MXPA01007649A - Alkynyl containing hydroxamic acid compounds as tace inhibitors - Google Patents

Alkynyl containing hydroxamic acid compounds as tace inhibitors

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Publication number
MXPA01007649A
MXPA01007649A MXPA/A/2001/007649A MXPA01007649A MXPA01007649A MX PA01007649 A MXPA01007649 A MX PA01007649A MX PA01007649 A MXPA01007649 A MX PA01007649A MX PA01007649 A MXPA01007649 A MX PA01007649A
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Mexico
Prior art keywords
phenyl
ynyloxy
butynyloxy
hydroxy
carbon atoms
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MXPA/A/2001/007649A
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Spanish (es)
Inventor
Jeremy Ian Levin
Aranapakam Mudumbai Venkatesan
George Theodore Grosu
Jamie Marie Davis
James Ming Chen
Derek Cecil Cole
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Wyeth Holdings Corporation
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Publication of MXPA01007649A publication Critical patent/MXPA01007649A/en

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Abstract

The invention concerns compounds of formula (I) which are useful in treating disease conditions mediated by TNF-&agr;, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative cartilage loss.

Description

ALQUINIL CONTAINING HYDROXAMIC ACID COMPOUNDS AS TACE INHIBITORS FIELD OF THE INVENTION This invention relates to acetylenic hydroxamic acids that act as inhibitors of the enzyme (TACE) that converts to TNF-a. The compounds of the present invention are useful under conditions of diseases mediated by TNF-a, such as arthritis. rheumatoid, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative loss of cartilage.
BACKGROUND OF THE INVENTION Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basal membranes. These endopeptidas containing zinc consist of several subgroups of enzymes that include collagenases, is tromelisinas and gelatinasas. Of these classes, 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 high in malignancies, and that gelatinase can degrade REF: 131086 the basement membrane that leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has recently also been shown to have a gelatinase component for its pathology. In addition, there is • evidence to suggest that gelatinase is involved in the rupture of plaques associated with atherosclerosis. Other conditions mediated by '"MMPs are restenosis, osteopenias mediated with MMP, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, ulceration of the cornea, scarring of abnormal wounds, bone disease, proteinuria , aortic aneurysmal disease, degenerative loss of cartilage followed by traumatic joint damage, demyelinating diseases of the central nervous system, liver cirrhosis, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, macular degeneration age-related diabetic retinopathy, vi treorret proliferative inopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, eye tumors, ocular angiogenesis / neovascularization and corneal graft rejection For recent examinations, see: 1) Recent Advances in Matrix Mecalloproteinase 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.The enzyme (TACE) which converts to TNF-a catalyzes the formation of TNF-a from the TNF-a precursor protein bound to the membrane TNF-a is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, MG; Muller, GW Exp. Opin. Ther, Patents 1998, 8 (5), 531; Grossman, JM; Brahn, EJ 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.], rejection of the graft [Piguet, P. F., Grau, G. E .; et al. J. Exp. Med. 1987, 166, 1280.], cachexia [Beutler, B .; Cerami, A. Ann. Rev. Biochem. 1988, 51, 505.], anorexia, inflammation [Ksontini, R .; MacKay, S. L. D .; Molda er, L. L., Arch. Surg. 1998, 133, 558.], congestive heart failure [Packer, M. Circ? Lation, 1995, 92 (6), 1379; Ferrari, R .; Bachetti, T .; et al., Circulation, 1995, 92 (6), 1479.], injury of post-ischemic reperfusion, inflammatory disease of the central nervous system, bowel disease, inflammatory, resistance to insulin. [1] [Hotamisligil, GS; 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; Pallars-Truj i 1 lo, J .; Lopez-Soriano, F. J. Argües, J.M. Med. Res. Reviews, 1995, 15 (6), 533.]], in addition to its well-documented antitumor properties [Oíd, L. Science, 1985, 230, 630.]. For example, the search with anti-TNF-α antibodies and transgenic animals have been shown to block the formation of TNF-α which 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. Rhematol. 1995, 34, 334; Pha rmaproj ects, 1996; Therapeutic Updates 17 (Oct.), aul97-M2Z.]. This observation has recently spread in humans as well as was described in "TNF-a in Human Diseases", Current Pha rma ce uti ca l Des i gn, 1996, 2, 662. It is expected that small molecular inhibitors of TACE will have the potential to treat a variety of disease states. Although a variety of TACE inhibitors are known, many of these molecules are peptides and peptides that suffer from problems of bioavailability and pharmacokinetics. In addition, many of these molecules are non-selective, being potent inhibitors of the 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]. Non-peptidic, bioavailable, selective TACE inhibitors that act for a long time in this manner would be highly desirable for the treatment of the disease states discussed above. The hydroxamic acid inhibitors with sulfon of MMPs, of the general structure I have been described [Burgess, L.E .; Rizzi, J.P .; Rawson, D.J. European Patent Application 818442. Groneberg, R.D Neuenschwander, K.W .; Djuric, S.W .; McGeehan, G.M Burns, C.J .; Condom, S.M .; Morrissette, M.M Salvino, J.M .; Scotese, A.C .; Ullrich, J.W. PCT International Application WO 97/24117. Bender, S.L .; Broka, C.A .; Campbell, J.A .; Castelhano, A.L .; Fisher, L.E .; Hendricks, R.T .; Sarma, K. European Patent Application 780386. Venkatesan, A.M .; Grosu, G. T .; Davis, J.M .; Hu, B .; O'Dell, M. J. PCT International Application WO 98/38163.] An exemplification of this class of the MMP inhibitor is RS-130830, "shown below.
RS-130830 Within the sulfone hydroxamic acid class of the MMP inhibitor, the linker between the sulfone and hydroxamic acid portions have 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 International Application WO 98/39316. McDonald, J. J.: Barta. TEA.; Becker, D. P .; Bedell, L. J.; Rao, S. N.; Freskos, J. N .; Mischke, B. V. PCT International Application WO 98/38859.]. Hydroxamic acids with piperidinsulphone, 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 International Application WO 98/39315.]. Similar piperidine derivatives wherein the methylene linking the piperidine ring to the sulfone have been deleted (II, n = 0) have been reported [Venkatesan, A. M.; Grosu, G. T .; Davis, J. M .; Baker, J. L. PCT International Application WO 98/37877.].
Hydroxamic acids with sulfone III, wherein an hydroxyl group alpha has been placed on hydroxamic acid, have been described [Freskos, J. N .; Boehm, T. L .; Mischke, B. V .; Heintz, R. M.; McDonald, J. J .; DeCrescenzo, G. A .; Howard, S. C International PCT Application WO 98/39326. Robinson, R P. PCT International Application WO 98/34915.]. lll The 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 International Application WO 98/03164].
IV The inhibitors of es t romellsina with the general structure V have been described [Shuker, S.B .; P.J .; Hajduk, P.J .; Meadows, R.P .; Fesik, S.W. Sci en ce, 1996, 2 74, 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, 1 1 9, 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. Ch em. So c. 1997, 1 1 9, 5828- 5 32. Fesik, S. W .; Summers, J. B .; Davidsen, S. K .; • 'Sheppard, G. S .; Steinman, D. H .; Carrera, G. M .; Florjancic, A .; Holms, J. H. PCT International Application WO 97/18188.].
Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some thio-substituted acetohydroxamic acid derivatives with aryl and aryl-substituted sulfonyl of the general formula 1_. These compounds were prepared to study the Mannich reaction. Subsequently, they were tested for their fungicidal activity.
Some carboxylic acids with sulfone are described in U.S. Patent 4,933,367. These compounds were shown to exhibit hypoglycemic activity.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to inhibitors of the non-peptide, low molecular weight, novel metalloproteinase (MMPs) matrix and the enzyme (TACE) that converts TNF-a to the treatment of arthritis, tumor metastasis, tissue ulceration, scarring of abnormal wounds, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection. In accordance with this invention there is provided a group of compounds of the general formula I: wherein: Ri 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 cycloheteroalkyl with 5-carbon atoms. to 8 carbon atoms having 1 to 2 heteroatoms selected from N, NR7, S and 0; '"R2 and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH; R5 is hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, or cycloheteroalkyl with 4 to 8 carbon atoms; R-7 is hydrogen, aryl, aralkyl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms, oxy, alkanoyl with 1 to 8 carbon atoms, C00R5, C0R5, -S02-alkyl with 1 to 8 carbon atoms, -S02-aryl, -S02-heteroaryl, -CO-NHRi; Rs, R9, Rio and R11 are each, independently, hydrogen, aryl, aralkyl, 5-10 heteroaryl members having 1-3 heteroatoms selected from N, NR7, O and S, heteroalkyl having from 1-3 selected heteroatoms of N, NR7, O and S, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl with 4 to 8 carbon atoms having 1-3 heteroatoms selected from N, NR7, 0 and S, alkyl of 1-18 carbon atoms. carbon, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; R12 is hydrogen, aryl or 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, NR7, S and O, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl having 5 to 8 carbon atoms having 1 to 2 heteroatoms selected from N, NR7, S and O, or alkyl of 1-6 carbon atoms; A is O, S, SO, S02, NR, or CH2; X is O, S, SO, S02, NR7, or CH2; And it is aryl or heteroaryl, with the proviso that A and X are not attached 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 R and R3 are each, independently, hydrogen or alkyl of 1-6 carbon atoms; R? _ Is hydrogen; and Y is phenyl. The compounds that inhibit the most preferred metalloproteinase and TACE matrix of this invention are: 2- (4-But-2-ynyloxy-benzenesulfonyl) -N-hydroxy-2-methyl-3-pyridin-3-yl-propionamide; 2- (4 -But -2-in i loxi-benzenesulfonyl) -N-hydroxy-2-methyl-3- [4- (2-pyridin-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-phenyl-sulfanyl) -octanoic acid hydroxyamide; 2- (But-2-ynyloxy-benzenesulfonyl) -octanoic acid hydroxyamide; 2- [(R) - (4-Butyl-2-ynyloxy) -sulfinyl-N-hydroxy-octanamide; 2 - [(S) - (4-Butyl-2-ynyloxy) -sulfinyl-N-hydroxy-octanamide; 3- (4 -But-2-inyloxy-phenoxy) -N-hydroxy-propionamide; 4- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-but-iramide; 2- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-acetamide; 4- (4-But-2-ynyloxy-phenyl) -N-hydroxy-but-iramid; [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxy-ca rbamoi-pentyl] -amide of quinoline-2-carboxylic acid; Hydroxyamide of 2- (4-but-2-ynyloxy-phenylisulfanyl) -6- [2- (1,3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] -hexanoic acid; 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; '"[5- (4 -But -2-ynyloxy-phenylsulfanyl) -5-hydroxy-ca rbamoi-pentyl] -amide of quinoline-3-carboxylic acid; 2- (4-But-2-ynyloxy-phenylsulfanyl) -6- (4-t-iofen-2-yl-butylamino) -hexanoic acid hydroxyamide; [5- (4 -But-2-ynyloxy-phenylsulfanyl) -5-hydroxy-ca rbamoi-pentyl] -amide of 9H-Xanthen-9-carboxylic acid; 2- (4-But-2-ynyloxy-phenylsulfanyl) -6-diphenylacetylaminohexanoic acid hydroxyamide; [5- (4 -But-2-aminoloxy-phenylsulfanyl) -5-hydroxy-carbamoyl-1-pentyl] -amide of isoquinoline-1-carboxylic acid; Hydroxyamide 6- (2-benzo [b] thiophen-3-yl-acetylamino) -2- (4-bt-2-ynyloxy-phenyl-sulfanyl) -hexanoic acid hydroxyamide; [5- (4 -But -2-linoxy-benzenesulfinyl) -5-hydroxy-carbamoyl-pentyl] -amide of quinoline-2-carboxylic acid; 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; Hydroxyamide 2- (butyl-2-ynyloxy-benzenesulfinyl) -6- [2- (3,4-dichloro-phenyl) -acetyl-amino] -hexanoic acid hydroxyamide; '"[5.- (4 -But-2-yl loxi-benzenesulfinyl) -5-hydroxy-ca rbamoi-pentyl] -amide of quinoline-3-carboxylic acid; 2 - (4-But-2-ynyloxy-benzenesulfinyl) -6- (4-thiophen-2-yl-butylamino) -hexanoic acid hydroxyamide; [5- (4 -But-2-yl loxi-benzenesulfinyl) -5-hydroxy-ca rbamoi-pentyl] -amide of 9H-Xanthen-9-carboxylic acid; Hydroxyamide of 2- (4-but-2-ynyloxy-benzenesulfinyl) -6-diphenylacetyl-0-hexanoic acid [5- (4 -But -2-linoxy-benzenesulfinyl) -5-hydroxy-carbamoyl-pentyl] - isoquinoline-1-carboxylic acid amide; Hydroxyamide 6- (2-benzo [b] t -pheno-3-yl-acetylamino) -2- (4-but-2-linoxy-benzenesulfinyl) -hexanoic acid hydroxyamide; Hydroxyamide 2- (4 -But-2-ynyloxy-benzenesulfinyl) -6- (2-lH-indol-3-yl-acetylamino) -hexanoic acid hydroxyamide; [5- (4 -But-2-yl loxi-benzenesulfinyl) -5-hydroxy-carbamoyl-1-pentyl] -amide of quinoline-2-carboxylic acid; Hydroxyamide 2 - (4-but-2-ynyloxy-benzenesulfonyl) -6-- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -acetylamino] - hexanoic; N- [5- (-But-2-ynyloxy-benzenesulfonyl) -5-hydroxy-carbamoyl-pentyl] -2-phenethi-1-benzamide; 2- (4-But-2-ynyloxy-benzenesulfonyl) -6- [2- (3, -dichloro-phenyl) -acetyl-amino] -hexanoic acid hydroxyamide; [5- (4 -But -2-ynyloxy-benzenesulfonyl) -5,5-hydroxy-carbamoyl-pentyl] -amide of quinoline-3-carboxylic acid; [5- (4 -But-2-yl loxi-benzenesulfonyl) -5-hydroxy-carbamoyl-1-pentyl] -amide of 9H-Xanthen-9-carboxylic acid; Hydroxyamide 2- (4-but-2-ynyloxy-benzenesulfonyl) -6-di-phenylacetylaminohexanoic acid hydroxyamide; [5- (4 -But-2-aminoloxy-benzenesulfonyl) -5-hydroxycarbamoyl-1-pentyl] -aminoquinoline-1-carboxylic acid amide; Hydroxyamide 6- (2-benzo [b] thiophen-3-yl-acetylamino) -2- (4-but-2-inyloxy-benzenesul-fonyl) -hexanoic acid hydroxyamide; . { [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} -quinoline-2-carboxylic acid amide; Hydroxyamide of 2- (-but-2-ynyloxy-phenylsulfanyl) -6- acid. { 2- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] acetylamino} hexanoic; N-. { [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pent i 1 -carbamoi 1] -methyl} -2-phenethyl-benzamide; Hydroxyamide of 2- (4-but-2-loxy-phenylsulfanyl) -6- acid. { 2- [2- (3,4-dichloro-phenyl) -acetylamino] -acetylamino} -hexanoic; . { [5- (4-But-2-ynyloxy-phenylsul-phenyl) -5-hydroxy-carbamoyl-pentylcarbamoyl] -methyl} quinoline-3-carboxylic acid amide; . { [5- (4 -But -2-linoxyphenylsulfanyl) -5-hydroxycarbamoyl-1-pentylcarbamoyl-1] -met-il} 9H-Xanten-9-carboxylic acid amide; Hydroxyamide 2- (4-but-2-ynyloxy-phenylsulphyl) -6- (2-di-phenylacetylamino-acetylamino) -hexanoic acid hydroxyamide; . { [5- (-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -met-yl} isoquinoline-1-carboxylic acid amide; . { [5- (-But-2- ini loxyphenyl sulphonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} 1-methyl-1H-pyrrole-2-carboxylic acid amide; Hydroxyamide 6- [2- (2-benzo [b] thiophen-3-yl-acetylamino) -acetylamino] -2- (4-but-2-ynyloxy-phenylsulfanylhexanoic acid; { [5- (4- But-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -met-yl.} - quinoline-2-carboxylic acid amide; 2- (4-but-2-ynyloxy) -hydroxyamide; benzenesulfinyl) -6-. {2- [2- (1, 3-dioxo-1,3-dihydro-isoindol-2-yl) -acetylamino] -acetylamino} -hexanoic acid; N- { [5- (-But-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentyl-carbamoyl] -methyl} -2-phenethyl-benzamide; 2- (4-but-2-ynyl) -hydroxyamide; -benzene-sulfinyl) -6- { 2- [2- (3,4-dichloro-phenyl) -acetylamino] -acet-ylamino} -hexanoic; {. [5- (4-But-2- inyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pent i lcarbamoi 1] -met i 1.} quinolic acid amide 3-carboxylic acid hydroxyamide 2- (4-but-2-ynyloxy-benzene) sulfinyl) -6- [2- (4-thiophen-2-yl-butyrylamino) -acetylamino] -hexanoic; {. [5- (4-But-2-inil oxy-benzenesulfinyl) -5-hydroxy-carbamoyl-1-pentylcarbamoyl] -met-il} 9H-Xanten-9-carboxylic acid amide; 2- (4-But-2-ynyloxy-benzenesulfinyl) -6- (2-diphenylacetylamino-acetylamino) -hexanoic acid hydroxyamide; . { [5- (4-But-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} l-methyl-lH-pyrrole-2-carboxylic acid amide; Hydroxyamide of 2- (4-but-2-ynyloxy-benzenesulfonyl) -6- acid. { 2- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] -acetylamino} -hexanoic; N-. { [5- (-but-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} -2-phenethylbenzamide; Hydroxyamide of 2- (4-but-2-ynyloxy-benzenesulfonyl) -6- acid. { 2- [2- (3,4-dichloro-phenyl) -acetylamino] -acetylamino} -hexanoic; . { [5- (4-but-2-inkyloxy-benzenesul fonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -met-il} quinoline-3-carboxylic acid amide; . { [5- (4 -But-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -met-il} -amide of acid 9H-Xanten-9-carboxylic acid; 2- (4-But-2-ynyloxy-benzenesulfonyl) -6- (2-diphenylacetylamino-acetylamino) -hexanoic acid hydroxyamide; . { [5- (4-But-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} isoquinol in-1-carboxylic acid amide; Hydroxyamide 6- [2 - (2-benzo [b] t iofen-3-i-acetylamino) -acetylamino] -2- (4-but-2-ynyloxybenzenesulfonylhexanoic acid; 2- (4- Hydroxyamide but-2-ynyloxy-benzenesulfonyl) -6- [2- (2-1H-indol-3-yl-acetylamino) -acetylamino] -hexanoic acid; 2- { [4- (2-butynyloxy) phenyl] sulfonyl.} - N-hydroxy-4 -. {4- [2- (1-piperidinyl) -ethoxy phenyl Jbutanamide; 2- {[4- (2-butynyloxy) phenyl] sulfonyl}. -7-cyano-N-hydroxy-heptanamide; 2- {[[4- (2-butynyloxy) phenyl] sulfanyl} -2-cyclohexyl-N-hydroxyacet amide; 2-. {[4- ( 2-butynyloxy) phenyl] sulfinyl} -2-cyclohexyl-N-hydroxyacetamide; 2- {[[4- (2-butynyloxy) phenyl] sulfonyl} -2-cyclohexyl-N-hydroxyacetamide; {. [4- (2-Butynyloxy) phenyl] sulfanyl} - N-hydroxy-2- (4-methoxyphenyl) acetamide; (2R) -2- { [4- (2-Butynyloxy) phenyl] sulfanil .} - N-hydroxy-2- (4-methoxyphenyl) ethanamide; (2S) -2- { [4- (2-but in i lox i) phenyl] sulfanyl.} - N-hydroxy-2- (4-methoxy phenyl) Ethanamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (4-methoxyphenyl) acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (4-chlorophenyl) N-hydroxyacetamine; 2- . { [4- (2-Butynyloxy) phenyl] sulfinyl} -2- (4-chlorophenyl) N-hydroxyacetamide; 2- . { [4- (2-butynyloxy) phenyl] sulfonyl} -2- (4-chloro phenyl) N-hydroxyacetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (3-chlorophenyl) N-hydroxyacetamide; 2- . { [4- (2-butynyloxy) phenyl] sulfonyl} -2- (3-chlorophenyl) N-hydroxyacetamide; 2- (4-bromo-phenyl) -2-. { [4- (2-Butynyloxy) phenyl] sulfanil} N-hydroxyacetamide; (2S) -2- (4-bromo-phenyl) -2-. { [4- (2-Butynyloxy) phenyl] -sulfinyl} -N-hydroxyacetamide; (2R) -2- (4-bromophenyl) -2-. { [4- (2-Butynyloxy) phenyl] -sulfinyl} -N-hydroxyacetamide; 2- (4-bromo phenyl) -2-. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -N-hydroxyacetamide; 2-. { [4- (2-butynyl oxy) phenyl] sul fanil} -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) phenyl] -acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (1-naphthyl) acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -N-hydroxy -2 - (1-naphthyl) acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1-naphthyl) acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (4-fluorophenyl) -N-hydroxy-2- (1 -naphthyl) acetamide; 2-. { [4- (2-butynyloxy) phenyl] sulfinyl} -2- (4- fluorophenyl) -N-hydroxy acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -2- (4- fluorophenyl) -N-hydroxyacetamide; 2- (2-methoxyphenyl) -2-. { [- (2-Butyloxy) phenyl] -sulfanyl} -N-hydroxyacetamide; 2- (2-methoxyphenyl) -2-. { [4- (2-Butynyloxy) phenyl] -sulfinyl} -N-hydroxyacetamide; 2-. { [4- (2-butynyloxy) phenyl] sulfanyl-N-hydroxy-2- (4-ethoxyphenyl) acet amide; 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-bromo phenyl) -N-hydroxyacetamide; 2- . { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-acetamide; R-2-Í [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] sulfanil} -2-phenyl-N-hydroxyacetamide; R-2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2-phenyl-N-hydroxyaceta ida; S-2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2-phenyl-N-hydroxyacetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -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; 4- [l-. { [4- (2-butynyloxy) phenyl] sulfonyl} -2- (hydroxy-amino) -2-sxoethyl] -1-piperidinecarboxylate tert-butyl; 2-. { [4- (2-Butynyloxy) phenyl] sulphonyl} -N-hydroxy -2- (4-piperidinyl) acetamide; 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- [1- (4-methoxybenzyl) -piperidinyl] acetamide; 2- (l-benzoyl-4-piperidinyl) -2-. { [4 - (2-Butyloxy) -phenyl] sulfonyl} -N-hydroxy-acetamide; 2- (l-acetyl-4-piperidinyl) -2-. { [4- (2-Butynyloxy) -phi] 1] sulphonyl} -N-hydroxy-acetamide; 2- . { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2-tetrahydro-2H-pyran-4-yl-acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} - -hydroxy-2-tetrahydro-2H-thiopyran-4-yl-acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1-oxidotetrahydro-2H-t-pyroran-4-yl) -acetamide; and 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -acetamide.
Heteroaryl, as used throughout the disclosure, is a 5-10 membered mono- or bicyclic aromatic ring having 1-3 heteroatoms selected from N, NR7, S and O. Heteroaryl is preferred: where K is defined as 0, S or -NR7, and R7 is as defined above. Preferred heteroaryl rings include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindol, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole , indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole. The heteroaryl groups of the present invention may be mono or disubstituted.
Cycloheteroalkyl with 4 carbon atoms is defined as where K is O, S or NR7 and R7 is as defined above. Preferred heterocycloalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. The heterocycloalkyl groups of the present invention can 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 a straight chain as well as branched portions. The alkyl, alkenyl, alkynyl, and cycloalkyl groups can be unsubstituted (carbons, bonded to hydrogen, or other carbons in the chain or ring) or can be mono- or poly-substituted. Lower alkyl is alkyl with 1 to 6 carbon atoms. Aralkyl as used herein refers to a substituted alkyl, -alkyl-aryl group, wherein alkyl is lower alkyl and preferably from 1 to 3 carbon atoms, and aryl is as previously defined. Heteroaralkyl as used herein refers to a substituted alkyl, alkyl-heteroaryl group wherein alkyl is lower alkyl and preferably from 1 to 3 carbon atoms, and heteroaryl is as previously defined. Halogen means bromine, chlorine, fluorine and iodine.
Suitable substituents of aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl, alkenyl, alkynyl and cycloalkyl include, but are not limited to, 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, -0R5, -CN, -C0R5, perfluoroalkyl of 1-4 carbon atoms, -0- perfluoroalkyl of 1-4 carbon atoms, -C0NR5R6 , -S (0) nR5, -OPO (OR5) 0R6, -PO (OR5) R6, -0C (0) 0R5, -OR5NR5R6, -OC (0) NR5R6, -C (0) NR50R6, -C00R5, - S03H, -NR5R6, -N [(CH2) 2] 2NR5, -NR5COR6, -NR5COOR6, -S02NR5R6, -N02, -N (R5) S02R6, -NR5CONR5R6, -NR5C (= NR6) NR5R6, -NR5C (= NR6 ) N (S02) R5R6, -NR5C (= NR6) N (C = OR5) R6, -tetrazol-5-yl, -S02NHCN, -S02NHCONR5R6, phenyl, heteroaryl or cycloheteroalkyl of 5 to 8 carbon atoms; wherein -NR5Re can form a pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine or azetidine ring; R5 and R1 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl or cycloheteroalkyl of 5 to 8 carbon atoms; R7 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, and n is 0-2. When a portion contains more than one substituent with the same designation, each of these substituents may be the same or different. The pharmaceutically acceptable salts can be formed of organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrochemical, phosphoric, nitric acids, sulfuric, methanesulfonic, naphthalenesulonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic portion. The salts may also be formed of organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium or potassium, when a compound of this invention contains an acidic portion. The compounds of this invention may contain an asymmetric carbon atom and any of the compounds of this invention may contain one or more asymmetric centers and may in this way give rise to optical isomers and diastereomers. While shown to be 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 stereoisomers -R and S and pharmaceutically acceptable salts thereof. It is recognized that an optical isomer, including the diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus, when describing and claiming the invention, when a racemic mixture is described, it is clearly contemplated that both optical isomers, including the diastereomers and enantiomers, or stereoisomers substantially free of the other, are also described and claimed. The compounds of this invention are shown to inhibit the enzymes MMP-1, MMP-9, MMP-13 and the enzyme (TACE) which converts to TNF-a and are therefore useful in the treatment of arthritis, tumor metastasis, tissue ulceration, healing • of abnormal wounds, periodontal disease, graft rejection, insulin resistance, bone disease, and HIV infection. In particular, the compounds of the invention provide improved levels of inhibition of TACE i n vi tro activity and in cell assay and / or improved selectivity on 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, which processes comprise one of the following: a) reacting a compound of the formula wherein n, X, Y, A, Ri, R2, R3, R8, Rg, Rio, and Rii are as defined above or a reactive derivative thereof, with a compound of the formula R12NHOH wherein Ri2 is as defined above, to give a compound of formula I; or b) deprotect a compound of the formula: wherein n, X, Y, A, Ri, R 2, R 3, R 8, R 9, R o, R n and R 12 are as defined above, and R 30 is a suitable protecting group such as t-butyl, benzyl, and trialkyl ilo, to give a corresponding compound of the formula I c) separating a supported hydroxamate derivative with resin containing the group wherein n, X, Y, A, R, R2, R3, Rs, Rg, Rio, and Rn are as defined above to give a compound of the formula I; or d) dissolving a mixture (e.g. racemate) of optically active isomers of a compound of formula I to isolate an enantiomer or diastereomer substantially free of the other enantiomer or diastereomers; or e) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to give a pharmaceutically acceptable salt; or f) converting a compound of the formula I having a reactive substituent group or site to a compound of the formula I having a different substituent group or site. With respect to process a) the reaction can be carried out by processes known in the art, for example by the reaction of an acid chloride or an anhydride reactive derivative mixed with the compound of the formula R? 2NHOH. The removal of the protecting groups, as illustrated by process b) can be carried out by processes known in the art to provide the hydroxamic acid. Process c) can be carried out as described herein with reference to the Reaction Scheme 11 for example using a strong acid such as TFA to separate the hydroxamate from the resin. standard separation techniques for the isolation of particular enantiomeric or diastereomeric forms For example, a racemic mixture can be converted to a mixture of optically active diastereoisomers by reaction with a simple enantiomer of a "resolving agent" (for example by of the diastereomeric salt or formation of a covalent bond.) The resulting mixture of optically active diastereomers can be separated by standard techniques (e.g., crystallization or chromatography) and the individual optically active diastereoisomers then treated to remove the resolution "thereby liberating the simple enantiomer of the compound of the invention You can also use chiral chromatography (using a chiral support, eluent or ion pair-forming agent) to directly separate the enantiomeric mixtures. The compounds of the formula I can be isolated in the form of a salt of a pharmaceutically acceptable acid, for example an organic or inorganic acid by treatment with an acid as described above. With respect to process e) compounds of the formula I having a reactive substituent group such as hydroxy or amino or a site such as -S- can be converted to other compounds of the formula I in known manner, for example alcohol a ester or ether. Reactive sites such as a sulfur atom can be oxidized to SO or S02, (for example as shown in the Schemes, Reaction 2 and 8 below). If necessary, the reactive substituent groups can be protected during the synthesis of compounds of the formula I and eliminated as a last step. The compounds of the present invention, wherein n = 0, X = 0, S or NHR7 and A = S, SO or S02 can be conveniently prepared according to one of the general processes described below. As described in Reaction Scheme 1, the appropriately substituted mercaptan derivative is alkylated using a derivative of a-bromoacetic acid ester in chloroform which is brought to reflux using N, N-di isopropylethylamine as a base. The sulfide derivative obtained in this way is reacted with an appropriately substituted propargyl bromide derivative in acetone which is brought to reflux using K2CO3 as the base. In the case of X = -N-R7, N-'alkylation in DMF / NaH can be carried out at room temperature. The sulfide derivative obtained in this way is oxidized using m-chloroperbenzoic acid in CH2C12 or using Oxone in methanol / water. The sulfone obtained from the aforementioned process can be either alkylated further using a variety of alkyl halides to obtain the disubstituted derivatives or it can be hydrolyzed using NaOH / MeOH at room temperature. However, instead of using the ethyl ester, if the tertiary butyl ester is present, the hydrolysis can be carried out with TFA / CH2C12 at room temperature. Subsequently, the carboxylic acid obtained is converted to the hydroxamic acid derivative by the reaction with oxalyl chloride / DMF (catalytic) and hydroxylamine / triethylamine.
REACTION SCHEME 1 a: Et 3 N / CHCl 3 / TA; b: Derivative of propargyl bromide / K2C03 / Acetone / Reflux; c: 'Oxona / TH: MeOH / TA; d: R9Br / K2C03 / 18-Corona-6 / Acetone / Ref luxury; e: NaOH / THF: MeOH / TA; f: (COCÍ) 2 / DMF / NH2OH. HCl / Et3N. According to Reaction Scheme 2, the sulfur derivative can be hydrolyzed to carboxylic acid using NaOH / MeOH at room temperature and subsequently converted to the hydroxamic acid derivative described in Reaction Scheme 1. Monosulfurized sulfide derivatives can to be further alkylated using potassium bis (trimethylsilyl) -amide and the alkyl halides appropriately substituted to form the disubstituted sulfide derivatives. These may be subsequently hydrolyzed and converted to the hydroxamic acid derivative described in Reaction Scheme 1. The sulfinyl derivatives were prepared by oxidizing the hydroxamic acid derivatives of sulfur with 30% H202 in methanol at room temperature.
Reaction Scheme 2: a: NaOH / THF: MeOH / TA; b: (COCÍ) 2 / NH2OH. HCl / Et3N; c: H202 / MeOH / TA; 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 Reaction Scheme 3. In this way, the salts of sulphonic acid 1 , wherein XRso is a hydroxy, thiol or substituted amino propion, can be alkylated with acetylenes 2, where J is a suitable leaving group such as mesylate, tosylate or halogen triflate to give 3.
Acetylenes 2 are commercially available or known compounds, or can be synthesized by methods known to those skilled in the art. The sulfonic acid salts 3 can be converted to the corresponding sulfonyl chloride or other sulfonylating agent 4 by known methods, such as the reaction with oxalyl chloride, phosphorus oxychloride or another reagent compatible with the substituents Rx, R2 and R3 and acetylene The sulfonyl chloride 4 can then be reduced to the corresponding thiol by using triphenylphosphine in a suitable solvent mixture such as dichloromethane / DMF at a temperature between -20 ° C and 30 ° C. Alternatively, the disulfide 6 can be converted to di-acetylene 7 by reaction with compounds 2, followed by reduction of the disulfide bond to provide the desired thiols 5. The bisacetylenes 7 can also be converted to thiols via the sulfonyl chlorides 4. The alkylation of the phenol, thiophenol, aniline or protected aniline 8 with 2 to give 9, followed by the reaction with chlorosulfonic acid provides sulphonic acids 10 which are easily converted to 4 with oxalyl chloride or similar reagents and subsequently reduced to thiols 5. The thiophenols 11 are also precursors for 5 via thiol protection with a triphenylmethyl or other suitable protecting groups, XH alkylation, where X is O, N or S, and the deprotection of sulfur.
Reaction Scheme 3: RaX jL + R, x x SOjNa Ri soX - O-O X » The compounds of the invention wherein X is N, O, S, SO or S02, can be synthesized according to Reaction Scheme 4 and Reaction Scheme 5.
Alkylation of para-disusyl 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 between 20 ° C and 120 ° C provides the propargyl mono-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 the protecting group for a particular reaction is known to those skilled in the art. The reaction of this compound with "-propiolactone, or a substituted propiolactone derivative (wherein the substituents have been omitted from the Reaction Scheme for clarity), in the presence of a base such as potassium t-butoxide in a solvent polar, or solvent mixture, such as THF or DMF produces the carboxylic acid 16. The conversion of the carboxylic acid 16 to the corresponding hydroxamic acid, 17, is carried out via the formation of an activated ester derivative such as an acid chloride or an acid anhydride followed by the reaction with hydroxylamine. It is understood by those skilled in the art that when A is sulfur, in Reaction Scheme 4 and all subsequent relevant Reaction Schemes, the sulfur can be oxidized to the corresponding sulfoxide or sulfone at any stage after the 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 Reaction Scheme for clarity), to provide 18, wherein R3o is hydrogen or a suitable carboxylic acid protecting group. The deprotection of the ester portion then provides carboxylic acid 16 which can be converted into the analogous hydroxamic acid, 17. Similarly, the Michael addition of mono-protected mono-protected 1, 4-aryl, wherein ZR2s is hydroxy or protected hydroxy, thiol or amine, gives the compound 20. The non-masking of the protecting group gave the thiol, aniline or phenol 21 which can be alkylated with the propargyl derivative 2 to provide 18. The mono-protected compound 19 can also be reacted with b-propiolactone to provide 22.
The esterification of 22 gave 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.
Reaction Scheme 4: The synthesis of the compounds of the invention wherein X is N, O, S, SO or S02, and the linker between the proximal heteroatom and the hydroxamic acid is a one or three carbon chain that can be synthesized according to the Scheme Reaction 5. Compound 19, wherein XR25 is hydroxy or protected hydroxy, thiol or amine, can react with ester 24 or lactone 24a, wherein R3o is -hydrogen or a suitable carboxylic acid protecting group, with a group appropriately substituted projection such as halogen, tosylate, mesylate, or triflate, to provide 25. The non-masking of the heteroatoms X of compound 25 then provides 26, which can then be alkylated with the propargyl derivative 2 to give the acet i leno-és ter 27. The ester 27 can be converted to the corresponding hydroxamic acid 28 through conversion of the ester to the carboxylic acid by hydrolysis of acid or base, followed by conversion to the hydroxamic acid as described in Reaction Scheme 4. Alternatively, compound 15, prepared as shown in Reaction Scheme 2, can be directly alkylated with ester 24 or lactone 24a to give 27 and then 28. Substituents on alpha carbon to the hydroxamic, although omitted from the Reaction Scheme for clarity, may be added through the deprotonation and rapid cooling of compounds 25 or 27 with a suitable electrophile.
Reaction Scheme 5: The compounds of the invention wherein A is a methylene or substituted methylene group, and X is oxygen, can be obtained according to Reaction Scheme 6. Esters or carboxylic acids 29, commercially available or known in the literature, are they can convert to the corresponding phenols, 30. Alkylation of the phenol with acetylene 2 gave the propargyl ethers, 31, which can be converted to the corresponding carboxy acids and then to the hydroxamic acids, 33, as described in the Scheme. Reaction 4. The substituents on the alpha to the hydroxamic carbon, although omitted from the Reaction Scheme for clarity, can be added through the deprotonation and rapid cooling of the compounds 29 or 31 with an appropriate electrophile.
Reaction Scheme 6: The compounds of the invention wherein A is -S02-, and R8 and R9 are not hydrogen, are initially available from the -fluorobenzyl iol 34 as shown in Reaction Scheme 7. The deprotonation of the thiol followed by the reaction with β-propiolactone, or an acrylate ester, or an ester derivative 24, and subsequent oxidation of the resulting thioether provides the sulfone-acid 35. The displacement of the 4-fluoro substituent of 35, or its corresponding ester, with the propargyl derivative 36 , wherein X is N, O or S, then provides sulfone 16. Compound 16 can be converted to the compounds of the invention according to Reaction Scheme 4. Fluoroaryl 35 can also react with a hydroxyl group, thio or masked amino (HXR, where R or 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 c on the acetylene derivative 2 then gives 16.
Reaction Scheme 7: Compounds of the invention wherein X is NH are also available starting from the commercially available, appropriate nitro aryl compound 38. In this way, the anion of the compound 38 can be used to alkylate the -propiolactone, or a substituted derivative, or an acrylate ester to provide 39. The reduction of the nitro group followed by the alkylation of the resulting aniline then gives 16. The compound 38 can also be alkylated with the ester derivative 24 to produce the nitro-ester 40, followed by the reduction to give the corresponding aniline, analogous to the compound 26 of the Reaction Scheme 5.
Reaction Scheme 8: 40 26 The compounds of the invention wherein Rn, alpha for the hydroxamic acid, is a hydroxy group, can be obtained via the epoxides 41, as shown in Reaction Scheme 9. These epoxides are available through the oxidation of the esters of corresponding acrylate or by the Darzens reaction of an alpha-haloester with an aldehyde or ketone. Reaction of the epoxide with thiol phenol or aniline 19 in the presence of a base provides the alpha hydroxy ester 42. Deprotection of 42 followed by alkylation with the propargyl derivative 2 gives 44. The conversion of the ester of 44 to the analogous hydroxamic acid as described in Reaction Scheme 4 then provides 45. Compounds 45, wherein A is sulfur, can be converted to the analogous sulfoxides or sulfones through oxidation with hydrogen peroxide, air, Oxone or other suitable reagent at this point . Similarly, the thiol, phenol or aniline can be reacted with 41 to give 44. The hydroxyl group of compound 43 can also be manipulated through conversion into a suitable leaving group, such as halide or sulphonate tea. , followed by displacement with several nucleophiles including amines to provide 44.
Reaction Scheme 9: Another route for the alpha-hydroxy hydroxamic acids of the invention is shown in Reaction Scheme 10. Compound 15 can be alkylated with alcohol 46 to give 47. Oxidation of the alcohol, with or without concomitant thioether oxidation (for A = S), gave the aldehyde 48. The reaction of the aldehyde 48 with trimethylsilyl cyanide or another suitable reagent then provides the cyanohydrin 49. The hydrolysis of the nitrile from 49 to the corresponding carboxylic acid followed by the conversion to the hydroxamic acid as described in the Scheme of Reaction 4 gave 50.
Reaction Scheme 10 TMSCN Reaction Scheme 11 shows alternative methods for the preparation of the hydroxamic acid compounds using a solid phase support.
Reaction Scheme 11 Reagents and Conditions: a) 2-bromo-6-f taloyl-caproic acid, DIC, HOBt, DMF; b) p-hydroxybenzothiol, DBU, Nal, THF; c) 2-bromobutine, 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. 4-O-methylhydroxylamine-phenoxymethyl-copoly (styrene-1% -divinyl-benzene) -resin (hydroxylamine resin) can be coupled with 2-bromo-6-f-taloylcaproic acid to give the hydroxyamide resin. The coupling reaction can be carried out in the presence of carbodiimide, such as DIC, in an inert solvent such as DMF at room temperature. The bromide group can be displaced with hydroxybenzene in the presence of a base, such as DBU, in an inert solvent such as THF at room temperature. The sulfide can be oxidized to the sulfoxide by reaction with an oxidizing agent such as tert-butyl hydroperoxide in the presence of an acid catalyst such as benzenesulfonic acid, in an inert solvent such as DCM at room temperature. Alternatively, the sulfide can be oxidized to the sulfone by reaction with an oxidizing agent such as meta-chloroperoxy-benzoic acid, in an inert solvent such as DCM at room temperature. The phthaloyl protecting group can 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. Again the phthaloyl protecting group can be removed by reaction with hydrazine in a solvent such as ethanol or THF. The free amine can 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 can be treated with acid, such as trifluoroacetic acid, in an inert solvent such as DCM to liberate the free hydroxamic acid.
REACTION SCHEME 12 Reaction Scheme 12 illustrates an alternative route for hydroxamic acid derivatives, alpha-substituted, (where A = S02 and n = 0). The reaction 51 with substituted sulfonyl fluorides can give derivatives of α-sulfoners ter 52 and subsequently can be converted to their respective hydroxamic acid derivatives. The following examples are presented to illustrate rather than to limit the scope of the invention.
Example 1 Preparation of 2- (4-but-2-ynyloxy-benzenesulfonyl) -N-hydroxy-2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] -propionamide Step 1: To a stirred solution of 4-mercaptophenol (12.6 g, 100 mmol) and diisopropylethylamine (13.0 g, 101 mmol) in chloroform (200 ml) was slowly added ethyl-2-bromopropionate (18.2 g, 100 mmol) in a solution of chloroform (50 ml). The reaction mixture was refluxed slightly during the addiction. After the addition of ethyl 2-bromo propionate, the reaction mixture was refluxed for two hours and cooled to room temperature. The reaction mixture was washed with water and extracted with chloroform. It was dried over Na2SO4; it was filtered and concentrated. The product of 2- (4-hydroxy-phenylsulphylene 1) -propionic acid ethyl ester was taken for the next step without purification. Colorless oil; Yield 22.0 g (97%); MS: 227 (M + H) +.
Step 2: A mixture of 2- (4-hydroxy-phenylsulfanyl) -propionic acid ethyl ester (22.6 g, 100 mmol), l-bromo-2-butyne (13.2 g, 100 mmol) and anhydrous K2C03 (50 g, excess) was brought to reflux in acetone (300 ml) for 8 hours. After the reaction was completed, it was cooled to room temperature and filtered. The acetone layer was removed by distillation and the residue was extracted with chloroform, washed well with water; dried and concentrated. 2- (4-Buty-2-ynyloxy-phenylsulphyl) -propionic acid ethyl ester was isolated as "colorless oil; Yield 26.0 g 93%; MS: 279 (M + H) +.
Step 3: To a stirred solution of 2- (4-buty-2-ynyloxy-phenylsulfanyl) -propionic acid ethyl ester (2.78 g, 10 mmol) in methanol: THF (3: 1) (100 ml) oxone (10 g) , excess) was added in water (25 ml) at room temperature. The reaction mixture was stirred at room temperature for 8 hours and filtered. The organic layer was removed under reduced pressure and 2- (4-but i-2-yn-loxyphenylsulfonyl) -propionic acid ethyl ester was isolated as a colorless oil. Yield 3.0 g (96%); MS: 311 (M + H) +.
Step 4: A mixture of 2- (4-buty-2-ynyloxy-phenylsulfonyl) -propionic acid ethyl ester (3.1 g, 10 mmol), 4- (2-pyridin-1-yl-ethoxy) chloride hydrochloride -benzyl (2.9 g, 10 mmol), 18-crown-6 (500 mg), tetrabutylammonium bromide (500 mg) and K2C03 (10 g, excess) was brought to reflux in acetone (200 ml) for 8 hours. At the end, the reaction mixture was cooled to room temperature, filtered and concentrated. The residue was extracted with chloroform, washed well with water; dried and concentrated. The crude product was purified by column chromatography eluting with 70% ethyl acetate; Hexane 2- (4-But i-2-ynyloxy-phenylsulfonyl) -2-met il-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] propionic acid ethyl ester was isolated as a red oil. Yield 3.2 g, (60%); MS: 528 (M + H) +.
Step 5: To a stirred solution of 2- (4-buty-2-ynyloxy-phenylsulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] propionic acid ethyl ester ( 3.0 g, 5.4 mmol) in THF: MeOH (1: 1) (100 mL), 10 N NaOH (10 mL) was added at room temperature. The reaction mixture was heated at 60 ° C for 24 hours. The reaction mixture was concentrated and carefully neutralized with 5N HCl and extracted with chloroform. The product was washed well with water and dried over anhydrous Na 2 SO and concentrated. 2- (-but i-2-ynyloxy-phenylsulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] propionic acid was isolated as a yellow solid. P.f. 84 ° C; Yield 2.0 g (74%); MS: 500 (M + H).
Step 6: To a stirred solution of 2- (4-buty-2-ynyloxy-phenylsulfonyl) -2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) -phenyl] propionic acid (4.99 g), 10 mmol) and DMF (4 mL) in methylene chloride (100 mL), oxalyl chloride (6.3 g, 50 mmol) was added slowly at 0 ° C in a methylene chloride solution. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. In a separate flask, NH20H.HC1 (3.5 g, 50 mmol) was dissolved in DMF (20 ml) and Et3N (10 g, 100 mmol) was added. The reaction mixture was diluted with acetonitrile (25 ml) and cooled to 0 ° C. The acid chloride prepared in the separate flask was concentrated to remove excess oxalyl chloride and redissolved in 100 ml of methylene chloride added slowly to NH2OH. The reaction mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue obtained was extracted with chloroform; washed well with water; dried over anhydrous Na2SO4. The chloroform layer was filtered and concentrated. The obtained product was purified by silica gel column chromatography eluting with 10% methanol; chloroform. Isolated in this way 2- (4-buty-2- ini loxyphenylsulfonyl) -N-hydroxy-2-methyl-3- [4- (2-piperidin-1-yl-ethoxy) phenyl] propionamide was converted to its hydrochloride salt by reacting it with methanolic acid chloride. Colorless solid, P.f. 114-116 ° C; Performance 4.5 (87%); MS: 515 (M + H).
Example 2 3-Biphenyl-4-yl-2- (4-Buty-2-ynyloxy-phenylsulfonyl) -N-hydroxy-2-methyl-propionamide The ethyl ester of 3-biphenyl-4-yl-2- ( 4-Buty-2-ynyloxy-phenylsulfonyl) -2-methyl-propionic following the procedure of Example 1 (Stage 4) Starting from the acid ethyl ester 2- (4-But i-2-ynyloxy-phenylsulfonyl) -propionic acid (3.1 g, 10 mmol) and 4-phenylbenzyl chloride (20.2 g, 10 mmol), 4.2 g of the product was isolated as a yellow oil. Performance (88%); MS: 477 (M + H) +. 3-Biphenyl-4 -yl-2- (-But i-2-ynyloxy-phenylsulfonyl) -2-methyl-1-propionic acid was prepared starting from the ethyl ester of 3-biphenyl-4-yl-2- (4-biphenyl) acid. -Buti-2-ynyloxy-phenylsulfonyl) -2-methyl-propionic acid (4.0 g, 8.4 mmol) dissolved in MeOH (100 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 5). Yield 3.2 g (85%); MS: 449 (M + H) +. Starting from 3-biphenyl-4-yl-2- (4-Buty-2-ynyloxy-phenylsulfonyl) -2-methyl-propionic acid. { 3.0 g, 6.7 mmol) and following the procedure described in Example 1 (Step 6) was isolated 2.8 g of 3-biphenyl-4-yl-2- (4 -Buti-2-ini loxyphenyl sulphonyl) - N-hydroxy-2-met il-propionamide as a colorless solid. P.f. 92-4 ° C; Yield 90%; MS: 464 (M-f H) +.
Example 3 2- (4-Buty-2-ynyloxy-phenylsulfonyl) -N-hydroxy-2-methyl-3-pyridin-3-ylpropionamide The ethyl ester of 2- (4-Buty-2-ynyloxy) acid was prepared. phenylsulfonyl) -2-met il-3-pyridin-3-ylpropionic following the procedure of Example 1 (Step 4). Starting from 2- (4-buty-2-ynyloxy-phenylsulfonyl) -propionic acid ethyl ester (7.0 22.5 mmoles) and 3-picolyl chloride hydrochloride (4.5 g, 27.4 mmoles), 9.0 g of the product was isolated as a yellow oil Performance (98%); MS: 402 (M + H) +. 2- (4-But-i-2-ynyloxy-phenylsulfonyl) -2-methyl-3-pyridin-3-yl-propionic acid was prepared starting from the ethyl ester of 2- (4-Butyl-2-ynyloxy) acid phenylsulfonyl) -2-methyl-3-pyridin-3-ylpropionic acid (8.0 g, 19.9 mmol) dissolved in MeOH (100 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 5). Yield 5.1 g (69%); MS: 374 (M + H) +. Starting from 2- (4-buty-2-ynyloxy-phenylsulfonyl) -2-methyl-3-pyridin-3-ylpropionic acid (6.0 g, 16 mmol) and following the procedure described in Example 1 (Step 6) , 4.8 g of 2- (4-Buty-2-ynyloxy-phenylsulfonyl) -N-hydroxy-2-methyl-3-pyridin-3-ylprcpionamide was isolated as a colorless solid. The hydrochloride salt was prepared as described in example 1. P.f. 154-56 ° C; Performance 89%; MS: 389 (M + H) +.
EXAMPLE 4 2- (4-Buty-2-ynyloxy-phenylsulfanyl) -N-hydroxy-propionamide The 2- (4 -But i-2-ynyloxy-phenylsulfanyl) -propionic acid was prepared starting from the ethyl ester of acid 2- (4-buty-2-ynyloxy-phenyl-sullyl) -propionic acid (5.56 g, 20 mmol) dissolved in MeOH (100 ml) and 10 N NaOH. The resulting reaction mixture was worked up as described in Example 1 (Step 5). Yield 4.8 g (96%); MS: 249 (MH). "Starting from 2- (4-buty-2-ynyloxy-phenylsulphyl) -propionic acid (6.0 g, 24 mmol) and following the procedure described in Example 1 (Step 6), 500 mg of 2- (4 -But i-2-ini loxyphenylsulfonyl) -N-hydroxy-propionamide was isolated as a colorless solid, mp 102-4 ° C, yield 8%, MS: 266 (M + H) +.
Example 5 2- (4-But-2-ynyloxybenzenesulonyl) -octanoic acid hydroxyamide 2- (Hydroxy-phenylsulfanyl) -octanoic acid ethyl ester was prepared according to the general method described in Example 1 (Step 1) . Starting from 4-mercapto phenol (12.6 g, 100 mmol) and 2-bromoethyl octanoate (25.2 g, 100 mmol), 25 g of 2- (4-hydroxy-phenyl-sulfanyl) -octanoic acid ethyl ester was isolated. as a colorless liquid. Performance 84%; MS: 297 (M + H) +. 2- (4-But-2-ynyloxy-phenylsulfanyl) -octanoic acid ethyl ester was prepared according to the general method described in Example 1 (Step 2).
Starting from the 2- (4-hydroxy-phenylsulfanyl) -octanoic acid ethyl ester 13.6 g, 46 mmoles) and l-bromo-2-but-ina (6.23 g, 47 mmoles). Yield 13.78 g (86%); amber oil; MS: 349.0 (M + H) +. 2- (4-But-2-ynyloxy-phenylsul-phenyl) -octanoic acid was prepared according to the general method described in Example 1 (Step 5). Starting from the 2- (4-but-2-ynyloxy-phenylsulfanyl) -octanoic acid ethyl ester 4.77 g, 13.7 mmol), 4.16 g of the product was isolated. Yield 96%; MS: 321.0 (M + H) +. 2- (4-But-2-ynyloxy-benzenesulfonyl) -octanoic acid ethyl ester was prepared according to the general method described in Example 1 (Step 3). Starting from the 2- (4-but-2-ynyloxy-phenylsulfanyl) -octanoic acid ethyl ester (7.26 g, 21 mmol), 6.78 g of the product was isolated. Performance (85%); yellow oil; MS: 381.2 (M + H) +. 2- (-but-2-ynyloxy-benzenesulfonyl) -octanoic acid was prepared starting from the ethyl ester of 2- (4-but-2-ynyloxy-benzenesulfonyl) -octanoic acid (6.52 g, 17 mmol) dissolved in THF: Methanol (100: 50 ml) and NaOH ION (10 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 5). Yield 2.42 g (42%); colorless gum; MS: 352.9 (M + H) +. Starting from 2- (4-but-2-ynyloxy-benzenesulfonyl) -octanoic acid (2.21 g, 6 mmol) and following the procedure described in Example 1 (Step 6), 270 mg of 2-hydroxyamide was isolated. - (4-But-2-ynyloxy-benzenesulfonyl) -octanoic acid as an amber colored gum. Yield 42%; MS: 369.7 (M + H) +; 'XH NMR (300 MHz, DMSO-d6): d 0.826 (m, 3H), 1.33 (m, 9H), 1.77 (s, 3H), 1.89 (d, J = 2.2, 1H), 3.03 (d, J = 4 Hz, 1H), 4.73 (m, 2H), 5.78 (s, 1H), 6.56 (s, 1H), 7.1 (d, 2H), 7.92 (m, 2H).
EXAMPLE 6 2- (4-But-2-ynyloxy-phenylsulfanyl) -octanoic acid hydroxyamide 2- (-but-2-ynyloxy-phenylsulfanyl) -octanoic acid was prepared according to the general method described in Example 1 (Stage 5) Starting from the 2- (4-but-2-ynyloxyphenylsulfanyl) -octanoic acid ethyl ester (4.77 g, 13.7 mmol), 4.16 g of product was isolated. Yield 96%; MS: 321.0 (M + H) +. Starting from 2- (4-but-2-ynyloxy-phenylsulfanyl) -octanoic acid (4.12 g, 12.9 mmol) and following the procedure described in Example 1 (Step 6), 2.23 g of 2-hydroxyamide was isolated. - (4-But-2-ynyloxy-phenylsulfanyl) -octanoic acid as a white solid, mp. 125 ° C; Performance 73%; MS: 335.9 (M + H) +; AH NMR (300 MHz, DMSO-d6): d 0.856 (m, 3H), 1.24 (m, 6H), 1.57 (m, 2H), 1.71 (m, 2H), 1.83 (t, 3H), 2.55 (m , 2H), 4.78 (d, 2H), 6.95 (d, 2H), 7.36 (d, 2H), 8.96 (s, 1H), 10.62 (s, 1H).
Example 7 (S) -2- [(R) - [4- (2-Butynyloxy) phenylsulfinyl)] - N -hydroxy-octanamide & Example 8 (S) -2- [(S) - [4- (2-Butynyloxy) phenylsulfinyl)] -N-hydroxy-octanamide The hydroxyamide of 2- (-but-2-ynyloxy-phenylsulfanyl) -octanoic acid (prepared in Example 6) (1.78 g, 5 mmol) was dissolved in methanol (50 ml) and H202 (30%, 10 ml) was added. The reaction mixture was stirred at room temperature for 96 hours and cooled rapidly with ice-cooled solution of NaHS03 solution. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. Examination of the reaction mixture showed the formation of two diastereomers and were separated by column chromatography on silica gel eluting with 50% ethyl acetate; Hexane 411 g of (S) -2- [(R) -4-but-2-ynyloxy-phenylsulfinyl) -octanoic acid hydroxamide was isolated as a white solid, m.p. 132.3 ° C; Performance 24%; MS: 352.0 (M + H) +; 1R NMR (300 MHz, DMS0-d6): d 0.834 (m, 3H), 1.19 (m, 9H), 1.76 (m, 1H), 1.84 (t, 3H), 3.11-3.17 (dd, 2H), 3.33 (t, 3H), 4.81 (d, 2H), 7.15 (d, J = 2.8, 2H), 7.36 (d, J = 2.3, 2H), 9.00 (s, 1H), 10.56 (s, 1H). Starting from the hydroxyamide of 2- (4-but-2-ynyloxy-phenylsulfanyl) -octanoic acid (1.78 g, 5.0 mmol) and following the procedure described in Example 7, 0.411 g of acid hydroxamide (S) was isolated. ) -2 - [(S) - -but-2-ynyloxy-phenylsulfinyl) -octanoic acid as a white solid, mp 112.2 ° C; Yield 12%; MS: 352.0 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6): d 0.804 (m, 3 H), 1.01 (m, 9 H), 1.59 (m, 1 H), 1.84 (t, 3 H), 3.33 (s, 3 H), 4.84 (d , 2H), 7.16 (d, J = 2.5, 2H), 7.61 (d, J = 2.7, 2H), 9.21 (s, 1H), 10.82 (s, 1H).
E n p lo 9 3- (4-But-2-ynyloxy-f-enoxy) -N-hydroxy-propionamide Stage 1: 4-But-2-ynyloxy-phenol To a solution of 4.13 g, (0.038 mole) of hydroquinone in 80 ml of acetone was added 5.19 g (0.375 moles) of potassium carbonate and 5.0 g (0.038 moles) of l-bromo-2-but-ina. The resulting mixture was heated to 55-60 ° C for 8 hours and then stirred overnight at room temperature. The reaction mixture was then poured into ice and extracted with ether. The combined organic materials were washed with IN sodium hydroxide solution. The combined aqueous layers were acidified with IN HCl solution and extracted with dichloromethane. The dichloromethane layers were washed with water and brine, dried over Na 2 SO 4, filtered through Magnesol® and concentrated in vacuo to provide 2.0 g of the phenol as a brown oil.
Step 2: 3- (4-But-2-ynyloxy-phenoxy) -propionic acid To a 0 ° C solution of 1015 g (8.60 mmoles) of potassium t-butoxide suspended in 10 ml of dry THF was added a solution of 1.40 • (8.60 mmoles) of -but-2-ynyloxy-phenol, dissolved in 30 ml of THF / DMF (5: 1). The reaction was stirred at room temperature for 10 minutes and then re-cooled to 0 ° C followed by the addition of 0.66 ml (9.46 mmol) of the pure -propiolactone. The resulting mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution. The alkaline aqueous extracts were acidified to pH2 with concentrated HCl solution and the solid precipitate was collected by filtration, washed with water and dried to give 0.089 g of the carboxylic acid as a black solid; p.f. 88-92 ° C. Electrospray Mass Spectrum 232.9 (M-H) ".
Step 3: 3- (4-But-2-ynyloxy-enoxy) -N-hydroxy-propionamide To a solution of 0 ° C of 0.089 g, (0.379 mmole) of 3- (4-but-2-ynyloxy) acid phenoxy) propionic, dissolved in 1 ml of dichloromethane and 0.059 ml of DMF was added 0.379 ml (0.758 mmoles) of a 2M solution of oxalyl chloride. The reaction was warmed to room temperature and stirred for 2 hours and then re-cooled to 0 ° C. A mixture of 0.139 ml (2.27 mmol) of a 50% hydroxylamine solution, 0.73 ml of THF and 0.21 ml of triethylamine was then added to the reaction. The reaction was stirred at room temperature for 12 hours and then concentrated in vacuo. The residue was extracted with dichloromethane and the combined organic materials were washed with water, 2N citric acid solution and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate / hexanes to give the hydroxamic acid as a white solid; p.f. 116-118 ° C. Electrospray Mass Spectrum: 249.9 (M + H) +.
Example 10 4- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-butyramide Step 1: 4- (4-Benzyloxy-phenoxy) -butyric acid ethyl ester To a suspension of 1.2 g (0.030 mole) of hydride of sodium at 60% in 100 ml of toluene was added 6.12 g (0.030 mole) of 4- (benzyloxy) phenol and the reaction was stirred at room temperature for 30 minutes followed by the addition of 5.85 g (0.030 mole) of 3- bromobut ethyl ethyl. The resulting mixture was heated to reflux overnight and then filtered. The filtrate was washed with 0.5 N sodium hydroxide solution, 3% sodium carbonate solution, water and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to provide 5.45 g of the bis-ether as a white solid. . Mass Spectrum Electrospray: 314.8 (M + H) +.
Stage 2: 4- (4-hydroxy-phenoxy) -butyric acid ethyl ester To a solution of 3.58 g (0.011 mole) of 4- (4-benzyloxy-phenoxy) -butyral ethylester in 200 ml of ethanol was added. added 0.81 g of 5% palladium on charcoal and the resulting mixture was stirred under 2.46 kg / cm2 (35 psi) of hydrogen for 4 hours. The resulting mixture was filtered through Magnesol® and concentrated in vacuo to provide 1.97 g of the phenol as a gray solid. Electrospray Mass Spectrum: 225 (M + H) +.
Step 3: 4- (4-But-2-ynyloxy-phenoxy) -butyric acid ethyl ester To a solution of 524 mg (2 mmol) of triphenylphosphine dissolved in 20 ml of benzene and 50 ml of THF was added 0.175 ml (2.3 mmoles) of 2-butin-1-ol. After five minutes, 0.39 g (21.28 mmol) of the 4- (4-hydroxy-phenoxy) butyl ether ethyl ester, dissolved in 10 ml of THF, was added to the reaction followed by 0.369 ml (2.34 mmol) of diethyl azodicarboxylate. The resulting reaction mixture was stirred for 18 hours at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl ilohexanes (1:10) to provide 0.28 g (58%) of 4- (4-but-2-ynyloxy-phenoxy) -butyl ethyl ester. irico desired as a clear liquid. Mass Spectrum: 276.9 M +.
Step 4: 4- (4-But-2-ynyloxy-phenoxy) -butyric acid To a solution of 0.37 g, (1.34 mmol) of 4 - (4 -But-2-ynyloxy-phenoxy) -butyric acid ethyl ester in 6 ml of THF / methanol (5: 1) was added 1.6 ml of a solution of sodium hydroxide IN and the resulting mixture was stirred for 1.5 hours at 70 ° C. The reaction mixture was then concentrated, triturated with ether, filtered and dried to give 0.36 g of the carboxylate salt as a white solid. Electrospray Mass Spectrum: 247 (M-H) ".
Step 5: 4- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-butyramide. According to the procedure of Example 9 (step 3) 0.36 g (1.33 mmoles) of 4- (4-But-2-ynyloxy-phenoxy) butyric acid provides 0.237 g (68%) of the hydroxamic acid as a white solid; p.f. 123-125 ° C. Electrospray Mass Spectrum: 263.9 (M-H) ".
Example 11 2- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-acetamide Ethyl ester (4-But-2-ynyloxy-phenoxy) -acetic acid To a suspension of 600 mg (0.015 mole) of 60% sodium hydride in 100 ml of toluene was added 3.0 g (0.015 mole) of 4-benzyloxy ) phenol and the reaction was stirred at room temperature for 30 minutes followed by the addition of 1.61 ml (0.015 mole) of ethyl chloroacetate. The resulting mixture was heated to reflux overnight and then filtered. The filtrate was washed with 0.5N sodium hydroxide solution, 3% sodium carbonate solution, water and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to provide 2.62 g of the bis-ether as a solid. White. P.f. 65-67 ° C. To a solution of 2.58 g (8.74 mmol) of the product mentioned in the above in 200 ml of ethanol, 0.81 g of palladium on carbon at 5% was added and the resulting mixture was stirred under 2.46 kg / cm2 (35 psi) of hydrogen for 4 hours. The resulting mixture was filtered through Magnesol® and concentrated in vacuo to provide 1.7 g of the phenol as a gray solid. P.f. 100-105 ° C. According to the procedure of Example 10 (Step 3), 1.65 g (8.41 mmol) of the phenol and 0.63 ml of 2-butyn-1-ol provide 1.2 g (60%) of the butynyl ether as a yellow oil.
Electrospray: 248.8 (M + H) +. (4-But-2-ynyloxy-phenoxy) -acetic acid According to the procedure of Example 10 (Step 4), 1.0 g, 4.00 mmol) of (4-but-2-ynyloxy-phenoxy) -acetic acid ethyl ester provides 0.47 g of the carboxylic acid as a white solid; p.f. 114-116 ° C. Electrospray Mass Spectrum: 218.9 (M-H) ". 2- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-acetamide In accordance with the procedure of Example 9 (Step 3), 0.40 g, (1.82 mmol) of (4-But-2-ynyloxy) acid phenoxy) -acetic affords 0.20 g of the hydroxamic acid as a white solid; p.f. 130-132 ° C.
Electrospray Mass Spectrum: 235.9 (M + H) +.
Example 12 4- (4-But-2-ynyloxy-phenyl) -N-hydroxy-butyramide 4- (4-But-2-ynyloxy-phenyl) -butyric acid To a solution of 1.00 g (5.15 mmoles) of 4 - (-methoxyphenyl) butyric acid in 100 ml of dichloromethane at 0 ° C was added 15.5 ml (15.5 mmoles) of boron tribromide and the reaction was then allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was then poured into 200 ml of saturated sodium bicarbonate solution and the organic layer was separated. The aqueous layer was acidified with concentrated HCl solution and then extracted with dichloromethane. The combined organic materials were dried over MgSO4were filtered and concentrated in vacuo to give 0.696 g of impure 4- (4-hydroxyphenyl) buty ric acid. To a solution of 0.69 g of 4- (4-hydroxyphenyl) butyric acid in 10 ml of DMF was added 0.956 g of sodium bicarbonate followed by 0.36 ml of iodomethane and the resulting mixture was stirred at room temperature for 5 hours. The reaction was diluted with water, extracted with ether, dried over MgSO4, filtered and concentrated in vacuo to give 0.553 g of methyl 4- (4-hydroxy phenyl) butyrate.
According to the procedure of Example 10 (step 3), 0.553 g (2.851 mmol) of methyl 4- (4-hydroxy phenyl) butyrate and 0.256 ml of 2-butyn-1-ol provide 0.294 g of the butynyl ether-methyl ester. after chromatography on silica gel eluting with ethyl acetate / hexanes (1:10). To a solution of 0.294 g (1195 mmol) of the butynyl ether methyl ester in 12 ml of THF / methanol (1: 1) was added 6.0 ml of 1N sodium hydroxide solution and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then acidified with 5% HCl solution, extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo to provide 0.223 g of the carboxylic acid as a brown solid. Electrospray Mass Spectrum: 231 (M-H) ". 4- (4-But-2-ynyloxy-phenyl) -N-hydroxy-butyramide To a solution of 0.189 g (0.815 mmoles) of 4 - (-but-2-ynyloxy-phenyl) -butyric acid in 4.3 ml of DMF 0.132 g (0.978 mmol) of 1-hydroxy-benzotriazole was added followed by 0.208 g (1.083 mmol) of 1- [3- (dimethylamino) propyl] -3-ethyl-carbodiimide hydrochloride and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was then added 0.23 ml of 50% aqueous hydroxylamine solution and the reaction was stirred overnight at room temperature. The reaction was then diluted with water and extracted with ethyl acetate. The combined organics were washed with water and saturated sodium bicarbonate, dried over Na 2 SO, filtered and concentrated in vacuo to give 0.156 g of the hydroxamic acid as a brown solid. Electrospray Mass Spectrum: 248.0 (M + H) +.
Example 13 2- (4-But-2-ynyloxy-phenylsulfanyl) -6- [2- (1, 3-dioxo-1,3-dihydro-iso-indol-2-yl) -acetylamino] -hexanoic acid hydroxyamide Step: Coupling of 2-bromo-6-phthaloyl-caproic acid to the hydroxylamine resin. 4-O-Methylhydroxylamine-phenoxymethyl-copoly (styrene-1% -divinylbenzene) -resin1 (20 g, 1.1 meq / g) was placed in a peptide synthesis vessel (Chemglass Inc. Part Number CG-1866) and it was suspended in DMF (60 ml). 2-Bromo-N-phthaloyl-caproic acid (15 g, 2.0 eq.), 1-hydroxybenzotriazole hydrate (HOBt, 18 g, 6.0 eq.) And 1,3-diisopropyl-carbodiimide (DIC, 14 ml. 4.0 eq.). The reaction was stirred on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with DMF (3 x 50 ml). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of the free amine (resin turned blue), the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 50 ml), MeOH (2 x 50 ml), and DCM (2 x 50 ml). (One wash consisted of the addition of the solvent and stirring either by bubbling nitrogen or stirring on the orbital stirrer for 1-5 minutes, then filtration under vacuum). The resin was dried in vacuo at room temperature.
Stage B: Displacement of the bromide with 4-hydroxybenthiol. The hydroxyamide resin of 2-bromo-6-ft aloyl-hexanoic acid prepared in Step A (20 g, 1.1 meq./g) was suspended in THF (50 ml). They added -hydroxybenzene iol (12 g, 5.0 eq.), Sodium iodide (13 g, 5.0 eq.) And 1, 8 -dia zabi cycle [5.4.0] undec-7-ene (DBU, 8.9 ml, 3.0 eq.). The reaction was stirred at room temperature for 12-16 hours. The mixture of 11 The reaction was filtered and washed with DMF (2 x 20 ml), DMF: water 9: 1) (2 x 20 ml), DMF (20 ml), MeOH (2 x -20 ml), and DCM (2 x 20 ml) ). The resin was dried at room temperature.
Stage C: Alkylation with 2-bromobutin The hydroxyamide resin of 2- (4-hydroxy-phenylsulphyl) -6-phthaloyl-hexanoic acid prepared '' in Step B (20 g, 1.1 meq / g) was suspended in THF (50 ml) and cooled to 0 ° C. 2-Bromobutyne (8.0 ml, 2.0 eq.) And sodium hydride (2.4 g, 3.0 eq.) Were added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and washed with DMF (2 x 20 ml), MeOH (2 x 20 ml), and DCM (2 x 20 ml). The resin was dried at room temperature.
Step D: Removal of the phthaloyl group The hydroxyamide resin of 2- (4-but-2-inoxyphenyl sulphyl) -6-phthaloyl-hexanoic acid prepared in Step C (3.4 g, 1.1 meq / g) was suspended in THF (150 ml) and ethanol (150 ml) and hydrazine was added (30 ml). The reaction mixture was stirred on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2 x 50 ml), DMF (2 x 50 ml), MeOH (2 x 50 ml), and DCM (2 x 50 ml). The resin was dried at room temperature.
Step E: Acylation of the primary amine The hydroxyamide resin of 6-amino-2- (4-but-2-inoxi-phenyl sulphyl) -hexanoic acid prepared in Step D (0.33 g, 1.1 meq / g) it was suspended in DMF (60 ml). N-phthaloylglycine (1.5 g, 4.0 'eq.) 1-hydroxybenzot-riazole hydrate (HOBt, 1.43 g, 6.0 eq.) And 1,3-diisopropyl-1-carbodiimide (DIC, 0.18 ml, 4.0 eq.) Were added. . The reaction was stirred on an orbital shaker at room temperature for 2-16 hours. The reaction was filtered and washed with DMF (3 x 5 mL). A sample of resin was removed and subjected to the Kaiser test. If the test showed the presence of the free amine (resin turned blue), the coupling described above was repeated, otherwise the resin was washed with DCM (3 x 5 ml). MeOH 2 x 5 ml), and DCM (2 x 5 ml). The resin was dried at room temperature.
Stage F: Separation of the hydroxyamide of 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -acet-ylamino acid ] -hexanoic of the resin The hydroxyamide resin of 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- [2- (1, 3-dioxo-l, 3-dihydro-iso-indole-2) -yl) -acetylamino] -hexanoic prepared in step E (0.33 g, 1.1 meq / g) was suspended in DCM (1.0 ml) and TFA (1.0 ml) was added. The reaction was stirred for 1 hour at room temperature. The reaction was filtered and the resin was washed with DCM (2 x 1 ml). The filtrate and the washing were combined and concentrated to dryness in a Savant SpeedVac Plus apparatus. Methanol (1 ml) was added and the mixture was concentrated. The crude product was purified by reverse phase CLAP under the following conditions: Column: OdS-AM, 20 mm x 50 mm, size 5 particulate (YMC, Inc. Wilmington, North Carolina) Solvent Gradient Time Water Acetonitrile 0.0 95 5 16 min. 5 95 Flow Rate: 22.5 ml / min.
Example 13 The hydroxyamide of 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -acetylamino] -hexanoic acid had a retention time of 4.5 min of CLAP and EM "of 510 (M + H).
The following compounds of hydroxamic acids were synthesized following the steps in Example 13, and using quinaldic acid, 2-bibenylcarboxylic acid, 3,4-dichlorophenylacetic acid, 3-quinolinecarboxylic acid, 4 - (2-t) acid ienyl) -butyric acid, xanthen-9-carboxylic acid, diphenylacetic acid, 1-isoquinolinecarboxylic acid, N-met ilpyrrole-2-carboxylic acid, t-phthalen-3-acetic acid, or indole- 3-acetic Use 23 [quinoline-2-carboxylic acid 5- (4-but-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentyl] -amide. Stage A: Oxidation of sulphide to sulfoxide. The hydroxyamide resin of 2 - (4-but-2-ynyloxy-phenylsulfanyl) -6-phthaloylhexanoic acid prepared in Example 13, Step C (6.7 g, 1.1 meq / g) was "suspended in DCM (200 ml). and 70% tert-butyl hydroperoxide (45 ml) and benzenesulfonic acid (2 g) were added.The reaction mixture was stirred on an orbital shaker at room temperature for 12-24 hours.The reaction was filtered and washed with DCM (2 x 50 ml), DMF (2 x 50 ml), MeOH (2 x 50 ml), and DCM (2 x 50 ml) The resin was dried in vacuo or at room temperature.
Step B: Removal of the phthaloyl group The hydroxyamide resin of 2- (4-but-2-inoxi-benzenesulfinyl) -6-phthaloyl-hexanoic acid prepared in Step A was deprotected to give the hydroxyamide resin of 6-amino acid -2- (4-But-2-inoxi-benzenesulfinyl) -hexanoic acid according to the procedure in Example 13, Step D.
Step C: Acylation of the primary amine The hydroxyamide resin of 6-amino-2- (4-but-2-inoxi-benzenesulfinyl) -hexanoic acid (0.33 g, 1.1 meq / g) prepared in step B was acylated with quinadic acid (1.2 g, 4.0 eq.) according to the procedure in Example 13, Step E to give the resin of [5- (4-but-2-ynyloxy-benzenesul fini 1) -5-hydroxycarbamoyl-pentyl ] -quinoline-2-carboxylic acid amide.
Step D: Separation of the [5- (-but-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentyl] -amide of quinoline-2-carboxylic acid from the resin The resin of [5- (4-buty -2-inyloxy-benzenesulfini 1) -5-hydroxy-carbamoyl-pentyl] -amide of quinol in-2-carboxylic acid prepared in Step C (0.33 g, 1.1 meq / g) was separated according to the procedure in Example 13, Step F to give the Example 23: [5- (4-But-2-ynyloxy-benzenesul-f-yl) -5-hydroxy-carbamoyl-pentyl] -amide of quinoline-2-carboxylic acid as a mixture of erythroid days which had a time2 of CLAP retention of 4.35 / 4.5 min. and EM3 of 494 (M + H). The following hydroxamic acid compounds were synthesized following the steps in Example 23, and using N-phthaloylglycine, 2-bibenylcarboxylic acid, 3,4-dichlorophenylacetic acid, 3-quinolinecarboxylic acid, 4- (2-thienyl) acid -butyric, xant-9-carboxylic acid, diphenyl-acetic acid, 1-isoquinolinecarboxylic acid, N-methylpyrrole-2-carboxylic acid, t-thaphthalene-3-acetic acid, or indole-3-acetic acid.
Example 34 N- [5- (4-B-2-ynyloxy-benzenes-l-phonyl) -5-hydroxycarbamoyl-pentyl] -2-phenethyl-benzamide. Step A: Oxidation of Sulfide to Sulfone The hydroxyamide resin of 2- (4-but-2-inoxi-phenylsulfanyl) -6-phthaloylhexanoic acid prepared in Example 13, Step C (6.7 g, 1.1 meq / g) was suspended in DCM (200 ml) and mCPBA (8 g) was added. The reaction mixture was stirred on an orbital shaker at room temperature for 12-24 hours. The reaction was filtered and washed with DCM (2 x 50 ml), DMF (2 x 50 ml), MeOH (2 x 50 ml), and DCM (2 x 50 ml). The resin was dried in vacuo at room temperature.
Step B: Removal of the phthaloyl group The hydroxyamide resin of 2- (4-but-2-inoxi-benzenesulfonyl) -6-phthaloyl-hexanoic acid prepared in Step A was deprotected to give the 6-amino acid hydroxyamide resin -2- (4-but-2 -inoxy-benzenesulfinyl) -hexanoic acid according to the procedure in Example 13, Step D.
Step C: Acylation of the primary amine The hydroxyamide resin of 6-amino-2- (4-but-2-inoxi-benzenesulfonyl) -hexanoic acid (0.33 g, 1.1 meq / g) prepared in step B was acylated with 2-bibenylcarboxylic acid (1.6 g, 4.0 eq.) according to the procedure in Example 13, Step E to give the N- [5- (4-but-2-ynyloxy-benzenesulfonyl) -5-hydroxy resin carbamoyl -pent il] -2-fenet i 1 -benzami da.
Step D: Separation of the N- [5- (4-but-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentyl] -2-phenethyl-benzamide from the resin. The N- [5- (4-but-2-ynyloxy-benzenesulfonyl) -5-hydroxy carbamoyl-pentyl] -2-phenethyl-benzamide resin prepared in Step C (0.33 g, 1.1 meq / g) was separated according to the procedure in Example 13, Step F to give Example 34: of N- [5- (4-but-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentyl] -2-fenethe -benzamide which had a CLAP retention time2 of 5.0 min. and EM3 of 541 (M + H). The following compounds of hydroxamic acids were synthesized following the steps in Ex. 34, and using quináldico acid, N-phthaloylglycine, 3,4-dichlorophenylacetic acid, 3-quinol incarboxylic acid, xanthen-9-carboxylic acid, acid di-phenylacetic acid, 1-isoquinol incarboxylic acid, or t-thaphthalene-3-acetic acid.
Example 43 Hydroxyamide of 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- acid. { 2- [2- (3,4-dichloro-phenyl) -acetylamino] acetylamino} -hexanoic.
Stage A: Elimination of the phthaloyl group The hydroxyamide resin of 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- [2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) hydroxyamide. ) -acetylamino] -hexanoic prepared in Example 13, Step E was deprotected to give the hydroxyamide resin of 6- (amino-acetylamino) -2 - (4-but-2-inyloxy-benzenesulfinyl) -hexanoic acid according to the procedure in Example 13, Step D.
Stage B: Acylation of the primary amine The hydroxyamide resin of 6- (α-n-acetylamino) -2- (4-but-2-inoxi-benzenesulfinyl) -hexanoic acid (0.33 g, 1.1 meq / g) prepared in Step A was acylated with 3,4-dichlorophenylacetic acid (1.5 g, 4.0 eq.) according to the procedure in Example 13, Step E to give the hydroxyamide resin of 2- (4- but-2-) acid. inyloxy-phenylsulfanyl) -6- { 2- [2- (3, -dichloro-phenyl) -acetylamino] -acetylamino} -hexanoic acid.
Step C: Separation of the hydroxamide from 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- acid. { 2- [2- (3,4-Dichlorophenyl) -acetylamino] -acetylamino} -hexanoic of the resin The hydroxyamide resin of 2 - (.4-but-2-ynyloxy-phenylsulfanyl) -6-. { 2- [2- (3,4-dichloro-phenyl) -acetylamino] -acetylamino] -hexanoic prepared in Step B (0.33 g, 1.1 meq / g) was separated according to the procedure in Example 13, Step F to give Example 43: of 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- hydroxyamide. { 2- [2- (3,4-dichloro-phenyl) -acetylamino] -acetylamino} -hexanoic that had a CLAP retention time2 of 4.94 min. and EM3 of 567 (M + H). The following hydroxamic acid compounds were synthesized following the steps in Example 43, and using quinaldic acid, N-phthaloylglycine, 2-bibenylcarboxylic acid, 3-quinolinecarboxylic acid, xanthen-9-carboxylic acid, diphenylacetic acid, acid 1 isoquinolinecarboxylic acid, N-met ilpyrrole-2-carboxylic acid or t-thaphthalen-3-acetic acid.
Use 53 [5- (4-But-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentyl] -aminoquin-3-carboxylic acid amide. Stage A: Oxidation of sulphide to sulfoxide. The hydroxyamide resin of 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] -hexanoic acid prepared in Example 13, Step E was oxidized to the hydroxyamide resin of 2- (-but-2-linoxy-benzenesulfinyl) -6- [2- (1,3-dioxo-1,3-dihydroxy) acid hydroxyamide. isoindol-2-yl) -acetylamino] -hexanoic acid according to the procedure in Example 23, Step A.
Stage B: Elimination of the phthaloyl group The hydroxyamide resin of 2- (4-but-2-ynyloxy-benzenesulfinyl) -6- [2- (l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) ) -acetylamino] -hexanoic prepared in Step A was deprotected to give the hydroxyamide resin of 6- (amino-acetylamino) -2- • (4-but-2-ynyloxy-benzenesul fini 1) -hexanoic acid of according to the procedure in Example 13, Step D.
Step C: Acylation of the primary amine The hydroxyamide resin of 6- (amino-acetylamino) -2- (4-but-2-inoxi-benzenesulfinyl) -hexanoic acid (0.33 g, 1.1 meq / g) prepared in the step B was acylated with 3-quinolinecarboxylic acid (1.2 g, 4.0 eq.) According to the procedure in Example 13, Step E to give the resin of [5- (4-but-2-ynyloxy-benzenesulfinyl) -5 -hydroxycarbamoyl-pentyl] -aminoquin-3-carboxylic acid amide.
Step D: Separation of the [5- (4-but-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentyl] -amide of quinoline-3-carboxylic acid from the resin The resin of [5- ( 4-but-2-ynyloxy-benzenesulfinyl) -5-hydroxy-carbamoyl-pentyl] -amide of quinoline in-3-carboxylic acid prepared in Step C (0.33 g, 1-1 meq / g) was separated according to the procedure in Example 13, Step F to give Example 53: of [5- (4-but-2-ynyloxy-benzenesul finyl) -5-hydroxy-carbamoyl-pentyl] -amide of quinolin-3 acid -carboxylic acid as a mixture of diastereomers that had a CLAP retention time2 of 3.49 min. and EM3 of 551 (M + H). The following hydroxamic acid compounds were synthesized following the steps in Example 53, and using quinaldic acid, N-phthaloylglycine, 2-bibenylcarboxylic acid, 3,4-dichlorophenylacetic acid, 4 - (2-thienyl) butyrate, acid xanthen-9-carboxylic acid, di-phenyl-acetic acid, or N-methylpyrrole-2-carboxylic acid.
Example 62 2- (4-But-2-ynyloxy-benzenesulfonyl) -6- (2-diphenylacetylamino-acetylamino) -hexanoic acid hydroxyamide Step A: Oxidation of sulphide to sulfoxide. The hydroxyamide resin of 2- (4-but-2-ynyloxy-phenylsulfanyl) -6- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] -hexanoic prepared in Example 13, Step E was oxidized to the hydroxyamide resin of 2- (4-but-2-ynyloxy) acid. benzenesulfonyl) -6- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] -hexanoic acid according to the procedure in Example 34, Step A. Step B : Elimination of the phthaloyl group The hydroxyamide resin of 2- (4-but-2-ynyloxy-benzenesul fonyl) -6- [2- (l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] -hexanoic prepared in Step A was deprotected to give the hydroxyamide resin of 6- (amino-acetylamino) -2- (4-but-2-ynyloxy-benzenesulfinyl) -hexanoic acid according to the procedure in Example 13, Step D.
Step C: Acylation of the primary amine The hydroxyamide resin of 6- (amino-acetylamino) -2- (4-but-2-inoxi-benzenesulfonyl) -hexanoic acid (0.33 g, 1.1 meq / g) prepared in the step B was acylated with diphenylacetic acid (1.5 g, 4.0 eq.) According to the procedure in Example 13, Step E to give the hydroxyamide resin of 2- (4-but-2-ynyloxy-benzenesulfonyl) -6- acid. (2-diphenylacetylaminoacetylamino) -hexanoic acid.
Stage D: Separation of 2- (4-but-2-ynyloxy-benzenesulfonyl) -6- (2-diphenylacetylamino-acetylamino) -hexanoic acid hydroxyamide from the resin The hydroxyamide resin of 2- (4-but -2-loxi-benzenesulfonyl) -6- (2-diphenylacetylamino-acetylamino) -hexanoic prepared in Step C (0.33 g, 1.1 meq / g) was separated according to the procedure in Example 13, Step F to give the Example 62: 2- (4-But-2-ynyloxy-benzenesulfonyl) -6- (2-di-phenylacetylamino-acetylamino) -hexanoic acid hydroxyamide which had a CLAP retention time of 4.90 min. and EM3 of 606 (M + H). The following hydroxamic acid compounds were synthesized following the steps in Example 62, and using N-phthaloylglycine, 2-bibenylcarboxylic acid, 3,4-dichlorophenylacetic acid, 3-quinolinecarboxylic acid, xanthen-9-parboxylic acid, -isoquinolinecarboxylic acid, t-phthalic acid-3-acetic acid, or indole-3-acetic acid.
References: 1"Ricter, LS; Desai, MC Te t rah edron Le tt ers, 1997, 38, 321-322 2. LC Conditions: Hewlett Packard 1100; YMC ODS-A 4.6 mm x 50 mm column 5 ua 23 ° C, 10 uL injection, Solvent A: TFA / 0.05% water, Solvent B: 0.05% TFA / acetonitrile, Gradient: Time "0: 98% A; 1 minute: 98% A; 7 minutes: 10% A; 8 minutes: 10% A; 8.9 minutes: 98% A; After 1 minute of time. Flow rate 2.5 ml / minute; Detection: DDA of 220 and 254 nm. 3. EM conditions: API -electropulveri zador Example 71 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-. { 4- [2- (1-piperidinyl) ethoxyphenyl} butanamide Step 1: 2- [4 - (2-Piperidin-l-yl-ethoxy) -phenyl] -ethanol To a solution of 4-hydroxyphenetyl alcohol (5.02 g, 36.3 mmol) and chloroethyl-piperidine (7.36 g, 39.96 mmoles) in 30 ml of DMF, 5 g of K2C0 was added. The reaction was stirred at 80 ° C overnight. After cooling, the mixture was rapidly cooled with water, then extracted into CHC13. The organic layer was separated, dried over Na2SO4, filtered and concentrated. 2 - [- (2-Piperidin-1-yl-ethoxy) -phenyl] -ethanol (4.58 g, 18.4 mmol) was isolated as a brown oil; Yield 51%; MS: 250.3 (M + H) +.
Stage 2: 1-. { 2- [4 - (Chloro-ethyl) -phenoxy] -ethyl} -piperidine 2 - [4 - (2-Piperidin-1-yl-ethoxy) -phenyl] -ethanol (4.23 g, 16.98 mmol) was dissolved in 200 ml of THF. HCl gas was bubbled through the solution at 0 ° C for 5 minutes. Thionyl chloride (2.48 ml, 33.9 mmol) was added dropwise at 0 ° C. The reaction mixture was heated to reflux for 2 hours before it was concentrated. It was isolated 1-. { 2 - [4-chloroethyl] -phenoxy] -ethyl} -piperidine (4.74 g, 15.6 mmol) as a brown semi-solid; Yield 92%; E: 268.3 (M + H) +.
Stage 3: Prepared 2-. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -4-. { Ethyl 4- [2- (1-piperidinyl) ethoxyphenyljbutanoate according to the general method described in Example 1 (Step 4) starting from l-. { 2- [4- (Chloro-ethyl) -phenoxy] -ethyl} -piperidine (4.74 g, 15.64 mmol) and (4-but-2-inyloxy-benzenesulfonyl) -acetic acid ethyl ester (3.56 g, 12 mmol); 1.21 g of the crude product. Performance 19%; coffee oil; MS: 528.1 (M + H) +.
Step 4: 2- acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -4-. { 4- [2- (1-piperidinyl) ethoxy] phenyljbutanoic according to the general method described in Example 1 (Step 5). Starting from 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -4-. { 4- [2- (1-piperidinyl) -ethoxyphenyl} ethyl butanoate (1.21 g, 2.29 mmol), 750 mg of off-white solid was isolated. Performance 65%; MS: 500.3 (M + H) +.
Stage 5: Starting from acid 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -4-. { 4- [2- (1-piperidinyl) -ethoxy] phenyl} butanoic (660 mg, 1.32 mmol) and following the procedure described in Example 1 (Step 6), 50 mg of 2- was isolated. { [4 - (2-Butyloxy) -phenyl] sulfonyl} -N-hydroxy-4-. { 4- [2- (1-piperidinyl) -ethoxyphenyl} Butanamide as a pale yellow solid. P.f. 68 ° C; Yield 7%; MS: 515.2 (M + H) +; 1 R NMR (300 MHz, DMS0-d6): d 0.853 (m, 2H), 1.36 (s, 2H), 1.67-1.82 (band, 4H), 1.84 (s, 3H), 1.95 (q, 2H), 2.94 (m, 2H), 3.45 (m, 4H), 3.73 (t, 1H), 4.33 (t, J = 4.41 Hz, 2H), 4.88 (d, 2.25 Hz, 2H), 6.91 (m, 2H), 7.05 (d, 2H), 7.16 (m, 2H), 7.69 (m, 2H), 9.28 (s, 1H), 9.88 (s, 1H).
Example 72 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -7-cyano-N-hydroxy-heptanamide 2- was prepared. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -7-ethyl cyanoheptanoate according to the general method described in example 1 (step 4), starting from (4-but-2-ynyloxy-benzenesul-fonyl) -acetic acid ethyl ester (10 g, 33.8 mmol ) and 6-bromohexanoni trilo (4.48 ml, 33.8 mmol); 7.9 g of white solid. P.f. 63 ° C; Yield 60%; MS (El): 391.4 (M + H) +. 2 - acid was prepared. { [4 - (2-Butynyloxy) phenyl] -sulfonyl} -7-cyanoheptanoic acid according to the general method described in example 1 (step 5), starting from 2-. { [- (2-Butynyloxy) phenyl] sulphonyl} Ethyl-7-cyanoheptanoate (300 mg, 0.77 mmol); 230 mg of yellow gel. Yield 82%; MS: 362.4 (M-H). " Starting from acid 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -7-cyanoheptanoic acid (3.78 g, 10.4 mmol) and following the procedure described in Example 1 (step 6), 1.11 g of 2- was isolated. { [4- (2-butynyloxy) phenyl] sulfonyl} -7-cyano-N-hydroxy-heptanamide as a white powder. P.f .: 120 ° C; Yield: 28%; MS: 379.3 (M + H) +; 1 H-NMR (300 MHz, DMS0-d 6): d 1.16-1'.31 (band, 4H), 1.44 (m, 2H), 1.69 (m, 2H), 1.85 (s, 3H), 2.42 (t, J = 7 Hz, 2H), 3.71 (t, J = 7.3 Hz, 1H), 4.89 (d, 2.19 Hz, 2H), 7.18 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 9.24 (s, 1H), 10.88 (s, 1H).
Example 73 2-. { [4- (2-butynyloxy) phenyl [sulfanil} -2-cyclohexyl-N-hydroxyacetamide Step 1: 2-Bromocyclohexylacetic acid To a solution of cyclohexylacetic acid (10 g, 70 mmol) in 100 ml of CC1 was added red phosphorus (6.32 g, 204 mmol). The mixture was heated to reflux and bromine (70.7 ml, 1.38 mmol) was added dropwise over 3 hours through the condenser via an addition funnel. The reaction was heated to reflux for 5 hours before it was rapidly cooled with water, then washed with 10% Na 2 SO 4, water, then in NaHCO 3. The sodium bicarbonate solution was conducted to acidic pH using IN HCl. The solid was collected and the aqueous filtrate was extracted with CHC13, washed with saturated Na2HS04 solution, then with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated and combined with solid harvested previously to provide 3.22 g of 2-bromocyclohexylacetic acid as a white solid. Performance 21%; MS: 219.1 (M-H) ~.
Step 2: Ethylcyclohexyl [4- (hydroxyphenyl) sulfanyl] -acetic acid was prepared according to the general method described in Example 1 (step 1), starting from 2-bromocyclohexylacetic acid (3.08 g, 13.9 mmoles) and 4-mercaptophenol (2 g, 14.2 mmol); 3.10 g of yellow oil. The product was quite pure and was taken for other transformations. Performance 84%; MS: 265 (M + H) +.
Step 3: Cyclohexy-1 [4- (hydroxy phenyl) sulphyl] ethyl acetate To a solution of et-cyclohexyl [4- (hydroxyphenyl) sulfanyl] -acetic acid (3.1 g, 11.65 mmol) in 100 ml of ethanol, was added 1 ml of sulfuric acid. The mixture was heated to reflux overnight then concentrated, extracted into methylene chloride, washed first with saturated NaHC03 solution then with water. The organic layer was dried over Na 2 SO 4, filtered over magnesol and concentrated to provide 1.22 g of ethyl cyclohexyl [4- (hydroxyphenyl) sulfanyl] ethyl acetate as a yellow oil. Yield 35%; MS: 295.4 (M + H) +.
Stage 4: Prepared. { [4 - (2-butyloxy) phenyl] sulfanil} (cyclohexyl) ethyl acetate according to the general method described in example 1 (step 2), starting from cyclohexyl [4- (hydroxyphenyl) sulphyl] -acetic acid (1 g, 3.4 mmol) and -bromo -2-but ina (0.32 ml, 3.7 mmol); .1.25 g of yellow oil. 100% performance; MS (EI): 346.1 (M + H) +.
Step 5: Acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfanyl} (cyclohexyl) acetic acid according to the general method described in example 1 (step 5), starting from. { [4- (2-Butynyloxy) phenyl] sulfanil} (cyclohexyl) -ethyl acetate (1.2 g, 3.47 mmol); 1.19 g of yellow oil. 100% performance; MS: 317.4 (M-H). " Stage 6: Starting from acid. { [4- (2-Butynyloxy) phenyl] sulfanil} (cyclohexyl) acetic and following the procedure described in Example 1 (step 6), 672 mg of 2- was isolated. { [4 - (2-Butyloxy) -phenyl] sulfanil} -2-cyclohexyl-N-hydroxyacetamide as a white powder. P.f. 163 ° C; Yield 75%; MS: 334.1 (M + H) +; 1N NMR (300 MHz, DMSO-d6): d 0.86-1.12 (band, 5H), 1.62 (m, 5H), 1.83 (t, J = 2.25 Hz, 3H), 2.05 (d, J = 11.9 Hz, 1H ), 3.12 (d, J = 9.1 Hz, 1H), 4.73 (d, J = 2.34 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 8.92 (s, 1H), 10.5 (s, 1H).
Example 74 2-. { [4- (2-butynyloxy) phenyl] sulfinyl} -2-cyclohexyl-N-hydroxyacetamide Starting from 2 -. { [4 - (2-Butynyloxy) -phenyl] sulfanil} -2-cyclohexyl-N-hydroxyacetamide (580 mg, 1.74 mmol), and following the procedure described in Example 7, 230 mg of 2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2-cyclohexyl-N-hydroxy-, acetamide as a white solid. P.f. 188 ° C; Yield: 38%; MS: 350.2 (M + H) +; 1 H NMR (300 MHz, DMSO-de): d 1.05 (m, 3H), 1.24 (, 2H), 1.41-1.72 (band, 5H), 1.84 (t, J = 2.22 Hz, 3H), 2.5 (m, 1H), 3. 14 (d, J = 7.23 Hz, 1H), 4.89 (m, 2H), 7.16 (d, J = 9) Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 9.0 (d, 1H), 10.4 (d, 1H).
Example 75 2-. { [4- (2-Butynyloxy) enyl] sulfonyl} -2-cyclohexyl-N-hydroxyacetamide To a solution of 2-. { [4- (2-butyloxy) phenyl] -sulfinyl} -2-cyclohexyl-N-hydroxy-acetamide (180 mg, 0.52 mmol) in MeOH / THF at room temperature, oxone (5.0 g, excess) in water (20 ml) was added. The reaction mixture was stirred at room temperature for 6 hours and filtered. The methanol / THF layer was concentrated and extracted with chloroform. The organic layer was washed well with water, dried, filtered and concentrated. The product was purified by silica gel column chromatography eluting with 4: 1 ethyl acetate: hexane and isolated 2-. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -2-cyclohexyl-N-hydroxy-acetamide as a white solid. P.f. 191 ° C; Yield: 45 mg (24%); MS: 366.3 (M + H) +; H NMR (300 MHz, DMSO-d6): d 0. 95-1.12 (band, 5H), 1.58 (m, 5H), 1.85 (t, J = 2.22 Hz, 3H), 2.05 (m, 1H), 3.63 (d, J = 9.1 Hz, 1H), 4.87 (d, J = 2.34 Hz, 2H), 7.16 (d, J = 9 Hz, 2H), 7.76 ( d, J = 9 Hz, 2H), 9.01 (s, 1H), 10.7 (s, 1H).
Example 76 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (4-methoxyphenyl) acetamide Step 1: [(4-Hydroxyphenyl) sulfanyl] (4-methoxyphenyl) -acetic acid ethyl Bromine (4-methoxyphenyl) acetate (16.5 g, 60.4 mmol) ) to a stirred solution of triethylamine (10 ml), and 4-mercaptide ofenol (7.63 g, 60.4 mmol) in chloroform (200 ml). The mixture was refluxed overnight before it was concentrated and the residue was extracted into ethyl acetate and washed with water. The organic layer was dried over Na 2 SO, filtered and concentrated. The compound was isolated using silica gel column chromatography eluting with 20% ethyl acetate: hexane solution. [(4-Hydroxyphenyl) sul fani 1] (ethyl 4-methoxyphenyl) acetate was isolated as a yellow oil (15.82 g). Yield 82%; MS: 317.2 (M-H). "Was prepared { [4 - (2-Butynyloxy) phenyl] sullyl. (4-methoxyphenyl) ethyl acetate according to the general method described in example 1 (step 1), starting from [(4-hydroxyphenyl) sulphyl] (4-methoxyphenyl) ethyl acetate (15.82 g, 49.7 mmoles) and 4-bromo-2-butine (4.79 ml, 54.7 mmoles); 17.66 g of yellow oil. Yield 96%; MS (EI): 370.1 (M + H) +. Acid was prepared. { [4 - (2-Butynyloxy) phenyl] -sulfanyl} (4-methoxyphenyl) acetic acid according to the general method described in example 1 (step 5), (hydrolysis was carried out at room temperature for 24 hours) starting from. { [4- (2-Butynyloxy) phenyl] sulfanil} (4-methoxyphenyl) ethyl acetate (10 g, 27 mmol); 5.78 g of yellow oil. Performance 63%; MS: 341.2 (MH). "Starting from acid { [4- (2-Butynyloxy) phenyl] sulfanyl} - (-methoxy phenyl) acetic acid (5.59 g, 16.3 mmol) and following the procedure described in Example 1 (step 6), 450 mg of 2- {[4- (2-butynyloxy) phenyl] sulfanyl} -N-hydroxy-2- (4-methoxyphenyl) acetamide was isolated as a white solid. 156 ° C; Yield: 8%; MS: 358.3 (M + H) +; 1 H NMR (300 MHz, DMSO-d6): d 1.82 (t, J = 2.25 Hz, 3H), 3.72 (s, 3H) , 4.65 (s, 1H), 4.71 (q, J = 2.3 Hz, 2H), 6.89 (m, 4H), 7.26 (d, 2H), 7.53 (d, 2H), 9.0 (s, 1H), 10.8 (s, 1H).
Example 77 (2R) -2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (4-methoxyphenyl) ethanamide and (2S) -2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (4-methoxyphenyl) ethanamide Starting from 2-. { [4- (2-butyloxy) -phenyl] sulfanil} -N-hydroxy-2- (4-methoxy phenyl) acetamide (prepared in Example 76) (340 mg, 0.95 mmol), and following the procedure described in Example 7. The two diastereomers were separated by gel column chromatography of silica eluting with 50% ethyl acetate: hexane. The fastest moving isomer, namely, (2R) -2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (4-methoxy phenyl) ethanamide as a white powder. P.f .: 157 ° C; Yield: 49.0 mg (14%); MS: 374.3 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.83 (t, J = 2.25 Hz, 3 H), 3.70 (s, 3 H), 4.32 (s, 1 H), 4.76 (d, J = 2.37 Hz, 2 H), 6.8 (d, 2H), 6.99 (m, 4H), 7.13 (d, 2H), 9.2 (s, 1H), 11 (s, 1H). The slower moving isomer, namely (2S) -2- was isolated. { [4 - (2-Butyloxy) pheni 1] sul finyl} -N-Hydroxy-2- (4-methoxyphenyl) -etanamide as a white powder. P.f. 134 ° C; Yield: 39 mg (10%); MS: 374.2 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6): d 1.85 (t, J = 2.25 Hz, 3 H), 3.77 (s, 3 H), 4.29 (s, 1 H), 4.81 (d, J = 2.4 Hz, 2 H), 6.93 (d, J = 8.76 Hz, 2H), 7.12 (d, J = 8.85 Hz, 2H), 7.32 (d, J = 8.76 Hz, 2H), 7.48 (d, J = 8.79 Hz, 2H), 8.95 ( s, 1H), 10.6 (s, 1H).
Example 79 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (4-methoxyphenyl) acetamide Starting from the 2-. { [4- (2-butyloxy) -phenyl] sulfanil} -N-hydroxy-2- (4-methoxy-phenyl) acetamide (290 mg, 0.8 mmol), and following the procedure described in Example 75, 120 mg of 2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (4-methoxy-phenyl) acet amide as a white powder. P.f. 190 ° C; Yield: 39%; MS: 390.2 (M + H) +; X H NMR (300 MHz, DMSO-de): d 1.85 (t, J = 2.22 Hz, 3 H), 3.74 (s, 3 H), 4.85 (d, J = 2.31 Hz, 2 H), 4.94 (s, 1 H), 6.86 (d, J = 9 Hz, 2H), 7.08 (d, J = 7.2 Hz, 2H), 7.26 (> d, J = 9 Hz, 2H), 7.45 (d, J = 9 Hz, 2H), 9.24 (d, J = 1. 5 Hz, 1H), 10.9 (s, 1H).
Example 80 2-. { [4- (2-Butynyloxy) phenyl] sul anil} -2- (4-chlorophenyl) -N-hydroxyacetamide. Ethyl (4-chlorophenyl) [(4-hydroxyphenyl) -sulfanyl] acetate was prepared according to the general method described in example 1 (step 1), starting from of bromine (4-chlorophenyl) ethyl acetate (16.5 g, 59.6 mmoles) and 4-mercaptophenol (7.5 g, 59.6 mmoles); 18.8 g of white solid. P.f. 63 ° C; Yield 97%; EM 321.3 (M-H) ".
It was prepared. { [4 - (2-Butynyloxy) phenyl] sulfanyl} (4-chlorophenyl) ethyl acetate according to the general method described in example 1 (step 2), starting from (4-chlorophenyl) [(4-hydroxyphenyl) -sulfanyl] ethyl acetate (15.37 g, 47.7 mmoles) and 4-bromo-2-butine (4.26 ml, 48.7 mmoles); 12.57 g of yellow oil. Performance 69%; MS (EI): 374 (M + H) +. Acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfanyl} (4-chlorophenyl) acetic acid according to the general method described in example 1 (step 5), starting from. { [4- (2-butyloxy) phenyl] -sulfanyl} (4-chlorophenyl) ethyl acetate (3.91 g, 10.5 mmol); 2.63 g of yellow oil. Yield 72%; MS: 345.2 (MH). "Starting from acid { [4- (2-Butyloxy) -phenyl] sulfanyl} - (4-chlorophenyl) acetic (2.43 7.02 mmol), and following the procedure described in Example 1 (step 6), 65 mg of 2- {[4- (2-butynyloxy) phenyl] sulfanyl} -2- (4-chlorophenyl) -N-hydroxyacetamide was isolated as a white powder. 152 ° C; Yield: 3%; MS: 362.2 (M + H) +; 1 H NMR (300 MHz, DMSO-d6): 1.82 (t, J = 2.31 Hz, 3H), 4.72 (m, 3H), 6.89 (d, 2H), 7.26 (d, 2H), 7.4 (m, 4H), 9.1 (s, 1H), 10.9 (s, 1H).
Example 81 2-. { [4- (2-Butynyloxy) enyl] sulfinyl} -2- (4-chlorophenyl) - N-hydroxyacetamide Starting from 2-. { [4- (2-butyloxy) -phenyl] sulfanil} -2- (4-chlorophenyl) -N-hydroxy-acetamide (prepared from Example 80) (1.35 g, 3.74 mmol), and following the procedure described in Example 7, 70 mg of 2- was isolated. { [4- (2-Butynyloxy) -phenyl] sulfinyl} -2- (-chlorophenyl) -N-hydroxyacetamide as a white powder. This compound was tested as the mixture of diastereoisomers. P.f. 92 ° C; Yield: 5%; MS: 378 (M + H) +; 2 H NMR (300 MHz, DMSO-d 6): d 1.83 (t, J = 2.25 Hz, 3 H), 4.43 (s, 1 H), 4.77 (d, J = 2.37 Hz, 2 H), 6.98 (d, 2 H), 7.09 (d, 2H), 7.19 (d, 2H), 7.34 (d, 2H), 9.32 (s, 1H), 11 (s, 1H).
Example 82 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -2- (4-chlorophenyl) - N-hydroxyacetamide Starting from a mixture of 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (4-chlorophenyl) -N-hydroxyacetamide (from example 80) and 2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2- (4-chlorophenyl) -N-hydroxyacetamide (750 mg, 1.99 mmol), and following the procedure described in Example 75, 228 mg of 2- was isolated. { [4 - (2-Butyloxy) phenyl] sulfonyl} -2- (4-chlorophenyl) -N-hydroxyacetamide as a white solid. P.f. 140 ° C; Yield: 29%; MS: 394.2 (M + H) +; NMR * H (300 MHz, DMSO-d6): d 1.85 (t, J2.19 Hz, 3H), 4.86 (d, J = 2.28 Hz, 2H), 5.05 (s, 1H), 7.1 (d, 2H) , 7.4 (m, 4H), 7.5 (d, 2H), 9.33 (s, 1H), 10.8 (s, 1H).
Example 83 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (3-chlorophenyl) -N-hydroxyacetamide Step 1: Ethyl (3-chlorophenyl) [(-hydroxyphenyl) -sulfanyl] acetate was prepared according to the general method described in example 1 (step 1), starting from bromine (3-chlorophenyl) ethyl acetate (6.16 g, 16.5 mmol) and 4-mercaptophenol (2.08 g, 16.5 mmol); 4.36 g of clear oil. Yield 82%; MS: 321 (M-H). " Stage 2: . { [- (2-Butyloxy) phenyl] sulfanil} (3-Chlorophenyl) ethyl acetate [3-Chlorophenyl] [(-hydroxyphenyl) sulfanyl] -acetic acid ethyl ester (4.2 g, 13 mmol) was stirred with THF (100 ml) in a dry two-necked flask under inert. 2-Butyn-1-ol (0.97 ml, 13 mmol) and 1,1 '- (azodicarbonyl) dipiperidine (3.94 g, 15.6 mmol). Tributylphosphine (3.90 ml, 15.6 mmol) was added in drops at 0 ° C. The reaction mixture was allowed to stir at room temperature under nitrogen for 2 hours before it was concentrated. The residue was triturated with ether and the filtrate was concentrated. It was isolated. { [4- (2-Butynyloxy) phenyl] sulfanil} (3-chlorophenyl) -acetic acid ethyl ester as a yellow oil (4.08 g) after silica gel column chromatography, using methylene chloride as the mobile phase. Performance 84%; MS (EI): 375 (M + H) +. Acid was prepared. { [4 - (2-Butynyloxy) phenyl] -sulfanyl} (3-chlorophenyl) acetic acid according to the general method described in example 1 (step 5), starting from. { [4 - (2-butyloxy) phenyl] -sulfanyl} (3-chlorophenyl) ethyl acetate (4.08 g, 10.9 mmol); 2.04 g of whitish powder. P.f. 64 ° C; Yield: 54%; MS: 691.4 (2M-H) "Starting from the acid { [4- (2-Butynyloxy) phenyl] sulfanyl} - (3-chlorophenyl) acetic acid (1.86 g, 5.37 mmol), and following the procedure described in Example 1 (step 6), 130 mg of 2 - { [4- (2-Butynyloxy) phenyl] sulfanyl} -2- (3-chlorophenyl) -N-hydroxyacetamide was isolated as a white powder Mp: 127 ° C; Yield: 7%; MS: 362.1 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6): d 1.82 (t, J = 2.31 Hz, 3 H), 4.72 (m, 3 H), 6.91 (d, 2 H), 7.26 (d, 2 H), 7.34 (m, 3 H) ), 7.48 (s, 1H), 9.1 (s, 1H), 10.9 (s, 1H).
Example 84 2-. { [4- (2-Butynyloxy) enyl] sulfonyl} -2- (3-chlorophenyl) - N-hydroxyacetamide Starting from a mixture of 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (3-chlorophenyl) -N-hydroxyacetamide and 2-. { [4 - (2-Butyloxy) phenyl] sulfin 1} -2- (3-chiorophenyl) -N-hydroxyacetamide (210 mg, 0.56 mmol), and following the procedure described in Example 75, 60 mg of 2- was isolated. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -2- (3-chloro-phenyl) -N-hydroxyacetamide as a white powder. P.f .: 50 ° C; Yield: 27%; MS: 394.1 (M + H) +; 1 H NMR (300 MHz, DMS0-d6): d 1.84 (t, J = 2.22 Hz, 3H), 4.86 (d, J = 2.31 Hz, 2H), 5.06 (s, 1H), 7.12 (d, J = 8.97) Hz, 2H), 7.19-7.39 (band, 2H), 7.48 (m, 4H), 9.33 (d, J = 1. 2 Hz, 1H), 10.9 (s, 1H).
Example 85 2- (4-bromo-phenyl) -2-. { [4- (2-Butynyloxy) phenyl] sulfanil} - N-hydroxyacetamide Ethyl (4-bromo-phenyl) [(4-hydroxyphenyl) -sulfanyl] acetate was prepared according to the general method described in Example 1 (step 1), starting from bromine (4-bromo-phenyl) -acetate of ethyl (15 g, 45.6 mmol.) and 4-mercaptophenol (5.75 g, 45.6 mmol); 15.39 g of white solid. P.f. 55.6 ° C; Yield 92%; MS: 365.1 (MH). "(Ethyl 4-bromo-phenyl) - {. [4 - (2-butynyloxy) -phenyl] sulfani-1-ethyl acetate was prepared according to the general method described in Example 83 ( Step 2), starting from ethyl (4-bromophenyl) [(4-hydroxy-phenyl) sulfanyl] acetate (13.57 g, 36.9 mmol) and 2-butyn-1-ol (2.77 ml, 36.9 mmol); g of clear oil, Yield 59%, MS (EI): 420.8 (M + H) +, Acid (4-bromo-phenyl) { [4- (2-butynyloxy) phenyl] sulphyl). acetic acid according to the general method described in example 1 (step 5), starting from (4-bromophenyl) { [4- (2-Butynyloxy) phenyl] sulfanyl} ethyl acetate (1.2) g, 2.86 mmoles), 860 mg of brown oil, yield 77%, MS: 389.2 (MH). Starting from the acid (4-bromophenyl) -. { [4- (2-Butynyloxy) phenyl] sulfanil} acetic acid (790 mg, 2.02 mmol), and following the procedure described in Example 1 (step 6), 61 mg of 2- (4-brornophenyl) -2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-Hydroxyacetamide as a white solid. P.f .: 153 ° C; Yield: 24%; MS: 408 (M + H) +; X H NMR (300 MHz, DMSO-de): d 1.82 (t, J = 2.28 Hz, 3 H), 4.68 (s, 1 H), 4.71 (q, 2 H), 6.89 (d, 2 H), 7.25 (d, 2 H) ), 7.36 (d, 2H), 7.51 (d, 2H), 9.07 (s, 1H), 10.8 (s, 1H).
Example 86 (2S) -2- (4-bromophenyl) -2-. { [4- (2 -buyloxy) phenyl] -sulfinyl} -N-hydroxyacetamide and (2R) -2- (4-bromophenyl) -2-. { [4- (2-Butynyloxy) phenyl] -sulfinyl} -N-hydroxyacetamide Starting from 2- (4-bromo-phenyl) -2-. { [4- (2-Butynyloxy) phenyl] sulfanil} N-hydroxy-acetamide (from Example 85) (1.54 g, 3.7 mmol), and following the procedure described in Example 7, the two diastereoisomers were isolated. The two diastereoisomers were separated by silica gel column chromatography eluting with 50% ethyl acetate: hexane. The fastest-moving isomer, namely, (2S) -2- (4-bromophenyl) -2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2-N-hydroxy acetamimda as a white solid. P.f. 167 ° C; Yield: 170 mg (11%); E: 424 (M + H) +; X H NMR (300 MHz, DMSOde): d 1.85 (t, J = 2.22 Hz, 3H), 4.39 (s, 1H), 4.82 (d, J = 2.34 Hz, 2H), 7.1 (d, 2H), 7.3 ( d, 2H), 7.5 (d, 2H), 7.56 (d, 2H), 9.07 (s, 1H), 10.7 (s, 1H).
The slow-moving isomer, viz., Was isolated (2R) -2- (4-bromophenyl) -2-. { [4- (2-butyloxy) phenyl] -sulfinyl} -2-N-hydroxyacetamide as a whitish solid. P.f. 93 ° C; Yield: 20 mg, (1.3%); MS: 423.9 (M + H) +; 1K NMR (300 MHz, DMSO-d6): d 1.83 (t, J = 2.13 Hz, 3H), 4.42 (s, 1H), 4.77 (d, J = 2.28 Hz, 2H), 7.0 (m, 4H), 7.2 (d, 2H), 7.5 (d, 2H), 9.33 (s, 1H), 10.9 (s, 1H).
Example 88 2- (4-bromo-phenyl) -2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} - N-hydroxyacetamide Starting from a mixture of 2- (4-brornophenyl) -2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxyacetamide and 2- (4-bromophenyl) -2-. { [4- (2-Butynyloxy) -phenyl] sulfinyl} -2-N-hydroxyacetamide (1.42, 3.4 mmol), and following the procedure described in Example 75, 610 mg of 2- (4-bromo-phenyl) -2- was isolated. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-Hydroxyacetamide as a white solid. P.f. 187 ° C; Yield: 41%; MS: 440 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6): d 1.85 (t, J = 2.22 Hz, 3 H), 4.86 (d, J = 2.31 Hz, 2 H), 5.03 (s, 1 H), 7.11 (d, 2 H) , 7.31 (d, 2H), 7.47 (d, 2H), 7.55 (d, 2H), 9.32 (s, 1H), 10.9 (s, 1H).
Example 89 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- [4- (2-thienyl) phenyl] acetamide Step 1: ethyl [4 - (2-thienyl) phenyl] acetate Nitrogen was bubbled through a mixture of 2-tributylstannylthiophene (15.68 ml, 49.4 mmoles) and (4-bromophenyl) ethyl acetate (6 g, 24.7 mmol) in toluene (250 ml) before adding 0.5 g of tetrakis (triphenylphosphine) palladium (0). The mixture was refluxed under nitrogen for 4 hours before it was filtered through magnesol and concentrated. The residue was purified using silica gel column chromatography eluting with 20% ethyl acetate: hexane solution. Ethyl [4 - (2-thienyl) phenyl] acetate was isolated as a yellow oil (4.15 g). Yield 68%; MS: 247.5 (M + H) +.
Step 2: Bromo [4 - (2 -1 ieni 1) pheny1] acetat or ethyl To a solution of ethyl [4- (2-thienyl) phenyl] -acetate (4.1 g, 16.6 mmol) in carbon tetrachloride (150 ml) benzoyl peroxide was added (0.5 g) and N-bromosuccinimide (3.26 g, 18.3 mmol).
The mixture was refluxed under nitrogen for 3 hours before it was filtered and concentrated. The residue was purified using silica gel column chromatography eluting with 15% ethyl acetate: hexane solution. Bromo [4 - (2-thienyl) phenyl] ethyl acetate was isolated as a white, low melting solid (2.19 g). Performance 40%; MS (EI): 325.2 (M + H) +. [(4-Hydroxyphenyl) sulphanyl] [4- (2-thienyl) phenyl] ethyl acetate was prepared according to the general method described in example 1 (step 1), starting from bromine [4 - (2 -thienyl) phenyl] -acetic acid ethyl ester (2 g, 6.15 mmol) and 4-mercaptophenol (0.82 g, 6.5 mmol); 1.68 g of white solid. P.f. 103 ° C; Performance 73%; MS: 369.1 (MH). "Ethyl. {- [4- (2-Butynyloxy) phenyl] sulfanyl} - - [4 - (2-thienyl) phenyl] acetate was prepared according to the general method described in Example 83 (step 2), starting from [(-hydroxyphenyl) sulphyl] [4- (2-thienyl) phenyl] ethyl acetate (1.6 g, 4.3 mmol) and 2-butyn-l-ol (0.33 ml 4.32 mmol), 1.34 g of yellow oil, Yield 74%, MS (El): 421.71 (M + H) +, acid was prepared, {. [4 - (2-butyloxy) phenyl] -sulfanyl. [4- (2-thienyl) phenyl] acetic acid according to the general method described in example 1 (step 5), starting from { [- (2-butynyloxy) phenyl] -sulfanyl. Ethyl [4- (2-thienyl) phenyl] acetate (1.34 g, 3.17 mmol), 1.07 g of white solid, mp 137 ° C, yield 85%, MS: 439.1 (M + FA-H). " Starting from acid. { [4- (2-Butynyloxy) phenyl] sulfanil} [4- (2-thienyl) -phenyl] acetic acid (840 mg, 2.13 mmol), and following the procedure described in Example 1 (step 6), 1052 g of 2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- [4 - (2-thienyl) -phenyl] acetamide as a white solid. P.f. 182 ° C; Yield: 99%; MS: 410 (M + H) +; X H NMR (300 MHz, DMS0-d 6): d 1.81 (t, J = 2.31 Hz, 3 H), 4.71 (m, 3 H), 6.9 (d, 2 H), 7.13 (m, 1 H), 7.28 (d, 2 H) ), 7.44-7.62 (band, 6H), 9.07 (s, 1H), 10.8 (s, 1H).
Example 90 (2R) -2-. { [4- (2-Butynyloxy) enyl] sulfinyl} -N-hydroxy-2- [4- (2-thienyl) phenyl] ethanamide Starting from 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- [4- (2-thienyl) -phenyl] acetamide (1 g, 2.13 mmol), and following the procedure described in Example 7, was isolated 160 mg of (2R) -2-. { [- (2-Butyloxy) phenyl] sulfinyl} -N-hydroxy-2- [4- (2-thienyl) phenyl] ethanamide as an off-white solid. P.f .: 158 ° C; Yield: 18%; EM: 425.9 (M + H) +; 1 R-NMR (300 MHz, DMSO-de): d 1.79 (t, J = 2.1 Hz, 3 H), 4.43 (s, 1 H), 4.75 (d, J = 2.31 Hz, 2 H), 6.98 (d, J = 8.85 Hz, 2H), 7.12 (m, 3H), 7.22 (d, J = 8.79 Hz, 2H), 7.54 (m, 4H), 9.31 (d, 1H), 11 (s, 1H).
Example 91 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- [4- (2-thienyl) phenyl] acetamide Starting from a mixture of 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- [4- (2-thienyl) -phenyl] acetamide and 2-. { [4- (2-butyloxy) phenyl] sulfinyl} -N-hydroxy-2- [4- (2-thienyl) phenyl] ethanamide (410 mg, 0.96 mmol), and following the procedure described in Example 75, 110 mg of 2- was isolated. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- [4- (2-thienyl) -phenyl] acetamide as a gray solid. P.f .: 175 ° C; Yield: 26%; MS: 442.2 (M + H) +; 1 H NMR (300 MHz, DMSO-de): d 1.83 (t, 3 H), 4.85 (d, J = 2.01 Hz, 2 H), 5.04 (s, 1 H), 7.11 (m, 4 H), 7.39 (d, 2 H) ), 7.49-7.63 (band, 5H), 9.30 (s, 1H), 10.9 (s, 1H).
Example 92 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (1-naphthyl) acetamide. [(4-Hydroxyphenyl) sulfanyl] (1-naphthyl) ethyl acetate was prepared according to the general method described in Example 1 (Step 1). Starting from bromine (1-naphthyl) ethyl acetate (11.0 g, 38 mmol) and 4-mercaptophenol (4.8 g, 38 mmol), 8.14 g of [(4-hydroxyphenyl) sulfanyl] (1-naphthyl) was isolated. -ethyl acetate. Performance (64%); amber oil; MS 337.1 (MH). "{. [4- (2-Butynyloxy) phenyl] sulfanyl} - (1-naphthyl) acetate was prepared according to the general method described in Example 1 (Step 2). from (4-hydroxyphenyl) sulfanyl] (1-naphthyl) ethyl acetate (7.74 g, 23 mmol) and l-bromo-2-but-ina (3.4 g, 25 mmol), 7.64 g of the product was isolated. (85%); amber oil; EM 390.5 (M + H) + { [- (2-Butyloxy) phenyl] -sulfanyl} - (1-naphthyl) acetic acid was prepared according to the method General description described in Example 1 (Step 5) Starting from { [4- (2-Butynyloxy) phenyl] sulfanyl} - (1-naphthyl) acetate (7.64 g, 19.6 mmol), 4.92 g was isolated. of the product Yield (69%), white solid, mp 98.7 ° C; MS 722.8 (2M-H) ". Starting from acid. { [4- (2-butyloxy) phenyl] sulfanil} (1-naphthyl) acetic (4.69 g, 12.95 mmoles) and following the procedure described in Example 1 (Step 6), 2.95 g of 2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (1-naphthyl) -acetamide as a white solid. P.f .: 139.6 ° C; MS 378.1 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.87 (t, 3H), 4.62 (m, 2H), (s, 1H), 6.87 (d, J = 10 Hz, 2H), 7. 37 (d, J = 8 Hz, 2H), 7.46 (broad m, 4H), 7.80 (d, J = 3 Hz, 1H), (d, J = 4 Hz), 8.03 (d, J = 8 Hz, 2H), 9.2 (s, 1H).
E n 93 93 2-. { [4- (2-butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (1-naphthyl) acetamide Starting from the 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (1-naphthyl) -acetamide (1.95 g, 5.2 mmol), and following the procedure described in Example 7, 0.19 g of 2- was isolated. { [4 - (2-Butyloxy) phenyl] sulfinyl} -N-hydroxy-2- (1-naphthyl) acetamide as a white solid. P.f .: 159.4 ° C; MS 394.1 (M + H) +; 1N-NMR (300 MHz, DMSOde): d 1.55 (t, 3H), 4.60 (m, 2H), 5.51 (s, 1H), 6.72 (d, J = 11.7 Hz, 2H), 7.24 (2H), 7.37 ( m, 3H), 7.77 (m, 3H), 8.19 (s, 1H), 10.68 (s, 1H).
Example 94 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1-naphthyl) acetamide Starting from the 2-. { [4- (2-butyloxy) -phenyl] sulfanil} -N-Hydroxy-2- (1-naphthyl) -acetamide (6 g, 15.9 mmol), and following the procedure described in Example 75, 0.162 g of 2- was isolated. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1-naphthyl) -acetamide as a white solid. P.f .: 213.3 ° C; MS 410.0 (M + H) +; AH NMR (300 MHz, DMSO-d6): d 1.84 (t, 3H), 4.81 (d, J = 2.3 Hz, 1H), 6.00 (s, 1H), 7.0 (d, J = 9 Hz, 2H), 7.45 (d, J = ll Hz, 2H), 7.51 (m, 2H), 7.95 (m, 2H), 8.01 (d, J = 17 Hz, 2H), 9.28 (s, 1H), 11.0 (s, 1 HOUR) Example 95 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (4- fluorophenyl) -N-hydroxy-2- (1-naphthyl) acetamide. [(4-fluorophenyl) [(-hydroxyphenyl) -sul-fanyl] ethyl acetate was prepared according to the general method described in Example 1 (Step 1). Starting from bromine (4-fluorophenyl) ethyl acetate (7.2 g, 28 mmol) and 4-mercaptophenol (3.8 g, 30 mmol), 7.08 g of the product was isolated. performance (82.6%); amber oil; EM 305.3 (MH). "Ethyl { [4- (2-Butynyloxy) phenyl] sulfanyl}. -. (- (fluorophenyl) -acetate) was prepared according to the general method described in Example 1 (Step 2). Starting from [(4-fluorophenyl) [(4-hydroxyphenyl) sulphyl] ethyl acetate (7.05 g, 23 mmol) and l-bromo-2-butine (4.02 g, 30 mmol), 6.82 g of Product Yield (83%), amber oil, EM 358.0 (MH) ". Et and il acid was prepared. { [4 - (2-Butyloxy) -phenyl] sulfanil} (4-fluorophenyl) acetic acid according to the general method described in Example 1 (Step 5). Starting from [(4-fluorophenyl) [(4-hydroxy-phenyl) sulfanyl] ethyl acetate (4.73 g, 13 mmol), 3.26 g of product was isolated. Performance (75%); amber rubber; MS 329.3 (MH). "Starting from ethyl { [4- (2-Butynyloxy) phenyl] sulfanyl} - (4-fluorophenyl) acetic acid 3.0 g, 9.1 mmol), and following the procedure described in Example 1 (Step 6), 0.295 g of 2- {[[4- (2-butynyloxy) phenyl] sulphonyl} -2- (4-fluorophenyl) -N-hydroxyacetamide was isolated from the mixture of reaction as a white solid Mp: 105.7 ° C; MS 346.1 (M + H) +; XH NMR (300 MHz, DMSO-de): d 1.82 (t, 3H), 4.70-4.72 (m, 3H), 6.00 (s, 1H), 6.19-6.91 (d, J = 6.9 Hz, 2H), 7.15-7.21 (d, J = 17 Hz, 2H), 7.24-7.27 (d, J = 8.7 Hz, 2H), 7.4 ( m, 2H), 9.08 (s, 1H), 10.78 (s, 1H) Starting from 2- { [4- (2-Butynyloxy) phenyl] sulfanyl.} -2- (4-fluorophenyl) ) -N-hydroxyacetamide (1.29 g, 3.3 mmol), and following the procedure described in Example 7, 0.086 g was isolated as a white solid, Mp: 91.1 ° C, the main diastereoisomer was isolated EM 362.3 (M + H ) +; 1K NMR (300 MHz, DMSO-de): d 1.83 (t, 3H), 4.41 (s, 1H), 4.76-4.77 (d, J = 3 Hz, 2H), 6.97-7.01 (d, J = 9.9 Hz, 2H), 7.07-7.10 (dd, J = 8.9 Hz, 4H), 7.16-7.19 (d, J = 8.8 Hz, 2H), 9.3 ( s, 1H), 10.98 (s, 1H).
Example 97 Preparation of the 2 -. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -2- (4-fluorophenyl) -N-hydroxyacetamide Starting from 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (4-fluorophenyl) -N-hydroxyacetamide (1.29 g, 3.3 mmol), and following the procedure described in Example 75, 0.106 g was isolated as a white solid. P.f .: 160.1 ° C; MS 378.2 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.84 (t, 3 H), 4.85-4.86 (d, J = 2 Hz, 2 H), 5.04 (s, 1 H), 7.08-7.11 (d, J = 9.0 Hz, 2H), 7.16-7.19 (t, J = 9.0 Hz, 2H), 7.38-7.40 (d, J = 5.4 Hz, 2H), 7.45-7.47 (d, J = 6.9 Hz, 2H), 9.3 (s) , 1H), 10.90 (s, 1H).
EXAMPLE 98 2- (2-methoxyphenyl) -2-. { [4- (2-butynyloxy) phenyl] -sulfanyl} -N-Hydroxyacetamide Ethyl (2-methoxyphenyl) [(-hydroxyphenyl) -sulfanyl] acetate was prepared according to the general method described in example 1 (step 1), starting from bromine (2-methoxyphenyl) acetate of ethyl (24 g, 87.5 mmol) and 4-mercaptophenol (11.0 g, 87.5 mmol); 24.9 g of amber oil. Performance 89%; MS: 320 (M + H) +. Prepared (2-methoxyphenyl). { [4- (2-Butynyloxy) -phenyl] sulfanil} ethyl acetate according to the general method described in example 1 (step 2), starting from ethyl (2-methoxyphenyl) [(4-hydroxy-phenyl) sulfanyl] acetate (3.2 g, 10 mmol) and 1 -bromine -2 -but ina (1.5 g> 11.2 mmoles); 3.2 g of clear oil. Performance 87%; MS (EI): 371 (M + H) +. Acid (2-methoxyphenyl) was prepared. { [4- (2-Butynyloxy) phenyl] sulfanil} acetic acid according to the general method described in example 1 (step 5), starting from (2-methoxy phenyl). { [4 - (2-Butynyloxy) phenyl] sulfanyl} ethyl acetate (3.1 g, 8.3 mmol); 2.7 g of white solid was isolated. Yield 93%; MS: 341.4 (MH). "Starting from (2-methoxy-phenyl) {. [4- (2-butynyloxy) phenyl] sulfanyl} acetic acid (2.6 g, 7.6 mmol), and following the procedure described in Example 1 (step 6), 2.6 g of 2- (2-methoxyphenyl) -2 { [4- (2-butynyloxy) phenyl] sulfanyl} -N-hydroxyacetamide was isolated as a white solid. Mp: 172-173 ° C; Yield: 97%; MS: 358.4 (M + H) +; XH NMR (300 MHz, DMSO-de): d 1.85 (s, 3H), 3.80 (s, 3H), 4.72. (s, 2H), 5.12 (s, 1H), 6.62 (m, 4H), 7.3-7.5 (m, 4H), 9.3 (broad s, 1H).
Example 99 2- (2-methoxyphenyl) -2-. { [4- (2-butynyloxy) enyl] -sulfinyl} -N-hydroxyacetamide Starting from 2-. { [4- (2-butyloxy) -phenyl] sulfanil} -2- (2-methoxy phenyl) -N-hydroxy -acetamide (3.0 g, 8.37 mmol), and following the procedure described in Example 7, 2.75 g of 2- (2-methoxyphenyl) -2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfinyl} -N-Hydroxyacetamide as a white solid. P.f. 167.8 ° C; (Only the principal diastereoisomer was isolated: EM 374 (M + H) +; 2H NMR (300 MHz, DMSO-d6): d 1.83 (s, 3H), 3.32 (s, 3H), 4.41 (s, 2H), 5.2 (s, 1H), 6.31 (d, 1H), 6.44 (m, 3H), 7.22-7.40 (m, 3H), 7.81 (d, 1H), 8.62 (s, 1H), 10.41 (s, 1H) ).
Example 100 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-Hydroxy-2- (4-ethoxyphenyl) acetamide [(4-Hydroxyphenyl) sulfanyl] (4-ethoxyphenyl) -acetic acid methyl Bromo (4-ethoxyphenyl) acet atoate (7.6 g, 27.8 mmol) was added to stirring solution of triethylamine (30 ml), sodium sulfite (3.0 g, 23.8 mmol), and 4-mercaptophenol (3.5 g, 27.8 mmol) in methanol (200 ml). The mixture was stirred overnight before it was concentrated and the residue was extracted into ethyl acetate and washed with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated. The compound was isolated using silica gel column chromatography eluting with 20% ethyl acetate: hexane solution. [(4-hydroxyphenyl) sulfanyl] (4-ethoxyphenyl) -acetic acid methyl ester was isolated as a crude product (7.76 g, 24.4 mmol). 88% yield. MS: 317.1 (M-H). "Prepared { [" 4- (2-Butyloxy) phenyl] sulfanil} - Methyl (4-ethoxyphenyl) acetate according to the general method described in example 1 (step 2). Starting from [(4-hydroxyphenyl) sulfani] (4-methoxyphenyl) ethyl acetate (7.76 g, 24.4 mmol) and l-bromo-2-butine (3.26 g, 24.4 mmol), 8.65 g of. { [4- (2-butyloxy) phenyl] sulfanil} Methyl (4-ethoxyphenyl) -acetate. Yellow oil 95% yield; MS (El): 369.72 (M) +.
Acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfanyl} (4-ethoxyphenyl) acetic acid according to the general method described in example 1 (step 5), starting from. { [4- (2-butyloxy) phenyl] -sulfanyl} (4-ethoxyphenyl) ethyl acetate (8.55 g, 23 mmol); 7.86 g. Yield 96%; MS: 355.1 (MH). "Starting from the { [4- (2-Butynyloxy) phenyl] sulfanyl} - (4-ethoxyphenyl) acetic acid (7.61 g, 20.6 mmol), and following the procedure described in Example 1 (step 6), 2,904 g of 2 - { [4 - (2-Butynyloxy) phenyl] sulfanyl} - N-hydroxy-2- (-ethoxy phenyl) -acetamide was isolated. 38%; MS 372.2 (M + H) +; 1 H NMR (300 MHz, DMSO-de): d 1.25 (t, J = 2.22 Hz, 3H), 1.80 (s, 3H), 4.00 (q, J = 2.22 Hz, 3H), 4.60 (s, 1H), 4.65 (s, 2H), 6.80 (d, J = 9 Hz, 2H), 6.90 (d, J = 9 Hz, 2H), 7.20 (d, J = 9 Hz, 2H), 7.35 (d, J = 9 Hz, 2H), 9.00 (s, 1H), 10.8 (s, 1H).
Example 101 2 -. { [4- (2-Butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (4-ethoxyphenyl) acetamide Starting from 2-. { [4 - (2-Butynyloxy) -phenyl] sulfanil} -N-hydroxy-2- (4-ethoxyphenyl) acetamide (808 mg, 2.27 mmol) and following the procedure described in Example 27, 640 mg of 2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (4-ethoxy-phenyl) acetamide as a brown powder. Performance: 73%; MS: 388.2 (M + H) +. P.f. 192-193.
Example 102 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -2- (4-chlorophenyl) -N-hydroxyacetamide was prepared 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -2- (-chlorophenyl) -N-hydroxyacetamide starting from 2-. { [4 - (2-Butyloxy) phenyl] -sulfanyl} -N-hydroxy-2- (4-ethoxyphenyl) acetamide (808 mg, 2.27 mmol), and following the procedure described in Example 75, 1.1 g of 2- was isolated. { [4 - (2-Butyloxy) -phenyl] sulfonyl} -2- (4-chlorophenyl) -N-hydroxyacetamide as a white solid. MS: 404.2 (M + H) +, P.p. 138-140.
Example 103 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (3-bromophenyl) acetamide [(4-Hydroxyphenyl) sulfanyl] (3-bromophenyl) -acetate methyl Bromine (3-bromophenyl) acetate (7.2 g, 23.3 mmol) was added to a solution with stirring triethylamine (30 ml), sodium sulfite (3.0 g, 23.8 mmol), and 4-mercaptophenol (2.94 g, 23.3 mmol) in methanol (200 mL). The mixture was stirred overnight before it was concentrated and the residue was extracted into ethyl acetate and washed with water. The organic layer was dried over Na 2 SO, filtered and concentrated. The compound was isolated using silica gel column chromatography eluting with 20% ethyl acetate: hexane solution. Methyl [(4-hydroxyphenyl) sulfanyl] (3-bromophenyl) acetate was isolated as a crude product (8.64 g). MS: 353.0 (MH). "Starting from [(4-hydroxyphenyl) -sulfanyl] (-methoxyphenyl) ethyl acetate (8.0 g crude, 22.7 mmol) and 1-bromo-2-butyne (3.04 g, 22.7 mmoles) and following the procedure described in example 1 (step 2), 4.91 g of methyl {. [4- (2-butyloxy) phenyl) sulfanyl} - (3-bromophenyl) acetate was isolated as yellow oil Yield 52%; MS: 405.6 (M + H) + Starting from { [4 - (2-Butynyloxy) -phenyl] sulfanyl}. (3-bromophenyl) ethyl acetate (4.04 g, 10%). mmoles) and following the procedure described in Example 1 (step 5), 3.83 g of acid { [4- (2-Butynyloxy) phenyl] sulfanyl} - (3-bromophenyl) acetic acid was isolated as a semi-solid. 98%; MS: 389.0 (MH) ". Starting from acid 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} (3-bromophenyl) acetic acid (3.83 g, 9.8 mmol), and following the procedure described in Example 1 (step 6), 1,675 g of 2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (3-bromophenyl) -acetamide Yield: 42%; MS: 408.0 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.60 (m, 3H), 2.26 (s, 3H), 4.45 (s, 1H), 4.47 (m, 2H), 6.66 (d, J = 9 Hz, 2H ), 7.03 (d, J = 9 Hz, 2H), 7.06-7.38 (m, 5H), 8.87 (s, 1H), 10.41 (s, 1H).
Example 104 (2R) -2-[[4- (2-bunyloxy) phenyl] sulfinyl} -N-hydroxy-2- (3-bromophenyl) acetamide • and (2S) -2-. { [4- (2-butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (3-bromophenyl) acetamide Starting from 2-. { [4 - (2-Butyloxy) -phenyl] sulfanil} -N-hydroxy-2- (3-bromo-phenyl) -acetamide (470 mg, 1.2 mmol), and following the procedure described in Example 7, the sulfide was oxidized to sulfoxide. The mixture of two diastereoisomers was separated by silica gel column chromatography eluting with 50% ethyl acetate; Hexane The fastest moving isomer, namely, (2R) -2- was isolated. { [4- (2-butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (3-bromophenyl) acetamide as a brown powder. Yield: 230 mg, (47%); MS: 423.9 (M + H) +. The slower motion isomer, namely, was isolated (2S) -2-. { [4 - (2-Butyloxy) phenyl] sulfinyl} -N-hydroxy-2- (3-bromophenyl) acetamide as a brown powder. Yield: 100 mg (20%); MS: 423.9 (M + H) +.
Example 106 2-. { [4- (2 -Butynyloxy) enyl] sulfonyl} -2- (3-bromophenyl) - N-hydroxyacetamide Starting from 2-. { [4 - (2-Butyloxy) -phenyl] sulfanil} -N-hydroxy-2- (3-bromo-phenyl) -acetamide (480 mg, 1.2 mmol), and following the procedure described in Example 75, 270 mg of 2- was isolated. { [4- (2-butynyloxy) phenyl] sulfonyl} -2- (4-chlorophenyl) -N-hydroxyacetamide as a brown powder. Yield: 52%; MS: 440.1 (M + H) +. X H NMR (300 MHz, DMSO-d 6): d 1.60 (m, 3H), 2.26 (s, 3H), 4.45 (s, 1H), 4.47 (m, 2H), 6.66 (d, J = 9 Hz, 2H ), 7.03 (d, J = 9 Hz, 2H), 7.06-7.38 (m, 5H), 8.87 (s, 1H), 10.41 (s, 1H).
Example 107 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2-isopropy1-N-hydroxyace amide Step 1: [4 - (hydroxyphenyl) sulphyl] acetate of etisopropyl was prepared according to the general method described in example 1 (step 1), starting from 2-bromine ethyl isovalerate (2.09 g, 10 mmol) and 4-mercaptophenol (1.26 g, 10.0 mmol); 2.5 g of yellow oil. The product was quite pure and was taken for other transformations. Performance 99%; MS: 255 (M + H) +.
Stage 2: Prepared. { [4- (2-Butynyloxy) phenyl] sulfanil} - (isopropyl) ethyl acetate according to the general method described in example 1 (step 2), starting from [4 - (hydroxyphenyl) sulphyl] -acetoisopropyl acetate (2.54 g, 10 mmol) and 4 - Bromo-2-butine (1.34 g, 10 mmol); 3.0 g of yellow oil. Performance 99%; MS (EI): 307 (M + H) +.
Step 3: Acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfanyl} (isopropyl) acetic acid according to the general method described in example 1 (step 5), starting from. { [4 - (2-Butynyloxy) phenyl] sulfanyl} - (isopropyl) ethyl acetate (3.06 g, 10 mmol); 2.7 g of yellow oil. Performance 99%; MS: 277 (M-H). " Starting from the acid. { [4- (2-Butynyloxy) phenyl] sulfanil} (isopropyl) acetic acid (1.39 g, 5 mmol) and following the procedure described in Example 1 (step 6), 800 mg of 2- was isolated. { [4- (2-Butynyloxy) phenyl] sulfanil} -2-i sopropi 1-N-hydroxy acetamide as a white powder. P.f. 128 ° C; Yield: 54%; MS: 294.1 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 0.9 (d, 3 H), 1.02 (d, 3 H), 1.89 (s, 3 H), 1.98 (m, 1 H), 3.0 (d, 1 H), 3.2 (s) , 1H), 4.8 (s, 2H), 6.8 (d, J = 9 Hz, 2H), 7.4 (d, J = 9 Hz, 2H), 9.0 (s, 1H), 10.81 (s, 1H).
Example 108 R-2-. { t 4- (2-butynyloxy) phenyl] sulfinyl} -2-isopropy1-N-hydroxyacetamide Example 109 S-2-. { [4- (2-butynyloxy) phenyl] sulfinyl} -2-isopropyl-N-hydroxyacetamide Starting from 2-. { [4 - (2-Butyloxy) -phenyl] sulfanil} -2-isopropyl-N-hydroxyacetamide (1.45 g, 5 mmol), and following the procedure described in Example 7, 123 mg of R-2 was isolated. { [4- (2-Butynyloxy) -phenyl] sulfinyl} -2-Isopropyl-N-hydroxy-acetamide as a white solid. The two diastereoisomers were separated by silica gel column chromatography eluting with 50% ethyl acetate: hexane. P.f. 68 ° C; Yield: 15%; MS: 310 (M + H) +. The slow moving isomer, namely, was isolated S-2-. { [4- (2-butyloxy) phenyl] sulfinyl} -2-isopropyl-N-hydroxyacetamide as a white solid. P.f. 148 ° C; Yield: 135 mg (17%); MS: 310 (M + H) +.
Example 110 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -2-isopropyl-N-hydroxyacetamide Starting from 2-. { [4 - (2-Butyloxy) -phenyl] sulfanil} -N-hydroxy-2-isopropylacetamide (1.4 g, 5 mmol), and following the procedure described in Example 75, 800 mg of 2- was isolated. { [4- (2-butynyloxy) phenyl] sulfonyl} -2-isopropyl-N-hydroxy-acetamide as a white powder. Yield: 49%; MS: 326.1 (M + H) +. X H NMR (300 MHz, DMSO-d 6): d 0.8 (d, 3 H), 1.0 (d, 3 H), 2.0 (s, 3 H), 2.1 (m, 1 H), 3.51 (d, 1 H), 3.2 (s) , 1H), 5.01 (s, 2H), 7.0 (d, J = 9 Hz, 2H), 7.56 (d, J = 9 Hz, 2H), 9.5 (s, 1H), 11.41 (s, 1H).
Example 111 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2-phenyl-N-hydroxyacetamide Step 1: Ethylphenyl [4- (hydroxyphenyl) sulfanyl] acet ate was prepared according to the general method described in example 1 (step 1), starting from 2-bromo-phenylacetate of ethyl (2.42 g, 10 mmol) and 4-mercaptophenol (1.26 g, 10.0 mmol); 2.7 g, of yellow oil. The product was quite pure and was taken for other transformations. Yield 93%; MS: 289 (M + H) +.
Stage 2: Prepared. { [4- (2-butyloxy) phenyl] sulfanil} - (phenyl) ethyl acetate according to the general method described in example 1 (step 2), starting from [4 - (hydroxy phenyl) sulphyl] ethylphenyl acetate (2.88 g, 10 mmol) and 4 - Bromo-2-but ina (1.34 g, 10 mmol); 3.2 g of yellow oil. Yield 94%; MS (EI): 341 (M + H) +.
Step 3: Acid was prepared. { [- (2-Butynyloxy) phenyl] -sulfanyl} (phenyl) acetic acid according to the general method described in example 1 (step 5), starting from. { [4- (2-Butyloxy) phenyl] sullyl} (phenyl) -acetic acid ethyl ester (3.4 g, 10 mmol); 3.0 g of yellow oil. Yield 88%; MS: 311 (MH). "Starting from acid { [4- (2-Butynyloxy) phenyl] sulfanyl} - (phenyl) acetic acid (3.12 g, 10 mmol), and following the procedure described in Example 1 (step 6), 3.0 g of 2- {[4- (2-butynyloxy) phenyl] sulfanyl} -2-phenyl-N-hydroxyacetamide was isolated as a white powder, mp 151 ° C; 91%; MS: 328 (M + H) +. 1 H NMR (300 MHz, DMSO-d 6): d 1.8 (s, 3 H), 4.8 (s, 2 H), 4.9 (s, 1 H), 6.8-7.6 ( m, 9H), 9.2 (broad s, 1H), 11 (broad s, 1H).
Example 112 R-2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2-phenyl-N-hydroxyacetamide Example 113 S-2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2-phenyl-N-hydroxyacetamide Starting from 2-. { [4 - (2-Butynyloxy) -phenyl] sulfanil} -2-phenyl-N-hydroxyacetamide (1.5 g, 4.5 mmol), and following the procedure described in Example 7, 400 mg of R-2 was isolated. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2-phenyl-N-hydroxyacetamide as a white solid. The two diastereoisomers were separated by silica gel column chromatography eluting with 50% ethyl acetate: hexane. P.f. 153 ° C; Yield: 51%; MS: 344 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.8 (s, 3 H), 4.5 (s, 1 H), 4.9 (s, 2 H), 6.9-7.6 (m, 9 H), 9.0 (broad s, 1 H), 10.8 (broad s, 1H). The slow moving isomer, namely, was isolated S-2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -2-phenyl-N-hydroxyacetamide as a white solid. P.f. 55 ° C; Yield: 300 mg (38%); MS: 344 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.7 (s, 3 H), 4.4 (s, 1 H), 4.7 (s, 2 H), 7.0-7.6 (m, 9 H), 9.3 (s, 1 H), 11.0 (s, 1H).
Example 114 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (2-naphthyl) -N-hydroxyacetamide Step 1: Ethyl (2-naphthyl-2- [4- (hydroxyphenyl) -sulfanyl] acetate was prepared according to the general method described in example 1 (step 1), starting from ethyl ester of a-bromo-2-naphthyl-acetic acid (2.93 g, 10 mmol) and 4-mercaptophenol (1.26 g, 10.0 mmol), 3.3 yellow oil.The product was quite pure and took for other transformations, 99% yield, EM: 339 (M + H) +.
Stage 2: Prepared. { [4- (2-Butyloxy) phenyl] sullyl} -2- (2-naphthyl) ethyl acetate according to the general method described in example 1 (step 2), starting from (2-naphthyl) -2 - [4- (hydroxyphenyl) sulfani] -acetate of ethyl (2.54 g, 10 mmol) and 4-bromo-2-butine (1.34 g, 10 mmol); 3.7 g of yellow oil. Performance 99%; MS (EI): 377 (M + H) +.
Stage 3: Acid was prepared. { [4.- (2-Butyloxy) phenyl] -sulfanyl} -2- (2-naphthyl) acetic acid according to the general method described in example 1 (step 5), starting from. { [4 - (2-Butyloxy) phenyl] -sulfanyl} -2- (2-naphthyl) ethyl acetate (3.76 g, 10 mmol); 3.5 g of yellow oil. Yield 96%; MS: 361 (MH). "Starting from acid { [4- (2-Butynyloxy) phenyl] sulfanyl} -2- (2-naphthyl) acetic acid (3.6 g, 10 mmol), and following the procedure described in Example 1 (step 6), 3.2 g of 2-. {[[4- (2-butynyloxy) phenyl] sulfanyl} -2- (2-naphthyl) -N-hydroxy-acetamide was isolated as a white powder, mp 148 ° C, yield: 84%, MS: 378 (M + H) +. 1 H NMR (300 MHz, DMSO-d6): 1.8 (s, 3H), 4.7 (s, 2H), 4.95. (s, 1H), 6.8-8.0 (s, 11H), 9.0 (broad s, 1H), 11 (s broad, 1H).
Example 115 2-. { [4- (2-butynyloxy) phenyl] sulfinyl} -2- (2-naphthyl) -N- hydroacetamide Starting from 2-. { [4 - (2-Butynyloxy) -phenyl] sulfanil} -2- (2-naphthyl) -N-hydroxyacetamide (1.88 g, 5 mmol), and following the procedure described in Example 7, 900 mg of 2- was isolated. { [4- (2-Butynyloxy) -phenyl] sulfinyl} -2- (2-naphthyl) -N-hydroxy-acetamide as a white solid. The two diastereoisomers did not separate. P.f 157 ° C; Yield: 46%; MS: 394 (M + H) +.
Example 116 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -2- (2-naphthyl) -N-hydroxyacetamide Starting from 2-. { [4- (2-Butynyloxy) -phenyl] sulfanil} -N-hydroxy-2- (2-naphthyl) acetamide (1.81 g, 5 mmol), and following the procedure described in Example 75, 1.2 g of 2- was isolated. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -2- (2-naphthyl) -N-hydroxy-acetamide as a white powder. Yield: 61%; MS: 410 (M + H) +. 1 H-NMR (300 MHz, DMS0-d 6): d 2.5 (s, 3 H), 4.9 (s, 2 H), 5.2 (s, 1 H), 7.0-7.9 (m, 11 H), 9.3 (broad s, 1 H), 11 (s, 1H).
Example 117 4- [l-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -2- (Hydroxyamino) -2-oxoethyl] -1-piperidinecarboxylic acid tert -butyl 4- (2-ethoxy-2-oxoet yl) -1-piperidinecarboxylic acid tert -butyl ester was made according to the process of the literature of Ashwood, Michael S .; Gibson, Andrew,.; Houghton, Peter G .; Humphrey, Guy R .; Roberts, D. Craig; Wright, Stanley H. B .; J. Chem. Soc. Perkin Trans. 1; 6; nineteen ninety five; 641-643 in two stages starting from N-tert-butoxycarbonyl-4-piperidone; 4.69 g of clear oil. 95% yield (over two stages); MS: 272.2 (M + H) +.
Step 1: To a dry flask under nitrogen was added 4- (l- { [4- (2-Butynyloxy) phenyl] sulfonyl} -2-ethoxy-2-oxo-yl) -1-piperidinecarboxylate of tert-butyl, sodium bis- (rimethsilyl) amide (7.05 g, 38 mmol). THF (100 ml) was added slowly and the temperature was lowered to -15 ° C. 4 - (2-ethoxy-2-oxoethyl) -1-piperidine-carboxylic acid tert-butyl ester (4.6 g, 16.97 mmol) and 4-but-2-ynyloxy-benzenesulfonyl fluoride (4.08 g, 17.9 mmol) were combined in THF (50 ml) and added dropwise to the mixture, keeping the reaction temperature below -15 ° C. The mixture was stirred at -10 ° C for 1.5 hours before it was rapidly quenched with water and extracted into ethyl acetate. The organic layer was washed with water, then dried over Na 2 SO 4, filtered and concentrated. 4- (L- { [4- (2-Butynyloxy) phenyl] sulfonyl} -2-ethoxy-2-oxo-ethyl) -1-piperidinecarboxylic acid tert-butyl ester was isolated using gel column chromatography of silica eluting with 20% ethyl acetate: hexane solution; 3.74 g of clear gel. Yield 46%; MS: 480.2 (M + H) +.
Step 2: [1- (tert-Butoxycarbonyl) -4-piperidinyl] acid was prepared. { [4- (2-butynyloxy) phenyl] sulfonyl} -acetic according to the general method described in example 1 (step 5), starting from 4- (1- { [4- (2-butynyloxy) phenyl] sulfonyl.} -2-ethoxy-2 -oxoethyl) -1-piperidinecarboxylic acid tert-butyl ester (2.5 g, 5.2 mmol); 1.85 g of low melting yellow solid. Performance 79%; MS: 450.3 (M-H). " Step 3: Starting from [1- (tert-butoxycarbonyl) -4-piperidinyl] acid. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -acetic (1.75 g, 3.88 mmol), and following the procedure described in Example 1 (step 6), 283 mg of 4 - [1-. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -2- (hydroxyamino) -2-oxoethyl] -1-piperidine carboxylate of tert-butyl as a white solid. P.f. 80 ° C; Yield: 16%; MS: 467.1 (M + H) +; 1 H NMR (300 MHz, DMSO-de: d 1.08-1.25 (band, 3H), 1.37 (s, 9H), 1.53 (m, 1H), 1.85 (t, J = 2.22 Hz, 3H), 1.99-2.12 ( band, 2H), 2.70 (m, 1H), 3.67 (d, J = 19.8 Hz, 1H), 3.83 (m, 2H), 4.88 (d, J = 2.31 Hz, 2H), 7.17 (d, J = 9 Hz, 2H), 7.76 (d, J = 9 Hz, 2H), 9.1 (s, 1H), 10.65 (s, 1H).
Example 118 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (4-piperidinyl) acetamide Step 1: 4- [1-. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -2- (hydroxyamino) -2-oxoethyl] -1-piperidine-carboxylate of tert-butyl of 2-. { [- (2-Butynyloxy) -phenyl] sulfonyl} -N-hydroxy -2- (4-piperidinyl) -acetamide (160 mg, 0.34 mmol) in methanolic HCl (50 ml) and allowed to stir at room temperature for 1 hour. The mixture was concentrated. After drying overnight, 80 mg of 2- was isolated. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -N-hydroxy-2- (4-piperidinyl) acetamide as a pink powder. P.f. 140 ° C; Yield: 59%; MS: 367.2 (M + H) +; XH NMR (300 MHz, DMSO-d6): d 1.46-1.70 (band, 3H), 1.85 (t, 3H), 2.16-2.30 (band, 2H), 2.87 (m, 2H), 3.21 (m, 2H) , 3.79 (d, J = 8.79 Hz, 1H), 4.88 (d, J = 2.28 Hz, 2H), 7.17 (d, J = 9 Hz, 2H), 7.77 (d, J = 9 Hz, 2H), 8.52 (m, 1H), 8.73 (m, 1H), 9.18 (s, 1H), 10.9 (s, 1H).
Example 119 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- [1- (4-methoxybenzyl) -4-piperidinyl] acetamide Prepared. { [4- (2-Butynyloxy) phenyl] sulphonyl} - (4-piperidinyl) ethyl acetate according to the general method described in example 113 (step 1), starting from 4 - (1- {[4 - (2-butyloxy) phenyl] -sulfonyl .} -2-ethoxy-2-oxoethyl) -1-piperidinecarboxylic acid tert-butyl ester (2.5 g, 5.2 mmol); 1.88 g of yellow solid. Performance 87%; MS: 380.2 (M + H) +. Stage 2: . { [4 - (2-Butyloxy) phenyl] sulfonyl} [1- (4-methoxybenzyl) -4-piperidinyl] ethyl acetate To a solution of. { [- (2-Butyloxy) phenyl] -sulfonyl} (4-piperidinyl) ethyl acetate (1.08 g, 2.86 mmol) in chloroform (150 ml), triethylamine (2 ml) and p-methoxybenzyl chloride (0.39 ml, 2.86 mmol) were added. The mixture was heated to reflux overnight. The mixture was extracted into chloroform and washed twice with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated. The residue was purified using silica gel column chromatography eluting with 50% ethyl acetate: hexane solution. It was isolated. { [4- (2-Butynyloxy) phenyl] sulfonyl} [1- (-methoxybenzyl) -4-piperidinyl] ethyl acetate as a yellow oil (650 mg). Yield 46%; MS: 500.1 (M + H) +. Acid was prepared. { [4- (2-butyloxy) phenyl] -sulfonyl} [1- (4-methoxybenzyl) -4-piperidinyl] acetic acid according to the general method described in example 1 (step 5), starting from. { [4- (2-Butynyloxy) -phenyl] sulfonyl} [l- (-methoxybenzyl) -4-piperidinyl} ethyl acetate (650 mg, 1.3 mmol); 540 mg of white solid. Yield 88%; MS: 472.1 (M + H) +. Starting from the acid. { [4- (2-Butynyloxy) -phenyl] sulfonyl} [1- (4-methoxybenzyl) -4-piperidinyl] acetic (430 mg, 0.913 mmol), and following the procedure described in Example 1 (step 6), 220 mg of 2- was isolated. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -N-hydroxy-2- [1- (4-methyl oxybenzyl) -4-piperidinyl] acet amide as a white solid. P.f. 138 ° C; Yield: 50%; MS: 487.1 (M + H) +. 1 H NMR (300 MHz, DMSO-d 6): d 1.67 (m, 3H), 1.85 (t, J = 2.04 Hz, 3H), 2.12.2.26 (band, 2H), 2.86 (m, 2H), 3.17 (s) , 1H), 3.27 (m, 2H), 3.77 (s, 3H), 4.12 (m, 2H), 4.88 (d, J = 2.22 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 9 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2h), 10.32 (s, 1H), 10.87 (s, 1H).
EXAMPLE 120 2- (l-Benzoyl-4-piperidinyl) -2-. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -N-hydroxyacetamide Step 1: (l-benzoyl-4-piperidinyl). { [4 - (2-Butyloxy) -phenyl] sulfonyl} ethyl acetate To a solution of. { [4 - (2-Butyloxy) phenyl] -sulfonyl} Ethyl (4-piperidinyl) acet ato (2 g, 4.8 mmol) in methylene chloride (100 ml) in an ice water bath was added triethylamine (1.34 ml, 9.6 mmol). Benzoyl chloride (0.56 ml, 4.8 mmol) was added dropwise maintaining the temperature at 0 ° C. The mixture was warmed to room temperature and stirred overnight before it was concentrated. The residue was extracted into chloroform and washed twice with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated. It was isolated (l-benzoyl-4-piperidinyl). { [4- (2-butynyloxy) phenyl] sulfonyl} ethyl acetate using silica gel column chromatography eluting with 50% ethyl acetate: hexane solution; yellow solid (1.8 g). P.f. 120 ° C; Yield 72%; MS: 484.1 (M + H) +. Acid (l-benzoyl-4-piperidinyl) was prepared. { [4- (2-butynyloxy) phenyl] sulfonyl} acetic acid according to the general method described in example 1 (step 5) starting from (l-benzoyl-4-piperidinyl). { [4- (2-butyloxy) phenyl] sulfonyl} ethyl acetate (1.39 g, 2.88 mmol); 1.3 g of white solid. P.f. 90 ° C; Performance 99%; MS: 456.1 (M + H) +. Starting from acid (l-benzoyl-4-piperidinyl). { [4- (2-butynyloxy) phenyl] sulfonyl} -acetic (1.22 g, 2.68 mmol), and following the procedure described in Example 1 (step 6), 860 mg of 2- (l-benzoyl-4-piperidinyl) -2- was isolated. { [4- (2-butyloxy) -phenyl] sulfonyl} -N-Hydroxyacetamide as a white powder. P.f. 224 ° C; Yield: 68%; MS: 470.9 (M + H) +; 1R-NMR (300 MHz, DMSO-d6): d 1.16-1.62 (band, 3H), 1.84 (t, J = 2.1 Hz, 3H), 2.06-2.24 (band, 2H), 2.73-2.99 (band, 2H) , 3.52 (m, 1H), 3.71 (d, J = 8.61, 1H), 4.37 (m, 1H), 4.88 (d, J = 2.28 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.34 (m, 2H), 7.44 (m, 3H), 7.77 (d, J = 8.7 Hz, 2H), 9.14 (s, 1H), 10.7 (s, 1H).
Example 121 2- (l-acetyl-4-piperidinyl) -2-. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -N-Hydroxyacetamide was prepared (1-acetyl-piperidinyl). { [4- (2-Butynyloxy) phenyl] sulfonyl} ethyl acetate according to the general method described in example 116 (step 1), starting from. { [4 - (2-Butyloxy) -phenyl] sulfonyl} (4-piperidinyl) ethyl acetate (1.5 g, 3.61 mmol) and acetyl chloride (0.26 mL, 3.61 mmol); yellow oil (1.35 g). Performance 89%; MS: 422 (M + H) +. Acid (1-acetyl-4-piperidinyl) was prepared. { [4- (2-Butynyloxy) phenyl] sulfonyl-acetic acid according to the general method described in example 1 (step 5), starting from (1-acetyl-4-piperidinyl). { [4- (2-Butynyloxy) phenyl] sulfonyl} ethyl acetate (1.23 g, 2.92 mmol); 400 mg of white gel. Yield 35%; MS: 391.9 (MH). "Starting from (l-acetyl-4-piperidinyl) { [4- (2-Butynyloxy) phenyl] sulfonyl} acetic acid (290 mg, 0.74 mmole), and following the procedure described in Example 1 (step 6), 60 mg of 2- (l-acetyl-4-piperidinyl) -2- { [4- (2-butynyloxy) phenyl] -sul-fonyl} was isolated. -N-hydroxyacetamide as a white powder, mp 103 ° C, yield: 20%, MS: 408.9 (M + H) +, 1R-NMR (300 MHz, DMSO-d6): d 1.07-1.55 (m, 3H), 1.85 (s, 3H), 1.95 (m, 3H), 2.18 (m, 2H), 3.02 (, 2H), 3.67-3.76 (band, 1H), 4.29 (m, 1H), 4.88 (d, 2H), 7.16 (t, 2H), 7.78 (t, 2H), 9.15 (d, 1H), 10.7 (s, 1H).
Example 122 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-Hydroxy-2-tetrahydro-2H-pyran-4-yl-acetamide Step 1: Tetrahydro-4H-pyran-4-ylidene-ethyl acetate was prepared from tetrahydropyran-4-one (9.0 g, 90 mmol) and Phosphonoethoxyethyl acetate (20.16 g, 90 mmol) in DMF / K2C03 at 80 ° C. Colorless oil, Yield. 16.3 g, (96%), MS: 171 (M + H) +.
Step 2: Ethyl tet rahydro-4Hpyran-4-ylacetate was prepared from ethyl tetrahydro-4H-pyran-4-ylidenacetate (16.0 g, 94 mmol) and Pd / NH 4 COOH at 80 ° C. Colorless oil, Yield: 16.3 g, (quantitative), MS: 173.2 (M + H) +.
Step 3: 2- acetate was prepared. { [- (2-Butyloxy) -phenyl] sulfonyl} (tetrahydro-2H-pyran-yl) -ethyl according to the general method described in Example 113 (step 1). Starting from ethyl tetrahydro-4H-pyran-4-ylacetate (4.0 g, 23.3 mmoles) and 4-but-2-inyloxy-benzenesulfonyl fluoride (7.1 g, 26.0 mmoles); It was isolated. 7.0 g of product as a yellow oil. The product was purified by silica gel column chromatography eluting with 50% ethyl acetate: hexane. Performance: 89%; MS: 381 (M + H) +.
Step 4: 2- acid was prepared. { [- (2-Butynyloxy) phenyl] -sulfonyl} (tetrahydro-2H-pyran-4-yl) -acetic according to the general method described in Example 1 (step 5). Starting from 2 - acetate. { [4- (2-butynyloxy) phenyl] sulfonyl} (tetrahydro-2H-pyran-4-yl) -ethyl (7.0 g, 18.4 mmol), 6.1 g of product was isolated. Performance: quantitative; EM 351.4 (M-H) ".
Step 5: Prepare 2-. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -N-hydroxy-2-tetrahydro-2H-pyran-4-acetylamide according to the general method described in example 1 (step 6). Starting from acid 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} (tetrahydro-2H-pyran-4-yl) -acetic acid (4.0 g, 11.4 mmol), 3.4 g of the product was isolated. The product was purified by silica gel column chromatography eluting with 75% ethyl acetate: hexane. White solid, P.f. 208-211, Yield: 84%; MS: 368.4 (M-H) ~; X H NMR (300 MHz, DMSO-de): d 1.25 (m, 2H), 1.42-1.66 (m, 4H), 2.45 (m, 2H), 4.66 (s, 2H), 4.68 (d, 1H), 5.15 (m, 1H), 6.82 (d, 2H), 7.41 (d, 2H), 9.15 (broad s, 1H).
Example 123 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-Hydroxy-2-tetrahydro-2H-thiopyran-4-yl-acetamide Step 1: Ethyl rahydro-4H-thi-pyrn-4-ylidene-ethyl acetate was prepared from tet rahydropyran-4 -one (10.0 g, 86 mmol) and diethyl phosphonoethethylacetate (21.2 g, 95 mmol) in DMF / K2C03 at 80 ° C. Colorless oil, Yield. 15.4 g, (96%), MS: 187 (M + H) +.
Step 2: Ethyl tetrahydro-4-thiopyran-ylacetate was prepared from ethyl tetrahydro-4-thiopyran-4-ylidenacetate (8.0 g, 43 mmol), NaBH (8.2 g, 5 equivalents) and NiCl 2 (5.0 g) at 0 °. C for 1 hour. Colorless oil, Yield: 8.1 g, (quantitative), MS: 189 (M + H) +.
Step 3: 2- acetate was prepared. { [4 - (2-Butyloxy) -phenyl] sulfonyl} (tetrahydro-2H-t-thiopyran-4-yl) -ethyl according to the general method described in Example 113 (step 1). Starting from ethyl tetrahydro-4-thiopyran-4-ylacetate (5.0 g, 26.6 mmol) and -but-2-ynyloxy-benzenesulfonyl fluoride (5.5 g, 26.0 mmol); 9.3 g of product was isolated as a yellow oil. The product was purified by silica gel column chromatography eluting with 50% ethyl acetate: hexane. Yield: 88%; MS: 398 (M + H) +.
Step 4: 2- acid was prepared. { [4- (2-butyloxy) phenyl] -sulfonyl} (tetrahydro-2H-thiopyran-4-yl) acetic acid according to the general method described in Example 1 (step 5). Starting from 2- acetate. { [4- (2-butynyloxy) phenyl] sulfonyl} (tet rahydro-2H-t-thiopyran-4-yl) -ethyl (7.0 g, 17.7 mmol), 6.8 g of product was isolated as a white solid. P.f. 141-3, Performance: quantitative; MS: 370 (M-H). " Stage 5:. It was prepared 2-. { [- (2-Butyloxy) phenyl] -sulfonyl} -N-hydroxy-2-tetrahydro-2H-thiopyran-4-yl-acetamide according to the general method described in example 1 (step 6). Starting from acid 2-. { [4- (2-Butynyloxy) phenyl] sulphonyl} (tetrahydro-2H-thiopyran-4-yl) -acetic acid (4.5 g, 12.2 mmol), 4.6 g of the product was isolated. The product was purified by silica gel column chromatography eluting with ethyl acetate: hexane 1: 1. White solid, P.f. 175-177, Yield: 98%; MS: 385 (MH) "; XH NMR (300 MHz, DMSO-de): d 1.52 (m, 2H), 1.81 (s, 3H), 2.1 (m, 1H), 2.22 (, 1H), 2.38 (m , 1H), 2.69 (m, 4H), 3.73 (d, 1H), 4.71 (s, 2H), 7.05 (d, 2H), 7.79 (d, 2H), 9.18 (s broad, 1H), 10.62 (s) , 1 HOUR) .
Example 124 2-. { [4- (2-Butynyloxy-phenyl] sulfonyl] -N-hydroxy-2- (1-oxidotetrahydro-2H-thiopyran-4-yl) acetamide. 2- {[4- (2-butynyloxy) phenyl]] sulfonyl.}. N-hydroxy-2- (1-oxydotetrahydro-2H-thiopyranyl) acetamide, starting from 2- { [4 - (2-butynyloxy) phenyl] -sulfonyl.}. -N- hydroxy-2-tetrahydro-2H-thiopyran-4-acetamide (0.6 g, 1.6 mmol), and following the procedure described in Example 7, 600 mg of the product was isolated as a white solid, mp 219-220 ° C; : Quantitative, E: 401 (M + H) +. AH NMR (300 MHz, DMSO-d6): d 1.82 (s, 3H), 1.83-1.85 (m, 1H), 2.02-2.08 (m, 1H), 2.18-2.33 (m, 1H), 2.61-2.68 (m, 2H), 2.72-2.76 (m, 1H), 3.15-3.22 (m, 1H), 3.31 (s, 2H), 3.72 (d, 1H), 4.91 (s, 2H), 7.18 (d, 2H), 7.75 (d, 2H), 9.21 (s broad, 1H), 10.78 (s, 1H).
Example 125 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1,1- dioxidotetrahydro-2H-thiopyran-4-yl) acetamide Starting from 2-. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -N-hydroxy-2-tetrahydro-2H-thiopyran-4-yl-acetamide (0.5 g, 1.3 mmol), and following the procedure described in Example 75, 0.45 g of 2- was isolated. { [4 - (2-Butyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1, l-dioxidotetrahydro-2H-thiopyran-4-yl) -acetamide as a white powder. Yield: 93%; MS: 417 (M + H) +; TR NMR (300 MHz, DMSO-d6): d 1.88 (s, 3H), 2.12 (m, 1H), 2.15-2.23 (m, 2H), 2.55 (m, 2H), 2.92-3.15 (m, 4H) , 3.87 (d, 1H), 4.72 (s, 2H), 7.02 (d, 2H), 7.82 (d, 2H), 9.2 (broad s, 1H).
Pharmacology Representative compounds of this invention were evaluated as inhibitors of the enzymes MMP-1, MMP-9, MMP-13 and the enzyme that converts TNF-a (TACE). The standard pharmacological test procedures used, and results obtained that establish this biological profile are shown below.
Test procedures to measure the inhibition of MMP-1, MMP-9, and MMP-13 These standard pharmacological test procedures are based on the separation of thiopeptide substrates such as Ac-Pro-Leu-Gly (2-mercapto-4 - met il-pentanoi 1) 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 colorimetically with DTNB (5,5'-di-t-bis (2-nitro-benzoic acid)). The activity of the enzyme is measured by the speed of the color increase. The thiopeptide substrate becomes cooler as a 20 mM reservoir in 100% DMSO and the DTNB is dissolved in 100% DMSO as a 100 mM reservoir and stored in the dark at room temperature. Both the substrate and the DTNB are diluted together at 1 mM with substrate buffer (50 Mm HEPES, Ph 7.5, 5 mM CaCl2) before use.
The deposit of the enzyme is diluted with buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) for the desired final concentration. The buffer, the enzyme, the vehicle or the inhibitor, and the DTNB / substrate are added in this order to a 96-well plate (total reaction volume of 200 μl) and the increase in color is monitored spectrophotometrically for 5 minutes at 405 nm on a reading plate and the increase in color for a time is plotted as a line or linear trace. Alternatively, a fluorescent peptide substrate is used. In this test procedure, the peptide substrate contains a fluorescent group and a rapidly cooling group. After separation of the substrate by an MMP, the fluorescence that is generated is quantified in the fluorescence plate reader. The assay is run in an HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM Ca + 2, 0.02% Brij, 0.5% Cysteine), with MMP-1, MMP-9, or recombinant human MMP-13 . The substrate is dissolved in methanol and stored frozen in 1 mM aliquots. For the assay, the substrate and the enzymes are diluted in HCBC buffer for the desired concentrations. The compounds are added to the 96-well plate containing the enzyme and the reaction is stored by the addition of the substrate. The reaction is read (excitation 340 nm, emission 444 nm) for 10 minutes and the increase in fluorescence for a time is plotted as a linear trace. For any of the fluorescent or thiopeptide peptide test procedures, the slope of the line is calculated and represents the reaction rate. The linearity of the reaction rate is confirmed (r2> 0.85). The means (x ± sem) of the control rate is calculated and compared by statistical significance (p <0.05) with drug-treated rates using the Dunnett's multiple comparison test. Dose response ratios can be generated using multiple doses of drugs and IC50 values with 95% CI are estimated using linear regression.
Test Procedure for Measurement of TACE Inhibition Using 96-well dark microtiter plates, each well receives a solution composed of 10 μl of TACE (final concentration 1 μg / ml), Tris buffer 70 μl, pH 7.4 containing glycerol to 10% (final concentration of 10 mM), and 10 μl of the test compound solution in DMSO (final concentration of 1 μM, DMSO concentration of <1%) and incubated for 10 minutes at room temperature. The reaction is initiated by the addition of a fluorescent peptidyl substrate (final concentration of 100 μM) to each well and then by agitation on a shaker for 5 seconds. The reaction is read (excitation 340 nm, emission 420 nm) for 10 minutes and the increase in fluorescence for a time is plotted as a linear trace. The inclination of the line is calculated and represents the reaction speed. The linearity of the reaction rate is confirmed (r2> 0.85). The means (x + sem) of the control rate is calculated and compared by statistical significance (p <0.05) with drug-treated rates using the Dunnett's multiple comparison test. Dose response ratios can be generated using multiple doses of drugs and IC50 values with 95% CI are estimated using linear regression.
Cell Differentiation Test of Human Monocitic THP-1 for Soluble Proteins (THP-1 Soluble Protein Assay) Mitogenic stimulation of THP-1 cells causes differentiation into macrophages as cells with concomitant tumor necrosis factor (TNF-) secretion a) and the TNF receptor (TNF-R p75 / 80 and TNF-R p55 / 60) and Interlecin-8 (IL-8), among other proteins. In addition, unstimulated THP-1 cells are scattered or spilled in both p75 / 80 and p55 / 60 receptors for a time. The release of TNF-α bound to the membrane and possibly TNF-R p75 / 80 and TNF-R p55 / 60, but without IL-8, is measured by an enzyme called the enzyme that converts to TNF-a or TACE. This assay can be used to demonstrate either an effect of the inhibitor or stimulator compound on this TACE enzyme and any cytotoxic consequence of such a compound. THP-1 cells (from ATCC) are a human monocytic cell line obtained from the peripheral blood of a one-year-old male with acute monocytic leukemia. They can be developed in cultures and differentiated into macrophages as cells by stimulation with mitogens.
For the assay, THP-1 cells were seeded from an ATCC reservoir that was previously developed and frozen before at 5 x 106 / ml / vial. One vial is seeded in a T25 flask with 16 ml of RPMI-1640 with a glutamax medium (Gibco) containing 10% fetal bovine serum, penicillin 100 units / ml, streptomycin 100 μg / ml, and mercapto-ethanol 5 x 10"5 M 2 (THP-1 medium) Each vial of cells are cultured for approximately two weeks before being used and then used for a trial for only 4 to 6 weeks for protection compounds. they are subcultured on Monday and Thursday at a concentration of 1 x 105 / ml. To perform a test, THP-1 cells are co-incubated in a 24-well plate with 50 ml / well of a 24 mg / well reservoir ml of Lipopolysaccharides (LPS) (Calbiochem Lot # B13189) at 37 ° C in 5% C02 at a concentration of 1091 x 106 cells / ml (1.1 ml / well) for a total of 24 hours. 50 ml / well of drug, vehicle or THP-1 medium in appropriate wells to give a final volume of 1.2 ml / well. elve in DMSO at a concentration of 36 mM and diluted from here to the appropriate concentrations in the THP-1 medium and added to the wells at the beginning of the incubation period to give final concentrations of 100 mM, 30 mM, mM, 3 M, 1 mM, 300 nM and 100 nM. Cell exposure to DMSO was limited to 0.1% of the final concentration. The positive control wells were included in the experiment that has added the mitogen but not the drug. The vehicle control wells are also included, which were identical to the positive control wells, except that DMSO was added to give a final concentration of 0.083%. Negative control wells were included in the experiment that added the vehicle but not the mitogen or drug to the cells. Compounds can be evaluated for their basic (not stimulated) efflux of the recipients by replacing the LPS with 50 ml / well of the THP-1 medium. The plates were placed in a fixed incubator in C02 at 5% and at 37 ° C. After 4 hours of incubation, 300 ml / well of TCS tissue culture supernatant was removed for use in an ELISA test of TNF-α. After 24 hours of incubation, 700 ml / well of TCS was removed and used for analysis in the ELISA tests of TNF-R p75 / 80, TNF-R p55 / 60 and IL-8.
In addition, within 24 hours, the cells for each treatment group were harvested by resuspension in 500 μl / well of the THP-1 medium and transferred to a FACS tube. Two ml / tube was added from a 0.5 mg / ml deposit of propidium iodide (Pl) (Boerhinger Mannheim cat. # 1348639). The samples were run on a Becton Dickinson FaxCaliber FLOW cytometric machine and the amount of dye absorbed by each cell is measured at the deep red wavelength (FL3). Any of the cells with compromised membranes (dead or dying) can absorb Pl. The percentage of living cells is calculated by the number of cells not stained with Pl, it is divided by the total number of cells in the sample. The calculated viability values for the drug-treated groups are compared to the calculated viability value for the mitogen-stimulated vehicle-treated group ("vehicle positive control") to determine the "control percentage change". This value of the "control percentage change" is an indicator of the drug's toxicity. The amount of soluble TNF-α, TNF-R p75 / 80 and TNF-R p55 / 60 and IL-8 in TCS of THP-1 cell cultures are obtained with the commercially available ELISA tests of R & amp; amp; amp;; D Systems, by extrapolating a standard curve generated with standard equipment. The number of cells that absorb or exclude either Pl are measured by the FLOW cytometric machine and visualized by histograms using cytological software commercially available for each treatment group including all controls. The biological variability in the magnitude of the cell culture response of THP-1 requires that the experiments be compared on the basis of the percentage change of the "vehicle positive control" for each drug concentration. The percentage change in each soluble protein evaluated from the "vehicle positive control" is calculated for each concentration of compound with the following formula: % (_atbio = pg / ml (csrpuesto) - pg / ml (ccptrol positive vehicle) x 100 pg / ml (centro! positive efe vehicle) - pg / ml (negative control of vehicle For studies of soluble protein (TNF-α, p75 / 80, p55 / 60, IL-8) under stimulated conditions, the pg / ml media of duplicate wells were determined and the results expressed as percentage changes of the "positive vehicle control". For studies of the soluble protein (receptors of p75 / 80 and p55 / 60) under no stimulated conditions, the pg / ml media of duplicate wells were determined and the results expressed as percentage changes of the "positive vehicle control" using the following formula: % C = rrbio = pgftí (artarl nacptivo del caipLesto) - pg (cp ± rbL a i ce vé? üo) x 100 pg / frü. (negative control of vehicle) The IC50 values for each compound are calculated by non-linear regression analysis using software adapted using the JUMP statistical package. For cell viability studies, the viabilities (Pl exclusion) of combined duplicate wells and the results expressed as change of% of the "positive vehicle control" were determined. The viability values calculated for the compound of the treated groups were compared for the viability value calculated for the "positive vehicle control" to determine the "control percentage change" as follows. This "percentage change of control" value is an indicator of the drug's toxicity. % of Change% of living cells (compound) - 1 X 100 % of living cells (positive vehicle control) References: Bjornberg, F., Lantz, M., Olsson, I., and Gullberg, U. Mechanisms involved in the processing of tumor necrosis factor (TNF) receptors from p55 and p75 to soluble receptor forms. Lymphokine Cytokine Res. 13: 203-211, 1994. Gatanaga, T., Hwang, C., Gatanaga, M., Cappuccini, F., Yamamoto, R., and Granger, G. Regulation of the mRNA synthesis of the TNF, membrane expression and release by human monocytic THP-1 cells stimulated with PMA and LPS in vi tro. Cellular Immun. 138: 1-10, 1991. Tsuchiya, S., Yamabe, M., Yamagughi, Y., Kobayashi, Y., Konno, T., and Tada, K. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int. J. Cancer. 26: 1711-176, 1980. The results of the inhibition of the metalloproteinase matrix in the above, the inhibition of TACE and the standard pharmacological test procedures of THP are given in Table 1 below.
Table 1 a is% @ 10 μM or IC50 (nM), unless otherwise specified b is THP (change of stock) Based on the results obtained in the standard pharmacological test procedures described in the foregoing, the compounds of this invention were shown to be inhibitors of the enzymes MMP-1, MMP-9, MMP-13 and the enzyme that converts to TNF- (TACE) and are therefore useful in the treatment of disorders such as arthritis, tumor metastasis, tissue ulceration, scarring of abnormal wounds, disease, periodontal, graft rejection, insulin resistance, bone disease and HIV infection . The compounds of this invention are also useful in the treatment and inhibition of pathological changes mediated by metalloproteinase matrixes such as atherosclerosis, atherosclerotic plaque formation, reduction of coronary thrombosis from rupture of the atherosclerotic plaque, restenosis, mediated osteopenias. by MMP, inflammatory diseases of the central nervous system, skin aging, angiogenesis, tumor metastasis, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, proteinuria, aneurysmal aortic disease, degenerative cartilage loss followed by injury traumatic joint, demyelinating diseases of the nervous system, liver cirrhosis, glomerular kidney disease, premature rupture of the fetal membranes, inflammatory bowel disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy due to prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, angiogenesis / neovascularization of the eye and rejection of cornea graft. The compounds of this invention can be administered pure or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier can be solid or liquid. Applicable solid carriers may 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 that 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 desired shape and size. 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, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting waxes, and ion exchange resins. Liquid carriers can be used in the preparation of 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 fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as in the above, for example, cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, example glycols) and their derivatives, and oils (for example, fractionated coconut oil and peanut 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 compositions of sterile liquid form for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered in ravenously. The oral administration may be in the form of a liquid or solid composition. The compounds of this invention can be administered rectally in the form of a conventional suppository. For intranasal administration or intrabronchial inhalation or insufflation, the compounds of this invention can be formulated in an aqueous or partially aqueous solution, which can then be used in the form of an aerosol. The compounds of this invention can 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 the delivery of the agent by systemic absorption into the skin. the bloodstream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous or semi-solid liquid emulsions of any type of oil in water or water in oil. Pastes that consist of absorbent 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 bloodstream such as a semipermeable membrane that covers 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 dose that is used in the treatment of a specific patient suffering from a condition dependent on MMP or TACE 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. The treatment will usually start with small doses less than the optimal dose of the compound. Therefore, the dose is increased to the optimum effect under the circumstances achieved. The precise doses for oral, parenteral, nasal, or intrabronchial administration will be determined by the physician administering them based on the experience of the individual treated subject and the standard medical principles. Preferably the pharmaceutical composition is in the unit dosage form, for example as tablets or capsules. In such manner, the composition is sub-divided into unit doses containing appropriate amounts of the active ingredient; the unit dosage form can be in packaged compositions, for example packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids. 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. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property.
1. A compound of the formula I characterized in that: Ri 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 cycloheteroalkyl with 5-carbon atoms. to 8 carbon atoms having 1 to 2 heteroatoms selected from N, NR7, S and O; R2 and R are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH; R5 is hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, or cycloheteroalkyl with 4 to 8 carbon atoms; R7 is hydrogen, aryl, aralkyl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms, oxy, alkanoyl with 1 to 8 carbon atoms, C00R5, C0R5, -S02-alkyl with 1 to 8 carbon atoms, -S02-aryl, -S02-heteroaryl, -CO-NHRi; R8, R9, R7 and Rn are each, independently, hydrogen, aryl, aralkyl, 5-10 heteroaryl members having 1-3 heteroatoms selected from N, NR7, O and S, heteroalkyl having from 1-3 heteroatoms selected from N, NR7, O and S, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl with 4 to 8 carbon atoms having 1-3 heteroatoms selected from N, NR7, 0 and S, alkyl of 1-18 atoms of carbon, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; R12 is hydrogen, aryl or 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, NR7, S and O, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl having 5 to 8 carbon atoms having 1 to 2 heteroatoms selected from N, NR7, S and O, or alkyl of 1-6 carbon atoms; A is O, S, SO, S02, NR7, or CH2; X is O, S, SO, S02, NR7, or CH2; And it is aryl or heteroaryl, with the proviso that A and X are not attached to adjacent atoms of Y; and n is 0 -2; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, characterized in that Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl, triazolyl or iadiazolyl.
3. A compound according to claim 1 or claim 2, characterized in that R2 and R3 are each, independently, hydrogen or alkyl of 1-6 carbon atoms.
4. A compound according to any of claims 1 to 3, characterized in that R2 and R are each, independently, hydrogen or alkyl of 1-6 carbon atoms.
5. A compound according to any of claims 1 to 4, characterized in that R 2 is hydrogen.
6. A compound according to claim 1, characterized in that it is selected from the group consisting of: 2- (4-But-2-ynyloxy-benzenesulfonyl) -N-hydroxy-2-methyl-3-pyridin-3-yl- propionamide; 2- (4-But-2-ynyloxy-benzenesulfonyl) -N-hydroxy-2-methyl-3- [4- (2-pyridin-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-phenyl-sulfanyl) -octanoic acid hydroxyamide; 2- (But-2-ynyloxy-benzenesulfonyl) -octanoic acid hydroxyamide; 2- [(R) - (4-Butyl-2-ynyloxy) -sulfinyl-N-hydroxy-octanamide; 2- [(S) - (4-Butyl-2-ynyloxy) -sulfinyl-N-hydroxy-octanamide; 3- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-propionamide; 4- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-but-iramide; 2- (4-But-2-ynyloxy-phenoxy) -N-hydroxy-acetamide; 4- (4-But-2-ynyloxy-phenyl) -N-hydroxy-butyramide; [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxy-carbamoyl-1-pentyl] -amide of quinoline-2-carboxylic acid; Hydroxyamide 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; [5- (4 -But -2-loxy-phenylsulfanyl) -5-hydroxy-carbamoyl-pentyl] -amide of quinoline-3-carboxylic acid; 2- (4-But-2-ynyloxy-phenylsulfanyl) -6- (-thiophen-2-yl-butyrylamino) -hexanoic acid hydroxyamide; [5- (4 -But -2-ynyloxy-phenylsulfanyl) -5-hydroxy-carbamoyl-pentyl] -amide of 9H-Xanthen-9-carboxylic acid; 2- (4-But-2-ynyloxy-phenylsulfanyl) -6-diphenylacetylaminohexanoic acid hydroxyamide; [5- (Isobutyl-1-carboxylic acid-5- (-But-2-ynyloxy-phenylsulfanyl) -5-hydroxy-carbamoyl-1-pentyl] -amide; Hydroxyamide 6- (2-benzo [b] t -pheno-3-yl-acetylamino) -2- (4-bt-2-ynyloxy-phenyl-sulfanyl) -hexanoic acid hydroxyamide; [5- (4 -But-2-quinloxy-benzenesulfinyl) -5-hydroxy-carbamoyl-pentyl] -amide of quinoline-2-carboxylic acid; 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; Hydroxyamide 2- (butyl-2-inyloxy-benzenesulfinyl) -6- [2- (3,4-dichloro-phenyl) -acetyl-amino] -hexanoic acid hydroxyamide; [5- (4 -But-2-yl loxi-benzenesulfinyl) -5-hydroxy-ca rbamoi-pentyl] -amide of quinoline-3-carboxylic acid; Hydroxyamide of 2- (4-but-2-ynyloxy-benzenesulfinyl) -6- (4-thiophen-2-yl-butyrylamino) -hexanoic acid; [5- (4 -But-2-aminoloxy-benzenesulfinyl) -5-hydroxy-carbamoyl-pentyl] -amide of 9H-Xanthen-9-carboxylic acid; Hydroxyamide of 2- (4-but-2-ynyloxy-benzenesulfinyl) -6-diphenylacetylamino-hexanoic acid [5- (4 -But-2-linoxy-benzenesulfinyl) -5-hydroxy-carbamoyl-1- pentyl] - isoquinoline-1-carboxylic acid amide; Hydroxyamide 6- (2-benzo [b] thiophen-3-yl-acetylamino) -2- (4-but-2-ynyloxy-benzenesulfinyl) -hexanoic acid hydroxyamide; 2- (4-But-2-ynyloxy-benzenesulfinyl) -6- (2-lH-indol-3-yl-acetylamino) -hexanoic acid hydroxyamide; [5- (4 -But-2 -i or loxi-benzenesulfinyl) -5-hydroxy-ca rbamoi-pentyl] -aminoquin-2-carboxylic acid amide; Hydroxyamide 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-1-pentyl] -2-phenethyl-benzamide; Hydroxyamide 2- (butyl-2-ynyloxy-benzenesulfonyl) -6- [2- (3,4-dichloro-phenyl) -acetyl-amino] -hexanoic acid hydroxyamide; [5- (4-But-2-ynyloxy-benzenesulfonyl) -5-5-hydroxycarbamoyl-pentyl] -amide of quinoline-3-carboxylic acid; [5- (4-But-2-ynyloxy-benzenesulfonyl) -5-hydroxy-carbamoyl-pentyl] -amide of 9H-Xanthen-9-carboxylic acid; Hydroxyamide 2- (4-but-2-ynyloxy-benzenesulfonyl) -6-diphenylacetylaminohexanoic acid hydroxyamide; [5- (4 -But-2-aminoloxy-benzenesulfonyl) -5-hydroxy-carbamoyl-1-pentyl] -aminoquinoline-1-carboxylic acid amide; Hydroxyamide 6- (2-benzo [b] thiophen-3-yl-acetylamino) -2- (4-but-2-ynyloxy-benzenesulfonyl) -hexanoic acid hydroxyamide; . { [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} -quinoline-2-carboxylic acid amide; 2- (4-But-2-ynyloxy-phenylsulfanyl) -6- acid hydroxyamide. { 2- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] acetylamino} hexanoic; N-. { [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pentyl-carbamoyl] -methyl} -2-phenethylbenzamide; Hydroxyamide 2- (4-but-2-ynyloxy-phenylsulphyl) -6- acid. { 2- [2- (3,4-dichloro-phenyl) -acetylamino] -acetylamino} -hexanoic; . { [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} quinoline-3-carboxylic acid amide; . { [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} 9H-Xant en-9-carboxylic acid amide; 2- (4-But-2-ynyloxy-phenyl-sulfanyl) -6- (2-diphenylacetylamino-acetylamino) -hexanoic acid hydroxyamide; . { [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} isoquinoline-1-carboxylic acid amide; . { [5- (4-But-2-ynyloxy-phenylsulfanyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} l-methyl-lH-pyrrole-2-carboxylic acid amide; Hydroxyamide of 6- f 2- (2-benzo [b] t -pheno-3-yl-acetylamino) -acetylamino] -2- (4-but-2-ynyloxy-phenylsulfanylhexanoic acid; { [5- (4 -But-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -met-yl.} - quinoline-2-carboxylic acid amide; 2- (butyl-2-ynyloxy-benzene) hydroxyamide; sulfinyl) -6-. {2- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] -acetylamino}. -hexanoic; N- { [ 5- (4-But-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl -pentyl-carbamoyl] -methyl} -2-phenethyl-benzamide; 2- (4-but-2-ynyloxy) hydroxyamide -benzene-sulfinyl) -6- { 2- [2- (3,4-dichloro-phenyl) -acetylamino] -acet-ylamino} -hexanoic; {. [5- (4 -But-2 - inyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} -quinol in-3 -carboxylic acid; hydroxyamide of 2- (4-but-2-ynyloxy-benzenesulfinyl) -6- [2- (4-thiophen-2-yl-butyrylamino) -acetylamino] -hexanoic; {. [5- (4 -Bu t-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} -amide of acid 9H-Xanten-9-carboxylic acid; 2- (4-But-2-ynyloxy-benzenesulfinyl) -6- (2-diphenylacetylamino-acetylamino) -hexanoic acid hydroxyamide; . { [5- (4-But-2-ynyloxy-benzenesulfinyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} -amide of acid 1-methyl-lH-pyrrole-2-carboxylic acid; Hydroxyamide of 2- (4-but-2-ynyloxy-benzenesulfonyl) -6- acid. { 2- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -acetylamino] -acetylamino} -hexanoic; N-. { [5- (4-but-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} -2-phenethylbenzamide; Hydroxyamide of 2- (4-but-2-ynyloxy-benzenesulfonyl) -6- acid. { 2- [2- (3,4-dichloro-phenyl) -acetylamino] -acetylamino} -hexanoic; . { [5- (4-but-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} quinoline-3-carboxylic acid amide; . { [5- (4-But-2-linoxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -met-il} -amide of acid 9H-Xanten-9-carboxylic acid; 2- (4-But-2-ynyloxy-benzenesulfonyl) -6- (2-diphenylacetylamino-acetylamino) -hexanoic acid hydroxyamide; . { [5- (4-But-2-ynyloxy-benzenesulfonyl) -5-hydroxycarbamoyl-pentylcarbamoyl] -methyl} isoquinoline-1-carboxylic acid amide; Hydroxyamide 6- [2- (2-benzo [b] t -pheno-3-yl-acetylamino) -acetylamino] -2- (4-but-2-ynyloxybenzenesulfonylhexanoic acid; 2- (4-buty) hydroxyamide -2-inyloxy-benzenesulfonyl) -6- [2- (2-lH-indol-3-yl-acetylamino) -acetylamino] -hexanoic acid; 2- {[[4- (2-butynyloxy) phenyl]] sulphonyl} -N-hydroxy -4 - {4- [2- (1-piperidinyl) -ethoxyphenyl} 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; {. [4- (2-Butynyloxy) phenyl] sulfanyl.} - N-hydroxy-2- (4-methoxyphenyl) acetamide; (2R) -2- { [4- (2-butynyl loxi) phenyl] sulfanyl) -N-hydroxy-2- (4-methoxyphenyl) ethanamide; (2S) -2- [4- (2-butyloxy) phenyl] sulfanyl} -N-hydroxy-2 - (-methoxyphenyl) ethanamide; 2-. { [4- (2-Butynyloxy) phenyl] sullyl} -N-hydroxy -2- (4-methoxyphenyl) acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (4-chlorophenyl) N-hydroxyacetamide; 2-. { [4- (2-butynyloxy) phenyl] sulfinyl} -2- (4-chlorophenyl) N-hydroxyacetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulphonyl} -2- (4-chlorophenyl) N-hydroxyacetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (3-chlorophenyl) N-hydroxyacetamide; 2-. { [4- (2-butynyl loxy) phenyl] sulphonyl} -2- (3-chloro phenyl) N-hydroxyacetamide; 2- (4-bromo-phenyl) -2-. { [4- (2-Butynyloxy) phenyl] sulfanil} N-hydroxyacetamide; (2S) -2- (4-bromo phenyl) -2-. { [4- (2-Butynyloxy) phenyl] -sulfinyl} -N-hydroxyacetamide; (2R) -2- (4-bromophenyl) -2-. { [4- (2-butyloxy) phenyl] -sulfinyl} -N-hydroxyacetamide; - (-bromophenyl) -2-. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -N-Hydroxyacetamide; -. { [4- (2-butynyl loxy) phenyl] sulfanil} -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-butynyl oxy) phenyl] sulfonyl} -N-hydroxy -2- [4 ' (2-thienyl) phenyl] -acetamide; 2- . { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-2- (1-naphthyl) acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfinyl} -N-hydroxy-2- (1-naphthyl) acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulphonyl} -N-hydroxy -2- (1-naphthyl) acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -2- (4- fluorophenyl) -N-hydroxy-2- (l-naphthyl) 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-butyloxy) phenyl] -sulfanyl} -N-hydroxyacetamide; 2- (2-methoxyphenyl) -2-. { [4- (2-butynyloxy) phenyl] -sulfinyl} -N-hydroxyacet amide; 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] sulphonyl-2- (4-chlorophenyl) N-hydroxyacetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanyl-N-hydroxy-2- (3-bromophenyl) acetamide; (2R) -2-[[4- (2-butynyloxy) phenyl] sul-finyl-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-phenyl bromide; N-hydroxyacetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfanil} -N-hydroxy-acetamide; 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-Í [4- (2-butynyloxy) phenyl] sulfinyl. -2-phenyl-N-hydroxyacetamide; 2- {[[4- (2-Butynyloxy) phenyl] sulphonyl} -2- (2-naphthyl) -N-hydroxyacetamide; 2-[[4- (2-butyl) phenyl] sulfinyl} -2- (2-naphthyl) - - hydroxyacetamide; 2-[[4- (2-butynyloxy) phenyl] sulfonyl} -2- (2-naphthyl) -N-hydroxyacetamide; 4- [1-. { [4- (2-butynyloxy) phenyl] sulfonyl} -2- (hydroxyamino) -2-oxoethyl] -1-piperidinecarboxylate terbutyl; 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy -2- (4-piperidinyl) acetamide; 2-. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- [1- (4-methoxybenzyl) -4-piperidinyl] acetamide; 2- (l-benzoyl-4-piperidinyl) -2-. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -N-hydroxy-acetamide; 2- (l-acetyl-4-piperidinyl) -2-. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -N-hydroxy-acetamide, • 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2-tetrahydro-2H-pyran-4-yl-acetamide; 2-[[4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2-tetrahydro-2H-thiopyran-4-yl-acetamide; 2-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1-oxidotetrahydro-2H-thiopyran-4-yl) -acetamide; and 2-[[4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-2- (1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) -acetamide.
7. A method for the inhibition of pathological changes mediated by the enzyme (TACE) that converts TNF-a into a mammal in need thereof, characterized in that it comprises administering to the mammal a therapeutically effective amount of a compound having the formula: wherein: Ri 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 cycloheteroalkyl with 5-carbon atoms. to 8 carbon atoms having 1 to 2 heteroatoms selected from N, NR7, S and 0; R2 and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH; R5 is hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, or cycloheteroalkyl with 4 to 8 carbon atoms; R7 is hydrogen, aryl, aralkyl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms, oxy, alkanoyl with 1 to 8 carbon atoms, C00R5, C0R5, -S02-alkyl with 1 to 8 carbon atoms, -S02-aryl, -S02-heteroaryl, -CO-NHRi; R8, Rg, Rio and Rii are each, independently, hydrogen, aryl, aralkyl, 5-10 heteroaryl members having 1-3 heteroatoms selected from N, NR7, O and S, heteroalkyl having from 1-3 selected heteroatoms of N, NR7, O and S, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl with 4 to 8 carbon atoms having 1-3 heteroatoms selected from N, NR7, O and S, alkyl of 1-18 carbon atoms. carbon, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; R12 is hydrogen, aryl or 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, NR7, S and O, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl having 5 to 8 carbon atoms having 1 to 2 heteroatoms selected from N, NR7, S and O, or alkyl of 1-6 carbon atoms; A is 0, S, SO, S02, NR7, or CH2; X is O, S, SO, S02, NR7, or CH2; And it is aryl or heteroaryl, with the proviso that A and X are not linked to adjacent atoms of Y; and n is 0-2; or a pharmaceutically acceptable salt thereof.
8. The method according to claim 7, characterized in that the condition treated is rheumatoid arthritis, rejection of the graft, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory disease of the intestine or HIV infection.
9. A pharmaceutical composition, characterized in that it comprises a compound having the formula: wherein: Ri 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 atoms, carbon or cycloheteroalkyl with 5 to 8 carbon atoms having from 1-2 heteroatoms selected from N, NR7, S and 0; R2 and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH; R5 is hydrogen, alkyl of 1-8 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl, or cycloheteroalkyl with 4 to 8 carbon atoms; R7 is hydrogen, aryl, aralkyl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon atoms, oxy, alkanoyl with 1 to 8 carbon atoms, COOR5, COR5, -S02-alkyl with 1 to 8 carbon atoms, -S02-aryl, -S02-heteroaryl, -CO-NHRi; Rs, Rg, Rio and Rii are each, independently, hydrogen, aryl, aralkyl, 5-10 heteroaryl members having 1-3 heteroatoms selected from N, NR7, O and S, heteroalkyl having from 1-3 selected heteroatoms of N, NR7, O and S, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl with 4 to 8 carbon atoms having 1-3 heteroatoms selected from N, NR7, 0 and S, alkyl of 1-18 carbon atoms. carbon, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms; R12 is hydrogen, aryl or 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, NR7, S and O, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl having 5 to 8 carbon atoms having 1 to 2 heteroatoms selected from N, NR7, S and 0, or alkyl of 1-6 carbon atoms; A is O, S, SO, S02, NR7, or CH2; X is 0, S, SO, S02, NR7, or CH2; 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 and a pharmaceutically acceptable carrier.
10. Processes for the preparation of a compound of the formula I according to claim 1, characterized in that the processes comprise one of the following: a) reacting a compound of the formula wherein n, X, Y, A, Ri, R2, R3, Rs, R9, ior and R11 are as defined in claim 1 or a reactive derivative thereof, with a compound of the formula R12NHOH wherein Ri2 is as defined in claim 1, to give a compound of the formula I; or b) deprotect a compound of the formula: wherein n, X, Y, A, Rlr R2, R3, R8, R9, R10 RX1 and R12 are as defined in claim 1, and R30 is a suitable protecting group such as t-butyl, benzyl, and tri- alkylsilyl, to give a corresponding compound of the formula I or c) to remove a supported hydroxamate derivative with resin containing the group wherein n, X, Y, A, Ri, R 2, R 3, R 8, R 9, Rio, and R 11 are as defined in claim 1 to give a compound of formula I wherein R 2 is hydrogen; or d) dissolving a mixture (e.g. racemate) of optically active isomers of a compound of formula I to isolate an enantiomer or diastereomer substantially free of the other enantiomer or diastereomers; or e) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to give a pharmaceutically acceptable salt; or f) converting a compound of the formula I having a reactive substituent group or site to a compound of the formula I having a different substituent group or site.
MXPA/A/2001/007649A 1999-01-27 2001-07-27 Alkynyl containing hydroxamic acid compounds as tace inhibitors MXPA01007649A (en)

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