This invention relates to acetylenic hydroxamic acids which act as inhibitors of TNF-xcex1 converting enzyme (TACE). The compounds of the present invention are useful in disease conditions mediated by TNF-xcex1, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn""s disease and degenerative cartilage loss.
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. 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. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology. Furthermore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. 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/neo-vascularization and corneal graft rejection. For recent reviews, see: (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5(12): 1287-1196: (6) Exp. Opin. Ther. Patents (1998) 8(3): 281-259.
TNF-xcex1 converting enzyme (TACE) catalyzes the formation of TNF-xcex1 from membrane bound TNF-xcex1 precursor protein. TNF-xcex1 is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp. Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J. Women""s Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613.] septic shock [Mathison, et. al. J. Clin. Invest. 1988, 81, 1925; Miethke, et. al. J. Exp. Med. 1992, 175, 91.], graft rejection [Piguet, P. F.; Grau, G. E.; et. al. J. Exp. Med. 1987, 166, 1280.], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988, 57, 505.], anorexia, inflammation [Ksontini, R,; MacKay, S. L. D.; Moldawer, L. L. Arch. Surg. 1998, 133, 558.], congestive heart failure [Packer, M. Circulation, 1995, 92(6), 1379; Ferrari, R.; Bachetti, T.; et. al. Circulation, 1995, 92(6), 1479.], post-ischaemic reperfusion injury, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B. M.; et. al. Science, 1993, 259, 87.] and HIV infection (Peterson, P. K.; Gekker, G.; et. al. J Clin. Invest. 1992, 89, 574; Pallares-Trujillo, J.; Lopez-Soriano, F. J. Argiles, J. M. Med Res. Reviews, 1995, 15(6), 533.]], in addition to its well-documented antitumor properties [Old, L. Science, 1985, 230, 630.]. For example, research with anti-TNFxcex1 antibodies and transgenic animals has demonstrated that blocking the formation of TNF-xcex1 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.), au97-M2Z.]. This observation has recently been extended to humans as well as described in xe2x80x9cTNF-xcex1 in Human Diseasesxe2x80x9d, Current Pharmaceutical Design, 1996, 2, 662.
It is expected that small molecule inhibitors of TACE will have the potential for treating a variety of disease states. Although a variety of TACE inhibitors are known, many of these molecules are peptidic and peptide-like which suffer from bioavailability and pharmacokinetic problems. In addition, many of these molecules are non-selective, being potent inhibitors of matrix metalloproteinases and, in particular, MMP-1. Inhibition of MMP-1 (collagenase 1) has been postulated to cause joint pain in clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20] Long acting, selective, orally bioavailable non-peptide inhibitors of TACE would thus be highly desirable for the treatment of the disease states discussed above.
Sulfone hydroxamic acid inhibitors of MMPs, of general structure I have been disclosed [Burgess, L. E.; Rizzi, J. P.; Rawson, D. J. Eur Patent Appl. 818442. Groneberg, R. D.; Neuenschwander, K. W.; Djuric, S. W.; McGeehan, G. M.; Burns, C. J.; Condon, S. M.; Morrissette, M. M.; Salvino, J. M.; Scotese, A. C.; Ullrich, J. W. PCT Int. Appl. WO 97/24117. Bender, S. L.; Broka, C. A.; Campbell, J. A.; Castelhano, A. L.; Fisher, L. E.; Hendricks, R. T.; Sarma, K. Eur. Patent Appl. 780386. Venkatesan, A. M.; Grosu, G. T.; Davis, J. M.; Hu, B.; O""Dell, M. J. PCT Int. Appl. WO 98/38163.]. An exemplification of this class of MMP inhibitor is RS-130830, shown below. 
Within the sulfone-hydroxamic acid class of MMP inhibitor, the linker between the sulfone and hydroxamic acid moieties has been extended to three carbons I, n=2) without significant loss in potency [Barta, T. E.; Becker, D. P.; Villamil, C. I.; Freskos, J. N.; Mischke, B. V.; Mullins, P. B.; Heintz, R. M.; Getman, D. P.; McDonald, J. J. PCT Into Appl. WO 98/39316. McDonald, J. J.; Barta, T. E.; Becker, D. P.; Bedell, L. J.; Rao, S. N.; Freskos, J. N.; Mischke, B. V. PCT Int. Appl. WO 98/38859.].
Piperidine sulfone hydroxamic acids, II (n=1) have been reported [Becker, D. P.; Villamil, C. I.; Boehm, T. L.; Getman, D. P.; McDonald, J. J.; DeCrescenzo, G. A. PCT Int. Appl. WO 98/39315.]. Similar piperidine derivatives in which the methylene linking the piperidine ring to the sulfone has been deleted (II, n=0) have been reported [Venkatesan, A. M.; Grosu, G. T.; Davis, J. M.; Baker, J. L. PCT Int. Appl. WO 98/37877.]. 
Sulfone-hydroxamic acids III, in which a hydroxyl group has been placed alpha to the hydroxamic acid, have been disclosed [Freskos, J. N.; Boehm, T. L.; Mischke, B. V.; Heintz, R. M.; McDonald, J. J.; DeCrescenzo, G. A.; Howard, S. C. PCT Int. Appl. WO 98/39326. Robinson, R. P. PCT Int. Appl. WO 98/34915.]. 
Sulfone-based MMP inhibitors of general structure IV, which utilize a thiol as the zinc chelator, have been reported [Freskos, J. N.; Abbas, Z. S.; DeCrescenzo, G. A.; Getman, D. P.; Heintz, R. M.; Mischke, B. V.; McDonald, J. J. PCT Int. Appl. WO 98/03164]. 
Inhibitors of stromelysin with general structure V have been disclosed [Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Science, 1996, 274, 1531-1534. Hajduk, P. J.; Sheppard, G.; Nettesheim, D. G.; Olejniczak, E. T.; Shuker, S. B.; Meadows, R. P.; Steinman, D. H.; Carrera, Jr., G. M.; Marcotte, P. A.; Severin, J.; Walter, K.; Smith, H.; Gubbins, E.; Simmer, R.; Holzman, T. F.; Morgan, D. W.; Davidsen, S. K.; Summers, J. B.; Fesik, S. W. J. Am. Chem Soc. 1997, 119, 5818-5827. Olejniczak, E. T.; Hajduk, P. J.; Marcotte, P. A.; Nettesheim, D. G.; Meadows, R. P.; Edalji, R.; Holzman, T. F.; Fesik, S. W. J. Am. Chem. Soc. 1997, 119, 5828-5832. Fesik, S. W.; Summers, J. B.; Davidsen, S. K.; Sheppard, G. S.; Steinman, D. H.; Carrera, G. M.; Florjancic, A.; Holms, J. H. PCT Int. Appl. WO 97/18188.]. 
Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of general formula 1. These compounds were prepared to study the Mannich reaction. Subsequently, they were tested for their fungicidal activity. 
Some sulfone carboxylic acids are disclosed in U.S. Pat. No. 4,933,367. Those compounds were shown to exhibit hypoglycemic activity.
The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-xcex1 converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.
In accordance with this invention there is provided compounds of general formula I: 
wherein:
R1 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or C5-C8-cycloheteroalkyl having from 1-2 heteroatoms selected from N, NR7, S and O;
R2 and R3 are each independently, hydrogen, alkyl of 1-6 carbon atoms, xe2x80x94CN, or xe2x80x94CCH;
R5 is hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, or C4-C8-cycloheteralkyl;
R7 is hydrogen, aryl, aralkyl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms, oxy, C1-C8 alkanoyl, COOR5, COR5, xe2x80x94SO2xe2x80x94C1-C8 alkyl, xe2x80x94SO2-aryl, xe2x80x94SO2-heteroaryl,xe2x80x94COxe2x80x94NHR;
R8, R9, R10, and R11 are each, independently, hydrogen, aryl, aralkyl, 5-10 membered heteroaryl having from 1-3 heteroatoms selected from N, NR7, O and S, heteroaralkyl having from 1-3 heteroatoms selected from N, NR7, O and S, cycloalkyl of 3-6 carbon atoms, xe2x80x94C4-C8-cycloheteroalkyl having from 1-3 heteroatoms selected from N, NR7, O and S, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms;
R12 is hydrogen, aryl or 5-10 membered heteroaryl having from 1-3 heteroatoms selected from N, NR7, S and O, cycloalkyl of 3-6 carbon atoms, xe2x80x94C5-C8-cycloheteroalky having from 1 to 2 heteroatoms selected from N, NR7, S and O, or alkyl of 1-6 carbon atoms;
A is O, S, SO, SO2, NR7, or CH;
X is O, S, SO, SO2, NR7, or C,
Y is aryl or heteroaryl, with the proviso that A and X are not bonded to adjacent atoms of Y; and
n is 0-2; or a pharmaceutically acceptable salt thereof.
In some preferred embodiments of the present invention Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl, triazolyl and thiadiazolyl.
Still more preferred compounds of the present invention are compounds of Formula I wherein R2 and R3 are each, independently, hydrogen or alkyl of 1-6 carbon atoms; R12 is hydrogen; and Y is phenyl.
The most preferred matrix metalloproteinase and TACE inhibiting compounds of this invention are:
2-(4-But-2-ynyloxy-benzenesulfonyl)-N-hydroxy-2-methyl-3-pyridin-3-yl-propionamide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-N-hydroxy-propionamide;
2-(4-But-2-ynyloxy-benzesulfonyl)-N-hydroxy-2-methyl-3-[4-(2-piperidin-1-yl-ethoxy)-phenyl)-propionamide;
3-Biphenyl-4-yl-2-(4-but-2-ynyloxy-benzenesulfonyl)-N-hydroxy-2-methyl-propionamide;
2-(4-But-2-ynyloxy-phenysulfanyl)-octanoic acid hydroxamide;
2-(But-2-ynyloxy-benzenesulfonyl)-octanoic acid hydroxamide;
2[(R)-(4-Butyl-2-ynyloxy)-sulfinyl-N-hydroxyoctanamide;
2[(S)-(4-Butyl-2-ynyloxy)-sulfinyl-N-hydroxyoctanamide;
3-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-propionamide;
4-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-butyramide;
2-(4-But-2-ynyloxy-phenoxy)-N-hydroxy-acetamide;
4-(4-But-2-ynyloxy-phenyl)-N-hydroxy-butyramide;
Quinoline-2-carboxylic acid [5-(4-but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-hexanoic acid hydroxyamide;
N-[5-(4-But-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl-benzamide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-[2-(3,4-dichloro-phenyl)-acetylamino]-hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-(4-thiophen-2-yl-butyrylamino)-hexanoic acid hydroxyamide;
9H-Xanthene-9-carboxylic acid [5-(4-but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-diphenylacetylamino-hexanoic acid hydroxyamide;
Isoquinoline-1-carboxylic acid [5-(4but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentyl]-amide;
6-(2-Benzo[b]thiophen-3-yl-acetylamino)-2-(4but-2-ynyloxy-phenyl-sulfanyl)-hexanoic acid hydroxyamide;
Quinoline-2-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-hexanoic acid hydroxyamide;
N-[5-(4-But-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl-benzamide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-[2-(3,4-dichloro-phenyl)-acetylamino]-hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-(4-thiophen-2-yl-butyrylamino)-hexanoic acid hydroxyamide;
9H-Xanthene-9-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-diphenylacetylamino-hexanoic acid hydroxyamide;
Isoquinoline-1-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentyl]-amide;
6-(2-Benzo[b]thiophen-3-yl-acetylamino)-2-(4-but-2-ynyloxy-benzene-sulfinyl)-hexanoic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-(2-1H-indol-3-yl-acetylamino)-hexanoic acid hydroxyamide;
Quinoline-2-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetylamino]-hexanoic acid hydroxyamide;
N-[5-(4-But-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentyl]-2-phenethyl-benzamide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-[2-(3,4-dichloro-phenyl)-acetylamino]-hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfonyl)-5-5-hydroxycarbamoyl-pentyl]-amide;
9H-Xanthene-9-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentyl]-amide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-diphenylacetylaminohexanoic acid hydroxyamide;
Isoquinoline-1-carboxylic acid [5-(4-but-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentyl]-amide;
6-(2-Benzo[b]thiophen-3-yl-acetylamino)-2-(4-but-2-ynyloxy-benzenesulfonyl)-hexanoic acid hydroxyamide;
Quinoline-2-carboxylic acid ([5-(4-but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl)-amide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-{2-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-acetylamino]-acetylamino}hexanoic acid hydroxyamide;
N-{[5-(4-But-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-2-phenethyl-benzamide;
2-(4-But-2-ynyloxy-phenylsulfanyl)-6-{2-[2-(3,4-dichloro-phenyl)-acetylamino]-acetylamino}-hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid {[5-(4-but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
9H-Xanthene-9-carboxylic acid {[5-(4-but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
2-(4But-2-ynyloxy-phenylsulfanyl)-6-(2-diphenylacetylamino-acetylamino)-hexanoic acid hydroxyamide;
Isoquinoline-1-carboxylic acid {[5-(4-but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
1-Methyl-1H-pyrrole-2-carboxylic acid {[5-(4-but-2-ynyloxy-phenylsulfanyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
6-[2-(2-Benzo[b]thiophen-3-yl-acetylamino)-acetylamino]-2-(4-but-2-ynyloxy-phenylsulfanyl hexanoic acid hydroxyamide;
Quinoline-2-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-{2-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-acetylamino]-acetylamino}-hexanoic acid hydroxyamide;
N-{[5-(4-But-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-2-phenethyl-benzamide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-{2-[2-(3,4-dichloro-phenyl)-acetylamino]-acetylamino}-hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-[2-(4-thiophen-2-yl-butyrylamino)-acetylamino]-hexanoic acid hydroxyamide;
9H-Xanthene-9-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
2-(4-But-2-ynyloxy-benzenesulfinyl)-6-(2-diphenylacetylamino-acetylamino)-hexanoic acid hydroxyamide;
1-Methyl-1H-pyrrole-2-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfinyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl)-amide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-52-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-acetylamino]-acetylamino)-hexanoic acid hydroxyamide;
N-{[5-(4-But-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-2-phenethyl-benzamide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-1 2-[2-(3,4-dichloro-phenyl)-acetylamino)-acetylamino}-hexanoic acid hydroxyamide;
Quinoline-3-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}amide;
9H-Xanthene-9-carboxylic acid {[5-(4but-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-(2-diphenylacetylamino-acetylamino)-hexanoic acid hydroxyamide;
Isoquinoline-1-carboxylic acid {[5-(4-but-2-ynyloxy-benzenesulfonyl)-5-hydroxycarbamoyl-pentylcarbamoyl]-methyl}-amide;
6-[2-(2-Benzo[b]thiophen-3-yl-acetylamino)-acetylamino]-2-(4-but-2-ynyloxy benzenesulfonyl hexanoic acid hydroxyamide;
2-(4-But-2-ynyloxy-benzenesulfonyl)-6-[2-(2-1H-indol-3-yl-acetylamino)-acetylamino]-hexanoic acid hydroxyamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy phenyl}butanamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-7-cyano-N-hydroxy heptanamide;
2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-cyclohexyl-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-cyclohexyl-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-cyclohexyl-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-(4-methoxyphenyl) acetamide;
(2R)-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-(4-methoxyphenyl)ethanamide;
(2S)-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-(4-methoxyphenyl)ethanamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(4-methoxyphenyl)acetamide;
2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(4-chlorophenyl)-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(4-chlorophenyl)-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl-2-(4-chlorophenyl)-N-hydroxy-acetamide;
2-{[4-(2-butynyloxy)phenyl]sulfanyl}-2-(3-chlorophenyl)-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(3-chlorophenyl)-N-hydroxyacetamide;
2-(4-bromophenyl)-2-{[4-(2-butynyloxy)phenyl]sulfanyl-N-hydroxyacetamide;
(2S)-2-(4-bromophenyl)-2-{[4-(2-butynyloxy)phenyl]sulfinyl-N-hydroxyacetamide;
(2R)-2-(4-bromophenyl)-2-{[4-(2-butynyloxy)phenyl]sulfinyl-N-hydroxyacetamide;
2-(4-bromophenyl)-2-{[4-(2-butynyloxy)phenyl]sulfonyl-N-hydroxy-acetamide;
2-{[4-(2-butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-(4-(2-thienyl)phenyl]-acetamide;
(2R)-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-[4-(2-thienyl)-phenyl]ethanamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-[4-(2-thienyl)-phenyl1acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl}-N-hydroxy-2-(1-napthyl)acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfinyl}-N-hydroxy-2-(1-napthyl)acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(1-napthyl)acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl}-2-(4-fluorophenyl)-N-hydroxy-2-(1-napthyl)acetamide;
2-{[4-(2-butynyloxy)phenyl]sulfinyl-2-(4-fluorophenyl)-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl-2-(4-fluorophenyl)-N-hydroxyacetamide;
2-(2-methoxyphenyl)-2-{[4-(2-butynyloxy)phenyl]sulfanyl-N-hydroxy-acetamide;
2-(2-methoxyphenyl)-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfanyl-N-hydroxy-2-(4-ethoxyphenyl)acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfinyl-N-hydroxy-2-(4-ethoxyphenyl)acetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl-2-(4-chlorophenyl)-N-hydroxyacetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl-N-hydroxy-2-(3-bromophenyl)acetamide;
(2R)-2-{[4-(2-butynyloxy)phenyl]sulfinyl-N-hydroxy-2-(3-bromophenyl)acetamide;
(2S)-2-{[4-(2-butynyloxy)phenyl]sulfinyl-N-hydroxy-2-(3-bromophenyl)acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-2-(3-bromophenyl)-N-hydroxyacetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl}-2-isopropyl-N-hydroxyacetamide;
R-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-isopropyl-N-hydroxyacetamide;
S-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-isopropyl-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-isopropyl-N-hydroxyacetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl}-2-phenyl-N-hydroxyacetamide;
R-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-phenyl-N-hydroxyacetamide;
S-2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-phenyl-N-hydroxyacetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfanyl}-2-(2-naphthyl)-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfinyl}-2-(2-naphthyl)-N-hydroxyacetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(2-naphthyl)-N-hydroxyacetamide;
Tert-butyl-4-[1-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-(hydroxyamino)-2-oxyethyl]-1-piperidine carboxylate;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(4-piperidinyl)acetamide;
2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-[2-(4-methoxybenzyl)-4-piperidinyl]acetamide;
2-(1-benzoyl-4-piperidinyl)-2-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxyacetamide;
2-(1-acetyl-4-piperidinyl)-2-{[4-(2-butynyloxy)phenyl]sulfonyl-N-hydroxyacetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-tetrahydro-2H-pyran-4yl-acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-tetrahydro-2H-thiopyran-4yl-acetamide;
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2-(1-oxidotetrahydro-2H-thiopyran-4yl)acetamide; and
2-{[4-(2-Butynyloxy)phenyl]sulfonyl)-N-hydroxy-2-(1,1-dioxidotetrahydro-2H-thiopyran-4yl)acetamide.
Heteroaryl, as used throughout, is a 5-10 membered mono- or bicyclic ring having from 1-3 heteroatoms selected from N, NR7, S and O. Heteroaryl is preferably 
wherein K is defined as O, S or xe2x80x94NR7 and R7 is as defined before. Preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole. Heteroaryl groups of the present invention may be mono or disubstituted.
xe2x80x94C4-C8-cycloheteroalkyl is defined as 
wherein K is O, S or NR7 and R7 is as defined before. Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. Heterocycloalkyl groups of the present invention may optionally be mono- or di-substituted.
Aryl, as used herein refers to phenyl or naphthyl aromatic rings which may, optionally be mono- or di-substituted.
Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both straight chain as well as branched moieties. Alkyl, alkenyl, alkynyl, and cycloalkyl groups may be unsubstituted unsubstituted (carbons bonded to hydrogen, or other carbons in the chain or ring) or may be mono- or poly-substituted. Lower alkyl is C1-C6 alkyl.
Aralkyl as used herein refers to substituted alkyl group, -alkyl-aryl, wherein alkyl is lower alkyl and preferably C1-C3, and aryl is as previously defined.
Heteroaralkyl as used herein refers to substituted alkyl group, -alkyl-heteroaryl, wherein alkyl is lower alkyl and preferably C1-C3, and heteroaryl is as previously defined.
Halogen means bromine, chlorine, fluorine, and iodine.
Suitable substituents of aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, alkenyl, alkynyl, cycloalkyl and include, but are not limited to halogen, alkyl of 1-6 carbon atoms; alkenyl of 2-6 carbon atoms; alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, xe2x80x94OR5, xe2x80x94CN, xe2x80x94COR5, perfluoroalkyl of 1-4 carbon atoms, xe2x80x94O -perfluoroalkyl of 1-4 carbon atoms, xe2x80x94CONR5R6, xe2x80x94S(O)nR5, xe2x80x94OPO(OR5)OR6, xe2x80x94PO(OR)R6, xe2x80x94OC(O)OR5, xe2x80x94OR5NR5R6, xe2x80x94OC(O)NR5R6, xe2x80x94C(O)NR5OR6, xe2x80x94COOR5, xe2x80x94SO3H, xe2x80x94NR5R6, xe2x80x94N[(CH2)2]2NR5, xe2x80x94NR5COR6, xe2x80x94NR5COOR6, xe2x80x94SO2NR5R6, xe2x80x94NO2, xe2x80x94N(R5)SO2R6, xe2x80x94NR5CONR5R6, xe2x80x94NR5C(xe2x95x90NR6)NR5R5, xe2x80x94NR5C(xe2x95x90NR)N(SO2)R5R6, xe2x80x94NR5C(xe2x95x90NR)N(Cxe2x95x90OR5)R6, xe2x80x94tetrazol-5-yl, xe2x80x94SO2NHCN, xe2x80x94SO2NHCONR5R6, phenyl, heteroaryl or xe2x80x94C5-C8-cycloheteroalkyl;
wherein
xe2x80x94NR5R6 may form a pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine, or azetidine ring;
R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl or xe2x80x94C5-C8-cycloheteroalkyl;
R7 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; and n is 0-2.
and n is 0-2.
When a moiety contains more than substituent with the same designation, each of those substituents may be the same or different.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains an acidic moiety.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. It is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
The compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-9, MMP-13 and TNF-xcex1 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 HIV infection. In particular, the compounds of the invention provide enhanced levels of inhibition of the activity of TACE in vitro and in cellular assay and/or enhanced selectivity over MMP-1 and are thus particularly useful in the treatment of diseases mediated by TNF.
Also according to the present invention, there are provided processes for producing the compounds of the present invention.
The compounds of the present invention, where n=0, X=O, S or NHR7 and A=S, SO or SO2 may be prepared according to one of the general processes out lined below.
As outlined in scheme 1, the appropriately substituted mercaptan derivative was alkylated using either substituted or unsubstituted a-bromo acetic acid ester derivative in refluxing chloroform using N,N-diisopropylethylamine as base. The sulfide derivative thus obtained was reacted with appropriately substituted propargyl bromide derivative in refluxing acetone using K2CO3 as base. In the case of X=xe2x80x94Nxe2x80x94R7 the N-alkylation can be carried out in DMF/NaH at room temperature. The sulfide derivative thus obtained was oxidized using m-chloroperbenzoic acid in CH2Cl2 or by using Oxone in methanol/water. The sulfone obtained from the above mentioned process can be either further alkylated using variety of alkyl halides to obtain the disubstituted derivative or it can be hydrolyzed using NaOH/MeOH at room temp. However instead of using the ethyl ester, if the tertiary butyl ester is present, the hydrolysis can be carried out with TFA/CH2C2 at room temperature. Subsequently, the carboxylic acid obtained was converted to the hydroxamic acid derivative by reaction with oxalyl chloride/DMF (catalytic) and hydroxyl amine/triethyl amine. 
a: Et3N/CHCl3/RT; b: Propargyl bromide derivative/K2CO3/Acetone/Reflux;
c: Oxone/THF:MeOR/RT; d: R9Br/K2CO3/18-Crown-6/Acetone/Reflux;
e: NaOH/THF:MeOH/RT; f: (COCl)2/DMF/NH2OH.HCl/Et3N.
As outlined in Scheme 2, the sulfide derivative can be hydrolyzed to carboxylic acid using NaOH/MeOH at room temperature and subsequently converted to the hydroxamic acid derivative as outlined in scheme 1. The mono substituted sulfide derivatives can be further alkylated using potassium bis(trimethylsilyl)amide and the appropriately substituted alkyl halides to form the disubstituted sulfide derivatives. These can be subsequently hydrolyzed and converted to the hydroxamic acid derivative as outlined in scheme 1. The sulfinyl derivatives were prepared by oxidizing the sulfide hydroxamic acid derivatives with 30% H2O2 in methanol at room temperature 
a: NaOH/THF:MeOH/RT; b: (COCl)2/NH2OH.HCl/Et3N; c: H2O2/MeOH/RT;
d: KN[Si(CH3)3]2/THF/R9Br
The thiols used as intermediates for the synthesis of compounds of the invention can be made according to Scheme 3. Thus, sulfonic acid salts 1, where XR50 is a hydroxy, thiol or substituted amino moiety may be alkylated with acetylenes 2, where J is a suitable leaving group such as halogen mesylate, tosylate, or triflate to give 3. Acetylenes 2 are commercially available or known compounds, or they may be synthesized by known methods by those skilled in the art. The sulfonic acid salts 3 may be converted into the corresponding sulfonyl chloride or other sulfonylating agent 4 by known methods, such as reaction with oxalyl chloride, phosphorus oxychloride or other reagent compatible with substituents R1, R2 and R3, and the acetylene. The sulfonyl chloride 4 can then be reduced to the corresponding thiol 5 using triphenylphosphine in a suitable solvent mixture such as dichloromethane/DMF at a temperature of between xe2x88x9220xc2x0 C. and 30xc2x0 C.
Alternatively, disulfide 6 may be converted into di-acetylene 7 by reaction with compounds 2, followed by reduction of the disulfide bond to provide the desired thiols 5. Bisacetylenes 7 may also be converted into thiols 5 via sulfonyl chlorides 4. Alkylation of the phenol, thiophenol, aniline or protected aniline 8 with 2 to give 9, followed by reaction with chlorosulfonic acid provides sulfonic acids 10 which are readily converted into 4 with oxalyl chloride or similar reagents and subsequently reduced to thiols 5. Thiophenols 11 are also precursors to 5 via protection of the thiol with a triphenylmethyl or other suitable protecting group, alkylation of XH, where X is O, N or S, and deprotection of the sulfur. 
Compounds of the invention wherein X is N, O, S, SO or SO2, can be synthesized according to Scheme 4 and Scheme 5. Alkylation of the para-disubstituted aryl 14, or its protected equivalent, with acetylene 2 in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetone or DMF at a temperature of between 20xc2x0 C. and 120xc2x0 C. provides the mono-propargylic ether 15. Those skilled in the art will recognize that protecting groups may be required to avoid undesirable side reactions and increase the yield of the reaction. The need and choice of protecting group for a particular reaction is known to those skilled in the art. Reaction of this compound with .-propiolactone, or a substituted propiolactone derivative (wherein the substituents have been omitted from the Scheme for clarity), in the presence of a base such as potassium t-butoxide in a polar solvent, or solvent mixture, such as THF or DMF affords the carboxylic acid 16. Conversion of carboxylic acid 16 into the corresponding hydroxamic acid, 17, is accomplished via formation of an activated ester derivative such as an acid chloride or acid anhydride followed by reaction with hydroxylamine. It is understood by those skilled in the art that when A is sulfur, in Scheme 4 and all relevant subsequent Schemes, the sulfur can be oxidized to the corresponding sulfoxide or sulfone at any stage after formation of the thioether, using a suitable oxidant such as oxone, air, m-chloroperbenzoic acid or hydrogen peroxide.
Compounds 17 are also accessible from the Michael addition of compound 15 to an acrylate ester, or substituted acrylate ester (substituents have been omitted from the Scheme for clarity), to provide 18, in which R,, is hydrogen or a suitable carboxylic acid protecting group. Deprotection of the ester moiety then provides carboxylic acid 16 which can be converted into the analogous hydroxamic acid, 17. Similarly, Michael addition of mono-protected 1,4-disubstituted aryl 19, where ZR25 is hydroxy or protected hydroxy, thiol or amine, gives compound 20. Unmasking of the protecting group gives thiol, aniline or phenol 21 which can be alkylated with propargyl derivative 2 to provide 18. Mono-protected compound 19 can also be reacted with b-propiolactone to provide 22. Esterification of 22 gives 20, which can then be converted into compounds 17 of the invention. Alternatively, 22 can be deprotected followed by alkylation to give 16 or 18. 
Synthesis of compounds of the invention wherein X is N, O, S, SO or SO2, and the linker between the proximal heteroatom and the hydroxamic acid is a one or three carbon chain can be synthesized according to Scheme 5. Compound 19, where XR25 is hydroxy or protected hydroxy, thiol or amine, can react with ester 24 or lactone 24a, in which R30, is hydrogen or a suitable carboxylic acid protecting group, with an appropriately substituted leaving group such as halogen, tosylate, mesylate or triflate, to provide 25. Unmasking of the heteroatom X of compound 25 then provides 26, which may next be alkylated with propargylic derivative 2 to give acetylene-ester 27. Ester 27 can be converted into the corresponding hydroxamic acid 28 through conversion of the ester into the carboxylic acid by acid or base hydrolysis, followed by conversion into the hydroxamic acid as described in Scheme 4. Alternatively, 5compound 15, prepared as shown in Scheme 2, can be alkylated directly with ester 24 or lactone 24a to give 27 and then 28. Substituents on the carbon alpha to the hydroxamic, though omitted from the Scheme for clarity, may be appended through deprotonation and quenching of compounds 25 or 27 with an appropriate electrophile. 
Compounds of the invention wherein A is a methylene or substituted methylene group, and X is oxygen, can be obtained according to Scheme 6. Esters or carboxylic acids 29, commercially available or known in the literature, can be converted into the corresponding phenols, 30. Alkylation of the phenol with acetylene 2 gives the propargylic ethers, 31, which can be converted into the corresponding carboxylic acids and thence the hydroxamic acids, 33, as described in Scheme 4. Substituents on the carbon alpha to the hydroxamic, though omitted from the Scheme for clarity, may be appended through deprotonation and quenching of compounds 29 or 31 with an appropriate electrophile. 
Compounds of the invention wherein A is xe2x80x94SO2xe2x80x94, and R8 and R9 are not hydrogen, are available stating from 4-fluorobenzenethiol 34 as shown in Scheme 7. Deprotonation of the thiol followed by reaction with p-propiolactone, or an acrylate ester, or ester deriavtive 24, and subsequent oxidation of the resulting thioether provides sulfone-acid 35. Displacement of the 4-fluoro substituent of 35, or its corresponding ester, with propargyl derivative 36, wherein X is N, O or S, then provides sulfone 16. Compound 16 can be converted into the compounds of the invention according to Scheme 4. Fluoroaryl 35 can also react with a masked hydroxyl, thiol or amino group (HXR40, wherein R40 is a suitable protecting group) in the presence of a base such as sodium hydride in a polar aprotic solvent such as DMF to provide 36. Deprotection of 36 followed by alkylation with acetylenic derivative 2 then gives 16. 
Compounds of the invention wherein X is NH are also available starting from the appropriate commercially available nitro aryl compound 38. Thus, the anion of compound 38 can be used to alkylate.-propiolactone, or a substituted derivative, or an acrylate ester to provide 39. Reduction of the nitro group followed by alkylation of the resulting aniline then gives 16. Compound 38 can also be alkylated with ester derivative 24 to afford nitro-ester 40, followed by reduction to give the corresponding aniline, analogous to compound 26 of Scheme 5. 
Compounds of the invention wherein R11, alpha to the hydroxamic acid, is a hydroxy group can be obtained via epoxides 41, as shown in Scheme 9. These epoxides are available through the oxidation of the corresponding acrylate esters or by the Darzens reaction of an alpha-halo ester with an aldehyde or ketone. Reaction of the epoxide with thiol, phenol or aniline 19 in the presence of base provides alpha-hydroxy ester 42. Deprotection of 42 followed by alkylation with propargyl derivative 2 gives 44. Conversion of the ester of 44 into the analogous hydroxamic acid as described in Scheme 4 then provides 45. Compounds 45, wherein A is sulfur, may be converted into the analogous sulfoxides or sulfones through oxidation with hydrogen peroxide, air, Oxone or other suitable reagent at this point. Similarly, thiol, phenol or aniline 15 can be reacted with 41 to give 44. The hydroxyl group of compound 43 can also be manipulated through its conversion into a suitable leaving group, such as halide or sulfonate ester, followed by displacement with various nucleophiles including amines to provide 44. 
Another route to alpha-hydroxy hydroxamic acids of the invention is shown in Scheme 10. Compound 15 can be alkylated with alcohol 46 to give 47. Oxidation of the alcohol, with or without concomitant oxidation of the thioether (for A=S), gives the aldehyde 48. Reaction of aldehyde 48 with trimethylsilyl cyanide or other suitable reagent then provides the cyanohydrin 49. Hydrolysis of the nitrile of 49 into the corresponding carboxylic acid followed by conversion into the hydroxamic acid as described in Scheme 4 gives 50. 
Scheme 11 shows alternative methods for the preparation of hydroxamic acid compounds using a solid phase support. 
Scheme 11
Reagents and Conditions: a) 2-bromo-6-phthaloyl caproic acid, DIC, HOBt, DMF; b) p-hydroxybenzenethiol, DBU, NaI, THF; c) 2-bromobutyne, NaH, THF; d) 70% t-butyl hydroperoxide, benzenesulfonic acid, DCM; e) mCPBA, DCM; f) Hydrazine, THF, EtOH; g) N-phthaloyl glycine, DIC, HOBt, DMF; h) RCOOH, DIC, HOBt, DMF; i) TFA, DCM.
The 4-O-methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenzene)-resin (hydroxylamine resin) may be coupled with 2-bromo-6-phthaloyl caproic acid to give the hydroxyamide resin. The coupling reaction may be carried out in the presence of carbodiimide, such as DIC, in an inert solvent such as DMF at room temperature. The bromide group may be displaced with hydroxybenzene thiol in the presence of a base, such as DBU, in an inert solvent such as THF at room temperature. The sulfide may be oxidized to the sulfoxide by reaction with an oxidizing agent such as tert-butylhydroperoxide in the presence of an acid catalyst such as benzenesulfonic acid, in an inert solvent such as DCM at room temperature. Alternatively, the sulfide may be oxidized to the sulfone by reaction with an oxidizing agent such as meta-chloroperoxybenzoic acid, in an inert solvent such as DCM at room temperature. The phthaloyl protection group may be removed by reaction with hydrazine in a solvent such as ethanol or THF. The free amine may then be extended by a glycine spacer by reaction with N-phthaloyl glycine in the presence of carbodiimide, such as DIC, in an inert solvent such as DMF at room temperature. Once again the phthaloyl protecting group may be removed by reaction with hydrazine in a solvent such as ethanol or THF. The free amine may be acylated by reaction with an acid in the presence of carbodiimide, such as DIC, in an inert solvent such as DMF at room temperature. The sulfide, sulfoxide, or sulfone may be treated with and acid, such as trifluoroacetic acid, in an inert solvent such as DCM to liberate the free hydroxamic acid. 
Scheme 12 illustrate an alternate route to alpha-substituted, (where A=SO2 and n=0) hydroxamic acid derivatives. Reaction of 51 with substituted sulfonyl fluorides can give xcex1-sulfonyl ester derivatives 52 and subsequently they can be converted to their respective hydroxamic acid derivatives.
USPTO Backgrounds
USPTO Backgrounds