WO1998016514A1 - Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors - Google Patents

Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors Download PDF

Info

Publication number
WO1998016514A1
WO1998016514A1 PCT/US1997/018281 US9718281W WO9816514A1 WO 1998016514 A1 WO1998016514 A1 WO 1998016514A1 US 9718281 W US9718281 W US 9718281W WO 9816514 A1 WO9816514 A1 WO 9816514A1
Authority
WO
WIPO (PCT)
Prior art keywords
carboxylic acid
hydroxyamide
amino
pyrazolo
pyridin
Prior art date
Application number
PCT/US1997/018281
Other languages
French (fr)
Inventor
Jeremy Ian Levin
Arie Zask
Yansong Gu
Jay Donald Albright
Xumei Dui
Original Assignee
American Cyanamid Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Cyanamid Company filed Critical American Cyanamid Company
Priority to AU49806/97A priority Critical patent/AU743901B2/en
Publication of WO1998016514A1 publication Critical patent/WO1998016514A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the discovery of novel, low molecular weight, non- peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF- ⁇ converting enzyme (TACE, tumor necrosis factor- ⁇ converting enzyme) which are useful for the treatment of diseases in which these enzymes arc implicated such as arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system and HIV infection.
  • matrix metalloproteinases e.g. gelatinases, stromelysins and collagenases
  • TACE tumor necrosis factor- ⁇ converting enzyme
  • MMPs Matrix metalloproteinases
  • endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of osteoarthritis [Howell, D.S.; Pelletier, J.-P. In Arthritis and Allied Conditions; McCarthy, D.J.; Koopman, W.J., Eds.; Lea and Febiger: Philadelphia, 1993; 12th Edition Vol. 2, pp. 1723; Dean, D.D. Sem. Arthritis Rheum.
  • Angiogenesis required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology [Crawford, H.C; Matrisian, L.M. Invasion Metast. 1994-95, 14, 234; Ray, J.M.; Stetler- Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323.].
  • MMPs diseases mediated by MMPs
  • Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection.
  • MMPs are important mediators of the tissue destruction that occurs in arthritis.
  • these enzymes are capable of degrading collagens and proteoglycans which are the major structural components of cartilage [Sapolsky, A.I.; Keiser, H.; Howell, D.S.; Woessner, J.F., Jr.; J. Clin. Invest. 1976, 58, 1030; Pelletier, J.-P.; Martel-Pelletier, J.; Howell, D.S.; Ghandur- Mnaymneh, L.; Enis, J.E.; Woessner, J.F., Jr., Arthritis Rheum.
  • MMP-13 collagenase-3
  • MMP-13 is produced by chondrocytes, and elevated levels of MMP-13 has been found in human osteoarthritic tissues [Reboul, P.; Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J. Arthritis Rheum. 1995, 38 (Suppl. 9), S268;Shlopov, B.V.; Mainardi, C.L.; Hasty, K.A. Arthritis Rheum. 1995, 38 (Suppl.
  • TNF- ⁇ converting enzyme catalyzes the formation of TNF- ⁇ from membrane bound TNF- ⁇ precursor protein.
  • TNF- ⁇ is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, insulin resistance and HIV infection in addition to its well documented antitumor properties.
  • anti-TNF- ⁇ antibodies and transgenic animals have demonstrated that blocking the formation of TNF- ⁇ inhibits the progression of arthritis [Rankin, E.C.; Choy, E.H.; Kassimos, D.; Kingsley, G.H.; Sopwith, A.M.; Isenberg, D.A.; Panayi, G.S. Br. J.
  • TNF- ⁇ thelial growth factor- ⁇
  • Other conditions mediated by TNF- ⁇ are congestive heart failure, cachexia, anorexia, inflammation, fever, inflammatory disease of the central nervous system, and inflammatory bowel disease.
  • patents 5,455,258, 5,506,242 and 5,552,419, as well as European patent application EP606,046A1 and WIPO international publications WO96/00214 and WO97 22587 disclose non-peptide matrix metalloproteinase inhibitors of which the compound CGS27023A is representative. The discovery of this type of MMP inhibitor is further detailed by MacPherson, et. al. in J. Med. Chem., (1997),40, 2525.
  • German patent application DE 19,542, 189- A 1 discloses additional examples of cylic sulfonamides as MMP inhibitors.
  • the sulfonamide-containing ring is fused to a phenyl ring to form an isoquinoline.
  • TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by the formula
  • hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons of group A where:
  • A is a 5-6 membered heteroaryl having from 1 to 2 heteroatoms independently selected from N, O, and S, and substituted by R 1 and R 2 on adjacent carbons wherein R 1 and R 2 together with the carbons to which they are attached form a fused phenyl ring or a 5-6 membered heteroaryl ring having from 1 to 3 heteroatoms selected independently from N, O and S, wherein either ring can be substituted by one or more substituents selected from R 4 ;
  • Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, where aryl is phenyl or naphthyl optionally substituted by R 1 , R 2 , R 3 and
  • heteroaryl is a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, O, and S, and optionally substituted by R 1 , R 2 , R 3 and R 4 ; and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R 1 , R 2 , R 3 and R 4 ;
  • R 1 , R 2 , R 3 and R 4 are independently -H, -COR 5 , -F,-Br, -Cl, -I,
  • R 5 and R 6 are independently defined as H, aryl and heteroaryl as defined above, -C3-C6-cycloalkyl as defined above, -C3-C6-cycloheteroalkyl as defined above, -C ⁇ -C4-perfluoroalkyl, or straight chain or branched -Ci- alkyl, -C2-C6-alkenyl, or -C2-C6-alkynyl each optionally substituted with -OH, -COR 8 , -CN, -C(O)NR8QR 9 , -C 2 -C 6 -alkenyl, -C 2 -C6-alkynyl, -OR 8 , -C ⁇ -C4-perfluoroalkyl, -S(O) x R 8 where x is 0-2, -OPO(OR )OR 9 , -PO(OR 8 )R9, -OC(O)NR R 9 ,
  • R 7 is hydrogen, straight chain or branched -C ⁇ -C6-alkyl, -C2-C6-alkenyl, or -C2- C ⁇ -alkynyl each optionally substituted with -OH, -COR 5 , -CN, -C2-C6- alkenyl, -C 2 -C 6 -alkynyl, -OR 5 , -Ci-Q-perfluoroalkyl, -S(O) x R 5 where x is 0-2, -OPO(OR 5 )OR 6 , -PO(OR 5 )R 6 , -OC(O)NR 5 R 6 , - COOR 5 , -CONR 5 R 6 , -SO3H, -NR 5 R 6 ,-NR 5 COR 6 , -NR 5 COOR 6 , - SO NR 5 R6, -NO2, -N(R )SO 2 R 6 , -NR 5 CONR 5 R 6
  • R 7 CH 2 -N-A- where A is as defined above, can form a non-aromatic 7-12 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring;
  • R 8 and R 9 are independently H, aryl or heteroaryl as defined above, -C3-C7- cycloalkyl or cycloheteroalkyl as defined above, -Ci-C perfluoroalkyl, straight chain or branched -C ⁇ -C6-alkyl, -C2-C6-alkenyl, or -C2-C6- alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy, -Ci- -perfluoroalkyl, amino, mono- and di-Ci- -alkylamino, carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono- and di-Ci-C ⁇ -alkylcarbamoyl; and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.
  • Preferred compounds are those wherein both of the carbons of A adjacent to the carbon bearing the sulfonamido group have a substituent other than hydrogen. Also preferred are compounds where Z is 4-alkoxyphenyl, 4-aryloxyphenyl or 4- heteroaryloxyphenyl.
  • heteroaryl as defined hereinabove includes, but is not limited to, pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine,triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole and oxazole.
  • heteroaryl fused to a phenyl includes, but is not limited to, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole.
  • Compound V a) Denzel, T; Hoehn, H J. Heterocyclic Chem. (1977), 14, 813-817. b) Al-Shaar, AHM; Chambers, RK; Gilmour, DW; Lythgoe, DJ; McClenaghan, I; Ramsden, CA J. Chem. Soc; Perkin Trans. I (1992) 21, 2789-2812. c) Elworthy, T.R.; Ford, A.P.D.; et.al. J. Med. Chem. (1997), 40(17), 2674-2687.
  • Compound VI a) Forbes, IT; Johnson, CN; Jones, GE; Loudon, J; Nicholass, JM J. Med.
  • the compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-
  • MMP-13 and TNF- ⁇ converting enzyme are therefore useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HTV infection.
  • the invention compounds are prepared using conventional techniques known to those skilled in the art of organic synthesis.
  • the following scheme (Scheme I) illustrates the reaction sequence employed.
  • the bicyclic heteroaryl group A shown is a quinoline, 4-chloro-7-trifluoromethylquinoUne-3-carboxyUc acid ethyl ester, prepared from the corresponding aniline, is reacted with N-benzyl-p- methoxybenzenesulfonamide, wherein Z is p-methoxybenzene, to provide the requisite N ⁇ V-disubstituted sulfonamido-ester which is then converted into the corresponding hydroxamic acid in two steps.
  • the 4-chloroquinoline carboxylic acid ester could be first reacted with R 7 -NH 2 and the resulting 4-(R 7 -amino)quinoline carboxylic acid ester then reacted with the appropriate Z-SO 2 -Cl. Hydrolysis of the ester and reaction with hydroxylamine hydro- chloride would then give the invention compound.
  • haloquinolines may also be accomplished via palladium catalyzed couplings of alkynes, as illustrated in Scheme HI. Hydrogenation of the alkynes accesses the olefins and alkanes as well.
  • Schemes IV and V illustrate two methods for incorporating amino groups into the substituent attached to the sulfonamide nitrogen of the compounds of the invention.
  • the NH- sulfonamide is alkylated with propargyl bromide to provide the propargyl sulfonamide.
  • This alkyne is reacted with paraformaldehyde in the presence of a primary or secondary amine and cuprous chloride to give the propargyl amine which is converted, as before, to the desired hydroxamic acid.
  • Schemes VI through VIII Methods for synthesizing variations of substituents on the sulfonyl aryl group are shown in Schemes VI through VIII.
  • biaryl sulfonyl groups are synthesized by Suzuki couplings on a bromo- substituted benzene sulfonamide.
  • the starting bromo-substituted benzene sulfonamide is synthesized from the commercially available bromobenzenesulfonyl chloride and the amino-acid or amino-ester, H 2 N-A-CO 2 R, followed by alkylation of the resulting NH- sulfonamide.
  • the bromo aryl sulfonamide is converted into the corresponding boronic acid by the method of Ishiyama, et.al. [J. Org. Chem. (1995), 60, 7508] followed by coupling with an appropriate aryl halide.
  • Schemes VII through IX Methods for synthesizing sulfonyl aryl ethers are shown in Schemes VII through IX.
  • biaryl ethers, or aryl heteroaryl ethers are synthesized starting from the known sulfonyl chlorides (see for example: Zook SE; Dagnino, R; Deason, ME, Bender, SL; Melnick, MJ WO 97/20824). 8/16514
  • the biaryl ethers may be prepared from the corresponding boronic acids or via the sulfonyl phenols as shown in Scheme VIH
  • Aryl ethers may also be prepared via displacement of the fluorine from a para- fluorobenzene sulfonamide, as shown in Scheme DC.
  • Aryl or alkyl ethers may be prepared in this manner.
  • Scheme X illusstrates the synthesis of pyrazolopyridines of the invention.
  • a substituted amino-pyrazole is condensed with ethoxymethylene malonate to provide the pyrazolylamino methylene malonate, B.
  • This compound is converted into the pyrazolopyridine, C, by heating at 240°C.
  • Compound C is then converted into the chloro- ester, D, via reaction with phosphorus oxychloride.
  • Displacement of the chloro substituent with a sulfonamide then gives compound E.
  • Hydrolysis of the ester and conversion of the carboxylate into the hydroxamate then gives compound G.
  • Scheme X illusstrates the synthesis of pyrazolopyridines of the invention.
  • Example 15 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-trifluoromethyl- quinoline-3-carboxylic acid hydroxyamide
  • Example 31 4-[Methyl-(4-methoxy-benzenesulfonyl)-amino]- 8-bromo-quinoline-3- carboxylic acid hydroxyamide
  • the mixture was heated in an oil bath at 50°C overnight and then was heated in an oil bath at 100° C for 1.5 days.
  • the mixture was poured into 800 ml of water and extracted with ethyl acetate.
  • the extract was washed with water, 2N citric acid, water, brine and dried (Na 2 SO_j).
  • the solvent was removed and the residue chromatographed on sihca gel with hexane-ethyl acetate (2:1) as eluent to give 0.64 g of product as a solid, mp 170-172°.
  • the mixture was stirred in a sealed tube under nitrogen in an oil bath at 90°C for 3 days.
  • the mixture was cooled, poured into water and extracted with ethyl acetate.
  • the extract was washed with H 2 0, brine and dried (Na 2 S0 ).
  • the solution was filtered through a thin pad of hydrous magnesuim silicate and the filter pad washed with ethyl acetate.
  • the filtrate was concentrated to dryness under vacuum to give 1.3 g of solid. Chromatography on silica gel with ethyl acetate as solvent gave 0.35 g of product as a solid, mp 152-154°C.
  • the solvent was removed under vacuum and the residue diluted with H 2 O, acidified with 2 N citric acid and extracted with two 30-ml portions of CH 2 C1 2 .
  • the aqueous layer was neutrallized with solid NaHCO 3 to bring the pH to 7.
  • the soUd which precipitated was filtered and washed with H 2 O to give 0.610 g of product as a solid, mp. 202-204°C.
  • the CH 2 C1 2 extract was extracted with 2 N citric acid and the aqueous layer neutralized with soUd NaHCO 3 .
  • the precipitated solid was filtered off and washed with water to give 0.226 g of product, mp 196-198°C. (mass spectrum (ES) 483.5 (M+l).
  • Example 47 Following the procedure of Example 49, the product of Example 47 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl- (4-methoxybenzenesulfonyl)amino]-l-phenyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 124°-126°C.
  • Example 47 Following the procedure of Example 53, the product of Example 47 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-phenyl-lH-pyrazolo[3,4- b]pyridine-5-carboxylate. m.p. 89°-91°C.
  • Example 65 Ethyl 4-chloro-l-phenyI-3-methyI-lH-pyrazolo [3,4-b]pyridine-5- carboxylate
  • Example 65 Following the procedure of Example 49, the product of Example 65 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl- (4-methoxybenzenesulfonyl)amino]-l-phenyl-3-methyl-lH-pyrazolo[3,4-b]pyridine-5- carboxylate. m.p. 164°-166°C.
  • Example 65 Following the procedure of Example 53, the product of Example 65 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl-4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]- 1 -phenyl-3- methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 148°-150°C.
  • Example 54 Following the procedure of Example 54, the above ester is hydrolyzed to provide 4- [(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-phenyl-3-methyl-lH- pyrazolo[3,4-b]pyridine-5-carboxylic acid. m.p. 235°-236°C.
  • the carboxyUc acid is converted into the corresponding hydroxamic acid, 4-[(4-memoxybenzenesulfonyl)pyridin-3-ylmethylarnino]- l-phenyl-3-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide. m.p. 192°-194°C.
  • Example 67 Following the procedure of Example 61, the product of Example 67 is converted into the corresponding hydrochloride salt. m.p.225°-226°C.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • Example 82 4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-methyI-3- phenyl-lH-pyrazoIo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • the tide compound may be prepared.
  • thiopeptide substrates such as Ac-Pro- Leu-Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt by the matrix metalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9 (gelatinase), which results in the release of a substrate product that reacts colorimetrically with DTNB (5,5'-dithiobis(2-nitro-benzoic acid)).
  • DTNB 5,5'-dithiobis(2-nitro-benzoic acid)
  • the thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl2) before use. The stock of enzyme is diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to the desired final concentration.
  • substrate buffer 50 mM HEPES pH 7.5, 5 mM CaCl2
  • assay buffer 50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij
  • the assay buffer, enzyme, vehicle or inhibitor, and DTNB/substrate are added in this order to a 96 weU plate (total reaction volume of 200 ⁇ l) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader and the increase in color over time is plotted as a linear line.
  • a fluorescent peptide substrate is used.
  • the peptide substrate contains a fluorescent group and a quenching group.
  • MMP Upon cleavage of the substrate by an MMP, the fluorescence that is generated is quantitated on the fluorescence plate reader.
  • the assay is run in HCBC assay buffer (50mM HEPES, pH 7.0, 5 mM Ca +2 , 0.02% Brij, 0.5% Cysteine), with human recombinant MMP-1, MMP-9, or MMP- 13.
  • the substrate is dissolved in methanol and stored frozen in 1 mM aliquots.
  • substrate and enzymes are diluted in HCBC buffer to the desired concentrations.
  • the slope of the line is calculated and represents the reaction rate.
  • the linearity of the reaction rate is confirmed (r >0.85).
  • the mean (x ⁇ sem) of the control rate is calculated and compared for statistical significance (p ⁇ 0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generated using multiple doses of drug and IC50 values with 95% Cl are estimated using linear regression.
  • a 2 cm piece of dialysis tubing (molecular weight cut-off 12-14,000, 10 mm flat width) containing matrix metalloproteinase enzyme (stromelysin, coUagenase or gelatinase in 0.5 mL of buffer) is implanted either ip or sc (in the back) of a rat (Sprague-Dawley, 150-200g) or mouse (CD-I, 25-50g) under anesthesia.
  • Drugs are administered PO, IP, SC or IV through a canula in the jugular vein. Drugs are administered in a dose volume of 0.1 to 0.25 mL/animal. Contents of the dialysis tubing is collected and enzyme activity assayed.
  • Enzyme reaction rates for each dialysis tube are calculated. Tubes from at least 3 different animals are used to calculate the mean ⁇ sem. Statistical significance (p ⁇ 0.05) of vehicle-treated animals versus drug- treated animals is determined by analysis of variance. (Agents and Actions 21: 331, 1987).
  • each well receives a solution composed of 10 ⁇ L TACE (Immunex, final concentration l ⁇ g/mL), 70 ⁇ L Tris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM), and 10 ⁇ L of test compound solution in DMSO (final concentration l ⁇ M, DMSO concentration ⁇ 1%) and incubated for 10 minutes at room temperature.
  • the reaction is initiated by addition of a fluorescent peptidyl substrate (final concentration 100 ⁇ M) to each well and then shaking on a shaker for 5 sec.
  • the reaction is read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the Une is calculated and represents the reaction rate.
  • the Unearity of the reaction rate is confirmed (r 2 >0.85).
  • the mean (x ⁇ sem) of the control rate is calculated and compared for statistical significance (p ⁇ 0.05) with drug- treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generate using multiple doses of drug and IC50 values with 95% Cl are estimated using linear regression.
  • Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof.
  • the pharmaceutical carrier may be solid or liquid.
  • Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabiUzers or osmo-regulators.
  • liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., ceUulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utiUzed by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or soUd composition form.
  • the compounds of this invention may be administered rectally in the form of a conventional suppository.
  • the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
  • the dosage to be used in the treatment of a specific patient suffering a MMP or TACE dependent condition must be subjectively determined by the attending physician.
  • the variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient.
  • Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached.
  • Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles.
  • the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing Uquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

Abstract

The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-α converting enzyme (TACE, tumor necrosis factor-α converting enzyme) which are useful for the treatment of diseases in which theses enzymes are implicated such as arthritis, tumor growth and metastasis, angiogenesis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, HIV infection, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization. The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by formula (I) where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons of the heteroaryl ring of group A where: A is a 5-6 membered heteroaryl having from 1 to 3 heteroatoms independently selected from N, O and S fused to a phenyl ring, or another 5-6 membered heteroaryl having from 1 to 3 heteroatoms independently selected from N, O and S, and either; and Z, R?1, R2, R3, R4, R5, R6, R7, R8 and R9¿ are described in the specification, and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.

Description

ORTHO-SULFONAMIDO BICYCLIC HETEROARYL HYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASE AND TACE INHIBITORS
Background of the Invention
The present invention relates to the discovery of novel, low molecular weight, non- peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF-α converting enzyme (TACE, tumor necrosis factor-α converting enzyme) which are useful for the treatment of diseases in which these enzymes arc implicated such as arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system and HIV infection.
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes [Woessner, J.F., Jr. FASEB J. 1991, 5, 2145; Birkedal-Hansen, H.; Moore, W.G.I.; Bodden, M.K.; Windsor, L.J.; Birkedal-Hansen, B.; DeCarlo, A.; Engler, J.A. Crit. Rev. Oral Biol. Med. 1993, 4, 197; Cawston, T.E. Pharmacol. Ther. 1996, 70, 163; Powell, W.C.; Matrisian, L.M. Cur. Top. Microbiol. and Immunol. 1996, 213, 1]. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors, while the collagenases have been associated with the pathogenesis of osteoarthritis [Howell, D.S.; Pelletier, J.-P. In Arthritis and Allied Conditions; McCarthy, D.J.; Koopman, W.J., Eds.; Lea and Febiger: Philadelphia, 1993; 12th Edition Vol. 2, pp. 1723; Dean, D.D. Sem. Arthritis Rheum. 1991, 20, 2; Crawford, H.C; Matrisian, L.M. Invasion Metast. 1994- 95, 14, 234; Ray, J.M.; Steder-Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323].
It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which may lead to tumor metastasis [Powell, W.C.; Matrisian, L.M. Cur. Top. Microbiol. and Immunol. 1996, 213, 1; Crawford, H.C; Matrisian, L.M. Invasion Metast. 1994-95, 14, 234; Ray, J.M.; Stetler- Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323; Hirnelstein, B.P.; Canete- Soler, R.; Bernhard, E.J.; Dilks, D.W.; Muschel, R.J. Invasion Metast. 1994-95, 14, 246; Nuovo, G.J.; MacConnell, P.B.; Simsir, A.; Valea, F.; French, D.L. Cancer Res. 1995, 55, 267-275; Walther, M.M.; Levy, A.; Hurley, K.; Venzon, D.; Linehen, W.M. Stetler-Stevenson, W. /. Urol. 1995, 755 (Suppl. 4), 403A; Tokuraku, M; Sato, H. Murakami, S.; Okada, Y.; Watanabe, Y.; Seiki, M. Int. J. Cancer, 1995, 64, 355 Himelstein, B.; Hua, J.; Bernhard, E.; Muschel, R.J. Proc. Am. Assoc. Cancer Res. Ann Meet. 1996, 37, 632; Ueda, Y.; Imai, K.; Tsuchiya, H.; Fujimoto, N.; Nakanishi, I. Katsuda, S.; Seiki, M.; Okada, Y. Am. J. Pathol. 1996, 148, 611; Gress, T.M.; Mueller- Pillasch, F.; Lerch, M.M.; Friess, H.; Buechler, M.; Adler, G. Int. J. Cancer, 1995, 62, 407; Kawashima, A.; Nakanishi, I.; Tsuchiya, H.; Roessner, A.; Obata, K.; Okada, Y. Virchows Arch., 1994, 424, 547-552.]. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology [Crawford, H.C; Matrisian, L.M. Invasion Metast. 1994-95, 14, 234; Ray, J.M.; Stetler- Stevenson, W.G. Exp. Opin. Invest. Drugs, 1996, 5, 323.]. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis [Dollery, CM.; McEwan, J.R.; Henney, A.M. Circ. Res. 1995, 77, 863; Zempo, N.; Koyama, N.; Kenagy, R.D.; Lea, H.J.; Clowes, A.W. Arterioscler. Thromb. Vase. Biol. 1996, 16, 28; Lee, R.T.; Schoen, F.J.; Loree, H.M.; Lark, M.W., Libby, P. Arterioscler. Thromb. Vase. Biol. 1996, 16, 1070.]. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection.
The hypothesis that MMPs are important mediators of the tissue destruction that occurs in arthritis has long been considered, since it was first recognized that these enzymes are capable of degrading collagens and proteoglycans which are the major structural components of cartilage [Sapolsky, A.I.; Keiser, H.; Howell, D.S.; Woessner, J.F., Jr.; J. Clin. Invest. 1976, 58, 1030; Pelletier, J.-P.; Martel-Pelletier, J.; Howell, D.S.; Ghandur- Mnaymneh, L.; Enis, J.E.; Woessner, J.F., Jr., Arthritis Rheum. 1983, 26, 63.], and continues to develop as new MMPs are identified. For example, collagenase-3 (MMP-13) was cloned from breast cancer cells in 1994, and the first report that it could be involved in arthritis appeared in 1995 [Freiji, J.M.; Diez-Itza, I.; Balbin, M.; Sanchez, L.M.; Blasco, R.; Tolivia, J.; Lopez-Otin, C. J. Biol. Chem. 1994, 269, 16766; Flannery, C.R.; Sandy, J.D. 102-17, 41st Ann. Meet. Orth. Res. Soc. Orlando, FL. February 13-16, 1995.]. Evidence is accumulating that implicates MMP-13 in the pathogenesis of arthritis. A major structural component of articular cartilage, type II collagen, is the preferred substrate for MMP-13 and this enzyme is significandy more efficient at cleaving type II collagen than the other collagenases [Knauper, V.; Lopez-Otin, C; Smith, B.; Knight, G.; Murphy, G. J. Biol. Chem., 1996, 271, 1544-1550; Mitchell, P.G.; Magna, H.A.; Reeves, L.M.; Lopresti-Morrow, L.L.; Yocum, S.A.; Rosner, P.J.; Geoghegan, K.F.; Hambor, J.E. J. Clin. Invest. 1996, 97, 761.]. MMP-13 is produced by chondrocytes, and elevated levels of MMP-13 has been found in human osteoarthritic tissues [Reboul, P.; Pelletier, J-P.; Hambor, J.; Magna, H.; Tardif, G.; Cloutier, J-M.; Martel-Pelletier, J. Arthritis Rheum. 1995, 38 (Suppl. 9), S268;Shlopov, B.V.; Mainardi, C.L.; Hasty, K.A. Arthritis Rheum. 1995, 38 (Suppl. 9), S313; Reboul, P.; Pelletier, J-P.; Tardif, G.; Cloutier, J-M.; Martel- Pelletier, J. /. Clin. Invest. 1996, 97, 2011]. Potent inhibitors of MMPs were described over 10 years ago, but the poor bioavailability of these early peptidic, substrate mimetic MMP inhibitors precluded their evaluation in animal models of arthritis. More bioavailable, non-peptidic MMP inhibitors may be preferred for the treatment of diseases mediated by MMPs.
TNF-α converting enzyme catalyzes the formation of TNF-α from membrane bound TNF-α precursor protein. TNF-α is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, insulin resistance and HIV infection in addition to its well documented antitumor properties. For example, research with anti-TNF-α antibodies and transgenic animals has demonstrated that blocking the formation of TNF-α inhibits the progression of arthritis [Rankin, E.C.; Choy, E.H.; Kassimos, D.; Kingsley, G.H.; Sopwith, A.M.; Isenberg, D.A.; Panayi, G.S. Br. J. Rheumatol. 1995, 34, 334; Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), aul97-M2Z.]. This observation has recently been extended to humans as well. Other conditions mediated by TNF-α are congestive heart failure, cachexia, anorexia, inflammation, fever, inflammatory disease of the central nervous system, and inflammatory bowel disease.
It is expected that small molecule inhibitors of gelatinase and TACE therefore have the potential for treating a variety of disease states. While a variety of MMP and TACE inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic or peptide-like compounds that may have bioavailability and pharmacokinetic problems that would limit their clinical effectiveness. Low molecular weight, potent, long-acting, orally bioavailable inhibitors of gelatinases, collagenases and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states. Several non-peptidc, sulfur-containing hydroxamic acids have recently been disclosed and are listed below. U. S. patents 5,455,258, 5,506,242 and 5,552,419, as well as European patent application EP606,046A1 and WIPO international publications WO96/00214 and WO97 22587 disclose non-peptide matrix metalloproteinase inhibitors of which the compound CGS27023A is representative. The discovery of this type of MMP inhibitor is further detailed by MacPherson, et. al. in J. Med. Chem., (1997),40, 2525. Additional publications disclosing sulfonamide based MMP inhibitors which are variants of the sulfonamide-hydroxamate shown below, or the analogous sulfonamide-carboxylates, are European patent application EP-757984-A1 and WIPO international pubhcations WO95/35275, WO95/35276, WO96/27583, WO97/19068 and WO97/27174.
Figure imgf000006_0001
CGS 27023A
Publications disclosing β-sulfonamide-hydroxamate MMP inhibitor analogs of CGS 27023A in which the carbon alpha to the hydroxamic acid has been joined in a ring to the sulfonamide nitrogen, as shown below, include WIPO international publications WO96/33172 and WO97/20824.
Figure imgf000006_0002
The German patent application DE 19,542, 189- A 1 discloses additional examples of cylic sulfonamides as MMP inhibitors. In this case the sulfonamide-containing ring is fused to a phenyl ring to form an isoquinoline.
Figure imgf000007_0001
Analogs of the sulfonamide-hydroxamate MMP inhibitors in which the sulfonamide nitrogen has been replaced by a carbon atom, as shown in the general structure below, are European patent application EP-780386-A1 and WIPO international pubUcation WO97/24117.
Figure imgf000007_0002
Summary of the Invention
The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by the formula
Figure imgf000007_0003
where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons of group A where:
A is a 5-6 membered heteroaryl having from 1 to 2 heteroatoms independently selected from N, O, and S, and substituted by R1 and R2 on adjacent carbons wherein R1 and R2 together with the carbons to which they are attached form a fused phenyl ring or a 5-6 membered heteroaryl ring having from 1 to 3 heteroatoms selected independently from N, O and S, wherein either ring can be substituted by one or more substituents selected from R4;
Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, where aryl is phenyl or naphthyl optionally substituted by R1, R2, R3 and
R4; heteroaryl is a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, O, and S, and optionally substituted by R1, R2, R3 and R4; and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R1, R2, R3 and R4;
R1, R2, R3 and R4 are independently -H, -COR5, -F,-Br, -Cl, -I,
-C(O)NR5OR6,-CN, -OR5,-Cι-C4-perfluoroalkyl, -S(O)xR5 where x is 0-2, -OPO(OR5)OR6, -PO(OR6)R5, -OC(O)NR5R6, -COOR5, -CONR5R6, -SO3H, -NR R6, -NR5COR6, -NR COOR6, -SO2NR5R6, -NO2, -N(R5)SO2R6, -NR5CONR5R6, -NR5C(=NR6)NR5R6, 3-6 membered cycloheteroalkyl having one to three heteroatoms independently selected from N, O, and S and optionally having 1 or 2 double bonds and optionally substituted by one to three groups each selected independently from R ; -aryl or heteroaryl as defined above, -SO2NHCOR5or -CONHSO2R5 where R5 is not H; -tetrazol-5-yl, -SO2NHCN, -SO2NHCONR5R6 or straight chain or branched -C1-C6 alkyl, -C2-C6-alkenyl, or -C2-C6-alkynyl, or -C3-C6- cycloalkyl optionally having 1 or 2 double bonds each optionally substituted with -COR5, -CN, -C2-C6 alkenyl, -C2-C6 alkynyl,-OR5, -C1-C4- perfluoroalkyl, -S(O)xR5 where x is 0-2, -OC(O)NR5R6, -COOR5, -CONR5R6, -SO3H, -NR5R6,-NR5COR6, -NR5COOR6, - SO2NR5R6, -NO2, -N(R )SO2R6, -NR5CONR5R6, -C3-C6 cycloalkyl as defined above, 3-6 membered cycloheteroalkyl as defined above, aryl or heteroaryl as defined above, -SO2NHCOR5 or-CONHSO2R5 where R5 is not hydrogen, -PO(OR5)OR6, -
PO(OR6)R5, -tetrazol-5-yl, -C(O)NR5OR6, -
Figure imgf000008_0001
R5 and R6 are independently defined as H, aryl and heteroaryl as defined above, -C3-C6-cycloalkyl as defined above, -C3-C6-cycloheteroalkyl as defined above, -Cι-C4-perfluoroalkyl, or straight chain or branched -Ci- alkyl, -C2-C6-alkenyl, or -C2-C6-alkynyl each optionally substituted with -OH, -COR8, -CN, -C(O)NR8QR9, -C2-C6-alkenyl, -C2-C6-alkynyl, -OR8, -Cι-C4-perfluoroalkyl, -S(O)xR8 where x is 0-2, -OPO(OR )OR9, -PO(OR8)R9, -OC(O)NR R9, -COOR8, - -CONR8R9, -SO3H, -NR8R9,-NCOR8R9, -NR8COOR9, -SO2NR8R9, -NO2, -N(R8)SO R9, -NR8CONR8R9, -C3- cycloalkyl as defined above, -C3-C6- cycloheteroalkyl as defined above, -aryl or heteroaryl as defined above, -SO2NHCOR8 or -CONHSO2R8 where R8 is not hydrogen, -tetrazol-5-yl, - -NR8C(=NR9)NR8R9, -SO2NHCONR8R9, or -SO2NHCN;
R7 is hydrogen, straight chain or branched -Cι-C6-alkyl, -C2-C6-alkenyl, or -C2- Cβ-alkynyl each optionally substituted with -OH, -COR5, -CN, -C2-C6- alkenyl, -C2-C6-alkynyl, -OR5, -Ci-Q-perfluoroalkyl, -S(O)xR5 where x is 0-2, -OPO(OR5)OR6, -PO(OR5)R6, -OC(O)NR5R6, - COOR5, -CONR5R6, -SO3H, -NR5R6,-NR5COR6, -NR5COOR6, - SO NR5R6, -NO2, -N(R )SO2R6, -NR5CONR5R6, -C3-C6 cycloalkyl as defined above, -C3-C6-cycloheteroalkyl as defined above, -aryl or heteroaryl as defined above, -SO2NHCOR5 or - CONHSO2R5 where R5 is not hydrogen, -tetrazol-5-yl, - NR5C(=NR6)NR5R6, -C(0)N R5OR6, -SO2NHCONR5R6or - SO2NHCN; or R7 is phenyl or naphthyl, optionally substituted by R1, R2, R3 and R4 or a 5 to 6 membered heteroaryl group having 1 to 3 heteroatoms selected independently from N, O, and S and optionally substituted by R1^2, R3 and R4; or R7 is C3-C6 cycloalkyl or 3-6 membered cycloheteroalkyl as defined above;
or R7CH2-N-A-, where A is as defined above, can form a non-aromatic 7-12 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring;
R8 and R9 are independently H, aryl or heteroaryl as defined above, -C3-C7- cycloalkyl or cycloheteroalkyl as defined above, -Ci-C perfluoroalkyl, straight chain or branched -Cι-C6-alkyl, -C2-C6-alkenyl, or -C2-C6- alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy, -Ci- -perfluoroalkyl, amino, mono- and di-Ci- -alkylamino, carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono- and di-Ci-Cό-alkylcarbamoyl; and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.
Preferred compounds are those wherein both of the carbons of A adjacent to the carbon bearing the sulfonamido group have a substituent other than hydrogen. Also preferred are compounds where Z is 4-alkoxyphenyl, 4-aryloxyphenyl or 4- heteroaryloxyphenyl.
The term "heteroaryl" as defined hereinabove includes, but is not limited to, pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine,triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole and oxazole. The term "heteroaryl fused to a phenyl" includes, but is not limited to, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole.
The following compounds (I-XXI) which may be used in preparing compounds of the invention are known and references are given hereinbelow.
Figure imgf000011_0001
VII VIII
Figure imgf000011_0002
XVIII
Figure imgf000011_0003
Compound I: a) Springer, RH; Scholten, MB; O'Brien, DE, Novinson, T; Miller, JP; Robins, RK J. Med. Chem. (1982), 25(3), 235-42. b) Elworthy, T.R.; Ford, A.P.D.; et.al. J. Med. Chem. (1997), 40(17), 2674-2687. Compound II:
Masui, T; TAkura, T; JP 46043792; JP 690307; CAN 76:59604
Compound HI:
Camparini, A; Ponticelli, F; Tedeschi, P J. Chem. Soc, Perkin Trans.l (1982), 10,
2391-4.
Compound IV:
Abdalla, GM; Sowell. JW J. Heterocycl. Chem. (1990), 27 (5), 1201-7.
Compound V: a) Denzel, T; Hoehn, H J. Heterocyclic Chem. (1977), 14, 813-817. b) Al-Shaar, AHM; Chambers, RK; Gilmour, DW; Lythgoe, DJ; McClenaghan, I; Ramsden, CA J. Chem. Soc; Perkin Trans. I (1992) 21, 2789-2812. c) Elworthy, T.R.; Ford, A.P.D.; et.al. J. Med. Chem. (1997), 40(17), 2674-2687. Compound VI: a) Forbes, IT; Johnson, CN; Jones, GE; Loudon, J; Nicholass, JM J. Med. Chem (1990) 2640- 2645. b) Kan, MA; Guarconi, AE J. Heterocyclic Chem (1977) 14, 807-812. Compound VII: a) Forbes, IT; Johnson, CN; Jones, GE; Loudon, J; Nicholass, JM J. Med. Chem (1990) 2640- 2645. b) Kan, MA; Guarconi, AE J. Heterocyclic Chem (1977) 14, 807-812. Compound VIU:
Richardson, TO; Neale, N; Carwell, N J. Heterocyclic. Chem. (1995), 32, 359-361. Baker, JM; Huddleston, PR; Keenan, GJ J. Chem Research Miniprint, (1982) 6, 1726-1746. Compound IX: a) Forbes, IT; Johnson, CN; Jones, GE; Loudon, J; Nicholass, JM J. Med. Chem (1990) 2640- 2645. b) Kan, MA; Guarconi, AE J. Heterocyclic Chem (1977) 14, 807-812. Compounds X, XI and XII:
Elworthy, T.R.; Ford, A.P.D.; et.al. J. Med. Chem. (1997), 40(17), 2674-2687. Compound XIII:
Heterocycles, (1997), 45, 980. Compound XIV: Yokoyama, Naokata. Eur. Pat. Appl., 61 pp. CODEN: EPXXDW. EP 115469 Al
840808.
Compound XV:
Mendes, Etienne; Vernieres, Jean Claude; Simiand, Jacques Edouard; Keane, Peter
Eugene. Eur. Pat. Appl., 12 pp. CODEN: EPXXDW. EP 346207 Al 891213.
Compound XVI:
Mendes, Etienne; Vernieres, Jean Claude; Simiand, Jacques Edouard; Keane, Peter
Eugene. Eur. Pat. Appl., 12 pp. CODEN: EPXXDW. EP 346207 Al 891213.
Compound XVII:
Morita, Yoshiharu; Wagatsuma, Kazuo. Japan. Kokai, 4 pp. CODEN: JKXXAF. JP
50058094 750520 Showa.
Compounds XVIII and XIX:
Armitage, Bernard John; Leslie, Bruce William; Miller, Thomas Kerr; Morley,
Christopher. PCT Int. Appl., 110 pp. CODEN: PIXXD2. WO 9500511 Al 950105.
Compound XX:
Minami, S.; Matsumoto, J.; Kawaguchi, K.; Mishio, S.; Shimizu, M.; Takase, Y.;
Nakamura, S. (Dainippon Pharmaceutical Co., Ltd., Japan) Japan. Kokai, 3pp. CODEN:
JKXXAF. JP 50014697 750215 Showa.
Compound XXI:
Kihara, N.; Tan, H.; Takei, M.; Ishihara, T. (Mitsui Pechochemical Industries, Ltd.,
Japan; Suntory, Ltd.) Jpn. Kokai Tokyo Koho,, 11pp. CODEN: JKXXAF. JP
62221686 A2 870929 Showa.
The compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-
9, MMP-13 and TNF-α converting enzyme (TACE) and are therefore useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, graft rejection, insulin resistance, bone disease and HTV infection.
Detailed Description of the Invention
The invention compounds are prepared using conventional techniques known to those skilled in the art of organic synthesis. The following scheme (Scheme I) illustrates the reaction sequence employed. For purposes of illustration only, wherein the bicyclic heteroaryl group A shown is a quinoline, 4-chloro-7-trifluoromethylquinoUne-3-carboxyUc acid ethyl ester, prepared from the corresponding aniline, is reacted with N-benzyl-p- methoxybenzenesulfonamide, wherein Z is p-methoxybenzene, to provide the requisite N^V-disubstituted sulfonamido-ester which is then converted into the corresponding hydroxamic acid in two steps. Alternatively, the 4-chloroquinoline carboxylic acid ester could be first reacted with R7-NH2 and the resulting 4-(R7-amino)quinoline carboxylic acid ester then reacted with the appropriate Z-SO2-Cl. Hydrolysis of the ester and reaction with hydroxylamine hydro- chloride would then give the invention compound.
Scheme I.
Figure imgf000014_0001
Figure imgf000014_0002
Functionalization of the quinoline ring via a palladium catalyzed Heck coupling between the iodoquinoline and tributylvinyltin is shown in Scheme II. α,β-Unsaturated esters and amides can be coupled to the haloquinoline via Heck reactions. A variety of other trialkyltin reagents are readily available and may be similarly used. Boronic acids, commercially available or readily prepared, may also be coupled to the iodoquinoline using the Suzuki reaction. Scheme JJ.
Figure imgf000015_0001
Figure imgf000015_0002
Functionahzation of haloquinolines may also be accomplished via palladium catalyzed couplings of alkynes, as illustrated in Scheme HI. Hydrogenation of the alkynes accesses the olefins and alkanes as well.
Scheme HI.
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0003
Schemes IV and V illustrate two methods for incorporating amino groups into the substituent attached to the sulfonamide nitrogen of the compounds of the invention. Thus, in Scheme IV the NH- sulfonamide is alkylated with propargyl bromide to provide the propargyl sulfonamide. This alkyne is reacted with paraformaldehyde in the presence of a primary or secondary amine and cuprous chloride to give the propargyl amine which is converted, as before, to the desired hydroxamic acid.
cheme IV
Figure imgf000017_0001
(CH2O)n CuCl f HNR5R6
NHOH M
Figure imgf000017_0002
Figure imgf000017_0003
In Scheme V, selective hydrolysis of the ester of the p-carboethoxybenzyl sulfonamide group provides a mono-carboxylic acid. This acid may be converted into an amide (not shown), followed by conversion of the second ester, A-CO2R, into the corresponding hydroxamate, or reduced to the corresponding alcohol with diborane. The alcohol may be converted into the analogous amine via the benzylic bromide, followed by conversion of the the ester, A-CO2R, into the corresponding hydroxamate.
Scheme V.
Figure imgf000017_0004
Methods for synthesizing variations of substituents on the sulfonyl aryl group are shown in Schemes VI through VIII. As shown in Scheme VI, biaryl sulfonyl groups are synthesized by Suzuki couplings on a bromo- substituted benzene sulfonamide. The starting bromo-substituted benzene sulfonamide is synthesized from the commercially available bromobenzenesulfonyl chloride and the amino-acid or amino-ester, H2N-A-CO2R, followed by alkylation of the resulting NH- sulfonamide. Alternatively, the bromo aryl sulfonamide is converted into the corresponding boronic acid by the method of Ishiyama, et.al. [J. Org. Chem. (1995), 60, 7508] followed by coupling with an appropriate aryl halide.
Figure imgf000018_0001
1. BisQ?inacolato)diboron (dppf)PdCl2; KOAc; DMSO ArX
2. aq. HC1 Pd(PPh3)4
Ishiyama, T; Murata, M.; Miyaura, N. Na2C03 (aq) /. Org. Chem. 1995, 60, 7508. DME
Figure imgf000018_0002
Methods for synthesizing sulfonyl aryl ethers are shown in Schemes VII through IX. In Scheme VII biaryl ethers, or aryl heteroaryl ethers, are synthesized starting from the known sulfonyl chlorides (see for example: Zook SE; Dagnino, R; Deason, ME, Bender, SL; Melnick, MJ WO 97/20824). 8/16514
Scheme VII.
Figure imgf000019_0001
Alternatively, the biaryl ethers may be prepared from the corresponding boronic acids or via the sulfonyl phenols as shown in Scheme VIH
Scheme VHL
Figure imgf000019_0002
Figure imgf000019_0003
Aryl ethers may also be prepared via displacement of the fluorine from a para- fluorobenzene sulfonamide, as shown in Scheme DC. Aryl or alkyl ethers may be prepared in this manner.
Scheme DC.
Figure imgf000020_0001
Scheme X illusstrates the synthesis of pyrazolopyridines of the invention. Thus, a substituted amino-pyrazole is condensed with ethoxymethylene malonate to provide the pyrazolylamino methylene malonate, B. This compound is converted into the pyrazolopyridine, C, by heating at 240°C. Compound C is then converted into the chloro- ester, D, via reaction with phosphorus oxychloride. Displacement of the chloro substituent with a sulfonamide then gives compound E. Hydrolysis of the ester and conversion of the carboxylate into the hydroxamate then gives compound G. Scheme X.
Figure imgf000021_0001
Figure imgf000021_0002
The following specific examples are provided to illustrate the preparation of compounds of this invention and are not to be construed as limiting this invention in any way. Other procedures for preparing the compounds of this invention will be apparent to those skilled in the art of organic synthesis. All starting materials, intermediates, and reagents are either commercially available or can be readily prepared following standard literature procedures by one skilled in the art of organic synthesis.
Example 1
4-[BenzyI-(4-methoxy-benzenesuIfonyI)-arnino]-7-trifluorornethyl- quinoline-3-carboxylic acid ethyl ester
To a solution of 1.85g (6.67 mmol) of N-benzyl 4-methoxyphenylsulphonamide in 15mL of DMF was added, in one portion, 0.267g (6.67 mmol) of 60% sodium hydride and the resulting mixture was stirred at room temperature under nitrogen for 15 min. Ethyl 4-chloro-7-trifluoromethyl-3-quinolinecarboxylate (2.02g, 6.67 mmol) was then added to the solution in one portion and the resulting mixture was heated at 85 °C for 24h. The reaction mixture was then cooled to room temperature, poured into a mixture of water (300 mL) and HCl (IN, aqueous, 100 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then chromatographed on silica gel eluting with 15%-50% ethyl acetate/ hexane to give 3.1 lg (88%) of the desired product. Electrospray Mass Spec 545.1 (M+H).
Example 2
4-[Benzyl-(4-methoxy-benzenesulfonyl)-arnino]-8-trifluoromethyl- quinoline-3-carboxylic acid ethyl ester
In the same manner as described in Example 1, 1.012g (3.34 mmol) of ethyl 4- chloro-8-trifluoromethyl-3-quinolinecarboxylate provided 1.509g (83%) of the desired quinoline ester as a white solid. Electrospray Mass Spec 545.1 (M+H).
Example 3 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]- 6-bromo-quinoline-3- carboxylic acid ethyl ester
In the same manner as described in Example 1, 0.848g (2.70 mmol) of ethyl 6- bromo-4-chloro-3-quinolinecarboxylate provided 1.418g (95%) of the desired quinoline ester as a white solid. Electrospray Mass Spec 557.1 (M+H).
Example 4 4-[Benzyl-(4-methoxy-benzenesuIfonyl)-amino]- 7-bromo-quinoline-3- carboxylic acid ethyl ester
In the same manner as described in Example 1, 0.777g (2.47 mmol) of ethyl 7- bromo-4-chloro-3-quinolinecarboxylate provided 1.169g (85%) of the desired quinoline ester as a white solid. Electrospray Mass Spec 557.1 (M+H).
Example 5
4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-trifluoromethyI- quinoline-3-carboxylic acid ethyl ester
In the same manner as described in Example 1, 1.216g (4.02 mmol) of ethyl 4- chloro-6-trifluoromethyl-3-quinolinecarboxylate provided 2.171g (99%) of the desired quinoline ester as a white solid. Electrospray Mass Spec 545.0 (M+H). Example 6 4-[BenzyI-(4-methoxy-benzenesulfonyl)-amino]-7-trifluorornethyI- quinoIine-3-carboxyIic acid
To a solution of 1.065g (2.00 mmol) of the product from Example 1 in 4mL of methanol/THF (1:1) was added 2mL of IN sodium hydroxide solution and the resulting mixture was stirred at 25 *C for 18h. The reaction was then acidified with IN HCl and extracted with ethyl acetate (200 mL). The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ethyl acetate hexane (1:9) and filtered to provide 828 mg (82%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec 517.1 (M+H)
Example 7 4-[Benzyl-(4-methoxy-benzenesulfonyI)-amino]-8-trifluoromethyl- quinoIine-3-carboxyIic acid
In the same manner as described in Example 6, 1.255g (2.64 mmol) of the product from Example 2 provided 0.988g (83%) of the desired quinoline acid as a white solid. Electrospray Mass Spec 517.1 (M+H).
Example 8 4-[BenzyI-(4-methoxy-benzenesulfonyl)-amino]-6-bromo-quinoline-3- carboxylic acid
In the same manner as described in Example 6, 1.198g (2.16 mmol) of the product from Example 3 provided 0.92 lg (81 ) of the desired quinoline acid as a white solid. Electrospray Mass Spec 529.0 (M+H).
Example 9 4-[BenzyI-(4-methoxy-benzenesuifonyl)-amino]- 7-bromo-quinoIine-3- carboxylic acid
In the same manner as described in Example 6, 0.969g (1.74 mmol) of the product from Example 4 provided 0.804g (87%) of the desired quinoline acid as a white solid. Electrospray Mass Spec 529.0 (M+H).
Example 10 4-[Benzyl-(4-methoxy-benzenesulfonyI)-amino]-6-trifluoromethyl- quinoline-3-carboxylic acid
In the same manner as described in Example 6, 2.043g (3.75 mmol) of the product from Example 5 provided 1.82g (88%) of the desired quinoline acid as a white solid. Electrospray Mass Spec 515.0 (M-H).
Example 11
4-[BenzyI-(4-methoxy-benzenesulfonyl)-amino]-7-trifIuoromethyI- quinoline-3-carboxylic acid hydroxyamide
To a solution of 0.636g (1.26 mmol) of the product from Example 6 in 12.5 mL of dichloromethane was added 0.05 mL of DMF followed by 1.26 mL (2.52 mmol) of 2 M oxalyl chloride and the resulting reaction mixture was stirred at room temperature for lh.
In a separate flask, 2.6 mL (19 mmol) of triethylamine was added to a 0°C mixture of 350 mg (13 mmol) of hydroxylamine hydrochloride in 14 mL of THF and 3.5 mL of water. After this mixture had been stirred for 15min at 0 "C , the acid chloride solution was added to it in one portion and the resulting solution was allowed to warm to room temperature and stirred for another 4h. Water was then added to the reaction flask and 0.488g (75%) product was collected via filtration. Electrospray Mass Spec 532.1 (M+H)
Example 12
4-[Benzyl-(4-methoxy-benzenesulfonyI)-amino]-8-trifluoromethyl- quinoline-3-carboxyIic acid hydroxyamide
In the same manner as described in Example 11, 0.444g (3.75 mmol) of the product from Example 7 provided 0.143g (31%) of the desired quinoline hydroxamic acid as a cream colored solid. Electrospray Mass Spec 532.1 (M+H).
Example 13 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]- 6-bromo-quinoIine-3- carboxylic acid hydroxyamide
In the same manner as described in Example 11, 0.527 g (1.00 mmol) of the product from Example 8 provided 0.367g (68%) of the desired quinoline hydroxamic acid as a off- white solid. Electrospray Mass Spec 541.9 (M+H).
Example 14 4-[Benzyl-(4-methoxy-benzenesulfonyI)-amino]- 7-bromo-quinoline-3- carboxylic acid hydroxyamide
In the same manner as described in Example 11, 0.527g (1.00 mmol) of the product from Example 9 provided 0.280g (52%) of the desired quinoline hydroxamic acid as a white solid. Electrospray Mass Spec 541.9 (M+H). Example 15 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-trifluoromethyl- quinoline-3-carboxylic acid hydroxyamide
In the same manner as described in Example 11, 0.527 g (1.06 mmol) of the product from Example 10 provided 0.435g (77%) of the desired quinoline hydroxamic acid as a cream colored solid. Electrospray Mass Spec 532.1 (M+H).
Example 16
4-[(4-Methoxybenzenesulfonyl)-pyridin-3-ylmethylamino]-7- trifluoromethyl-quinoline-3-carboxyIic acid hydroxyamide
Following the procedure of example 1 and substituting N-(3-pyridinylmethyl)-4- methoxybenzenesulfonamide for N-benzyl-4-methoxybenzenesulfonamide, the intermediate 4-[(4-methoxybenzenesulfonyl)-pyridin-3-ylmethylamino]-7-trifluoromethyl-quinoline-3- carboxylic acid ethyl ester is obtained. Following the procedures of example 6 and 11 , the title product is obtained. Electrospray Mass Spec 533.0 (M+H).
Example 17 4-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-t-butyl-quinoIine-3- carboxylic acid hydroxyamide
In the same manner as described in Example 1, 1.167g (4.00 mmol) of ethyl 4- chloro-8-butyl-3-quinolinecarboxylate provided 1.413g (66%) of the desired quinoline ester as a white solid. Electrospray Mass Spec 533.3 (M+H).
In the same manner as described in Example 6, 1.065g (2.00 mmol) of the ester provided 0.478g (47%) of the desired quinoline acid as a white solid. Electrospray Mass Spec 503.3 (M-H).
Following the procedures of example, the title compound is obtained from the carboxylic acid. Electrospray Mass Spec. 520.3 (M+H).
Example 18 4-[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-methyl-quinoIine-3- carboxylic acid hydroxyamide
In the same manner as described in Example 1, l.OOg (4.00 mmol) of ethyl 4-chloro-8-methyl-3-quinolinecarboxylate provided 0.53 lg (27%) of the desired quinoline ester as a white solid. Electrospray Mass Spec 491.3 (M+H).
In the same manner as described in Example 6, 0.470g (0.851 mmol) of the ester provided 0.160g (41%) of the desired quinoline acid as a white solid. Electrospray Mass Spec 461.3 (M-H). Following the procedure of example 11, the tide compound is obtained from the carboxylic acid. Electrospray Mass Spec. 478.3 (M+H).
Example 19 4-[Benzyl-(4-methoxybenzenesulfonyl)-amino]- 8-ethyl-quinoIine-3- carboxylic acid hydroxyamide
In the same manner as described in Example 1, 1.055g (4.00 mmol) of ethyl 4- chloro-8-ethyl-3-quinolinecarboxylate provided 0.670g (33%) of the desired quinoline ester as a white solid. Electrospray Mass Spec 505.3 (M+H).
In the same manner as described in Example 6, 0.615g (1.22 mmol) of the product from Example 7 provided 0.353g (60%) of the desired quinoline acid as a white solid. Electrospray Mass Spec 475.3 (M-H).
Following the procedure of example 11 , the tide compound is obtained from the carboxylic acid. Electrospray Mass Spec. 492.3 (M+H).
Example 20
4-[Benzyl-(4-methoxybenzenesuIfonyl)-amino]-8-(l-methylethyl)- quinoline-3-carboxyIic acid hydroxyamide
In the same manner as described in Example 1, 1.1 l lg (4.00 mmol) of ethyl 4- chloro-8-isopropyl-3-quinolinecarboxylate provided 0.754g (36%) of the desired quinoUne ester as a white solid. Electrospray Mass Spec 519.3 (M+H).
In the same manner as described in Example 6, 0.686g (0.127 mmol) of the ester provided 0.532g (82%) of the desired quinoline acid as a white solid. Electrospray Mass Spec 489.2 (M-H).
In the same manner as described in Example 11, 0.440g (0.897 mmol) of the hydroxamic acid provided 0.270 g (60%) of the desired quinoline hydroxamic acid. Electrospray Mass Spec. 506.3 (M+H).
Example 21 4-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]- 8-iodo-quinoline-3- carboxylic acid ethyl ester
In the same manner as described in Example 1 and substituting N-ethyl-4- methoxybenzenesulfonamide for N-benzyl-4-methoxybenzenesulfonamide, 1.076g (5.00 mmol) of ethyl 8-iodo-4-chloro-3-quinolinecarboxylate provided 2.438g (4.51 mmol, 90%) of the desired quinoline ester as a white solid. Electrospray Mass Spec 541.0 (M+H). Example 22 4-[Ethyl-(4-methoxy-benzenesulfonyI)-amino]-8-vinyl-quinoline-3- carboxylic acid ethyl ester
The product from example 21 (2.438g, 4.51mmol) in 150 mL DMF was added tributylvinyltin (1.43g, 4.51 mmol), tetrakis(triphenylphosphine)palladium(0) (520mg, 10%), cuprious iodide (171mg, 20%), and 5 mL triethylamine. The mixture was stirred under N2 and heated at 85°C for 18 hours. The it was poured into a mixture (1:1) of 400 mL saturated sodium bicarbonate and saturated amonium chloride and extracted with ethyl acetate (2x200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was column chromatographed using 300 mL silica gel and gradient elution with hexane/ethyl acetate (100-0%). This provided 1.706g (3.88 mmol, 86%) of the desired quinoline ester. Electrospray Mass Spec 441.1 (M+H).
Example 23 4-[Methyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethynyl-quinoline-
3-carboxylic acid ethyl ester
Combining the procedures of examples 1 and 22, and substituting phenylacetylene for vinyltin, N-ethyl-4-methoxybenzenesulfonamide for N-benzyl-4- methoxybenzenesulfonamide, the intermediate 4-[ethyl-(4-methoxy-benzenesulfonyl)- aπιino]-6-phenylethynyl-quinoline-3-carboxylic acid ethyl ester is obtained from ethyl -4- chloro-3-quinolinecarboxylate. Electrospray Mass Spec 515.3 (M+H).
Example 24 4-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-8-vinyl-quinoline-3- carboxylic acid
In the same manner as described in Example 6, 1.593g (3.62 mmol) of the product from Example 22 provided 1.333g (89%) of the desired quinoline acid as a white solid. Electrospray Mass Spec 411.1 (M-H).
Example 25 4-[MethyI-(4-methoxy-benzenesulfonyI)-amino]-6-phenylethynyI-quinoline-
3-carboxylic acid
In the same manner as described in Example 6, the tide compound was synthesized from the product of example 23. Electrospray Mass Spec 485.3 (M-H). Example 26 4-[Benzyl-(4-rnethoxy-benzenesuIfonyI)-amino]-6-nitro-quinoline-3- carboxylic acid
In the same manner as described in Example 1 and 6, 5.613g (20.0 mmol) ethyl 4- chloro-6-nitro-3-quinolinecarboxylate provided 2.676g (27% for two steps) of the tide compound as a white solid. Electrospray Mass Spec 492.3 (M-H).
Example 27 4-[Methyl-(4-methoxy-benzenesulfonyl)-amino]- 8-bromo-quinoIine-3- carboxylic acid
Combining the procedures of example 1 and 6, and substituting N-methyl-4- methoxybenzenesulfonamide for N-benzyl-4-methoxybenzenesulfonamide, the intermediate 8-bromo-4-[methyl-(4-methoxy-benzenesulfonyl)-amino]-quinoline-3-carboxylic acid is obtained. Electrospray Mass Spec 449.2 (M-H).
Example 28 4-{Methyl-(4-(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quiπoline-
3-carboxyIic acid
Combining the procedures of example 1 and 6, and substituting N-methyl-4- (pyridin-4-yloxy)-benzenesulfonamide the intermediate 6-iodo-4-{methyl-(4-(pyridin-4- yloxy)-benzenesulfonyl]-arnino}-quinoUne-3-carboxylic acid is obtained from ethyl 6-iodo- 4-chloro-3-quinolinecarboxylate. Electrospray Mass Spec 559.9 (M-H).
Example 29
4-[EthyI-(4-methoxy-benzenesulfonyl)-amino]-8-vinyI-quinoline-3- carboxylic acid hydroxyamide
In the same manner as described in Example 11, 0.484g (1.17 mmol) of the product from Example 24 provided 0.360g (72%) of the desired quinoline hydroxamic acid. Electrospray Mass Spec. 428.0 (M+H).
Example 30 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-nitro-quinoIine-3- carboxylic acid hydroxyamide
In the same manner as described in Example 11, 0.825g (1.67 mmol) of the product from Example 26 provided 0.227g (0.446 mmol, 26%) of the desired quinoUne hydroxamic acid. Electrospray Mass Spec. 509.0 (M+H). Example 31 4-[Methyl-(4-methoxy-benzenesulfonyl)-amino]- 8-bromo-quinoline-3- carboxylic acid hydroxyamide
In the same manner as described in Example 11 , 0.664g (1.47 mmol) of the product from Example 27 provided 0.145g (0.311 mmol, 21%) of the desired quinoUne hydroxamic acid. Electrospray Mass Spec. 468.0 (M+H).
Example 32 4-{MethyI-[4-(pyridin-4-yloxy)-benzenesulfonyl]-amino}-6-iodo-quinoline-
3-carboxylic acid hydroxyamide
To a 0 °C solution of of 4.5 mL oxalyl chloride (0.90 mmol, 2M in dichloromethane) was added dropwise 0.69 mL of DMF. The resulting solid was kept at 0 °C for another 15 minutes and followed by addition of 2.50g (4.46 mmol) of the product from Example 28 in 50 mL DMF. The mixture was stirred for 1 hour at room temperature and then kept at 0 °C for an additional 15 minutes. An aqueous solution of hydroxylamine (5mL, 50%) was then added all at once to the above solution and the mixture was stirred at room temperature for 3 hours. The mixture was next poured into 300mL water and extracted with dichloromethane (4xl00mL). The combined organic layers were washed with brine (300mL) and dried over magnesium sulfate. After filtration and concentration on a rotary evaporator the residue was column chromatographed using gradient methanol in ethyl acetate (20-100%) and it provided 1.36g (2.36mmol, 53%) of the desired quinoUne hydroxamic acid. Electrospray Mass Spec. 576.9 (M+H).
Example 33
4-{Methyl-(4-(pyridin-4-yIoxy)-benzenesulfonyl]-amino}-6-iodo-quinoIine-
3-carboxyIic acid hydroxyamide hydrochloride
The product from example 32 (0.952 g, 1.65 mmol) was dissolved in 100 mL methanol in a Parr reactor. Degussa catalyst (10% Pd-C, 200mg) was next added under N2. The mixture was then hydrogenated (35 psi) for one hour at room temperature. The mixture was then filtered through a pad of celite and concentrated on a rotary evaporator. The residue was chromatographed with methanol and ethyl acetate (5-35%). The product obtained was next dissolved in methanol and anhydrous hydrochloride was bubbled into the solution for 5 minutes. Removal of the solvent through rotary evaporation and vacuum pump gave 0.707g (1.45 mmol, 88%) product. Electrospray Mass Spec. 450.9 (M+H). Example 34 4-[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethynyl-quinoline-
3-carboxylic acid hydroxyamide
In the same manner as described in Example 11, 2.432g (5.00 mmol) of the product from Example 25 provided 2.159g (86%) of the desired quinoline hydroxamic acid. Electrospray Mass Spec. 502.1 (M+H).
Example 35 4-[Methyl-(4-methoxy-benzenesuIfonyl)-amino]-6-phenylethyl-quinoIine-3- carboxylic acid hydroxyamide
The product from example 34 (0.82g, 1.64 mmol) was dissolved in 50 mL methanol in a Parr reactor. Degussa Catalyst (10% Pd-C, 200mg) was next added under N2. The mixture was hydrogenated (45 psi) for one hour at room temperature. The mixture was then filtered through a pad of celite and concentrated on a rotary evaporator. This gave 0.76g (1.50 mmol, 92%) product. Electrospray Mass Spec. 506.0 (M+H).
Example 36
4-[(4-Methoxy-benzenesulfonyl)-pyridin-3-yImethyl-amino]- 8-methoxy- quinoline-3-carboxyIic acid hydroxyamide
Following the procedure of Example 16 and starting with ethyl 4-chloro-8- methoxy-3-quinolinecarboxylate the tide compound was obtained as a yellow powder. Electrospray Mass Spec. 495.3 (M+H).
Example 37
4-[(4-Methoxy-beπzenesulfonyl)-pyridin-3-ylmethyl-amino]- 8-bromo- quinoline-3-carboxylic acid hydroxyamide
Following the procedure of Example 16 and starting with ethyl 4-chloro-8-bromo- 3-quinoUnecarboxylate the title compound was obtained as a white powder. Electrospray Mass Spec. 543.2 (M+H).
Example 38
4-[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl amino]-8-Benzyl- quinoline-3-carboxylic acid hydroxyamide
FoUowing the procedure of Example 16 and starting with ethyl 4-chloro-8-benzyl- 3-quinolinecarboxylate the tide compound was obtained as a beige powder. Electrospray Mass Spec. 555.4 (M+H). Example 39
4-[(4-Methoxy-benzenesuIfonyl)-pyridin-3-ylmethyl-amino]- 8-iodo- quinoline-3-carboxylic acid hydroxyamide
Following the procedure of Example 16 and starting with ethyl 4-chloro-8-iodo-3- quinoUnecarboxylate the title compound was obtained as a yellow powder. Electrospray Mass Spec. 590.8 (M+H).
Example 40
4-[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyI-amino]-8-phenyl- quinoline-3-carboxyiic acid hydroxyamide
Following the procedure of Example 16 and starting with ethyl 4-chloro-8-phenyl- 3-quinolinecarboxylate the tide compound was obtained as a beige powder. Electrospray Mass Spec. 541.4 (M+H).
Example 41
4-[(4-Methoxy-benzenesuIfonyI)-pyridin-3-yImethyI-amino]-8-thiophen-2- yl-quinoline-3-carboxylic acid hydroxyamide
Combining the procedures of Examples 22, 6 and 11 and starting with4-[(4- methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]- 8-bromo-quinoline-3-carboxyUc acid ethyl ester and 2-tributylstannylthiophene the title compound was obtained as a yeUow powder. Electrospray Mass Spec. 545.0 (M+H).
Example 42
4-[(Biphenyl-4-suIfonyI)-pyridin-3-ylmethyI-amino]-7-trifluoromethyl- quinoiine-3-carboxyIic acid hydroxyamide
Following the procedure of Example 1 and substituting N-(3-pyridinylmethyl)-4- bromobenzenesulfonamide for N-benzyl-4-methoxybenzenesulfonamide, the intermediate 4-[(4-bromobenzenesulfonyl)-pyrimn-3-ylmemylamino]-7-trifluoromethyl-quinoline-3- carboxyUc acid ethyl ester is obtained.
To 8.5 mL of degassed ethylene glycol dimethyl ether, was added 500 mg (0.85 mmol) of the ester, 110 mg (0.93 mmol) of phenylboronic acid, 80 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium and 1.1 ml (2.2 mmol) of 2M aqueous Na2CO3 and the mixture ws heated to reflux under nitrogen for 36 hr. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to give 4-[(biphenyl-4-sulfonyl)-pyridin-3-ylmethyl- anτino]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester. This ester was converted to the title compound (off-white powder) as described in Examples 6 and 11. Electrospray Mass Spec. 579.1 (M+H).
Example 43
4-[(Octane-l-sulfonyl)-pyridin-3-yImethyl-amino]-7-trifluoromethyl- quinoline-3-carboxylic acid hydroxyamide
Combining the procedures of Examples 1, 6 and 11 and substituting N-(3- pyridinylmethyl)-octanesulfonamide for N-benzyl-4-methoxybenzenesulfonamide the tide compound was obtained as a yellow solid. Electrospray Mass Spec. 539.5 (M+H).
Example 44
4-[Pyridin-3-ylmethyI-(toIuene-4-suIfonyl)-amino]-7-trifluoromethyI- quinoline-3-carboxylic acid hydroxyamide
Combining the procedures of Examples 1, 6 and 11 and substituting N-(3- pyridinylmethyl)-toluenesulfonamide for N-benzyl-4-methoxybenzenesulfonamide the tide compound was obtained as a white powder. Electrospray Mass Spec. 517.1 (M+H).
Example 45 Diethyl{[ (l-phenyl-5-pyrazolyl) amino ] methylene} malonate
A mixture of 15.9 g. (0.10 mole) of l-phenyl-5-aminopyrazole and 21.6 g. (0.10 mole) of diethyl ethoxymethylenemalonate was heated at 115-120° in an oil bath for 2 hours. After cooling, the crystalline mass was recrystallized from hot hexane containing 1% of ethanol. CooUng to room temperature and filtering gave 24.8 g. (75%) of off-white crystals, m.p. 96-97°C.
Example 46 Ethyl 4-hydroxy-l-phenyl-lH-pyrazolo [3,4-b] pyridine-5-carboxylate
A mixture of 18.1 g. (0.055 mole) of diethyl {[(l-phenyl-5- pyrazolyl)amino]methylene} malonate and 150 ml of diethyl phthalate was heated at 240- 250° for 1 hour. The mixture was chilled and diluted with hexane. Chilling and filtering gave crystals which were washed with hexane and with hexane-ethanol (1:1) to give 11 g. (70%) of off white crystals m.p. 149-150°C. From a similar small scale run 1.75 g. was recrystallized from 110 ml. of ethanol to give 1.58 g. of off white crystals, m.p. 149-150° C. Example 47 Ethyl 4-chloro-l-phenyl-lH-pyrazolo [3,4-b]pyridine-5-carboxylate
A mixture of 5.76 g (20.33 mmol) of ethyl 4-hydroxy-l -phenyl- lH-pyrazolo[3,4- b] pyridine-5- carboxylate and 15.58 g of phosphorus oxychloride was refluxed 1.5 hr, chiUed and poured slowly onto crushed ice. The mixture was filtered and the solid washed with ice- water and dried to give 6.0 g of solid, m.p. 89-91° C.
Example 48 Ethyl 4-chloro-l,3-dimethyl-lH-pyrazolo [3,4-b]pyridine-5-carboxylate
Following the procedures of Examples 45, 46 and 47, starting from 1,3-dimethyl- 5-aminopyrazole, the chloro-ester is prepared, m.p. 89-90° C.
Example 49
Ethyl 4-[benzyl-(4-methoxybenzenesulfonyl)amino]- 1,3-dimethyl-lH- pyrazoIo[3,4-b] pyridine-5-carboxylate
To a solution of 1.16 g (4.2 mmol) of benzyl-(4-methoxybenzenesulfonyl)amine in 6 ml of anhydrous l-methyl-2-pyrrolidinone was added 0.168 g (4.2 mmol) of sodium hydride (60% in oil) and the mixture stirred at room temperature until gas evolution ceased. The preceding mixture was added to mixture of 1.01 g (4 mmol) of ethyl 4-chloro-l,3- dimethylpyrazolo[3,4-b]pyridine -5-carboxylate in 2 ml of 1 -methyl -2-pyrrolidinone.
The mixture was heated in an oil bath at 50°C overnight and then was heated in an oil bath at 100° C for 1.5 days. The mixture was poured into 800 ml of water and extracted with ethyl acetate. The extract was washed with water, 2N citric acid, water, brine and dried (Na2SO_j). The solvent was removed and the residue chromatographed on sihca gel with hexane-ethyl acetate (2:1) as eluent to give 0.64 g of product as a solid, mp 170-172°. From a larger scale run of 5.07 g (0.02 mmol) of ethyl 4-chloro-l,3-dimethylpyrazolo [3,4-b]pyridine-5-carboxylate and 8.0 g (0.0289 mmol) of benzyl -(4- methoxybenzenesulfonyl) amine (as sodium anion) in 30 ml of l-methyl-2-pyrroUdinone heated at 90° C for 3 days there was obtained 3.65 g of product.
Example 50
4-[Benzyl-(4-rnethoxybenzenesuIfonyl)amino]-l,3-dimethyI-lH-pyrazolo
[ 3,4-b] pyridine-5-carboxyIic acid.
A mixture of 0.48 g (0.97 mmol) of ethyl 4-[benzyl-(4-methoxybenzenesulfonyl) amino] -l,3-dimethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate and 0.29 ml of ION NaOH in 4 ml of tetrahydrofuran-methanol (1:1) was heated in an oil bath at 70° C for 2 hours and the solvent removed under vacuum. The residue was dissolved in 20 ml of H2O and the solution extracted with 10 ml of diethyl ether. To the aqueous layer was added 2N citric acid (pH 4-5) and the precipitated solid filtered and washed with H2O to give a white solid which was dried under vacuum overnight to give crystals, mp 165-167°C.
Example 51
4-[Benzyl-(4-methoxybenzenesulfonyl)amino]-l,3-dimethyI-lH- pyrazoIo[3,4-b] pyridine-5-carboxylic acid, potassium salt.
A mixture of 3.60 g (7.28 mmol) of ethyl 4-[benzyl-(4- memoxyrjenzenesulfonyl)amino]-l,3-dimethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate and 0.44 g (7.84 mmol) of potassium hydroxide (pellet) in 15 ml of methanol- water (1:1) was refluxed overnight. An additional 40 mg of potassium hydroxide was added and the mixture refluxed for 4 hours (all the solid dissolved). The solvent was removed under vacuum and toluene added and removed under vacuum. The residue was triturated with ethyl acetate, filtered and the solid washed with ethyl acetate to give 3.8 g of product as a white solid.
Example 52
4-[Benzyl-(4-methoxybenzenesulfonyl)amino]-l,3-dimethyl-lH- pyrazolo[3,4-b] pyridine-5-carboxylic acid, hydroxyamide
To a chilled solution of 1 ml (2 mmol) of oxalyl chloride in 8 ml of CH2 Cl2 was added dropwise 0.154 ml (2 mmol) of N, N-dimethylformamide and the solution stirred 15 min. To the preceding chilled solution was added 0.504 g (1 mmol) of 4-[benzyl-(4- methoxybenzenesulfonyl) amino]- l,3-dimethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, potassium salt and the mixture stirred under nitrogen for 2 hrs at room temperature (solution A). A solution of 0.278 g (4 mmol) of hydroxylamine hydrochloride and 0.834 ml (6 mmol) of triethylamine in 5 ml of H2O-tetrahydrofuran (1:4) was chilled at in an ice bath for 20 min. and to this solution was added dropwise the chilled solution of A. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed and the residue extracted with CH2C12. The CH2C12 extract was washed with 2N citric acid, H2O, IN NaHCO3, H2O, brine and dried (Na2SO4). The solvent was removed to give 0.53g of solid. Trituration with ethyl acetate gave 0.278 g of white solid, mp 184-186°C. Example 53
Ethyl 4-[(4-methoxybenzenesulfonyl)pyridin -3-yImethylamino] -1,3- dimethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate
To a solution of 1.39 g (5 mmol) of (4-methoxybenzenesulfonyl)(3- pyridinylmethyl) amine in 4 ml of anhydrous l-methyl-2-pyrrolidinone was added 0.2 g (5 mmol) of sodium hydride (60% in oil) and the mixture stirred at room temperature until gas evolution ceased. To this mixture was added 1.15 g (4.54 mmol) of ethyl 4-chloro-l,3- dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 2 ml of anhydrous l-methyl-2- pyrrolidinone. The mixture was stirred in a sealed tube under nitrogen in an oil bath at 90°C for 3 days. The mixture was cooled, poured into water and extracted with ethyl acetate. The extract was washed with H20, brine and dried (Na2S0 ). The solution was filtered through a thin pad of hydrous magnesuim silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness under vacuum to give 1.3 g of solid. Chromatography on silica gel with ethyl acetate as solvent gave 0.35 g of product as a solid, mp 152-154°C.
Example 54
4-[(4-Methoxybenzenesulfonyl) pyridin -3-ylmethylamino] -1,3- dimethyl - lH-pyrazo!o[3,4-b]pyridine -5-carboxylic acid
A mixture of 1.34 g (2.7 mmol) of ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3- ylmethylamino]-l,3-dimethyl-lH-pyrazolo[3,4-b]pyridin-5-carboxylate, 2.97 ml of IN potassium hydroxide in 7.8 ml of ethanol and 4.83 ml of water was refluxed for 20 hr. Another 0.54 ml of IN potassium hydroxide was added and the mixture refluxed 4 hrs. The solvent was removed under vacuum and toluene added and removed under vacuum. The residue was dissolved in water (20ml) and extracted with ethyl acetate. The aqueous layer was acidified with 2 N citric acid and the precipitated solid filtered off and washed with water. The solid was dried under vacuum to give 0.98 g of solid, mp 256-258°C.
Example 55
4-[(4-MethoxybenzenesulfonyI) pyridin -3-ylmethylamino] -1,3- dimethyl - lH-pyrazo!o[3,4-b]pyridine -5-carboxylic acid, potassium salt
A mixture of 0.34 g (0.68 mmol) of ethyl 4-[(4-methoxybenzenesulfonyl) pyridin- 3-ylmethylaπtino]-l,3-dimethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate and 0.748 ml of 1 N potassium hydroxide in 4 ml of ethanol- water (1:1) was refluxed for 24 hr. The solvent was removed under vacuum and to the residue was added toluene. The solvent was removed under vacuum to remove the water and the residue triturated with ethyl acetate to give the product as a solid, mp 160-167° C.
Example 60
4-[(4-Methoxybenzenesulfonyl)pyridin -3-ylmethylamino] -1,3- dimethyl - lH-pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide
A 1.5 g (2.459 mmol) sample of 4-[(4-methoxybenzenesulfonyl)pyridin-3- ylmethylaπtino]-l,3-dimethyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid was dissolved in 2.70 ml of IN KOH. The water was removed by repeated additions and removal of toluene under vacuum to give 1.34 g of solid (potassium salt of the acid). A solution of 2.65 ml (5.3 mmol) of oxalyl chloride was cooled in an ice bath and 0.389 ml of N,N- dimethylformamide added dropwise. After 5 min. the 1.34 g of the previously prepared potassium salt was added and the mixture stirred for 10 min. in an ice bath and then aUowed to warm to room temperature (mixture A). A mixture of 0.737 g (10.6 mmol) of hydroxylamine hydrochloride and 2.21 ml (15.9 mmol) of memyamine in 9.39 ml of tetrahydrofuran and 2.45 ml of water was chilled in an ice bath (mixture B). The mixture A was chilled in an ice bath and added to the chilled and stirred mixture B. The mixture of A and B was stirred at 0°C for 10 min and allowed to warm to room temperature and stir overnight. The solvent was removed under vacuum and the residue diluted with H2O, acidified with 2 N citric acid and extracted with two 30-ml portions of CH2C12. The aqueous layer was neutrallized with solid NaHCO3 to bring the pH to 7. The soUd which precipitated was filtered and washed with H2O to give 0.610 g of product as a solid, mp. 202-204°C. The CH2C12 extract was extracted with 2 N citric acid and the aqueous layer neutralized with soUd NaHCO3. The precipitated solid was filtered off and washed with water to give 0.226 g of product, mp 196-198°C. (mass spectrum (ES) 483.5 (M+l).
Example 61
4-[(4-MethoxybenzenesuIfonyl)pyridin-3-ylmethylamino] -1,3- dimethyl - lH-pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide hydrochloride
To a solution of 0.61 Og (1.265 mmol) of 4-[(4-methoxybenenzenesulfonyl)pyridin -3-ylmethylamino]- l,3-dimethyl-5-carboxylic acid, hydroxyamide in 40 ml of CH2C12- methanol (1:1) cooled to 10°C was added dropwise 1.51 ml of 1M hydrogen chloride in diethyl ether. The mixture was stirred at 10°C for 10 min. and allowed to warm to room temperature for 1 hr. The solvent was removed under vacuum and toluene (2ml) added twice and removed under vacuum after each addition. The residual solid was dried under vacuum to give 0.641 g of product as a solid, m.p. 170°-174°C.
Example 62
4-[Benzyl-(4-methoxybenzenesulfonyl)amino]-l-phenyl-lH-pyrazolo[3,4- b] pyridine -5-carboxylic acid, hydroxyamide
Following the procedure of Example 49, the product of Example 47 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl- (4-methoxybenzenesulfonyl)amino]-l-phenyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 124°-126°C.
Following the procedure of Example 50, the above ester is hydrolyzed to provide 4- [benzyl-(4-methoxybenzenesulfonyl)amino]- 1 -phenyl- lH-pyrazolo[3,4-b]pyridine-5- carboxylic acid. m.p. 108°-110°C.
Following the procedure of Example 52, the carboxylic acid is converted into the corresponding hydroxamic acid, 4-[benzyl-(4-methoxybenzenesulfonyl)amino]-l-phenyl- lH-pyrazolo[3,4-b] pyridine -5-carboxylic acid, hydroxyamide. m.p. 152°-154°C.
Example 63
4-[(4-MethoxybenzenesuIfonyI)pyridin -3-ylmethylamino] -1-phenyl- 1H- pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide
Following the procedure of Example 53, the product of Example 47 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-phenyl-lH-pyrazolo[3,4- b]pyridine-5-carboxylate. m.p. 89°-91°C.
Following the procedure of Example 54, the above ester is hydrolyzed to provide 4- [(4-methoxybenzenesuhcOnyl)pyridin-3-ylmethylamino] - 1 -phenyl- 1 H-pyrazolo[3,4b] pyridine-5-carboxylic acid. m.p. 136°-138°C.
Following the procedure of Example 60, the carboxylic acid is converted into the corresponding hydroxamic acid, 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]- 1-phenyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide. m.p. 114°C(dec).
Example 64
4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-phenyI-lH- pyrazoIo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide, hydrochloride
Following the procedure of Example 61, the product of Example 63 is converted into the corresponding hydrochloride salt. m.p. 161°C(dec). Example 65 Ethyl 4-chloro-l-phenyI-3-methyI-lH-pyrazolo [3,4-b]pyridine-5- carboxylate
Following the procedure of Example 45, starting with l-phenyl-3-methyl-5- aminopyrazole, diethyl { [( 1 -phenyl-3-methyl-5-pyrazolyl)amino]methylene } malonate is obtained. m.p. 70°-72°C.
Following the procedure of Example 46, the methylene malonate is converted into ethyl 4-hydroxy-l-phenyl-3-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 132°- 134°C.
Following the procedure of Example 47, the hydroxy-ester is converted into the chloro-ester, ethyl-4-chloro- 1 -phenyl-3-methyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 108°-110°C.
Example 66
4-[BenzyI-(4-methoxybenzenesulfonyl)amino]-l-phenyI-3-methyI-lH- pyrazo!o[3,4b] pyridine-5-carboxylic acid, hydroxyamide
Following the procedure of Example 49, the product of Example 65 is reacted with benzyl-(4-methoxybenzenesulfonyl)amine and sodium hydride to provide ethyl 4-[benzyl- (4-methoxybenzenesulfonyl)amino]-l-phenyl-3-methyl-lH-pyrazolo[3,4-b]pyridine-5- carboxylate. m.p. 164°-166°C.
Following the procedure of Example 50, the above ester is hydrolyzed to provide 4- [benzyl-(4-methoxybenzenesulfonyl)amino]-l-phenyl-3-methyl-lH-pyrazolo[3,4-b] pyridine-5-carboxylic acid. m.p. 246°-248°C.
Following the procedure of Example 52, the carboxylic acid is converted into the corresponding hydroxamic acid, 4-[benzyl-(4-methoxybenzenesulfonyl)amino]-l-phenyl- 3-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide. m.p. 207°-210°C.
Example 67 4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-lphenyl-3- methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide
Following the procedure of Example 53, the product of Example 65 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl-4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]- 1 -phenyl-3- methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 148°-150°C.
Following the procedure of Example 54, the above ester is hydrolyzed to provide 4- [(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-phenyl-3-methyl-lH- pyrazolo[3,4-b]pyridine-5-carboxylic acid. m.p. 235°-236°C. Following the procedure of Example 60, the carboxyUc acid is converted into the corresponding hydroxamic acid, 4-[(4-memoxybenzenesulfonyl)pyridin-3-ylmethylarnino]- l-phenyl-3-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide. m.p. 192°-194°C.
Example 68 4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethyIamino]-lphenyl-3- methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxyIic acid, hydroxyamide, hydrochloride
Following the procedure of Example 61, the product of Example 67 is converted into the corresponding hydrochloride salt. m.p.225°-226°C.
Example 69
4-[(4-Methoxybenzenesulfonyl)pyridin-2-yImethyl amino] -1,3- dimethyl - lH-pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4- amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 70
4-[(4-MethoxybenzenesulfonyI)pyridin-4-ylmethylamino] -1,3- dimethyl - lH-pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4- amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 71
4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethyIamino] -1-isopropyl - lH-pyrazolo[3,4-b]pyridin -5-carboxylic acid, hydroxyamide.
Following procedures described in Examples 45-68 for the preparation of the (substituted-4- amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the tide compound may be prepared. Example 72
4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino] -1-benzyI-lH- pyrazolo[3,4-b] pyridin -5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 73
4-[ (4-MethoxybenzenesulfonyI)amino] -l-benzyl -3-methyl -1H- pyrazolo[3,4-b] pyridine -5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 74
4-[(4-MethoxybenzenesuIfonyl) 2-thienylmethylamino] -1, 3- dimethyl - lH-pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 75
4-[(4-Methoxybenzenesulfonyl) -3-thienylmethylamino] -1, 3- dimethyl - lH-pyrazo!o[3,4-b]pyridine -5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4- amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the tide compound may be prepared.
Example 76
4-[(4-MethoxybenzenesulfonyI) pyridin-3-ylmethylamino] -1- (2,4- dimethoxyphenyl) - 3-methyl- lH-pyrazoIo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4- amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the tide compound may be prepared. Example 77
4-[(4-MethoxybenzenesuIfonyl)pyridin-3-ylmethylamino] -l-(2- methoxyphenyl)-3-methyI-lH-pyrazoIo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 78
4-{Methyl-[4-(4-pyridinyloxy)benzenesulfonyl]amino}-l,3-dimethyI-lH- pyrazolo[ 3,4-b] pyridine-5-carboxyIic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the tide compound may be prepared.
Example 79
4-{Methyl-[4-(phenoxybenzenesuIfonyl)amino]-l,3-dimethyl-lH-pyrazolo[
3,4-b] pyridine-5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4- amino) 1 ,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 80
4-[MethyI-(4-methoxybenzenesuIfonyl)amino]-l,3-dimethyl-lH-pyrazolo[
3,4-b] pyridine-5-carboxyIic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4- amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 81
4-[Methyl-(4-propyloxybenzenesuIfonyl)amino]-l,3-dimethyI-lH-pyrazolo[
3,4-b] pyridine-5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the tide compound may be prepared. Example 82 4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-methyI-3- phenyl-lH-pyrazoIo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared.
Example 83
4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethyIamino]-l-ethyl-3-phenyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1 ,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the tide compound may be prepared.
Example 84
4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-tert-butyl-3- methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxyIic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamides, the tide compound may be prepared.
Example 85
4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-methyI-3-tert- butyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide
Following procedures described in Examples 45-68 for the preparation of the (substituted-4-amino) 1,3-dimethyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamides, the tide compound may be prepared. Pharmacology
Procedures for Measuring MMP-1, MMP-9, and MMP-13 Inhibition
These assays are based on the cleavage of a thiopeptide substrates such as Ac-Pro- Leu-Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt by the matrix metalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9 (gelatinase), which results in the release of a substrate product that reacts colorimetrically with DTNB (5,5'-dithiobis(2-nitro-benzoic acid)). The enzyme activity is measured by the rate of the color increase. The thiopeptide substrate is made up fresh as a 20 mM stock in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. Both the substrate and DTNB are diluted together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM CaCl2) before use. The stock of enzyme is diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to the desired final concentration. The assay buffer, enzyme, vehicle or inhibitor, and DTNB/substrate are added in this order to a 96 weU plate (total reaction volume of 200 μl) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader and the increase in color over time is plotted as a linear line.
Alternatively, a fluorescent peptide substrate is used. In this assay, the peptide substrate contains a fluorescent group and a quenching group. Upon cleavage of the substrate by an MMP, the fluorescence that is generated is quantitated on the fluorescence plate reader. The assay is run in HCBC assay buffer (50mM HEPES, pH 7.0, 5 mM Ca+2, 0.02% Brij, 0.5% Cysteine), with human recombinant MMP-1, MMP-9, or MMP- 13. The substrate is dissolved in methanol and stored frozen in 1 mM aliquots. For the assay, substrate and enzymes are diluted in HCBC buffer to the desired concentrations. Compounds are added to the 96 well plate containing enzyme and the reaction is started by the addition of substrate. The reaction is read (excitation 340 nm, emission 444 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear Une.
For either the thiopeptide or fluorescent peptide assays, the slope of the line is calculated and represents the reaction rate. The linearity of the reaction rate is confirmed (r >0.85). The mean (x±sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generated using multiple doses of drug and IC50 values with 95% Cl are estimated using linear regression.
In vivo MMP Inhibition
A 2 cm piece of dialysis tubing (molecular weight cut-off 12-14,000, 10 mm flat width) containing matrix metalloproteinase enzyme (stromelysin, coUagenase or gelatinase in 0.5 mL of buffer) is implanted either ip or sc (in the back) of a rat (Sprague-Dawley, 150-200g) or mouse (CD-I, 25-50g) under anesthesia. Drugs are administered PO, IP, SC or IV through a canula in the jugular vein. Drugs are administered in a dose volume of 0.1 to 0.25 mL/animal. Contents of the dialysis tubing is collected and enzyme activity assayed.
Enzyme reaction rates for each dialysis tube are calculated. Tubes from at least 3 different animals are used to calculate the mean± sem. Statistical significance (p<0.05) of vehicle-treated animals versus drug- treated animals is determined by analysis of variance. (Agents and Actions 21: 331, 1987).
Procedure for Measuring TACE Inhibition
Using 96-well black microtiter plates, each well receives a solution composed of 10 μL TACE (Immunex, final concentration lμg/mL), 70μL Tris buffer, pH 7.4 containing 10% glycerol (final concentration 10 mM), and 10 μL of test compound solution in DMSO (final concentration lμM, DMSO concentration <1%) and incubated for 10 minutes at room temperature. The reaction is initiated by addition of a fluorescent peptidyl substrate (final concentration 100 μM) to each well and then shaking on a shaker for 5 sec.
The reaction is read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time is plotted as a linear line. The slope of the Une is calculated and represents the reaction rate.
The Unearity of the reaction rate is confirmed (r2 >0.85). The mean (x±sem) of the control rate is calculated and compared for statistical significance (p<0.05) with drug- treated rates using Dunnett's multiple comparison test. Dose-response relationships can be generate using multiple doses of drug and IC50 values with 95% Cl are estimated using linear regression.
Results of the above in-vitro and in-vivo matrix metalloproteinase inhibition and TACE inhibition pharmacological assays are given in Table I below.
Table I. Inhibition of MMP and TACE m
Figure imgf000045_0001
-vivo
Example MMP-11 MMP-91 MMP-131 TACE1 MMP2
11 172 11 7 >1000
12 933 2 1 190
13 82 15 9 3%
14 108 8 6 24%
15 139 25 12 7%
16 99 6 3 36% 64%(100:
17 3100 8 16 401
18 152 26 627
19 194 2 4 314
20 344 6 9 589
29 200 5 4
30 22 11 467 47
31 225 2 2 80
32 456 1 1 24
33 1012 1 1
34 301 9 12 20
35 234 4 5 49
36 46 2 1 226 81%(50)
37 65 2 1 124
38 100 4 3 336
39 75 2 2 53
40 151 3 4 120
41 136 2 2 161 65%(50)
42 5200 874 37 16%
43 43% 71% 63% 20%
44 65% 59% 73% 5%
52 45 2.4 1.4 236
60 39 2.9 2.5 160
61 36 2.3 2.3 214
62 1236 5.7 23 46%
63 721 6.8 23
64 913 5.5 19 l. IC50nM or % inhibition at 1 μM concentration
2. % inhibition (dose, mg/kg) , p.o. vs MMP-13 Pharmaceutical Composition
Compounds of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.
Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such a solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabiUzers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., ceUulose derivatives, preferable sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utiUzed by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or soUd composition form.
The compounds of this invention may be administered rectally in the form of a conventional suppository. For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
The dosage to be used in the treatment of a specific patient suffering a MMP or TACE dependent condition must be subjectively determined by the attending physician. The variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. Precise dosages for oral, parenteral, nasal, or intrabronchial administration will be determined by the administering physician based on experience with the individual subject treated and standard medical principles.
Preferably the pharmaceutical composition is in unit dosage form, e.g., as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be packaged compositions, for example packed powders, vials, ampoules, prefilled syringes or sachets containing Uquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

Claims

What is claimed:
1. A compound having the formula:
Figure imgf000048_0001
where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons of the heteroaryl ring of group A where:
A is a 5-6 membered heteroaryl having from 1 to 2 heteroatoms independently selected from N, O, and S, and substituted by R1 and R2 on adjacent atoms wherein R1 and R2 together with the carbons to which they are attached form a fused phenyl ring or a 5-6 membered heteroaryl ring having from 1 to 3 heteroatoms selected independendy from N, O and S, wherein either ring can be substituted by one or more substituents selected from R4;
Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, where aryl is phenyl or naphthyl optionally substituted by R1, R2, R3 and
R4; heteroaryl is a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, O, and S, and optionally substituted by R1, R2, R3 and R4; and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R1, R2, R3 and R4;
R1, R2, R3 and R4 are independendy -H, -COR5, -F,-Br, -Cl, -I,
-C(O)NR5OR6,-CN, -OR5,-Cι- -perfluoroalkyl, -S(O)xR5 where x is 0-2, -OPO(OR5)OR6, -PO(OR6)R5, -OC(O)NR5R6, -COOR5, -CONR5R6, -SO3H, -NR5R6, -NR5COR6, -NR5COOR6, -SO2NR5R6, -NO2, -N(R5)SO2R6, -NR5CONR5R6, -NR5C(=NR6)NR5R6, 3-6 membered cycloheteroalkyl having one to three heteroatoms independently selected from N, O, and S and optionally having 1 or 2 double bonds and optionally substituted by one to three groups each selected independently from R ; -aryl or heteroaryl as defined above, -SO2NHCOR5or -CONHSO2R5 where R5 is not H; -tetrazol-5-yl, -SO2NHCN, -SO2NHCONR5R6 or straight chain or branched - -Cό alkyl, -C2-C6-alkenyl, or -C2-C6-alkynyl, or -C3- - cycloalkyl optionally having 1 or 2 double bonds each optionally substituted with -COR5, -CN, -C2-C6 alkenyl, -C2-C6 alkynyl,-OR5, -C1-C4- perfluoroalkyl, -S(O)xR5 where x is 0-2, -OC(O)NR5R6, -COOR5, -CONR5R6, -SO3H, -NR5R6,-NR5COR6, -NR5COOR6, - SO2NR5R6, -NO2, -N(R5)SO2R6, -NR5CONR5R6, -C3-C6 cycloalkyl as defined above, 3-6 membered cycloheteroalkyl as defined above, aryl or heteroaryl as defined above, -SO2NHCOR5 or-CONHSO2R5 where R5 is not hydrogen, -PO(OR5)OR6, - PO(OR6)R5, -tetrazol-5-yl, -C(O)NR5OR6, - NR5C(=NR6)NR5R6,-SO2NHCONR5R6 or -SO NHCN;
R5 and R6 are independently defined as H, aryl and heteroaryl as defined above, -C3-C6-cycloalkyl as defined above, -C3-C6-cycloheteroalkyl as defined above, -Ci-C-j-perfluoroalkyl, or straight chain or branched -C1-C6 alkyl, -C2-C6-alkenyl, or -C2-C6-alkynyl each optionally substituted with -OH, -COR8, -CN, -C(O)NR8OR9, -C -C6-alkenyl, -C2-C6-alkynyl, -OR8, -Ci-C4-perfluoroalkyl, -S(O)xR8 where x is 0-2, -OPO(OR8)OR9, -PO(OR8)R9, -OC(O)NR8R9, -COOR8, - -CONR8R9, -SO3H, -NR8R9,-NCOR8R9, -NR0COOR9, -SO2NR8R9, -NO2, -N(R8)SO2R9, -NR8CONR8R9, -C3-C6 cycloalkyl as defined above, -C3-C6- cycloheteroalkyl as defined above, -aryl or heteroaryl as defined above, -SO2NHCOR8 or -CONHSO2R8 where R8 is not hydrogen, -tetrazol-5-yl, - -NR8C(=NR9)NR8R°, -SO2NHCONR8R9, or -SO2NHCN;
R7 is hydrogen, straight chain or branched -Ci- -alkyl, -C2-C6-alkenyl, or -C2- Qs-alkynyl each optionally substituted with -OH, -COR5, -CN, -C2-C6- alkenyl, -C2-C6-alkynyl, -OR5, -Ci- -perfluoroalkyl, -S(O)xR5 where x is 0-2, -OPO(OR5)OR6, -PO(OR5)R6, -OC(O)NR5R6, - COOR5, -CONR R6, -SO3H, -NR5R6,-NR5COR6, -NR5COOR6, SO2NR5Rθ, -NO2, -N(R )SO2R6, -NR5CONR5R6, -C3-C6 cycloalkyl as defined above, -C3-C6-cycloheteroalkyl as defined above, -aryl or heteroaryl as defined above, -SO2NHCOR5 or - CONHSO2R5 where R5 is not hydrogen, -tetrazol-5-yl, - NR5C(=NR6)NR5R6, -C(0)N R5OR6, -SO2NHCONR5R6or -
SO2NHCN; or R7 is phenyl or naphthyl, optionally substituted by R1, R2, R3 and R4 or a 5 to 6 membered heteroaryl group having 1 to 3 heteroatoms selected independendy from N, O, and S and optionally substituted by R1, R2, R3 and R4; or R7 is C3-C6 cycloalkyl or 3-6 membered cycloheteroalkyl as defined above;
or R7CH2-N-A-, where A is as defined above, can form a non-aromatic 7-12 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring;
R8 and R9 are independently H, aryl or heteroaryl as defined above, -C3-C7- cycloalkyl or cycloheteroalkyl as defined above, -Ci-C4-perfluoroalkyl, straight chain or branched -Ci-Cό-alkyl, -C2-C6-alkenyl, or -C2-C6- alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy, -Ci- CVperfluoroalkyl, amino, mono- and di-Ci-Cό-alkylamino, carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono- and di-Cι-C6-alkylcarbamoyl; a pharmaceutically acceptable salt thereof when one can be formed; an optical isomer or diastereomer thereof.
2. A compound according to claim 1 wherein both of the carbons of A adjacent to the carbon bearing the sulfonamido group have a substituent other than hydrogen.
3. A compound according to claim 2 wherein the Z group is para-alkoxyphenyl, para- aryloxyphenyl or para-heteroaryloxyphenyl.
4. A compound according to claim 1 which is selected from the group consisting of:
4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-trifluoromethyl-quinoline-3- carboxylic acid hydroxyamide, 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-8-trifluoromethyl-quinoline-3- carboxylic acid hydroxyamide, 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-bromo-quinoline-3-carboxyUc acid hydroxyamide, 4-[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-7-bromo-quinoline-3-carboxyUc acid hydroxyamide, -[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-trifluoromethyl-quinoline-3- carboxylic acid hydroxyamide, -[(4-me oxybenzenesulfonyl)-pyridm-3-ylmethylamino]-7-trifluoromethyl- quinoline-3-carboxylic acid hydroxyamide, -[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-t-butyl-quinoline-3- carboxylic acid hydroxyamide, -[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-methyl-quinoline-3- carboxyUc acid hydroxyamide, -Eώyl-4-[benzyl-(4-memoxybenzenesulfonyl)-amino]-quinoline-3- carboxylic acid hydroxyamide, -[Benzyl-(4-methoxybenzenesulfonyl)-amino]-8-(l-methylethyl)-quinoline-3- carboxylic acid hydroxyamide, -[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-8-vinyl-quinoline-3-carboxylic acid hydroxyamide, -[Benzyl-(4-methoxy-benzenesulfonyl)-amino]-6-nitro-quinoline-3-carboxylic acid hydroxyamide, -[Methyl-(4-methoxy-benzenesulfonyl)-amino]- 8-bromo-quinoline-3-carboxylic acid hydroxyamide, - { Methyl-[4-(pyridin-4-yloxy)-benzenesulfonyl]-amino } -6-iodo-quinoline-3- carboxylic acid hydroxyamide, - { Methyl-(4-(pyridin-4-yloxy)-benzenesulfonyl]-amino } -6-iodo-quinoline-3- carboxylic acid hydroxyamide hydrochloride, -[Ethyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethynyl-quinoline-3- carboxylic acid hydroxyamide, -[Methyl-(4-methoxy-benzenesulfonyl)-amino]-6-phenylethyl-quinoline-3- carboxyUc acid hydroxyamide, -[(4-Memoxy-benzenesulfonyl)-pyridm-3-ylmethyl-amino]- 8-methoxy-quinoUne-
3-carboxylic acid hydroxyamide, -[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]- 8-bromo-quinoline-3- carboxylic acid hydroxyamide, -[(4-methoxy-benzenesulfonyl)-pyridin-3-ylmethyl amino]-8-Benzyl-quinoline-3- carboxyUc acid hydroxyamide, -[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]- 8-iodo-quinoUne-3- carboxyUc acid hydroxyamide, -[(4-Memoxy-tenzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-phenyl-quinoline-3- carboxyUc acid hydroxyamide, -[(4-Methoxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-8-thiophen-2-yl- quinoline-3-carboxylic acid hydroxyamide, -[(Biphenyl-4-sulfonyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3- carboxylic acid hydroxyamide, -[(Octane-l-suhconyl)-pyridin-3-ylmethyl-amino]-7-trifluoromethyl-quinoline-3- carboxylic acid hydroxyamide, -[Pyrim^-3-ylmethyl-(toluene-4-sulfonyl)-amino]-7-trifluoromethyl-quinoline-3- carboxytic acid hydroxyamide, -[Benzyl-(4-methoxybenzenesulfonyl)amino]-l,3-dimethyl-lH-pyrazolo[3,4-b] pyridine-5-carboxylic acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin -3-ylmethylamino] -1,3- dimethyl - 1H- pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino] -1,3- dimethyl - 1H- pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide hydrochloride, -[Benzyl-(4-methoxybenzenesulfonyl)amino]-l-phenyl-lH-pyrazolo[3,4-b] pyridine -5-carboxylic acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin -3-ylmethylamino] -1 -phenyl- 1H- pyrazolo[3,4b]pyridine -5-carboxylic acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin -3-ylmethylamino] -1 -phenyl- 1H- pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide, hydrochloride, -[Benzyl-(4-methoxybenzenesulfonyl)amino]-l-phenyl-3-methyl-lH- pyrazolo[3,4b] pyridine -5-carboxylic acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]- 1 phenyl-3-methyl- 1H- pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-lphenyl-3-methyl-lH- pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide, hydrochloride, -[(4-Methoxybenzenesulfonyl)pyridin-2-ylmethyl amino] -1,3- dimethyl - 1H- pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin-4-ylmethylamino] -1,3- dimethyl - 1H- pyrazolo[3,4-b]pyridine -5-carboxyUc acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino] -1-isopropyl - 1H- pyrazolo[3,4b]pyridin -5-carboxylic acid, hydroxyamide, -[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino] - 1 -benzyl- 1H- pyrazolo[3,4-b] pyridin -5-carboxylic acid, hydroxyamide, -[ (4-Methoxybenzenesulfonyl)amino] -1-benzyl -3-methyl -lH-pyrazolo[3,4-b] pyridine -5-carboxylic acid, hydroxyamide, 4-[(4-Methoxybenzenesulfonyl) 2-thienylmethylamino] -1, 3- dimethyl - 1H- pyrazolo[3,4b]pyridine -5-carboxylic acid, hydroxyamide, 4-[(4-Methoxybenzenesulfonyl) -3-thienylmethylamino] -1, 3- dimethyl - 1H- pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide, 4-[(4-Methoxybenzenesulfonyl) pyridin-3-ylmethylamino] -1- (2,4- dimethoxyphenyl) - 3- methyl- lH-pyrazolo[3,4-b]pyridine -5-carboxyUc acid, hydroxyamide, 4-[(4-Methoxybenzenesulfonyl)pyridin- 3-ylmethylamino] - 1 -(2- methoxyphenyl)-
3-methyl-lH-pyrazolo[3,4-b]pyridine -5-carboxylic acid, hydroxyamide, 4- { Methyl-[4-(4-pyridinyloxy)benzenesulfonyl] amino } - 1 ,3-dimethyl- lH-pyrazolo
[3,4-b] pyridine-5-carboxylic acid, hydroxyamide, 4-{Methyl-[4-(phenoxybenzenesulfonyl)amino]-l,3-dimethyl-lH-pyrazolo[ 3,4-b] pyridine-5-carboxylic acid, hydroxyamide, 4-[Methyl-(4-methoxybenzenesulfonyl)amino]- 1 ,3-dimethyl- lH-pyrazolo[ 3,4-b] pyridine-5-carboxylic acid, hydroxyamide, 4-[Methyl-(4-propyloxybenzenesulfonyl)amino]-l,3-dimethyl-lH-pyrazolo[ 3,4-b] pyridine- 5-carboxylic acid, hydroxyamide, 4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]- 1 -methyl-3-phenyl- 1H- pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide, 4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]- 1 -ethyl-3-phenyl- 1H- pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide, 4-[(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-l-tert-butyl-3-methyl- lH-pyrazolo[3,4-b]pyridine-5-carboxyUc acid, hydroxyamide and 4- [(4-Methoxybenzenesulfonyl)pyridin-3-ylmethylamino]- 1 -methyl- 3-tert-butyl- lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, hydroxyamide.
5. A method of inhibiting pathological changes mediated by matrix metaUoproteinases in mammals which comprises administration to a mammal in need thereof a therapeuticaUy effective amount of a matrix metalloproteinase inhibiting compound according to claim 1.
6. A method according to claim 5 wherein the condition treated is atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from atherosclerotic plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, infammatory bowel disease, or periodontal disease.
7. A method according to claim 5 wherein the condition treated is age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization and corneal graft rejection.
8. A method of inhibiting pathological changes mediated by TNF-α converting enzyme (TACE) in mammals which comprises administration to a mammal in need thereof a therapeuticaUy effective amount of a TACE inhibiting compound according to claim 1.
9. The method according to claim 8 wherein the condition treated is rheumatoid arthritis, graft rejection, cachexia, anorexia, inflammation, fever, insuUn resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, or HIV infection.
10. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound according to claim 1.
PCT/US1997/018281 1996-10-16 1997-10-08 Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors WO1998016514A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49806/97A AU743901B2 (en) 1996-10-16 1997-10-08 Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloprote inase and tace inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US73200496A 1996-10-16 1996-10-16
US08/732,004 1996-10-16

Publications (1)

Publication Number Publication Date
WO1998016514A1 true WO1998016514A1 (en) 1998-04-23

Family

ID=24941797

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/018281 WO1998016514A1 (en) 1996-10-16 1997-10-08 Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors

Country Status (4)

Country Link
AR (1) AR009990A1 (en)
AU (1) AU743901B2 (en)
WO (1) WO1998016514A1 (en)
ZA (1) ZA979235B (en)

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018076A1 (en) * 1997-10-06 1999-04-15 American Cyanamid Company The preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
WO2000006577A1 (en) * 1998-07-28 2000-02-10 3M Innovative Properties Company OXAZOLO, THIAZOLO AND SELENAZOLO [4,5-c]-QUINOLIN-4-AMINES AND ANALOGS THEREOF
WO2000012478A1 (en) * 1998-08-31 2000-03-09 Astrazeneca Ab Arylpiperazines and their use as metalloproteinase inhibiting agents (mmp)
WO2000044713A1 (en) * 1999-01-27 2000-08-03 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as tace inhibitors
WO2000044749A1 (en) * 1999-01-27 2000-08-03 American Cyanamid Company Acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as tace inhibitors
US6200996B1 (en) 1999-01-27 2001-03-13 American Cyanamid Company Heteroaryl acetylenic sulfonamide and phosphinic acid amide hydroxamic acid tace inhibitors
US6225311B1 (en) 1999-01-27 2001-05-01 American Cyanamid Company Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
US6277885B1 (en) 1999-01-27 2001-08-21 American Cyanamid Company Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
WO2001062733A1 (en) * 2000-02-25 2001-08-30 Wyeth Ortho-sulfonamido aryl hydroxamic acids, process for their preparation and their use as matrix metalloproteinase inhibitors
WO2001062751A1 (en) * 2000-02-21 2001-08-30 Astrazeneca Ab Arylpiperazines and arylpiperidines and their use as metalloproteinase inhibiting agents
US6313123B1 (en) 1999-01-27 2001-11-06 American Cyanamid Company Acetylenic sulfonamide thiol tace inhibitors
WO2001082911A2 (en) * 2000-04-28 2001-11-08 Gerolymatos P N Sa TREATMENT OF PATHOLOGICAL CONDITIONS INFLUENCED BY THE ACTION OF MATRIX METALLOPROTEINASES (MMPs) USING CLIOQUINOL
US6326516B1 (en) 1999-01-27 2001-12-04 American Cyanamid Company Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors
US6340691B1 (en) 1999-01-27 2002-01-22 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors
US6358980B1 (en) 1999-01-27 2002-03-19 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors
WO2002034289A1 (en) 2000-10-27 2002-05-02 The Regents Of The University Of California Modulating angiogenesis
US6465508B1 (en) 2000-02-25 2002-10-15 Wyeth Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors
US6548524B2 (en) * 1996-10-16 2003-04-15 American Cyanamid Company Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors
WO2003032999A1 (en) * 2001-10-12 2003-04-24 Warner-Lambert Company Llc Alkyne matrix metalloproteinase inhibitors
WO2003037865A1 (en) * 2001-10-31 2003-05-08 Morphochem Aktiengesellschaft für kombinatorische Chemie Novel anticancer compounds
US6576644B2 (en) 2000-09-06 2003-06-10 Bristol-Myers Squibb Co. Quinoline inhibitors of cGMP phosphodiesterase
WO2004014377A1 (en) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc 4-hydroxyquinoline derivatives as matrix metalloproteinase inhibitors
WO2004033419A1 (en) * 2002-10-08 2004-04-22 Abbott Laboratories Sulfonamides having antiangiogenic and anticancer activity
US6734183B2 (en) 2000-02-21 2004-05-11 Astrazeneca Ab Compounds
US6747147B2 (en) 2002-03-08 2004-06-08 Warner-Lambert Company Oxo-azabicyclic compounds
US6753337B2 (en) 1999-01-27 2004-06-22 Wyeth Holdings Corporation Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors
US6762178B2 (en) 1999-01-27 2004-07-13 Wyeth Holdings Corporation Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
US6894057B2 (en) 2002-03-08 2005-05-17 Warner-Lambert Company Oxo-azabicyclic compounds
US6946473B2 (en) 1999-01-27 2005-09-20 Wyeth Holdings Corporation Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors
US6962922B2 (en) 2001-10-12 2005-11-08 Warner-Lambert Company Llc Alkynylated quinazoline compounds
US7098241B2 (en) 2002-12-16 2006-08-29 Hoffmann-La Roche Inc. Thiophene hydroxamic acid derivatives
WO2006117660A2 (en) * 2005-05-04 2006-11-09 Clio Pharmaceutical Corporation Method for treating cancer, coronary, inflammatory and macular disease, combining the modulation of zinc- and/or copper dependent proteins
US7153857B2 (en) 2001-08-09 2006-12-26 Astrazeneca Ab Arylpiperazines and arylpiperidines and their use as metalloproteinase inhibiting agents
US7199155B2 (en) 2002-12-23 2007-04-03 Wyeth Holdings Corporation Acetylenic aryl sulfonate hydroxamic acid TACE and matrix metalloproteinase inhibitors
US7282496B2 (en) 2001-11-01 2007-10-16 Wyeth Holdings Corporation Allenic aryl sulfonamide hydroxamic acids as matrix metalloproteinase and TACE inhibitors
US7491718B2 (en) 2002-10-08 2009-02-17 Abbott Laboratories Sulfonamides having antiangiogenic and anticancer activity
WO2011001088A1 (en) 2009-06-30 2011-01-06 Galderma Research & Development Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
WO2011001089A1 (en) 2009-06-30 2011-01-06 Galderma Research & Development Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
US20120076732A1 (en) * 2008-12-23 2012-03-29 Yan Feng Phosphodiesterase inhibitors and uses thereof
US20130165439A1 (en) * 2007-06-25 2013-06-27 Boehringer Ingelheim International Gmbh Chemical compounds
US8513421B2 (en) 2010-05-19 2013-08-20 Millennium Pharmaceuticals, Inc. Substituted hydroxamic acids and uses thereof
WO2014140861A2 (en) 2013-03-15 2014-09-18 Galderma Research & Development Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
WO2016147194A1 (en) 2015-03-19 2016-09-22 Yeda Research And Development Co. Ltd. Anti amphiregulin antibodies, compositions comprising same and uses thereof
WO2017117130A1 (en) 2015-12-28 2017-07-06 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Methods for inhibiting human immunodeficiency virus (hiv) release from infected cells
EP3199534A1 (en) 2016-02-01 2017-08-02 Galderma Research & Development Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine and cosmetics
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000049197A (en) * 1996-10-16 2000-07-25 윌리암 에이취 캘넌, 에곤 이 버그 The preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0606046A1 (en) * 1993-01-06 1994-07-13 Ciba-Geigy Ag Arylsulfonamido-substituted hydroxamic acids

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000049197A (en) * 1996-10-16 2000-07-25 윌리암 에이취 캘넌, 에곤 이 버그 The preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0606046A1 (en) * 1993-01-06 1994-07-13 Ciba-Geigy Ag Arylsulfonamido-substituted hydroxamic acids

Cited By (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6548524B2 (en) * 1996-10-16 2003-04-15 American Cyanamid Company Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors
WO1999018076A1 (en) * 1997-10-06 1999-04-15 American Cyanamid Company The preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
US6627640B2 (en) 1998-07-28 2003-09-30 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
US6323200B1 (en) 1998-07-28 2001-11-27 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c] quinolin-4-amines and analogs thereof
US6440992B1 (en) 1998-07-28 2002-08-27 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
US6110929A (en) * 1998-07-28 2000-08-29 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
US7148232B2 (en) 1998-07-28 2006-12-12 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
US6809203B2 (en) 1998-07-28 2004-10-26 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-C]-quinolin-4-amines and analogs thereof
WO2000006577A1 (en) * 1998-07-28 2000-02-10 3M Innovative Properties Company OXAZOLO, THIAZOLO AND SELENAZOLO [4,5-c]-QUINOLIN-4-AMINES AND ANALOGS THEREOF
US6627638B2 (en) 1998-07-28 2003-09-30 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]quinolin-4-amines and analogs thereof
US6703402B2 (en) 1998-07-28 2004-03-09 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
US6677334B2 (en) 1998-07-28 2004-01-13 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
US6734184B1 (en) 1998-08-31 2004-05-11 Astrazeneca Ab Arylpiperazines and their use as metalloproteinase inhibiting agents (MMP)
JP2002523493A (en) * 1998-08-31 2002-07-30 アストラゼネカ・アクチエボラーグ Arylpiperazines and their use as metalloproteinase inhibitors (MMPs)
JP4776778B2 (en) * 1998-08-31 2011-09-21 アストラゼネカ・アクチエボラーグ Aryl piperazines and their use as metalloproteinase inhibitors (MMPs)
WO2000012478A1 (en) * 1998-08-31 2000-03-09 Astrazeneca Ab Arylpiperazines and their use as metalloproteinase inhibiting agents (mmp)
US7342020B2 (en) 1998-08-31 2008-03-11 Astrazeneca Ab Arylpiperazines and their use as metalloproteinase inhibiting agents (MMP)
US6753337B2 (en) 1999-01-27 2004-06-22 Wyeth Holdings Corporation Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors
US6812227B2 (en) 1999-01-27 2004-11-02 Wyeth Holdings Corporation Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
US6358980B1 (en) 1999-01-27 2002-03-19 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors
US6946473B2 (en) 1999-01-27 2005-09-20 Wyeth Holdings Corporation Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors
EP1279674A2 (en) * 1999-01-27 2003-01-29 American Cyanamid Company Acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors
US6825354B2 (en) 1999-01-27 2004-11-30 Wyeth Holdings Corporation Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and TACE inhibitors
US6340691B1 (en) 1999-01-27 2002-01-22 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as matrix metalloproteinase and tace inhibitors
WO2000044713A1 (en) * 1999-01-27 2000-08-03 American Cyanamid Company Alkynyl containing hydroxamic acid compounds as tace inhibitors
US6200996B1 (en) 1999-01-27 2001-03-13 American Cyanamid Company Heteroaryl acetylenic sulfonamide and phosphinic acid amide hydroxamic acid tace inhibitors
US6225311B1 (en) 1999-01-27 2001-05-01 American Cyanamid Company Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
US6762178B2 (en) 1999-01-27 2004-07-13 Wyeth Holdings Corporation Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
US6326516B1 (en) 1999-01-27 2001-12-04 American Cyanamid Company Acetylenic β-sulfonamido and phosphinic acid amide hydroxamic acid TACE inhibitors
US6277885B1 (en) 1999-01-27 2001-08-21 American Cyanamid Company Acetylenic aryl sulfonamide and phosphinic acid amide hydroxamic acid TACE inhibitors
EP1279674A3 (en) * 1999-01-27 2003-10-01 Wyeth Holdings Corporation Acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors
US6313123B1 (en) 1999-01-27 2001-11-06 American Cyanamid Company Acetylenic sulfonamide thiol tace inhibitors
WO2000044749A1 (en) * 1999-01-27 2000-08-03 American Cyanamid Company Acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as tace inhibitors
US6716833B2 (en) 1999-01-27 2004-04-06 Wyeth Holdings Corporation Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors
US7122551B2 (en) 2000-02-21 2006-10-17 Astrazeneca Ab Metalloproteinase inhibitor compounds
US6734183B2 (en) 2000-02-21 2004-05-11 Astrazeneca Ab Compounds
WO2001062751A1 (en) * 2000-02-21 2001-08-30 Astrazeneca Ab Arylpiperazines and arylpiperidines and their use as metalloproteinase inhibiting agents
US6825352B2 (en) 2000-02-25 2004-11-30 Wyeth Preparation and use of ortho-sulfonamido arylhydroxamic acids as matrix metalloproteinase inhibitors
WO2001062733A1 (en) * 2000-02-25 2001-08-30 Wyeth Ortho-sulfonamido aryl hydroxamic acids, process for their preparation and their use as matrix metalloproteinase inhibitors
US6465508B1 (en) 2000-02-25 2002-10-15 Wyeth Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors
US7470794B2 (en) 2000-02-25 2008-12-30 Wyeth Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase inhibitors
WO2001082911A2 (en) * 2000-04-28 2001-11-08 Gerolymatos P N Sa TREATMENT OF PATHOLOGICAL CONDITIONS INFLUENCED BY THE ACTION OF MATRIX METALLOPROTEINASES (MMPs) USING CLIOQUINOL
WO2001082911A3 (en) * 2000-04-28 2003-03-13 Michel Xilinas TREATMENT OF PATHOLOGICAL CONDITIONS INFLUENCED BY THE ACTION OF MATRIX METALLOPROTEINASES (MMPs) USING CLIOQUINOL
US7384958B2 (en) 2000-09-06 2008-06-10 Bristol-Myers Squibb Company Quinoline inhibitors of cGMP phosphodiesterase
US6576644B2 (en) 2000-09-06 2003-06-10 Bristol-Myers Squibb Co. Quinoline inhibitors of cGMP phosphodiesterase
US6835737B2 (en) 2000-09-06 2004-12-28 Bristol-Myers Squibb Company Quinoline inhibitors of cGMP phosphodiesterase
US7173042B2 (en) 2000-09-06 2007-02-06 Bristol-Myers Squibb Company Quinoline inhibitors of cGMP phosphodiesterase
US7378430B2 (en) 2000-09-06 2008-05-27 Bristol-Myers Squibb Company Quinoline inhibitors of cGMP phosphodiesterase
EP1333856A4 (en) * 2000-10-27 2007-05-16 Univ California Modulating angiogenesis
EP1333856A1 (en) * 2000-10-27 2003-08-13 The Regents Of The University Of California Modulating angiogenesis
WO2002034289A1 (en) 2000-10-27 2002-05-02 The Regents Of The University Of California Modulating angiogenesis
US7153857B2 (en) 2001-08-09 2006-12-26 Astrazeneca Ab Arylpiperazines and arylpiperidines and their use as metalloproteinase inhibiting agents
US6962922B2 (en) 2001-10-12 2005-11-08 Warner-Lambert Company Llc Alkynylated quinazoline compounds
WO2003032999A1 (en) * 2001-10-12 2003-04-24 Warner-Lambert Company Llc Alkyne matrix metalloproteinase inhibitors
US6849648B2 (en) 2001-10-12 2005-02-01 Warner-Lambert Company Phenylene alkyne matrix metalloproteinase inhibitors
WO2003037865A1 (en) * 2001-10-31 2003-05-08 Morphochem Aktiengesellschaft für kombinatorische Chemie Novel anticancer compounds
US7282496B2 (en) 2001-11-01 2007-10-16 Wyeth Holdings Corporation Allenic aryl sulfonamide hydroxamic acids as matrix metalloproteinase and TACE inhibitors
US6747147B2 (en) 2002-03-08 2004-06-08 Warner-Lambert Company Oxo-azabicyclic compounds
US6894057B2 (en) 2002-03-08 2005-05-17 Warner-Lambert Company Oxo-azabicyclic compounds
WO2004014377A1 (en) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc 4-hydroxyquinoline derivatives as matrix metalloproteinase inhibitors
US7491718B2 (en) 2002-10-08 2009-02-17 Abbott Laboratories Sulfonamides having antiangiogenic and anticancer activity
WO2004033419A1 (en) * 2002-10-08 2004-04-22 Abbott Laboratories Sulfonamides having antiangiogenic and anticancer activity
US7098241B2 (en) 2002-12-16 2006-08-29 Hoffmann-La Roche Inc. Thiophene hydroxamic acid derivatives
US7199155B2 (en) 2002-12-23 2007-04-03 Wyeth Holdings Corporation Acetylenic aryl sulfonate hydroxamic acid TACE and matrix metalloproteinase inhibitors
US7485667B2 (en) 2002-12-23 2009-02-03 Wyeth Holdings Corporation Acetylenic aryl sulfonate hydroxamic acid tace and matrix metalloproteinase inhibitors
WO2006117660A3 (en) * 2005-05-04 2007-01-04 Clio Pharmaceutical Corp Method for treating cancer, coronary, inflammatory and macular disease, combining the modulation of zinc- and/or copper dependent proteins
WO2006117660A2 (en) * 2005-05-04 2006-11-09 Clio Pharmaceutical Corporation Method for treating cancer, coronary, inflammatory and macular disease, combining the modulation of zinc- and/or copper dependent proteins
US20130165439A1 (en) * 2007-06-25 2013-06-27 Boehringer Ingelheim International Gmbh Chemical compounds
US8697875B2 (en) * 2008-12-23 2014-04-15 The Trustees Of Columbia University In The City Of New York Phosphodiesterase inhibitors and uses thereof
US9974782B2 (en) 2008-12-23 2018-05-22 The Trustees Of Columbia University In The City Of New York Phosphodiesterase inhibitors and uses thereof
US20120076732A1 (en) * 2008-12-23 2012-03-29 Yan Feng Phosphodiesterase inhibitors and uses thereof
US9422242B2 (en) 2008-12-23 2016-08-23 The Trustees Of Columbia University In The City Of New York Phosphodiesterase inhibitors and uses thereof
WO2011001089A1 (en) 2009-06-30 2011-01-06 Galderma Research & Development Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
US8772478B2 (en) 2009-06-30 2014-07-08 Galderma Research & Development Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
EP2801568A1 (en) 2009-06-30 2014-11-12 Galderma Research & Development Benzene-sulphonamide compounds, method for synthesising and use in medicine and in cosmetics
WO2011001088A1 (en) 2009-06-30 2011-01-06 Galderma Research & Development Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
US8513421B2 (en) 2010-05-19 2013-08-20 Millennium Pharmaceuticals, Inc. Substituted hydroxamic acids and uses thereof
WO2014140861A2 (en) 2013-03-15 2014-09-18 Galderma Research & Development Novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
WO2016147194A1 (en) 2015-03-19 2016-09-22 Yeda Research And Development Co. Ltd. Anti amphiregulin antibodies, compositions comprising same and uses thereof
WO2017117130A1 (en) 2015-12-28 2017-07-06 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Methods for inhibiting human immunodeficiency virus (hiv) release from infected cells
EP3199534A1 (en) 2016-02-01 2017-08-02 Galderma Research & Development Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine and cosmetics
US10556883B2 (en) 2016-02-01 2020-02-11 Galderma Research & Development Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine and cosmetics
WO2020070239A1 (en) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Egfr inhibitors for treating keratodermas

Also Published As

Publication number Publication date
AU4980697A (en) 1998-05-11
AR009990A1 (en) 2000-05-17
ZA979235B (en) 1999-04-15
AU743901B2 (en) 2002-02-07

Similar Documents

Publication Publication Date Title
WO1998016514A1 (en) Ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
US6228869B1 (en) Ortho-sulfonamido bicyclic hydroxamic acids as matrix metalloproteinase and TACE inhibitors
EP0934300B1 (en) The preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
US6548524B2 (en) Preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors
US5929097A (en) Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
US5962481A (en) Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
EP0934259B1 (en) Beta-sulfonamido hydroxamic acids as matrix metalloproteinase and tace inhibitors
JP2001504809A (en) Preparation and use of ortho-sulfonamidoarylhydroxamic acids as inhibitors of matrix metalloproteinases and tace
US5977408A (en) Preparation and use of β-sulfonamido hydroxamic acids as matrix metalloproteinase and TACE inhibitors
EP1021413B1 (en) The preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
US6946473B2 (en) Preparation and use of acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as TACE inhibitors
EP1157024B1 (en) Acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as tace inhibitors
US20010051614A1 (en) Preparation and use of ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase and TACE inhibitors
MXPA00003324A (en) The preparation and use of ortho-sulfonamido bicyclic heteroaryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
CZ20001246A3 (en) Derivatives of hydroxamic acids
JP2003524000A (en) Ortho-sulfonamidoaryl hydroxamic acids, a process for their preparation and their use as matrix metalloproteinase inhibitors
MXPA01007572A (en) Acetylenic ortho-sulfonamido and phosphinic acid amido bicyclic heteroaryl hydroxamic acids as tace inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN

CFP Corrected version of a pamphlet front page
CR1 Correction of entry in section i

Free format text: PAT. BUL. 16/98 UNDER (51) REPLACE THE EXISTING SYMBOLS BY "C07D215/54, A61K 31/47, C07D401/12, 409/14, 471/04"

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA