710, WO 00/44716, WO 00/44740, WO 00/44713, and WO 00/44723 each of which is hereby incorporated by reference thereto.
Especially preferred TACE inhibitor compounds include those of formula I:
Figure imgf000003_0001
I wherein:
X is SO2 or -P(O)-R10;
Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;
Z is O, NH, CH2 or S;
R-l is hydrogen, aryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms; R2 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 3-6 carbon atoms, C4-C8 cycloheteroalkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms; or Ri and R2, together with the atom to which they are attached, may form a ring wherein R and R2 represent a divalent moiety of the formula:
Figure imgf000004_0001
wherein
Q = a carbon-carbon single or double bond, O, S, SO, SO2, -N-Rn, or -CONR14; m = 1-3; r = 1 or 2, with the proviso that when Q is a bond, r is equal to 2; R3 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, C4-C8 cycloheteroalkyl, aralkyl, or heteroaralkyl; or R1 and R , together with the atoms to which they are attached, may form a 5 to
8 membered ring wherein R^ and R3 represent divalent moieties of the formulae:
Figure imgf000004_0002
wherein Q and m are as defined above; A is aryl or heteroaryl; s is 0-3; u is 1-4;
R4 and R5 are each, independently, hydrogen or alkyl of 1-6 carbon atoms, -CN, or -CCH;
R6 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -
Cδ-Cδ-cycloheteroalkyl; R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, or -C4-Cs-cycloheteroalkyl; Rio is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl;
Rn is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, -S(O)nR8, -COOR8, -CONR8R9, -SO2NR8R9 or -COR8; Rι2and R13are independently selected from H, -OR8, -NR8R9, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, -COOR8; -CONR8R9; or
R12and R13 together form a -C3-C6-cycloalkyl of 3-6 carbon atoms or a - Cδ-Cδ-cycloheteroalkyl ring; or R12 and R13, together with the carbon to which they are attached, form a carbonyl group; with the proviso that R10 and R12 or Rn and R12 may form a cycloheteroalkyl ring when they are attached to adjacent atoms;
R14 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; and n is 0-2; or a pharmaceutically acceptable salt thereof. Heteroaryl, as used throughout, is a 5-10 membered mono- or bicyclic ring having from 1-3 heteroatoms selected from N, NR1 , S and O. Heteroaryl is preferably
Figure imgf000006_0001
wherein K is O, S or -NR14 and R14 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms. Preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole. Heteroaryl groups may optionally be mono or di substituted.
C4-C8 cycloheteroalkyl as used herein refers to a 5 to 9 membered saturated or unsaturated mono or bi-cyclic ring having 1 or 2 heteroatoms selected from N, NR14, S or O. Heterocycloalkyl rings of the present invention are preferably selected from;
Figure imgf000006_0002
wherein K is NRι , O or S and Rι4 is a bond, hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms.
Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. Cycloheteroalkyl groups of the present invention may optionally be mono- or di- substituted. Aryl, as used herein refers to a phenyl or napthyl rings which may, optionally be mono-, di- or tri-substituted.
Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chain as well as branched moieties. Alkyl, alkenyl, alkynyl, and cycloalkyl groups may be unsubstituted
(carbons bonded to hydrogen, or other carbons in the chain or ring) or may be mono- or poly-substituted. Lower alkyl moieties contain from 1 to 6 carbon atoms.
Aralkyl as used herein refers to a substituted alkyl group, -alkyl-aryl, wherein alkyl is lower alkyl and preferably from 1 to 3 carbon atoms, and aryl is as previously defined. Heteroaralkyl as used herein refers to a substituted alkyl group, alkyl-heteroaryl wherein alkyl is lower alkyl and preferably from 1 to 3 carbon atoms, and heteroaryl is as previously defined.
Halogen means bromine, chlorine, fluorine, and iodine.
Suitable substituents of aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, alkenyl, alkynyl, and cycloalkyl include, but are not limited to hydrogen, halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms; alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -OR8l -[[O(CH2)p]q]-OCH3,
CN, -COR8) perfluoroalkyl of 1-4 carbon atoms, -O-perfluoroalkyl of 1-4 carbon atoms,-CONR8Rg, -S(O)nR8, -S(O)nRι8C(O)OR8, -S(0)nR18OR9, -S(O)nRιsNR8R9, -S(O)nRι8NR8R9COOR8, -S(O)nR18NR8COR9,-
OPO(OR8)OR9, -PO(OR8)R9, -OC(O)NR8R9, -C(O)NR8OR9l-
C(O)R18NR8R9, -COOR8, -SO3H, -NR8R9, -N[(CH2)2]2NR8, -NR8COR9, -
NR8C(O)CH=CHaryl, -NR8C(O)(CH2)nNR8R9,
-NR8C(O)CH2NHCH2aryl, NR8C(O)R18, -NR8COOR9, -SO2NR8R9, -NO2, -N(R8)SO2R9, -NR8CONR8R9, -NR8C(=NR9)NR8R9,
-NR8C(=NR9)N(SO2R8)R9, NR8C(=NR9)N(C=OR8)R9 -tetrazol-5-yl, -
SO2NHCN, -SO2NHCONR8R9, -(OR18)NR8S(O)R9, -(OR18)NR8C(O)R9, - (OR18)NR8C(O)NR8R9, -(OR18)NR8COOR9, -(OR18)NR8R9, phenyl, heteroaryl, or -C -C8-cycloheteroalkyl; wherein -NR8R9 may form a heterocyclic group as previously defined, such as pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolid/ne, pyrazolidine, piperazine, and azetidine ring; p is 1 or 2, q is 1 through 3 and Ri8 is alkyl of 1-20 carbon atoms.
In some preferred embodiments of the present invention R8 and R18 may be further substituted with halogen, C|-C3 alkyl, Ci-C3 alkoxy and OH, and NO2. When a moiety contains more than substituent with the same designation (i.e., phenyl tri-substituted with Ri) each of those substituents R^ in this case) may be the same or different.
Especially preferred TACE inhibitor compounds of the present invention include compounds of formula II, III and IV:
Figure imgf000008_0001
wherein
R6 is as defined above with CH3 and CH2OH being preferred; R7 is H or alkyl with H or methyl being preferred; and R15 is alkyl, with isopropyl and CH(CH3)OH being preferred.
Figure imgf000008_0002
(III) wherein R6 is defined as above with methyl and CH2OH being preferred; R16 and R 7 are alkyl preferably methyl.
Figure imgf000009_0001
(IV)
wherein R6 is as defined above with methyi being preferred.
TACE inhibitor compounds which are especially useful in the present invention are 4-(4-but-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide; (3S)-N-hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2- dimethyl-3-thiomorpholinecarboxamide; (2R)-N-hydroxy-2-[({4-[(4-hydroxy-2- butynyl)oxy]phenyl}sulfonyl)(methyl)amino]-3-methylbutanamide; and (2R,3S)-2-({[4-(2- butynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxybutanamide.
The present invention also encompasses a method for the treatment of PKD by using a TACE inhibitors compound in combination with an EGF receptor kinase inhibitor. Preferred EGF receptor kinase inhibitor compounds are described in US Patent
6,002,008 which is hereby incorporated by reference thereto. The compound 4- dimethylamineo-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy- quinolin-6-yl]-amide is especially preferred.
Preferred TACE inhibitor compounds of the present invention are described in WO 00/44730, WO 00/44749, WO 00/44709, WO 00/44711 , WO 00/44710, WO
00/44716, WO 00/44740, WO 00/44713, and WO 00/44723. For example the following compounds are preferred compounds in the present invention: 4-(4-substituted- benzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-hydroxamic acids such as 1-Acetyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-
3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxy-benzene-sulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-1H- [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(2-furanylcarbonyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 4-(4-But-2-ynyloxybenzene-sulfonyl)-1 -(methanesulfonyl)-2,3,4,5-tetrahydro-1 H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-methoxyacetyl-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H- [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(4-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
1-Benzoyl-4-(4-t4-methoxybut-2-ynyloxy]benzenesulfonyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 4-(4-[4-Methoxybut-2-ynyloxy] benzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5- tetrahydro-1 H-[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-Pent-2-ynyloxy- benzene-sulfony!)-1-(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-[4-Hydroxybut-2-ynyloxy]benzenesulfonyl)-1-(4-pyridinylcarbonyl)-2,3,4,5- tetrahydro-1H-[1,4]benzo-diazepine-3-carboxylic acid, hydroxyamide;
4-(4-[4-Methoxybut-2-ynyloxy]-benzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro-
1 H-[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
1-(Benzoyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 1 -Propionyl-4-(4-[4-hydroxybut-2-ynyloxy]benzenesulfonyl)-2,3,4,5-tetrahydro-1 H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 1-(N,N-Dimethylaminoacetyl)-4-(4-[4-methoxybut-2-ynyloxy]benzenesulfonyl)-2,3,4,5- tetrahydro-1 H-[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
1-(Acetylaminoacetyl)-4-(4-but-2-ynyloxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 1 -(Ethoxyacetyl)-4-(4-[4-methoxybut-2-ynyloxy]benzenesulfonyl)-2,3,4,5-tetrahydro-1 H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
1-(Ethoxyacetyl)-4-(4-[4-ethoxybut-2-ynyloxy]benzenesulfonyl)-2,3,4,5-tetrahydro-1H- [1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
1-(Acetylaminoacetyl)-4-(4-[4-methoxybut-2-ynyloxy]benzenesulfonyl)-2,3,4,5-tetrahydro-
1 H-[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
1-(Cyclopropylcarbonyl)-4-(4-[4-methxybut-2-ynyloxy]benzenesulfonyl )-2,3,4,5- tetrahydro-1 H-[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 1-(Cyclobutylcarbonyl)-4-(4-but-2-ynyloxybenzeneulfonyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(propionyl)-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-[4-Methoxybut-2-ynyloxy]benzenesulfonyl)-1-(3-methyl-2-thienylcarbonyl)-2,3,4,5- tetrahydro-1 H-[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(3-methoxypropionyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(2-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-
1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(3-furanylcarbonyl)-2,3,4,5-tetrahydro-1H- [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(phenoxyacetyl)-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 4-(4-But-2-ynyloxybenzene-sulfonyl)-1-[2-(1-pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5- tetrahydro-1H-[1 ,4]-benzodiazepene-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(5-chloro-2-thienylcarbonyl)-2,3,4,5-tetrahydro-
1 H-[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(5-chloro-2-furanylcarbonyl)-2,3,4,5-tetrahydro-
1 H-[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-[4-Methoxybut-2-ynyloxy]-benzenesulfonyl)-1-propionyl-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-[4-Methoxybut-2-ynyloxy]benzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5-tetrahydro- 1 H-[1 ,4]benzo- diazepine-3-carboxylic acid, hydroxyamide;
1-(Aminoacetyl)-4-(4-but-2-ynyloxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
1-Hexanoyl-4-(4-[4-methoxybut-2-ynyloxy]benzenesulfonyl)-2,3,4,5-tetrahydro-1H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)-1 -(N,N-Dimethylaminoacetyl)-2,3,4,5-tetrahydro-1 H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzene-sulfonyl)-1-(cyclopropylcarbonyl)-2,3,4,5-tetrahydro-1H-
[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide;
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(cycloyhexylcarbonyl)-2,3,4,5-tetrahydro-1H-[1,4]- benzodiazepine-3-carboxylic acid, hydroxyamide;
1-Methoxyacetyl-4-(4-[4-methoxybut-2-ynyloxy]benzenesulfonyl)-7-methyl-2,3,4,5- tetrahydro-1 H-[1 ,4]-benzodiazepine-3-carboxylic acid, hydroxyamide;
1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro-1H-[1,4]- benzodiazepine-3-carboxylic acid, hydroxyamide; 1 -(Benzoyl)-4-(4-but-2-ynyloxybenzenesuIfonyl)-8-chIoro-2,3,4,5-tetrahydro-1 H-
[1 ,4]benzodiazepine-3-carboxylic acid, hydroxyamide; and
1-Acetyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-7-fluoro-N-hydroxy-2,3,4,5-tetrahydro-1H-
1,4-benzodiazepine-3-carboxamide.
Other preferred TACE inhibitor compounds include acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids such as
4-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-1,3-dimethyl-1H-pyrazolo[3,4- b]pyridine-5-carboxylic acid hydroxyamide; 4-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-3-methyl-isoxazolo[5,4-b]pyridine-5- carboxylic acid hydroxyamide;
4-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-8-methoxy-quinoline-3-carboxylic acid hydroxyamide; 4-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-3-methyl-isothiazolo[5,4-b]pyridine-
5-carboxylic acid hydroxyamide; and
8-Bromo-4-[{[4-(2-butynyloxy)phenyl]sulfonyl} (methyl) amino]-N-hydroxy-3- quinolinecarboxamide.
Still other preferred TACE inhibitor compounds include aryl sulfonamide hydroxamic acid MMP/TACE inhibitors in which the sulfonyl aryl group is para-substituted with a substituted butynyl moiety or a propargylic ether, amine or sulfide such as
2-[(4-But-2-ynyloxy-benzenesu!fonyl)-methyl-amino]-N-hydroxy-3-methyl-butyramide;
2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-acetamide
N-Hydroxy~2-[(4-methoxy-benzenesulfonyl)-methyl-amino]-3-methyl-butyramide; 2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hydroxy-acetamide hydrochloride;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-acetamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-methyl-butyramide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-propionamide; 2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hydroxy-propionamide hydrochloride;
2-(4-But-2-ynyloxy-benzenesulfony!amino)-N-hydroxy-2-methyl-propionamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-2,2-dimethy!-thiomorpholine-3-carboxylic acid hydroxyamide; 4-(4-Hept-2-ynyloxy-benzenesu!fonyi)-2,2-dimethyi-thiomorpholine-3-carboxylic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid hydroxyamide;
4-Benzoyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-[1,4]diazepane-2-carboxylic acid hydroxyamide;
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-methyl-piperazine-2-carboxylic acid hydroxyamide hydrochloride; 4-[4-(4-Hydroxy-but-2-ynyloxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholine-3- carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1 -carboxylic acid tert-butyl ester; 2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-2-methylpropionamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-5-guanidino-pentanoic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-5-(4-methylbenzenesulfonyl-guanidino)- pentanoic acid hydroxyamide;
3-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-succinamic acid cyclohexyl ester; 2-(4-But-2-ynyloxy-benzenesulfonylamino)-3-cyclohexyl-N-hydroxy-propionamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-2-cycIohexyl-N-hydroxy-acetamide
3-tert-Butylsulfanyl-2-(4-but-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-propionamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-(4-methoxy-benzylsulfanyl)- propionamide; ,2-(4-But-2-ynyloxy-benzenesulfonylamino)-N1 -hydroxy-succinamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-3-cyclohexyl-N-hydroxy-propionamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-2-cyclohexyl-N-hydroxy-acetamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-4-methyl-pentanoic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-4-methylsulfanyl-butyramide; 2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-phenyl-propionamide;
1 -(4-But-2-ynyloxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-(1H-indol-3-yl)-propionamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-(4-hydroxy-phenyl)- propionamide; 2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-methyl-butyramide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-4-methyl-pentanoic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-6-(2-chloro-benzylamino)-hexanoic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-hexanoic acid hydroxyamide; 2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-2-phenyl-acetamide;
3-Benzyloxy-2-(4-but-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-propionamide;
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-acetamide; (2R,3S)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-methyl pentanamide;
(2R)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3,3-dimethyl-butanamide;
(2S)-2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-propionamide;
2-[(4-But-2-ynyloxy-benzenesuIfonyl)-ethyl-amino]-N-hydroxy-3-methyl-butyramide; 2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-N-hydroxy-3- methylbutanamide;
2-[(4-But-2-ynyloxy-benzenesulfonyl)-propyl-amino]-N-hydroxy-3-methyl-butyramide;
2-[(4-But-2-ynyloxy-benzenesulfonyl)-(3-phenyl-propyl)-amino]-N-hydroxy-3-methyl- butyramide;
2-[(4-But-2-ynyloxy-benzenesulfonyl)-cycIopropylmethyl-amino]-N-hydroxy-3-methyl- butyramide;
2-[(4-But-2-ynyloxy-benzenesuIfonyl)-isobutyl-amino]-N-hydroxy-3-methyl-butyramide;
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hydroxy-3-methyl- butyramide;
2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-2-cyclohexyl-N-hydroxy-acetamide; 2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-2-cyclohexyl-N-hydroxy acetamide;
2-{(4-But-2-ynyloxy-benzenesuIfonyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amino}-2- cyclohexyl-N-hydroxy-acetamide;
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(diethylamino)propyl]amino}-N-hydroxy-3- methylbutanamide;
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(4-morpholinyl)propyl]amino}-N-hydroxy-3- methylbutanamide;
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(4-methyl-1-piperazinyl)propyl]-amino}-N- hydroxy-3-methylbutanamide hydrochloride; 2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(diethylamino)butyl]amino}-N-hydroxy-3- methylbutanamide;
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)butyl]amino}-N-hydroxy-3- methylbutanamide;
2-[[[4-(2-Butynyloxy)phenyl]sulfonyl][2-(4-morpholinyl)ethyl]amino]-N-hydroxy-3- methylbutanamide;
2-[{[4-(But-2-ynyloxy)phenyl]sulfonyl}(2-morpholin-4-yIethyl)amino]-N-hydroxyacetamide hydrochloride; 2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)-2-butynyl]amino}-N- hydroxy-3-methylbutanamide;
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(diethylamino)-2-butynyl]amino}-N-hydroxy-3- methylbutanamide; 2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(methylamino)-2-butynyl]amino}-N-hydroxy-3- methylbutanamide;
((2R)-{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino)[(4-diethylamino)-cyclohexyl]-N- hydroxyethamide;
(2R)-{[4-(2-Butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-2-(4-hydroxycyclo- hexyl)ethanamide;
(2R)-{[4-(2~Butynyloxy)phenyl]sulfonyl}(methyl)amino)-N-hydroxy-2-(4- hydroxycyclohexyl)-ethanamide;
2-[(6-But-2-ynyloxy-pyridine-3-sulfonyl)-methyl-amino]-N-hydroxy-acetamide;
2-[[(4-{[3-(4-Chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]-N- hydroxyacetamide;
N-Hydroxy-2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetamide;
2-[(4-But-2-ynylthiophenylsulfonyl)methylamino]-N-hydroxyacetamide;
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)-2-yl}[4-(4-methyl-1- piperazinyl)-2-butynyl]amino}-N-hydroxypropanamide; 1-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-sulfonyl}(methyl)-amino]-N- hydroxycyclohexanecarboxamide;
1-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(3-pyridinylmethyl)amino]N-hydroxy- cyclohexanecarboxamide;
1-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxycyclohexane-carboxamide; 1-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxycyclopentane-carboxamide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-[(2-(4- morpholinylethyl)sulfanyl]-butanamide hydrochloride;
2-({[4-(2-Butynyloxy)phenyl] sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-{[2-(4- methyl-1 -ethyl-1 -piperazinyl)ethyl]sulfanyl}butanamide; 2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-{[2-
(diethylamino)ethyl]sulfanyl}butanamide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-{[2-(1- pyrrolidinyl)ethyl]sulfanyl}butanamide; 2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-{[2-(1H- imidazol-1-yl)ethyl]sulfanyl}butanamide;
Methyl 1 -[2-({2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)]amino]-3-(hydroxyamino)-1 , 1 - dimethyl-3-oxopropyl}sulfanyl)ethyl]-2-pyrrolidine-carboxylate;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-[(2(4- morpholinylpropyl)sulfanyl]-butanamide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-{[2(4-methyl-
1 -ethyl-1 -piperazinyl)propyl]sulfanyl}butanamide; 2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-{[2-
(diethylamino)propyl]sulfanyl}butanamide;
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3- methylsulfanyl-butyramide;
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3-ethylsulfanyl- butyramide;
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]τN-hydroxy-3-methyl-3-propylsulfanyl- butyramide;
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3-(pyridin-3- ylmethylsulfanyl)-butyramide; 2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3- benzylsulfanyl-butyramide;
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-(methyIsulfanyl)- butyramide;
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-(pyridin-3- ylmethylsulfanyl)-butyramide;
3-(Benzylthio)-2-[[[4-(2-butynyloxy)phenyl]sulfonyl]methylamino]-N-hydroxy- propanamide;
'3-(Benzylthio)-2-[[[4-(2-butynyloxy)phenyl]sulfonyl]pyridin-3-ylmethylamino]-N- hydroxypropanamide; 2-[[[4-(2-Butynyloxy-phenyl]sulfonyl]amino]-N-hydroxy-3-methyl-(3-methylthio)- butyramide;
2-[(4-But-2-ynyloxy-benenesulfonyl)-amino]-N-hydroxy-3-methyl-3-ethylsulfanyl- butyramide; 2-[(4-But-2-ynyloxy-benenesulfonyl)-amino]-N-hydroxy-3-methyl-3-propylsulfanyl- butyramide;
2-[(4-Butynyloxy-phenylsulfonyl)-amino]-N-hydroxy-3-methyl-[(3-pyridinyl-methyl)thio] butyramide;
2-[(4-Butynyloxy-phenyl)sulfonyl)-amino]-N-hydroxy-3-methyl-(3-benzyl-sulfanyl) butyramide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-3-{[(-methyl-1H-imidazol-2- yl]methylsulfanyl}butanamide; 2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-3-methyl-3-{[2-(4-morpholinyl) ethyl]sulfanyl}butanamide; fe/f-Butyl{[2-({[4-2-butynyloxy)phenyl]sulfonyl}amino)-3-(hydroxyamino)-1 , 1 -dimethyl-3- oxopropyl]sulfanyl}acetate; fetf-Butyl {[2-({[4-2-butynyloxy)phenyl]sulfonyl}amino)-3-(hydroxyamino)-1 ,1 -dimethyl - 3-oxopropyl]sulfanyl acetic acid, sodium salt;
2-[(4-Butynyloxy-phenylsulfonyl)-amino]-N-hydroxy-3-(methylthio)-propanamide;
2-[[4-Butynyloxy-phenylsulfonyl]-amino]-N-hydroxy-3-(benzylthio)-propanamide;
2-[[4-ButynyIoxy-phenylsulfonyl]-amino]-N-hydroxy-3-(pyridinylthio)-propanamide;
2-({[4-(2-Butynyloxy)phenyl]suIfonyl}amino)-N-hydroxy-3-[(Z)-11- tetradecenylsulfanyljpropanamide;
(2S)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hydroxy- propyl)sulfanyl]-3-methylbutanamide;
(2S)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hydroxy- propyl)sulfanyl]-3-propanamide; (3S)-4-({[4-(2-Butyny!oxy)phenyl]sulfonyl}-N-hydrσxy-2,2-dimethyl-1,4-thiazepane-3- carboxamide;
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepane-3-carboxamide;
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepane-3-carboxamide 1,1- dioxide; 2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-hydroxy-phenyl)acetamide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-[4-(2-propynyloxy)- phenyljacetamide; 2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-(4- methoxyphenyl)acetamide;
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(4- morpholinyl)ethoxy]phenyl}acetamide; tetf-Butyl 2-{4-[1 -[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2- oxoethyl]phenoxy}ethylcarbamate;
2-[4-(2-Aminoethoxy)phenyl]-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}-(methyl)amino]-N- hydroxyacetamide;
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-{4-[2-(dimethyIamino)- ethoxy]phenyl}-N-hydroxyacetamide;
2-[{[4-(2-Butynyloxy)phenyl]suIfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(1- pyrrolidinyl)ethoxy]phenyl}acetamide;
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(2-oxo-1- pyrrolidinyl)ethoxy]phenyl}acetamide; 4-(2-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-
2-oxoethyl]phenoxy}ethyl)-1-piperazinecarboxylate;
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(1- piperazinyl)ethoxy]phenyl}acetamide; e^f-Butyl 3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2- oxoethyl]phenoxy}propylcarbamate;
2-[4-(3-Aminopropoxy)phenyl]-2-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]-N- hydroxyacetamide; terf-Butyl (3S)-3-{4-[(1 R)-1 -[{[4-(2-butynyloxy)phenyl]sulfonyl}-(methyl)amino]-2-
(hydroxyamino)-2-oxoethyl]phenoxy}-1-pyrrolidine-carboxylate; (2R)-2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[(3S)- pyrrolidinyloxy]phenyl}ethanamide;
.erf-Butyl (2-{4-[1 -({[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino)-2-(hydroxyamino)- 2- oxoethyl)phenoxy]ethyl)-(methyl)carbamate;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino)-N-hydroxy-2-{4-[2-(methylamino) ethoxy]phenyl}acetamide;
Ethyl 3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2- oxoethyl]phenoxy}propylcarbamate; 2-{4-[3-(Acetylamino)propoxy]phenyl}-2-[{[4-(2-butynyloxy)phenyl]- sulfonyl}(methyl)amino]-N-hydroxyacetamide;
Butyl-3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2- oxoethyl]phenoxy}propylcarbamate; Benzyl-3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2- oxoethyl]phenoxy}propylcarbamate;
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-(4-{3-
[(methylsulfonyl)amino]propoxy}phenyl)acetamide;
2-(4-{3-[(Anilinocarbonyl)amino]propoxy}phenyl)-2-[{[4-(2-butynyloxy)- phenyl]sulfonyl}(methyl)amino]-N-hydroxyacetamide; terf-Butyl 2-{4-[(1 R)-1 -({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxyamino)-2- oxoethyl]phenoxy}ethylcarbamate;
(2R)-2-[4-(2-Aminoethoxy)phenyl]-2-({[4-(2-butynyloxy)phenyl]-sulfonyl}-amino)-N- hydroxyethanamide; (2R)-2-{4-[2-(Acetylamino)ethoxy]phenyl}-2-({[4-(2-butynyloxy)phenyl]-sulfonyl}amino)-N- hydroxyethanamide; tetf-Butyl 4-(2-{4-[1 -({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxyamino)-2 - oxoethyl)phenoxy]ethyl)-1-piperazinecarboxylate; terf-Butyl 4-(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxyamino)-2- oxoethyl)phenoxy]ethyl)-(methyl)carbamate; ^
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-
(methylamino)ethoxy]phenyl})acetamide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(1- pyrrolidinyl)ethoxy]phenyl}acetamide; 2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(4- morpholinyl)ethoxy]phenyl}acetamide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino){4-[2-(dimethylamino)ethoxy]-phenyl}-N- hydroxyacetamide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(4-methyl-1,3-thiazol-5- yl)ethoxy]phenyl}acetamide;
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-{2-[2-(2- thoxyethoxy)ethoxy]ethoxy}phenyl)acetamide; 2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(2-methoxy- ethoxy)ethoxy]phenyl}acetamide;
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-phenyl-acetamide;
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophenyl)-N- hydroxyacetamide;
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-[(4-chlorophenyl)-sulfanyl]-N- hydroxypentanamide;
1 -(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide;
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piperazine-2-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1 ,3-dicarboxylic acid 1-diethylamide 3- hydroxyamide;
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(pyrrolidine-1-carbonyl)-piperazine-2-carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 1-diisopropylamide
3-hydroxyamide;
Benzyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-3-[(hydroxyamino)carbonyl]-1- piperazinecarboxylate;
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic acid 3-hydroxyamide 1- (methyi-phenyl-amide);
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-3-hydroxy-N-1-(4-methoxyphenyl)-1,3- piperazinedicarboxamide;
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-1-(4-fluorophenyl)-N-3-hydroxy-1 ,3- piperazinedicarboxamide; 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-1 -(3,5-dichlorophenyl)-N-3-hydroxy-1 ,3- piperazinedicarboxamide;
4-Acetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide;
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-propionyl-piperazine-2-carboxylic acid hydroxyamide;
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(thiophene-2-carbonyl)-piperazine-2-carboxylic acid hydroxyamide; 1-(4-But-2-ynyloxy-benzenesulfonyl)-4-methanesulfonyl-piperazine-2-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1-carboxylic acid methyl ester; {2-[4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazin-1-yl]-2-oxo- ethyl}-carbamic acid tetf-butyl ester;
4-Aminoacetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide;
1-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-[(2,2,5-trimethyl-1,3-dioxan-5- yl)carbonyl]-2-piperazinecarboxamide;
1-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-[3-hydroxy-2-(hydroxy-methyl)-2- methylpropanoyl-2-piperazinecarboxamide;
4-(4-Bromo-benzyl)-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide; 1 -(4-But-2-ynyloxy-benzenesulfonyl)-4-pyridin-3-ylmethyl-piperazine-2-carboxylic acid hydroxyamide;
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
9-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-6-thia-9-azaspiro[4,5]-decane-10- carboxamide;
9-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4-azaspiro[5,5]-undecane-5- carboxamide;
4-({[4-(2-Butynyloxy)phenyl]sulfonyl)-2,2-diethyl-thiomorpholine-3-carboxylic acid hydroxyamide; 4-({[4-(2-Butynyloxy)phenyljsulfonyl)-N-hydroxy-thiomorpholine-3-carboxamide;
4-([4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-3-morpholinecarboxamide;
9-Benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4,9- diazaspiro[5.5]undecane-5-carboxamide;
9-Methyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4,9- diazaspiro[5.5]undecane-5-carboxamide;
N-Hydroxy-2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2- pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide; N-Hydroxy-4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3- thiomorpholine carboxamide; tert-Butyl 5-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4- thiomorpholinyl}sulfonyl)phenoxy]-3-pentynylcarbamate; 4-({4-[(5-Amino-2-pentynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3- thiomorpholine carboxamide;
4-[(4-{[4-(Benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-N-hydroxy-2,2-dimethyl-3- thiomorpholine carboxamide;
N-Hydroxy-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]- oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide;
N-Hydroxy-4-({4-[(6-hydroxy-2-hexynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3- thiomorpholine carboxamide; tet -Butyl 6-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2- dimethyl- thiomorpholinyl}sulfonyl)phenoxy]-4-hexynylcarbamate; (3S)-4-({4-[(6-Amino-2-hexynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3- thiomorpholine carboxamide; te/f-Butyl 7-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2- di ethyl- thiomorpholinyl}sulfonyl)phenoxy]-5-heptynylcarbamate;
(3S)-4-({4-[(7-Amino-2-heptynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3- thiomorpholine carboxamide;
(3S)-N-Hydroxy-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]-phenyl}sulfonyl)-3- thiomorpholine carboxamide;
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide (1S)-oxide; (3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide (1 R)-oxide;
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide 1 , 1 -dioxide;
(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxamide;
(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2-pentynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxamide; (3S)-N-Hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3- thiomorpholine carboxamide;
4-[4-({(3S)-3-[(Hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}-sulfonyl)phenoxy]-2- butynyl acetate; (3S)-N-Hydroxy-4-({4-[(6-hydroxy-2,4-hexadiynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3- thiomorpholine carboxamide;
(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2,4-pentadiynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxamide;
(3S)-4-({4-[(4-Fluoro-2-butynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3- thiomorpholine carboxamide;
4-({4-[(4-Amino-2-butynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide; te/ -Butyl 4-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholinyl}- sulfonyl)phenoxy]-2-butynylcarbamate; tert-Butyl 4-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholinyl}- sulfonyl)phenoxy]-2-butynyl(methyl)carbamate;
7-[4-({(3S)-3-[(Hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}-sulfonyl)phenoxy]-
5-heptynyl acetate;
(3S)-N-Hydroxy-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3- thiomorpholinecarboxamide;
(3S,5S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,5-trimethyl-3- thiomorpholinecarboxamide;
(3S,5R)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,5-trimethyI-3- thiomorpholinecarboxa ide; (3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,6-trimethyl-3- thiomorpholinecarboxamide; fe/f-Butyl{(2R,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)-carbonyl]-6,6- dimethylthiomorpholinyljmethylcarbamate; terf-Butyl{(2S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)-carbonyl]-6,6- dimethylthiomorpholinyl}methylcarbamate;
(3S,6R)-Trans-6-(aminomethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2- dimethyl-3-thiomorpholinecarboxamide hydrochloride; (3S,6S)-Cis-6-(aminomethyI)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2- dimethyl-3-thiomorpholinecarboxamide hydrochloride; tetf-Butyl{(2S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)-carbonyl]-6,6- dimethylthiomorpholinyljacetate; {(2S,5S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)carbonyl]-6,6- dimethylthiomorpholinyl}acetic acid;
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-6-[2-(hydroxyamino)-2-oxoethyl]-
2,2-dimethyl-3-thiomorpholinecarboxamide;
(3S,6S)-6-(2-Amino-2-oxoethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2- dimethyl-3-thiomorphoIinecarboxamide;
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-6-[2-(dimethylamino)-2-oxoethyl]-N- hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyI}-N-hydroxy-2,2-dimethyl-6-[2-(4- morpholinyl)-2-oxoethyl]-3-thiomorpholinecarboxamide; (3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyI}-N-hydroxy-2,2-dimethyl-6-[2-(4-methyl-1- piperazinyl)-2-oxoethyl]-3-thiomorpholinecarboxamide hydrochloride;
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-6-(2-{[2-(dimethylamino)-ethyl]amino}-2- oxoethyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholine-carboxamide;
Methyl (3S,6S)-6-{[(tet -butoxycarbonyl)amino]methyl}-4-{[4-(2- butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate;
(4S)-3-{[4-(2-ButynyIoxy)phenyl]sulfonyl}-N-hydroxy-5,5-dimethyl-1,3-thiazolidine-4- carboxamide; ferf-Butyl 4-({[4-(2-butynyloxy)phenyI]sulfonyl}amino)-4-[(hydroxyamino)-carbonyl]-1- piperidinecarboxylate; 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-4-piperidine-carboxamide;
1-Benzoyl-4-{[4-(2-butynyIoxy)phenyl]suIfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide;
1-Benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide; terf-Butyl 4-{[4-(2-butynyloxy)phenyl]suIfonyl}-5-[(hydroxyamino)carbonyl]-1 ,4- diazepane-1 -carboxylate; 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide;
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-methyl-1,4-diazepane-5-carboxamide;
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepine-5-carboxamide; (2R)-5-(Acetylamino)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N- hydroxypentanamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyl]thiophene-2-carboxamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[(ethylamino)carbonyl]-amino}-N- hydroxypentanamide;
(2R)-5-[(Anilinocarbonyl)amino]-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}-amino)-N- hydroxypentanamide;
Octyl (4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyI}amino)-5-(hydroxyamino)-5- oxopentylcarbamate;
4-Methoxyphenyl (4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentylcarbamate;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[(diethylamino)-carbonyl]amino}-N- hydroxypentanamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-
{[(methylanilino)carbonyl]amino}pentanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[(1-methyl-1H-imidazol-
4-yl)sulfonyl]amino}pentanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(2-morpholin-4- ylacetyl)amino]pentanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[2-(4-methyIpiperazin-1- yl)acetyl]amino}pentanamide;
(2R)-5-{[2-(Benzylamino)acetyl]amino}-2-({[4-(but-2-ynyloxy)phenyl]-sulfonyl}amino)-N- hydroxypentanamide; (3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3,4-dihydro-2H-1,4- thiazine-3-carboxamide;
(2R)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(imino{[(4-{[(4-methoxy-
2,3,6-trimethylphenyl)sulfonyl]amino}methyl)amino]pentanamide;
(2R)-2-(4-But-2-ynyloxy-benzenesulfonylamino)-5-guanidino-pentanoic acid hydroxyamide;
(2R)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(imino{[(4- methylphenyl)sulfonyl]amino}methyl)amino]pentanamide; (3R)-3-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-4-(hydroxyamino)-4-oxobutanoic acid;
(2S)-3-(tetf-Butylthio)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N- hydroxypropanamide;
(2S)-3-{[(Acetylamino)methyl]thio}-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N- hydroxypropanamide;
(2S)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(4- methylbenzyl)thio]propanamide;
(2S)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(4- methoxybenzyl)thio]propanamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxypentanediamide;
(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentanoic acid;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-4-phenyl-butanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-(1 H-imidazol-5- y propanamide;
(2R,4S)-1-{[4-(But-2-ynyloxy)phenyl]sulfonyl}-N,4-dihydroxypyrrolidine-2-carboxamide;
(2R)-6-Amino-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-hexanamide;
Benzyl (5R)-5-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-
6-oxohexylcarbamate; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-(1-naphthyl)- propanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-(2-naphthyl)- propanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxyhexanamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxypentanamide;
(2R)-5-Amino-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxypentanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-3-(3,4-difluorophenyl)-N- hydroxypropanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-3-(4-fluorophenyl)-N- hydroxypropanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-(4-nitrophenyl)- propanamide;
(2R)-1-{[4-(But-2-ynyloxy)phenyl]sulfonyl}-N-hydroxypiperidine-2-carboxamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxypropanamide;
(2R)-3-(Benzyloxy)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-propanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-thien-2-yl-propanamide; (2R,3S)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxybutanamide;
(2R,3S)-3-(Benzyloxy)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N- hydroxybutanamide;
(4S)-3-{[4-(But-2-ynyloxy)phenyl]sulfonyl}-N-hydroxy-1,3-thiazolidine-4-carboxamide;
(3R)-2-{[4-(But-2-ynyloxy)phenyl]sulfonyl}-N-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3- carboxamide;
(2R)-3-[4-(Benzyloxy)phenyl]-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N- hydroxypropanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-phenyl-ethanamide;
(2R)-5-(Acetylamino)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy- pentanamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentyl]-1H- benzimidazole-5-carboxamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyljbenzamide; 4-Bromo-N-[(4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxy-amino)-5- oxopentyljbenzamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(butyrylamino)-N- hydroxypentanamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentyl]-3- chlorothiophene-2-carboxamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentyl]-4- chlorobenzamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyljcyclohexanecarboxamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[2-(3,4-dichlorophenyl)- acetyl]amino}-N-hydroxypentanamide; N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentyl]-2,5- dimethyl-3-furamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentyl]-3,5- dimethylisoxazole-4-carboxamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(3-phenyl- propanoyl)amino]pentanamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyljisonicotinamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyljnicotinamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentyl]-2- methoxybenzamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentyl]-4- methoxybenzamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[2-(4- nitrophenyl)acetyl]amino}pentanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(2- phenylacetyl)amino]pentanamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyl]quinoline-3-carboxamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyl]thiophene-3-carboxamide;
(E)-N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-oxopentyl]-
3-phenylprop-2-enamide; N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6-oxohexyl]-1 H- benzimidazole-5-carboxamide;
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6- oxohexyljbenzamide;
4-Bromo-N-[(5R)-5-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxy-amino)-6- oxohexyljbenzamide;
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6-oxohexyl]-3- chlorothiophene-2-carboxamide; N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6-oxohexyl]-4- chlorobenzamide;
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6- oxohexyl]cyclohexanecarboxamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-{[2-(3,4-dichlorophenyl)- acetyl]amino}-N-hydroxyhexanamide;
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6-oxohexyl]-2,5- dimethyl-3-furamide;
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6-oxohexyl]-3,5- dimethylisoxazole-4-carboxamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-6-[(3-phenyl- propanoyl)amino]hexanamide;
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6- oxohexyljisonicotinamide; N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6-oxohexyl]-2- methoxybenzamide;
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6-oxohexyl]-4- methoxybenzam ide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-6-{[2-(4- nitrophenyl)acetyl]amino}hexanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-6-[(2- phenylacetyl)amino]hexanamide;
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyI]sulfonyI}amino)-6-(hydroxyamino)-6- oxohexyl]quinoline-3-carboxamide; N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6- oxohexyl]thiophene-3-carboxamide;
(E)-N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamino)-6-oxohexyl]-
3-phenylprop-2-enamide;
(Z)-N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyl]octadec-9-enamide;
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentyl]thiophene-2-carboxamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[(ethylamino)carbonyl]-amino}-N- hydroxypentanamide;
(2R)-5-[(Anilinocarbonyl)amino]-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N- hydroxypentanamide; Octyl (4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentylcarbamate;
4-Methoxyphenyl (4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5- oxopentylcarbamate;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]suIfonyl}amino)-5-{[(diethylamino)-carbonyl]amino}-N- hydroxypentanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-
{[(methylanilino)carbonyl]amino}pentanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[(1-methyl-1H-imidazol-
4-yl)sulfonyl]amino}pentanamide; (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(2-morpholin-4- ylacetyl)amino]pentanamide;
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[2-(4-methylpiperazin-1- yl)acetyl]amino}pentanamide; and
(2R)-5-{[2-(Benzylamino)acetyl]amino}-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N- hydroxypentanamide.
Other preferred TACE inhibitor compounds of the present invention include acetylenic β- sulfonamido and phosphinic acid amide hydroxamic acids such as
(1R,2R)-2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N- hydroxycyclohexanecarboxamide; (1R, 2R)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N- hydroxycyclohexanecarboxamide;
3-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxypropanamide; 3-({[4-(2-Butynyloxy)phenyl]sulfonyl} (methyl) amino)-N-hydroxypropanamide; (1 R, 2S)-2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N- hydroxycyclopentanecarboxamide;
(1 R, 2S)-2-[{[4-(2-Butynyloxy)phenyl]sulfonyl} (methyl) amino] N- hydroxycyclopentanecarboxamide; (Cis)-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N- hydroxycyclohexanecarboxamide;
(Cis)-2-[{[4-(2-butynyloxy)phenyl]sulfonyl} (methyl) amino]-N- hydroxycyclohexanecarboxamide; (1R, 2R, 3S, 4R)-(Cis)-3-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N- hydroxybicyclo [2.2.1] heptane-2-carboxamide; and
(1 R, 2R, 3S, 4R)-(Cis)-3-({[4-(2-butynyloxy)phenyl]sulfonyl} (methyl) amino)-N- hydroxybicyclo [2.2.1] heptane-2-carboxamide.
Another group of preferred TACE inhibitor compounds include acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acids such as
5-Bromo-2-{[4-(4-cyclobutylamino-but-2-ynyloxy)-benzenesulfonyl]-methyl- amino}-N-hydroxy-3-methyl-benzamide; 5-Bromo-N-hydroxy-3-methyl-2-{methyl-[4-(4-methylamino-but-2-ynyloxy)- benzenesulfonyl]-amino}-benzamide; 5-Bromo-2-({4-[4-(3-dimethylamino-propylamino)-but-2-ynyloxy]- benzenesulfonyl}-methyl-amino)-N-hydroxy-3-methyl-benzamide; 5-Bromo-2-({4-[4-(2-dimethylamino-ethylamino)-but-2-ynyloxy]-benzenesulfonyl}- methyI-amino)-N-hydroxy-3-methyl-benzamide; 4-[(4-But-2-ynyloxy-benzenesulfonyl)-methyI-amino]-5-methyl-biphenyl-3- carboxylic acid hydroxyamide;
5-Bromo-N-hydroxy-3-methyl-2-[methyl-(4-prop-2-ynyloxy-benzenesulfonyl)- amino]-benzamide; 5-Bromo-N-hydroxy-3-methyl-2-[methyl-(4-pent-2-ynyloxy-benzenesulfonyl)- aminoj-benzamide; 5-Bromo-2-[(4-hept-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-3- methyl-benzamide; 5-Bromo-2-[(4-hex-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-3- methyl-benzamide; 5-Bromo-N-hydroxy-2-{[4-(4-methoxy-but-2-ynyloxy)-benzenesulfonyl]-methyl- amino}-3-methyl-benzamide;
5-Bromo-N-hydroxy-3-methyl-2-{methyl-[4-(3-phenyl-prop-2-ynyloxy)- benzenesulfonyl]-amino}-benzamide; 5-Bromo-N-hydroxy-2-({4-[3-(3-methoxy-phenyl)-prop-2-ynyloxy]- benzenesulfonyI}-methyl-amino)-3-methyl-benzamide; 5-Bromo-N-hydroxy-2-({4-[3-(2-methoxy-phenyl)-prop-2-ynyloxy]- benzenesulfonyl}-methyl-amino)-3-methyl-benzamide; 5-Bromo-N-hydroxy-2-({4-[3-(4-methoxy-phenyl)-prop-2-ynyloxy]- benzenesulfonyl}-methyl-amino)-3-methyl-benzamide; 2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-5-iodo-3-methyl- benzamide; 2-[Benzyl-(4-but-2-ynyloxy-benzenesulfonyl)-amino]-N-hydroxy-3,5-dimethyl- benzamide;
5-Bromo-N-hydroxy-3-methyl-2-{methyl-[4-(4-pyrrolidin-1-yl-but-2-ynyloxy)- benzenesulfonyl]-amino}-benzamide; 5-Bromo-2-{[4-(4-diethylamino-but-2-ynyloxy)-benzenesulfonyl]-methyl-amino}-N- hydroxy-3-methyl-benzamide; 5-Bromo-2-[(4-but-2-ynyloxy-benzenesulfonyl)-(4-methyl-piperazin-1-ylmethyl)- amino]-N-hydroxy-3-methyl-benzamide; 5-Bromo-N-hydroxy-3-methyl-2-(methyl-{4-[4-(tetrahydro-pyran-2-yloxy)-but-2- ynyloxy]-benzenesulfonyl}-amino)-benzamide; 5-Bromo-N-hydroxy-2-{[4-(4-hydroxy-but-2-ynyloxy)-benzenesulfonyl]-methyl- amino}-3-methyl-benzamide; and
4-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-5-(4-methyl-piperazin-1-ylmethyl)- biphenyl-3-carboxylic acid hydroxyamide dihydrochloride salt. Still another preferred group of TACE inhibitor compounds of the present invention includes acetylenic aryl sulfonamide thiols such as 4-But-2-ynyloxy-N-((1 R)-2-mercapto-1-methyl-ethyl)-N-methylbenzene-sulfonamide; (2R)-2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[2-(4-morpholinyl)ethyl]amino}-3- sulfanylpropanamide; and
4-(2-Butynyloxy)-N-[(1 R)-1 -methyl-2-sulfanylethyl]-N-[2-(4- morpholinyl)ethyl]benzenesulfonamide. Yet another group of preferred TACE inhibitor compounds of the present invention includes acetylenic aryl and heteroaryl sulfonamide and phosphinic acid amide hydroxamic acids such as (3-[methyl-(4-but-2-ynyloxy-benzenesulfonyl-amino]-N- hydroxy-2,6-dimethoxy-isonicotinamide and 3-(4-But-2-ynyloxy-benzenesulfonylamino)- N-hydroxy-2,6-dimethoxy-isonicotinarnide.
Other preferred TACE inhibitor compounds of the present invention include alkynyl containing hydroxamic acid compounds such as 2-(4-But-2-ynyloxy-benzenesulfonyl)-N-hydroxy-2-methyl-3-pyridin-3-yl- propionamide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-N-hydroxy-propionamide;
2-(4-But-2-ynyloxy-benzesulfonyl)-N-hydroxy-2-methyl-3-[4-(2-piperidin-1-yl- ethoxy)-phenyl]-propionamide; 3-Biphenyl-4-yl-2-(4-but-2-ynyloxy-benzenesulfonyl)-N-hydroxy-2-methyl- propionamide;
2-(4-But-2-ynyloxy-phenysulfanyl)-octanoic acid hydroxamide;
2-(But-2-ynyloxy-benzenesuIfonyl)-octanoic acid hydroxamide;
2[(R )-(4-Butyl-2-ynyloxy)-sulfinyl-N-hydroxyoctanamide; 2[(S )-(4-Butyl-2-ynyloxy)-sulfinyl-N-hydroxyoctanamide;
3-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-propionamide
4-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-butyramide;
2-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-acetamide;
4-(4-But-2-ynyloxy-phenyl)-N-hydroxy-butyramide; Quinoline-2-carboxylic acid [5-(4-but-2-ynyloxy-phenylsulfanyl)-5- hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-[2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)- acetylamino]-hexanoic acid hydroxyamide;
N-[5-(4-But-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl- benzamide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-[2-(3,4-dichloro-phenyl)-acetylamino]- hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-phenylsulfanyl)-
5-hydroxycarbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy-phenylsulfanyl)-6-(4-thiophen-2-yl-butyrylamino)-hexanoic acid hydroxyamide;
9H-Xanthene-9-carboxyIic acid [5-(4-but-2-ynyloxy-phenylsulfanyl)-
5-hydroxycarbamoyl-pentyl]-amide; 2-(4-But-2-ynyloxy-phenylsulfanyl)-6-diphenylacetylamino- hexanoic acid hydroxyamide; lsoquinoline-1 -carboxylic acid [5-(4-but-2-ynyloxy-phenylsulfanyl)-
5-hydroxycarbamoyl-penty!]-amide; 6-(2-Benzo[b]thiophen-3-yl-acetylamino)-2-(4-but-2-ynyloxy-phenyl-sulfanyl)- hexanoic acid hydroxyamide;
Quinoline-2-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-
5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-[2-(1,3-dioxo-1 ,3-dihydro-isoindol-2-yl)- acetylamino]-hexanoic acid hydroxyamide;
N-[5-(4-But-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl- benzamide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-[2-(3,4-dichloro-phenyl)-acetylamino]- hexanoic acid hydroxyamide; Quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5- hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-(4-thiophen-2-yl-butyrylamino)-hexanoic acid hydroxyamide;
9H-Xanthene-9-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)- 5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-diphenylacetylamino-hexanoic acid hydroxyamide; lsoquinoline-1 -carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-
5-hydroxycarbamoyI-pentyl]-amide; 6-(2-Benzo[b]thiophen-3-yl-acetylamino)-2-(4-but-2-ynyloxy-benzene-sulfinyl)- hexanoic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-(2-1 H-indol-3-yl-acetylamino)-hexanoic acid hydroxyamide;
Quinoline-2-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfonyl)-5- hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-[2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)- acetylamino]-hexanoic acid hydroxyamide; N-[5-(4-But-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl- benzamide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-[2-(3,4-dichloro-phenyl)-acetyl-amino]- hexanoic acid hydroxyamide; Quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfonyl)-5-
5-hydroxycarbamoyl-pentyl]-amide;
9H-Xanthene-9-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfonyl)-
5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-diphenylacetylaminohexanoic acid hydroxyamide; lsoquinoline-1 -carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfonyl)-
5-hydroxycarbamoyl-pentyl]-amide;
6-(2-Benzo[b]thiophen-3-yl-acetylamino)-2-(4-but-2-ynyloxy-benzene-sulfonyl)- hexanoic acid hydroxyamide; Quinoline-2-carboxylic acid {[5-(4-but-2-ynyloxy-phenylsulfanyl)-5- hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-{2-[2-(1,3-dioxo-1,3-dihydro- isoindol-2-yl)-acetylamino]-acetylamino}hexanoic acid hydroxyamide;
N-{[5-(4-But-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentyl-carbamoyl]- methyl}-2-phenethyl-benzam ide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-{2-[2-(3,4-dichloro-phenyl)-acetylamino]- acetylaminoj-hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid {[5-(4-but-2-ynyIoxy-phenylsulfanyl)-
5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 9H-Xanthene-9-carboxylic acid {[5-(4-but-2-ynyloxy-phenylsulfanyl)-
5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-(2-diphenylacetylamino-acetylamino)- hexanoic acid hydroxyamide; lsoquinoline-1 -carboxylic acid {[5-(4-but-2-ynyloxy-phenylsulfanyl)- 5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
1-Methyl-1 H-pyrrole-2-carboxylic acid {[5-(4-but-2-ynyloxy-phenyl-sulfanyl)-5- hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide; 6-[2-(2-Benzo[b]thiophen-3-yl-acetyIamino)-acetylamino]-2-(4-but-2-ynyloxy- phenylsulfanyl hexanoic acid hydroxyamide;
Quinoline-2-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfinyI)-
5-hydroxycarbamoyl-pentyIcarbamoyl]-methyl}-amide; 2-(4-But-2-ynyloxy-benzenesulfinyl)-6-{2-[2-(1 ,3-dioxo-1 ,3-dihydro- isoindol-2-yI)-acetylamino]-acetylamino}-hexanoic acid hydroxyamide;
N-{[5-(4-But-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl-carbamoyl]- methyl}-2-phenethyl-benzamide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-{2-[2-(3,4-dichloro-phenyl)-acetylamino]- acetylaminoj-hexanoic acid hydroxyamide;
Quinoline-3-carboxyIic acid {[5-(4-but-2-ynyloxy-benzenesulfinyI)- 5-hydroxycarbamoyl-pentyIcarbamoyl]-methyI}amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-[2-(4-thiophen-2-yl- butyrylamino)-acetylamino]-hexanoic acid hydroxyamide; 9H-Xanthene-9-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfinyl)-
5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-(2-diphenyIacetylamino-acetyIamino)- hexanoic acid hydroxyamide;
1 -MethyI-1 H-pyrrole-2-carboxylic acid {[5-(4-but-2-ynyIoxy-benzene-sulfinyl)-5- hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide ;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-{2-[2-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-yl)- acetylamino]-acetylamino}-hexanoic acid hydroxyamide;
N-{[5-(4-But-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentylcarbamoyl]- methyl}-2-phenethyl-benzamide; 2-(4-But-2-ynyloxy-benzenesulfonyl)-6-{2-[2-(3,4-dichloro-phenyl)-acetylamino]- acetylamino}-hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfonyl)- 5-hydroxycarbamoyl-pentylcarbamoyl3-methyl}amide;
9H-Xanthene-9-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfonyl)- 5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-(2-diphenylacetyIamino-acetylamino)- hexanoic acid hydroxyamide; lsoquinoline-1 -carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfonyQ- 5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
6-[2-(2-Benzo[b]thiophen-3-yl-acetylamino)-acetylamino]-2-(4-but-2-ynyloxy benzenesulfonyl hexanoic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-[2-(2-1H-indol-3-yl-acetylamino)- acetylaminoj-hexanoic acid hydroxyamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy phenyl}butanamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-7-cyano-N-hydroxy heptanamide; 2-{[4-(2-butynyloxy)phenyI]sulfanyl}-2-cyclohexyl-N-hydroxyacetamide; 2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-cyclohexyI-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-cyclohexyl-N-hydroxyacetamide; 2-{[4-(2-butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-(4-methoxyphenyl) acetamide; (2R)-2-{[4-(2-butynyloxy)phenyl] sulfinyl}-N-hydroxy-2-(4-methoxyphenyl) ethanamide; (2S)-2-{[4-(2-butynyIoxy)phenyl] sulfinyl}-N-hydroxy-2-(4-methoxyphenyl) ethanamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(4-methoxyphenyl) acetamide; 2-{[4-(2-butynyIoxy)phenyl]sulfanyl}-2-(4-chlorophenyl)-N-hydroxyacetamide; 2-{[4-(2-butynyloxy)phenyl] sulfinyl}-2-(4-chlorophenyl) N-hydroxyacetamide; 2-{[4-(2-butynyloxy)phenyl]sulfonyl-2-(4-chIorophenyI)-N-hydroxy-acetamide;
2-{[4-(2-butynyIoxy)phenyl]suIfanyl}-2-(3-chlorophenyl)-N-hydroxyacetamide; 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(3-chIorophenyl)-N-hydroxyacetamide; 2-(4-bromophenyl)-2-{[4-(2-butynyloxy)phenyl]sulfanyl-N-hydroxyacetamide; (2S)-2-(4-bromophenyl)-2-{[4-(2-butynyloxy)phenyl]sulfinyl-N-hydroxy-acetamide; (2R)-2-(4-bromophenyl)-2-{[4-(2-butynyloxy)phenyl] sulfinyl-N-hydroxy- acetamide;
2-(4-bromophenyl)-2-{[4-(2-butynyloxy)phenyl]sulfonyl-N-hydroxy-acetamide; 2{[4-(2-butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-[4-(2-thienyl)phenyl]-acetamide; (2R)-2-{[4-(2-butynyloxy)phenyl] sulfinyl}- N-hydroxy-2-[4-(2-thienyl)- phenyl]ethanamide;
2-{[4-(2-butynyloxy)phenyl]suIfonyl}-N-hydroxy-2-[4-(2-thienyl)-phenyl]acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-(1-napthyl)acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-(1-napthyI)acetamide; 2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(1-napthyl)acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl}-2-(4-fluorophenyl)-N-hydroxy-2-(1- napthyl)acetamide;
2-{[4-(2-butynyloxy)phenyl]sulfinyl-2-(4-fluorophenyl)-N-hydroxyacetamide; 2-{[4-(2-butynyloxy)phenyl]sulfonyl-2-(4-fluorophenyl)-N-hydroxyacetamide;
2-(2-methoxyphenyl)-2-{[4-(2-butynyloxy)phenyl]sulfanyl-N-hydroxy-acetamide;
2-(2-methoxyphenyl)-2-{[4-(2-butynyloxy)phenyl]sulfinyI}-N-hydroxy-acetamide;
2-{[4-(2-butynyloxy)phenyl]suIfanyl-N-hydroxy-2-(4-ethoxyphenyl) acetamide;
2-{[4-(2-ButynyIoxy)phenyl] sulfinyI-N-hydroxy-2-(4-ethoxyphenyl) acetamide; 2-{[4-(2-butynyloxy)phenyl]sulfonyl-2-(4-chlorophenyl)-N-hydroxyacetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl-N-hydroxy-2-(3-bromophenyl) acetamide;
(2R)-2-{[4-(2-butynyloxy)phenyl]sulfinyI-N-hydroxy-2-(3-bromophenyl) acetamide;
(2S)-2-{[4-(2-butynyloxy)phenyl] sulfinyl-N-hydroxy-2-(3-bromophenyl) acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-2-(3-bromophenyI)-N-hydroxyacetamide; 2-{[4-(2-Butynyloxy)phenyl]sulfanyl}-2-isopropyl-N-hydroxyacetamide;
R-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-isopropyl-N-hydroxyacetamide;
S-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-isopropyl-N-hydroxyacetamide;
2-{[4-(2-butynyIoxy)phenyl]sulfonyl}-2-isoprpyl-N-hydroxyacetamide; -{[4-(2-Butynyloxy)phenyl]sulfanyI}-2-phenyl-N-hydroxyacetamide; R-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-phenyl-N-hydroxyacetamide;
S-2-{[4-(2-butynyloxy)phenyl]suIfinyl}-2-phenyl-N-hydroxyacetamide; -{[4-(2-Butynyloxy)phenyl]sulfanyl}-2-(2-naphthyl)-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-(2-naphthyl)-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(2-naphthyl)-N-hydroxyacetamide; Tert-butyl-4-[1-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(hydroxyamino)-2-oxoethyl]-1- piperidine carboxylate;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(4-piperidinyl) acetamide;
2-{[4-(2-butynyloxy)phenyl]suIfonyl}-N-hydroxy-2-[1-(4-methoxybenzyl)-4- piperidinyl] acetamide; 2-(1-benzoyl-4-piperidinyl)-2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy- acetamide;
2-(1-acetyl-4-piperidinyI)-2-{[4-(2-butynyloxy)phenyl]suIfonyl-N-hydroxy- acetamide; 2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-tetrahydro-2H-pyran-4yI- acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-tetrahydro-2H-thiopyran-4yl- acetamide; 2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(1-oxidotetrahydro-2H- thiopyran-4yl) acetamide; and
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(1,1-dioxidotetrahydro-2H- thiopyran-4yl) acetamide. Other preferred TACE inhibitor compounds of the present invention include carboxamides and hydroxamides such as
1-(4-Bromo-benzyl)-4-(4-but-2-ynyxoy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)-1 -(4-chloro-benzyl)-piperdine-4-carboxylic acid hydroxyamide; 1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxamide;
1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide;
1-(4-Bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperdine-4-carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-benzenesulfonyl)-1 -(4-cyano-benzyl)-piperidine-4- carboxylic acid hydroxamide;
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4- carboxylic acid hydroxamide;
4-(4-But-2-ynyIoxy-benzenesulfonyl)-1-(3,4- dichloro-benzyl)-piperidine-4- carboxylic acid hydroxamide;
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide; 1-(4-Bromo-benzyl)-4-[4-(4-piperdin-4-yl-but-2-ynyloxy)-benzenesulfonyl]- piperdine-4-carboxylic acid hydroxyamide;
1-(4-Bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzene-sulfonyl]- piperdine-4-carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1 -carboxylic acid tert-butyl ester;
4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide
1-(4-Bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid hydroxyamide; 4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide;
4-(4-But-2-ynyIoxy-benzenesulfinylmethyl)-tetrahydro-pyran-4-carboxylic acid hydroxyamide;
4-{[4-(2-butynyIoxy)phenyl]sulfonyl}-N-hydroxytetrahydro-2H-pyran-4- carboxamide;
1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperdine carboxamide; 4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-isopropyl-4-piperidine carboxamide;
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-(3-pyridinylmethyl)-4-piperidine carboxamide;
3-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-ethyl-N-hydroxy-3-piperidine-carboxamide; 3-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-(4-chlorobenzyl)-N-hydroxy-3- piperidinecarboxamide;
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4- carboxylic acid hydroxyamide;
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-carboxylic acid hydroxyamide;
1-(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide; 1-(4-Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid hydroxyamide; tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4-[(hydroxyamino)-carbonyl]-1- piperidinecarboxylate; 4-({[4-(But-2-ynyloxy)phenyl]thio}methyl)-N-hydroxypiperidine-4- carboxamide; tert-Butyl-4-({[4-(2-butynyloxy)phenyl]sulfinyl}methyl)-4-[(hydroxyamino)- carbonyl]-1-piperidinecarboxylate;
4-[[[4-(2-Butynyloxy)phenyl]sulfinyl]methyl]-N-hydroxy-4-piperidine-carboxamide; tert-Butyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)- carbonyl]piperidine-1 -carboxylate; tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyI)-4-[(hydroxyamino)- carbonyl]-1-piperidinecarboxyla;
1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4- piperidinecarboxamide; 1 -(2-Butynyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4- piperidinecarboxamide hydrochloride;
N-1-(tert-Butyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1 ,4-[4-
(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1 ,4-l]sulfonyl}-methyl)-N~4~- hydroxy-1 ,4-piperidinedicarboxamide; Methyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-carbonyl]- -piperidinecarboxylate;
Benzyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-carbonyl]-
1 -piperidinecarboxylate;
1 -Benzyl-4-({[4-(2-butynyloxy)phenyl] sulfonyl} methyl)-N-hydroxy-4- butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide;
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(2,2,5-trimethyl-1 ,3- dioxan-5-yl)carbonyl]-4-piperidinecarboxamide;
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[3-hydroxy-2-
(hydroxymethyl)-2-methylpropanoyl]-4-piperidinecarboxamide; 1-[Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4- l]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4- oxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide; 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)- henyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)-4- piperidinecarboxamide;
4-({[4-(But-2-ynyloxy)phenyI]sulfonyl}methyl)-1-ethyl-N-hydroxypiperidine-4- carboxamide triflouroacetic acid salt;
2-chloro-5-(chloromethyl) thiophene4-({[4-(But-2-ynyloxy)phenyl]-sulfonyl}- methyl)-1-[(5-chlorothien-2-yl)methyl]-N- hydroxypiperidine-4-carboxamide triflouroacetic acid salt;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-4- ylmethyl)piperidine-4-carboxamide triflouroacetic acid salt;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-3 ylcarbonyl)piperidine-4-carboxamide triflouroacetic acid salt;
1-Benzoyl-4-({[4-(but-2-ynyloxy)phenyI]sulfonyl}methyl)-N-hydroxy-piperidine-4- carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyI}methyl)-N-hydroxy-1 -(thien-2- ylcarbonyl) piperidine-4-carboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-1-ethyl-N-4-hydroxy-piperidine-
1 ,4-dicarboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1- phenyl- piperidine-1 ,4-dicarboxamide;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-1-,N-1-diethyl-N-4- hydroxypiperidine-1 ,4-dicarboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(morpholin-4- ylcarbonyl)piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]suIfonyl}methyl)-N-4-hydroxy-N-1 -methyl-N-1 - phenylpiperidine-1 ,4-dicarboxamide;
Octyl-4-({[4-(but-2-ynyIoxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-carbonyl] piperidine-1 -carboxylate;
4-Methoxyphenyl4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxy-amino) carbonyl]piperidine-1 -carboxylate;
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(phenyIsulfonyl) piperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1 -[(1 -methyl-1 H- imidazol-4-yl)sulfonyl]piperidine-4-carboxamide;
1-[2-(BenzyIamino)acetyl]-4-({[4-(but-2-ynyloxy)phenyl]-sulfonyl}methyI)-N- hydroxypiperidine-4-carboxamide; 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(2-morpholin-4- ylacetyl)piperidine-4-carboxamide;
4-({[4-(But-2-ynyIoxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[2-(4-methyl-piperazin-
1-yl)acetyI]piperidine-4-carboxamide;
1-Acetyl-4-(4-but-2-ynyloxybenzenesuIfonyl)piperidine-4-carboxylic acid hydroxamide;
1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic acid hydroxamide;
1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxy benzenesulfonyl)piperidine-4-carboxylic acid hydroxamide; 4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1 -(pyrrolidine-1 -carbonyl)-4- piperidinecarboxamide;
Ethyl 4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1- piperidinecarboxylate;
4-(4-But-2-ynyIoxybenzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl)sulfonyl]-4- piperidinecarboxamide;
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinyIcarbonyl)- 4- piperidinecarboxamide;
4-(4-but-2-ynyIoxybenzenesuIfonyl)-N-hydroxy-1-(2-thienylcarbonyl)- 4- piperidinecarboxamide; 4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl)-sulfonyl]-4- piperidinecarboxamide;
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1 ,3-dioxan-5- yl)carbonyl]-4-piperidinecarboxamide;
Tert-butyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1- piperidinecarboxalate;
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperidinecarboxamide hydrochloride; Methyl ({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-1- piperidinyl}methyl)benzoate hydrochloride;
4-({4-{[4-(2-butynyloxy)phenyI]sulfonyl}-4-[(hydroxyamino)carbonyl]-1- piperidinyl}methyl)benzoic acid hydrochloride; 1-[4-(Aminocarbonyl)benzyl]-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4- piperidinecarboxamide hydrochloride;
Tert-butyl 4-{[4-(but-2-ynyloxy)phenyI]sulfinyl}-4-[(hydroxyamino)- carbonyl]piperidine-1-carboxalate;
4-(4-(But-2-ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic acid hydroxamide hydrochloride; and
1-(4-Bromo-benzyI)-4-(4-But-2-ynyIoxy-benzenesulfinyl)-piperidine-4-carboxylic acid hydroxamide hydrochloride;
In the present invention "an effective amount" of the EGF receptor kinase inhibitor compound will vary with inter alia the individual patient and the severity of the disease, however generally it will be at least about 5 mg/kg. A preferred range is about 10 to 50 mg/kg.
In the present invention "an effective amount" of the TACE inhibitor compound will vary with a variety of factors including the individual patient and the severity of the disease. Typically the effective amount will be at least about 5 mg/kg. A preferred range is about 20 to 40 mg/kg.
The dosing schedule of the drug(s) may be from once to several times per day or may be less frequent. Preferably the dosing will be less frequent, for example dosing every other day, every third day or once a week.
In the present invention, the terms TACE inhibitor, TACE inhibitor compound, EGF receptor kinase inhibitor, and EGF receptor kinase inhibitor compound include all optical isomers and diastereomers as well as pharmaceutically acceptable salts.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains an acidic moiety.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomericaliy pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. It is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well. An effective amount of the compoundfs] of the invention are provided to the patient. The compounds may be provided orally, in liquid or solid form, or by injection. In addition the compound may be provided to the patient via a pro-drug route wherein the patient actually converts in vivo a substance given to him or her to one or more of the TACE inhibitors or EGF receptor kinase inhibitors of the present invention. The following examples are merely illustrative of the present invention. The invention is not to be limited thereby. Example 1 The bpk model of ARPKD
This model arose from a spontaneous mutation in a colony of BALB/C mice. Affected animals have many similarities to the human disease including collecting tubule (CT) cysts and biliary ectasia and fibrosis. The kidney disease has a consistent and severe phenotype. Mice homozygous for the bpk mutation have microscopic evidence of cyst formation at birth. Proximal tubule (PT) cysts are present at birth, which are gradually replaced by CT cysts as the disease progresses. Cyst expansion and kidney fibrosis result in death due to renal failure at 24-28 days. Heterozygotes show no phenotypic abnormalities and are identified by their ability to breed affected offspring. Unaffected (noncystic) littermates of cystic bpk mice are either wild-type or heterozygous at the bpk locus. TGF-α expression in bpk mice
Kidneys were obtained from cystic bpk mice and noncystic littermates at postnatal days 7, 14 and 21. Immunohistology was performed formaldehyde-fixed specimens embedded in plastic [See Sweeney WE et al.: Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor, Kidney Int. 57:33-40, 2000.] Primary antibody was a polyclonal anti-TGF-α (Chemicon, Temecula, CA) directed against recombinant 6 kD human TGF-α and reactive to mouse. Tubular localization of antibody staining was assessed by staining of serial sections with segment-specific biotinylated lectins. Protein was isolated from whole kidneys by homogenization in RIPA buffer
(phosphate buffered saline containing 1% nonidet P-40, 0.5% sodium deoxycholate, 0.1% SDS) with inhibitors (0.1 mg/ml aprotinin, 5μg/ml leupeptin, 50μg/ml pepstatin, 1mM EDTA, 1 mM PMSF and 1 : 100 v/v phosphatase inhibitor cocktail). Protein content of all samples was determined using the BCA protein assay kit (Pierce, Rockford, IL) and equal loading confirmed by Ponseau S solution staining of membranes following transfer. For Western blotting, 30μg of total protein lysate was diluted in SDS reducing buffer (62.5mM Tris-HCL, pH 6.8, 25% v/v glycerol, 2% w/v SDS, 0.01% w/v bromophenol blue, 5% v/v β-mercaptoethanol) and subjected to SDS-PAGE electrophoresis using a 12% separating gel. Samples were transferred to a nitrocellulose membrane, hybridized with blocking buffer (5% dry milk, 0.05% Tween 20), then hybridized with mouse monoclonal anti-TGF-α (Research Diagnostics, Flanders, NJ). Membranes were washed and hybridized with peroxidase conjugated anti-mouse antibody. Membranes were treated with ECL chemiluminesence reagent (Amersham Pharmacia Biotech, Piscataway, NJ) and exposed to autoradiography film. Cyst fluid from day 21 bpk mice was also examined for the presence of TGF-α by immunoprecipitation. 200 μg of total cyst fluid protein was immunoprecipitated with 2μg of primary antibody (polyclonal anti-TGF-α, Santa Cruz, CA), then Protein A G PLUS- agarose (Santa Cruz) added and the incubation continued. Pellets were collected by centrifugation, washed and resuspended in 1X SDS reducing buffer and boiled for 2-3 minutes. Example 2 Comparison Of 1 -Acetyl-4-(4-But-2-ynyloxy-Benzenesulfonyl)-2,3,4,5-Tetrahydro-
1H-[1,4]Benzodiazepine-3-Carboxylic Acid Hydroxyamide Treatment Of bpk Mice
And 1-Benzyl-4-[4-(4-Chloro-Phenoxy)-Benzenesulfonyl]-Piperidine-4-CarboxyIic
Acid Hydroxamide, (An MMP Inhibitor Without TACE Activity) Treatment Of bpk Mice
1-Acetyl-4-(4-But-2-vnyloxy-Benzenesulfonyl)-2,3,4.5-Tetrahydro-1H- f 1 ,41Benzodiazepine-3-Carboxylic Acid Hydroxyamide Treatment
Cystic bpk mice and phenotypically normal littermates were injected with a dose of 100 mg/kg/dose of 1 -acetyl-4-(4-but-2-ynyloxy-benzenesu!fonyl)-2,3,4,5-tetrahydro- 1 h-[1 ,4]benzodiazepine-3-carboxylic acid hydroxyamide given intraperitoneally once daily, in a vehicle containing 0.5% methocellulose (Fluka Biochemica, Ronkonkoma, NY) and 2% Tween 80 (JT Baker, Phillipsburg, NJ), beginning at postnatal day 7. Age- matched untreated cystic bpk mice and their noncystic littermates served as controls. At day 21 , mice were sacrificed. Blood was obtained by orbital puncture prior to sacrifice. Kidney weight and body weight for treated and untreated cystic and noncystic mice were measured at sacrifice. Blood urea nitrogen (BUN) was assessed using a colorimetric assay. Serum creatinine was assessed using standard techniques in the hospital laboratory. Differences in clinical and laboratory parameters between treated and untreated cystic and noncystic mice were analyzed by two-tailed Student's t-test.
Kidneys were fixed in 4% paraformaldehyde and embedded in plastic. Segment- specific localization of cysts was assessed using lectins specific to proximal tubule (Lotus tetragonolobus, LTA), and collecting tubule (Dolichos biflorus agglutinin, DBA). Serial LTA and DBA stained sections were examined by light microscopy and assessed for severity of cystic dilatations in PTs and CTs, expressed on a scale of 0 to 5 using a modified cystic index:
0 = No cysts
1 = < 0.11 mm
2 = 0.12-0.19 mm 3 = 0.20-0.27 mm
4 = 0.28-0.35 mm
5 = > 0.36 mm
The total number of CT (DBA+/LTA-) cysts and PT (LTA+/DBA-) cysts within a section were counted and expressed as a ratio. In order to determine if inhibition of secreted TGF-α affected total kidney expression of TGF-α protein, TGF-α expression in 1 -acetyI-4-(4-but-2-ynyloxy- benzenesulfonyl)-2,3,4,5-tetrahydro-1 h-[1 ,4]benzodiazepine-3-carboxylic acid hydroxyamide-treated and untreated cystic and noncystic animals was assessed by Western analysis as described in Example 1.
Treatment With 1 -Benzyl-4-r4-(4-Chloro-Phenoxy)-Benzenesulfonyll-Piperidine-4- Carboxylic Acid Hydroxamide. An MMP Inhibitor Without TACE Activity
Two litters of bpk mice and their noncystic littermates were treated with dosages of 50 mg/kg/day of 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]- piperidine-4-carboxylic acid hydroxamide given as once daily IP injections. Mice were treated from day 7 of life until day 21 , then sacrificed. Analysis of 1-benzyl- 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid hydroxamide treated mice included assessment of kidney weight to body weight ratio. The results are listed below in Tables 1, 2, and 3.
AM100599
Table 1. Clinical Parameters of 1-Acetyl-4-(4-But-2-ynyloxy-Benzenesulfonyl)-2,3,4,5-Tetrahydro-1H- [1 ,4]Benzodiazepine-3-Carboxylic Acid Hydroxyamide Treated and Untreated Mice
Figure imgf000050_0001
A=1-Acetyl-4-(4-But-2-ynyloxy-Benzenesulfonyl)-2,3,4,5-Tetrahydro-1 H-[1 ,4]Benzodiazepine-3-CarboxyIic Acid Hydroxyamide ** p<0.01 cystic treated compared to cystic untreated
AM100599
Table 2. Kidney Histology of 1 -Acetyl-4-(4-But-2-vnyloxy-Benzenesulfonyl)-2.3.4.5-Tetrahydro-1 H-H ,41Benzodiazepine-3- Carboxylic Acid Hydroxyamide Treated and Untreated Cystic Mice
Treatment Group CT Cystic Index CT Cyst Size PT Cystic Index PT Cyst Size Cystic CT/PT (graded 1-5) Range (mm) (graded 1-5) Range (mm) Ratio
Cystic No Treatment 4.8 +/- 0.4 0.012-0.41 1.4 +/- 0.5 0.012-0.13
Cystic +A 3.2 +/- 0.4 0.012-0.29 1.8 +/- 0.4 0.012-0.17 1.2*
A = 1-acetyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid hydroxyamide ** p<0.01 cystic treated compared to cystic untreated Table 3. MMP activity (IC 50) and treatment effect of A versus B
A = 1-acetyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[1 ,4]benzodiazepine-3-carboxylic acid hydroxyamide B = 1-BeπzyI-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidiπe-4-carboxylic acid hydroxamide

Claims

What is claimed is:
1. A method for treating, inhibiting the progression of, or eradicating polycystic kidney disease in a mammal in need thereof which comprises providing to said mammal an effective amount of a TACE inhibitor compound.
2. A method for treating, inhibiting the progression of, or eradicating polycystic kidney disease in a mammal in need thereof which comprises providing to said mammal a combination of an effective amount of a TACE inhibitor compound and an effective amount of an EGF receptor kinase inhibitor.
3. The method according to claim 1 or 2 wherein the TACE inhibitor compound is a compound of formula I:
Figure imgf000052_0001
wherein:
X is SO2 or -P(O)-R10;
Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;
Z is O, NH, CH2 or S; R-| is hydrogen, aryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms; R2 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 3-6 carbon atoms, C4-C8 cycloheteroalkyl, alky! of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms; or Ri and R2, together with the atom to which they are attached, may form a ring wherein R^ and R2 represent a divalent moiety of the formula:
Figure imgf000052_0002
wherein Q = a carbon-carbon single or double bond, O, S, SO, SO2, -N-Rn, or
-CONR14; m = 1-3; r = 1 or 2, with the proviso that when Q is a bond, r is equal to 2; R3 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, C4-C8 cycloheteroalkyl, aralkyl, or heteroaralkyl; or Ri and R3, together with the atoms to which they are attached, may form a 5 to
8 membered ring wherein R^ and R3 represent divalent moieties of the formulae:
Figure imgf000053_0001
f wherein Q and m are as defined above; A is aryl or heteroaryl; s is 0-3; u is 1-4; R and R5 are each, independently, hydrogen or alkyl of 1-6 carbon atoms,
-CN, or -CCH;
R6 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or - C5-C8-cycIoheteroalkyI; R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, or -C4-C8-cycloheteroalkyl; R-io is alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl; R11 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, -S(O)nR8, -COOR8, -CONR8R9, -SO2NR8R9 or -COR8; R12 and R13 are independently selected from H, -OR8, -NR8R9, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, -COOR8; -CONR8R9; or R12 and R13 together form a -C3-C6-cycloalkyl of 3-6 carbon atoms or a - C5-Cδ-cycloheteroalkyl ring; or R12and R13ι together with the carbon to which they are attached, form a carbonyl group; with the proviso that R-io and R-ι2 or Rn and Rι2 may form a cycloheteroalkyl ring when they are attached to adjacent atoms; R14 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; and n is 0-2; or a pharmaceutically acceptable salt thereof.
4. The method according to claim 3 wherein the compound is a compound of formula II:
Figure imgf000054_0001
wherein
R6 is as defined in claim 3; R7 is H or alkyl; and R15 is alkyl.
5. The method according to claim 4 wherein R6 is CH3 or CH2OH; R7 is H or methyl; and R15 is isopropyl or CH(CH3)OH.
6. The method according to claim 3 wherein the compound is a compound of formula
Figure imgf000054_0002
(III) wherein R6 is defined as in claim 3 with methyl and CH2OH being preferred; and Rι6 and R17 are alkyl preferably methyl.
7. The method according to claim 6 wherein R6 is methyl or CH2OH; and Rι6 and R-i7 are methyl.
8. The method according to claim 3 wherein the compound is selected from the group consisting of 4-(4-but-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3- carboxylic acid hydroxyamide; (3S)-N-hydroxy-4-({4-[(4-hydroxy-2- butynyl)oxy]phenyl}sulfonyI)-2,2-dimethyI-3-thiomorpholinecarboxamide; (2R)-N- hydroxy-2-[({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyI)(methyl)amino]-3- methylbutanamide; and (2R,3S)-2-({[4-(2-butynyIoxy)phenyl]sulfonyl}amino)-N,3- dihydroxybutanamide; or a pharmaceutically acceptable salt thereof.
9. A method for treating, inhibiting the progression of, or eradicating polycystic kidney disease in a mammal in need thereof which comprises providing to said mammal an effective amount of a TACE inhibitor compound of formula IV:
Figure imgf000055_0001
(IV)
wherein R6 is as defined in claim 3.
10. The method according to claim 9 wherein R6 is methyl.
11. The method according to claim 2 wherein the EGF receptor kinase inhibitor is 4- dimethylamineo-but-2-enoic acid [4-(3-chIoro-4-fluoro-phenylamino)-3-cyano-7- ethoxy-quinolin-6-yI]-amide.
PCT/US2002/010751 2001-04-11 2002-04-05 Method for the treatment of polycystic kidney disease WO2002083112A2 (en)

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US10/473,857 US7488754B2 (en) 2002-04-05 2002-04-05 Method for the treatment of polycystic kidney disease
AU2002256095A AU2002256095A1 (en) 2001-04-11 2002-04-05 Method for the treatment of polycystic kidney disease

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Cited By (9)

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Publication number Priority date Publication date Assignee Title
US7629341B2 (en) 2002-06-12 2009-12-08 Symphony Evolution, Inc. Human ADAM-10 inhibitors
US7989661B2 (en) 2002-06-12 2011-08-02 Symphony Evolution, Inc. Human ADAM-10 inhibitors
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EP1781318A2 (en) * 2004-06-23 2007-05-09 Genzyme Corporation Methods and compositions for the treatment of polycystic diseases
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WO2006042100A2 (en) * 2004-10-08 2006-04-20 Wyeth Method for the treatment of polycystic kidney disease
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