MXPA01007573A - Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (mmp) inhibitors/tnf-alpha converting enzyme (tace) inhibitors - Google Patents

Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (mmp) inhibitors/tnf-alpha converting enzyme (tace) inhibitors

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MXPA01007573A
MXPA01007573A MXPA/A/2001/007573A MXPA01007573A MXPA01007573A MX PA01007573 A MXPA01007573 A MX PA01007573A MX PA01007573 A MXPA01007573 A MX PA01007573A MX PA01007573 A MXPA01007573 A MX PA01007573A
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Mexico
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phenyl
sulfonyl
ynyloxy
hydroxy
carboxylic acid
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MXPA/A/2001/007573A
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Spanish (es)
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Jeremy Ian Levin
Arie Zask
Aranapakam Mudumbai Venkatesan
Jannie Lea Baker
James Ming Chen
Vincent Premarana Sandanayaka
Mila Ti Du
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American Cyanamid Company
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Publication of MXPA01007573A publication Critical patent/MXPA01007573A/en

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Abstract

Compounds of formula (I) wherein R1 is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or -C4-C8-cycloheteroalkyl;R2 and R3 are hydrogen, alkyl of 1-6 carbon atoms, -CN, or CCH;R8, R9, R10 and R11 are hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, -C4-C8-cycloheteroalkyl, alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon atoms;with the proviso that one of the pairs R8 and R9, R9 and R10 or R10 and R11, together with the carbon atom or atoms to which they are attached, form a cycloalkyl ring of 3-6 carbon atoms, or a -C4-C8-cycloheteroalkyl ring;R12 is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms;-C4-C8-cycloheteroalkyl, or alkyl of 1-6 carbon atoms;A, X are O, S, SO, SO2, 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;useful in the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.

Description

HYDROXAMIC ACID DERIVATIVES CONTAINING ALQUINILO, ITS PREPARATION AND ITS USE AS INHIBITORS OF THE METALOPROTEINASE MATRIX (MMP) / INHIBITORS OF THE ENZYME (TACE) THAT CONVERTS TO TNF-ALPHA 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-α, such as rheumatoid arthritis, osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple sclerosis, Crohn's disease and degenerative loss of cartilage.
BACKGROUND OF THE INVENTION The matrix metalloproteinase (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 tromelis inas and gelatinases. Of these classes, gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known REF: 131087 that the level of expression of gelatinase is high in malignancies, and that gelatinase can degrade 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, aging of the skin, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, disease bone, proteinuria, aortic aneurysmal disease, degenerative loss of cartilage followed by traumatic joint damage, demyelinating diseases of the central nervous system, liver cirrhosis, glomerular kidney disease, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease , age-related macular degeneration, diabetic retinopathy, treorret proliferative inopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis / neovascularization and rejection of cornea graft. For recent reviews, see: (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, RP Beckett, AH Davidson, AH 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) that converts to TNF-a catalyzes the formation of TNF-a from the protein of the precursor of TNF-α bound to the membrane. TNF-a is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis [Shire, M. G .; Muller, G. Exp. Opin. Ther, Patents 1998, 8 (5), 531; Grossman, J. M .; Brahn, E. J. Women's Health 1997, 6 (6), 627; Isomaki, P .; Punnonen, J. Ann. Med. 1997, 29, 499; Camussi, G .; Lupia, E. Drugs, 1998, 55 (5), 613.] Septic shock [Mathison, et al. , J. Clin. Invest. 1988, 81, 1925; Miethke, et al. , J. Exp. Med. 1992, 175, 91.], 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 .; Moldawer, L. L., Arch. Surg. 1998, 133, 558.], congestive heart failure [Packer, M. Circulation, 1995, 92 (6), 1379; Ferrari, R .; Bachetti, T .; et al., Circulation, 1995, 92 (6), 1479.], injury of post-ischemic reperfusion, inflammatory disease of the central nervous system, bowel disease, inflammatory, insulin resistance [Hotamisligil, G. S.; Shargill, N. S .; Spiegelman, B. M .; et al. Science, 1993, 259, 87.] and HIV infection [Peterson, P. K .; Gekker, G .; et al. J. Clin. Invest. 1992, 89, 574; Pa 1 lares -Truj i lio, J .; Lopez-Soriano, F. J. Argües, J. M. Me d. 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; Pharmaproj ects, 1996; Therapeutic Updates 11 (Oct.), aul97-M2Z.]. This observation has recently spread in humans as well as was described in "TNF-a in Human Diseases", Curren t Pharma ceuti cal Desi gn, 1996, 2, 662. It is expected that small molecular inhibitors of TACE would 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 bioavailability and pharmacokinetics problems. 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]. Orally selective, non-peptidic, non-peptidic 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 sulfone hydroxamic acid inhibitors of MMPs, of the general structure I have been described [Burgess, L.E .; Rizzi, J.P .; Ra are, D.J. European Patent Application 818442. Groneberg, R.D .; Neuenschwander, K.W .; Djuric, S.; McGeehan, G.M .; Burns, C.J .; Condom, S.M .; Morrissette, M.M .; Salvíno, J.M .; Scotese, A.C .; Ullrich, J. 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 piperidinesulfone, 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.].
II 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.].
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 stromelysin inhibitors 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 14, 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. Ch em. So c. 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, 5828-5832. Fesik, S. W .; Summers, J. B .; Davidsen, S. K .; Sheppard, G. S .; Steinman, D. H .; Carrera, G. M .; Florjancic, A .; Holms, J. H. PCT International Application WO 97/18188. ] Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some thio substituted aryl and aryl substituted sulfonated acetohydroxamic acid derivatives 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 the United States 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-peptidic, low molecular weight, novel allo-metalloprotein (MMPs) 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 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 atoms, carbon or cycloheteroalkyl with 4 to 8 carbon atoms; R2 and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, or -CCH; R7 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -C (0) -R ?, -S02-R ?, -C (0) -NHR ?, -C (0) NR5R6, -C (O) R? NR5R6, -C (0) -OR_., -C ( NH) -NH2; R5 and Re are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or cycloheteroalkyl of 4 to 8 carbon atoms; R8, R9, Rio and R11 are each, independently, hydrogen, aryl, or heteroaryl, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl of 4 to 8 carbon atoms, alkyl of 1-18 carbon atoms, alkenyl of 2 -18 carbon atoms, alkynyl of 2-18 carbon atoms; with the proviso that one of the pairs R8 and R9, R9 and RIO or RIO and Rll, together with the carbon atom or atoms to which they are attached, form a cycloalkyl ring of 3-6 carbon atoms, or a cycloheteroalkyl ring of 4 to 8 carbon atoms; Ri2 is hydrogen, aryl or heteroaryl, cycloalkyl 3-6 carbon atoms, cycloheteroalkyl of 4 to 8 carbon atoms, 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; Y 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 aspects of the invention, Y is phenyl, pyridyl, thienyl, furanyl, imidazolyl, triazolyl or thiadiazolyl, with the proviso that A and X are not bonded to adjacent Y atoms. In still other preferred embodiments of the invention and is phenyl, thienyl or furanyl. According to certain preferred embodiments of the invention R8 and Rg, together with the carbon atom to which they are attached form a cycloheteroalkyl ring of 4 to 8 carbon atoms and K is NR7. The compounds that inhibit the most preferred etalopro teinase and TACE matrix of this invention are: 1- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4- (4-but-2-ynyloxy-benzenesul fonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4- (4-but-2-ynyloxy-benzenesul fonyl) -1- (4-chloro-benzyl) -piperidin-4-carboxylic acid hydroxyamide; Hydroxyamide of l-benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4- (butyl-2-ynyloxy-benzenesul fonyl) -1- (4-fluoro-benzyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-benzenesulfonyl) -1- (3,4-dichloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (bromo-benzyl) -4 - (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4 - [4- (4-piperidin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4 - [4- (-morpholin-4-yl-but-2-ynyloxy) benzenesulfonyl] -piperidin-4-carboxylic acid hydroxyamide; Ter-Butyl ester of 4- (4-but-2-ynyloxy-phenylsulfani 1) -4-hydroxycarbamoyl-piperidine-1-carboxylic acid; 4 - (4-But-2-ynyloxy-phenylsulfanyl) -piperidin-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4 - (4-but-2-ynyloxy-phenylsulfanyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide; Hydroxyamide of 4- (-but-2-ynyloxy-benzenesulfoniylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4 - (4-But-2-ynyloxy-benzenesulfinylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxytetrahydro-2H-pi ran-4 -carboxamide; l-Benzyl-4-. { [3- (2-Butynyloxy) phenyl] -sulfonyl} -N-hydroxy-4-piperidinecarboxamide; 4- . { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-1-isopropyl-4-piperidinecarboxamide; 4-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-1- (3-pyridinylmethyl) -4-piperidinecarboxamide; 3-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -l-ethyl-N-hydroxy-3-piperidinecarboxamide; 3-. { [4- (2-Butynyl oxy) phenyl] sulfonyl} -l- (4-cloxobenzyl) -N-hydroxy-3-piperidinecarboxamide; Hydroxyamide of 4 - acid. { [4 - (2-Butyloxy) -phenyl] sulfonyl} -1- [4- (2-piperidin-yl-ethoxy) -benzyl] -piperidin-4-carboxylic acid; Hydroxyamide of acid 4-. { [4- (2-butyloxy) -phenyl] sulfonyl} -l- (3-pentanyl) -piperidine-4-carboxylic acid; Hydroxyamide 1- (4-methoxy-benzyl) -4 - (4-prop-2-ynyloxy-benzenesul-fonyl) -piperidin-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-chloro-benzyl) -4 - (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfanyljramethyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid tert -butyl ester; 4- ( { [4- (But-2-ynyloxy) phenyl] thio.} Methyl) -N-hydroxypiperidin-4-carboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfinyl] methyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid tert-butyl ester; 4- [[[4- (2-Butynyloxy) phenyl] sulfinyl] methyl] -N-hydroxy-4-piperidinecarboxamide; 4- ( { [4- (2-But-2-ynyloxy) phenyl] sulfonylmethyl) -4- [(hydroxyamino) -carbonyl] -piperidine-1-carboxylic acid tert-butyl ester; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl} ethyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid tert-butyl ester; 1-Acetyl- - [[[4- (2-butynyloxy) phenyl] -sulfonyl] methyl] -N-hydroxy-4-piperidinecarboxamide; 1- (2-Butyl) -4 - ( { [4 - (2-Butynyloxy) phenyl] sulfonyl} -methyl) -N-hydroxy-4-piperidinecarboxamide hydrochloride; Nl- (tert-Butyl) -4- ( { [4- (2-Butynyloxy) phenyl] -sulfonyl-J-methyl) -N-4-hydroxy-l, 4- [4- (2-butynyloxy) -phenyl] sulfonyl } methyl) -N-4-hydroxy-l, 4-1] sulfonyl} -methyl) -N-4-hydroxy-1,4-piperidinecarboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl-methyl-methyl) -4- (hydroxyamino) -carbonyl] -1-piperidinecarboxylate; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl} methyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid benzyl ester; l-Benzyl-4- ( { [4- (2-Butynyloxy) phenyl] -sulfonyl} methyl) -N-hydroxy-4-butynyloxy) phenyl] -sulfonyl} methyl) -N-hydroxy-piperidinecarboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) -carbonyl] - 4-piperidinecarboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl.] Methyl) -N-hydroxy-1- [3-hydroxy-2- (hydroxymethyl) -2-methyl-propanoyl] -4-piperidine -carboxamide; 1- [Amino (imino) methyl] -4- ( { [4- (2-Butynyloxy) -phenyl] sulfonyl.} Methyl) -N-hydroxy-4 -1] -4- ( { [ 4- (2-Butynyloxy) phenyl] sulfonyl, methyl) -N-hydroxy-4-oxy) -phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl.] Methyl) -N-hydroxy-1- (4-hydroxy-2-butynyl) -henyl] sulfonyl} -methyl) -N-hydroxy-1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl.} Methyl) -1-yl-N-hydroxypiperidin-4-carboxamide of the trifluoroacetic acid salt; 2-Chloro-5- (chloromethyl) thiophene-4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl} methyl) -1- [(5-chlorothien-2-yl) -met i 1] -N-hydroxypiperidine-carboxamide of the trifluoroacetic acid salt; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl.] Methyl) -N-hydroxy-1- (pyridin-4-ylmethyl) piperidine-4-carboxamide of the trifluoroacetic acid salt; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl-Jethyl) -N-hydroxy-1- (pyridin-3-ylcarbonyl) piperidine-4-carboxamide of the salt of trifluoroacetic acid; l-Benzoyl-4- ( { [4- (but-2-ynyloxy) phenyl] -sulfonyl.} methyl) -N-hydroxy-piperidin-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (thien-2-ylcarbonyl) piperidine-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl.] Methyl) -N-l-ethyl-N-4-hydroxy-piperidin-1,4 -dicarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl} methyl) -N-4-hydroxy-N-1-phenyl-piperidin-1,4 -dicarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl.] Methyl) -N-l-, N-l-diethyl-N-4-hydroxypiperidin-1,4 -dicarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (morpholin-4-ylcarbonyl) piperidin-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-4-hydroxy-N-l-methyl-N-l-phenylpiperidin-1,4-dicarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl-Jethyl} -4- [(hydroxyamino) -carbonyl] piperidin-1-carboxyl octyl; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jethyl) -4 - [(hydroxy-amino) carbonyl] piperidin-1-carboxylic acid 4-methoxyphenyl ester; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (phenyl sulfonyl) iperidin-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-l- [(1-met yl-lH-imidazol-4-yl) sulfonyl] -piperidin-4- carboxamide; 1- [2- (Benzylamino) acetyl] -4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxypiperidine-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (2-morpholin-4-ylacetyl) piperidine-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl.] Methyl) -N-hydroxy-1- [2- (4-methyl-piperazin-1-yl) acetyl] -piperidine- 4-carboxamide; L-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid hydroxyamide; L-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-carboxylic acid hydroxyamide; 1- (4-Methoxybenzoyl) -4 - (-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid hydroxyamide; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyrrolidin-1-carbonyl) -4-piperidinecarboxamide; 4- (4 -But-2-ynyloxybenzenesulfonyl) -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxylic acid ethyl ester; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(tri fluoromethyl) sulfonyl] -4-piperidinecarboxamide; 4- (4-But-2-ynyloxybenzenesulphonyl) -N-hydroxy-1- (3-pyridinylcarbonyl) -4-piperidinecarboxamide; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (2-thienylcarbonyl) -4-piperidinecarb? -xamide; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(4-methoxy phenyl) -sulfonyl] -4-yperidinecarboxa ida; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(2, 2, 5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxamide; 4-. { [4- (2-Butyroxy) phenyl] sulfonyl} -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxialate tert -butyl; 4- Hydrochloride. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -N-hydroxy-4-piperidinecarboxamide; (. {4- {[[4- (2-Butynyloxy) phenyl] -sulfonyl} -4- [(hydroxyamino) -carboyl] -1-piperidinyl} -ethyl) -benzoate hydrochloride; Acid chlorohydrate (. {4- {[4- (2-butyloxy) -phenyl] sulfonyl} -4- [(hydroxyamino) carbonyl] -1-piperidyl-yl} -methyl) -benzoic acid; 1- [4- (aminocarbonyl) benzyl] -4- hydrochloride. { [4- (2-Butynyloxy) phenyl] sulphonyl} -N-hydroxy-4-piperidinecarboxamide; 4- . { [4- (But-2-ynyloxy) phenyl] sulfinyl} -4- [(hydroxyamino) carbonyl] piperidine-1-carboxalate of tert-butyl; 4- (4- (But-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride and l- (4-bro o-benzyl) -4- (4- hydroxamide hydrochloride but-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid, and pharmaceutical salts thereof Heteroaryl, as used throughout the description, is a 5-10 membered mono- or bicyclic aromatic ring having from 1- 3 heteroatoms selected from N, NR7, S and O. Heteroaryl is preferably: a > - co. or - or where K is defined as O, S or -NR7, and R7 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -C (0) -R ?, -S02-R ?, -C (0) -NHR ?, -C (0) NR5R6, -C (0) Rx, NR5R6, -C (0) -OR ?, -C (NH) -NH2. Preferred heteroaryl ring include pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole, indole, isoindole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole, benzimidazole, benzothiazole, benzisoxazole, and benzoxazole. The heteroaryl groups of the present invention may be mono or disubstituted. Ccycloheteroalkyl of 4 to 8 carbon atoms is defined as where K is 0, S or NR7 and R7 is as defined above. Preferred heterocyanoalkyl rings include piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine. The heterocycloalkyl groups of the present invention can optionally be mono- or di-sus tuted. Aryl, as used herein, refers to phenyl or naphthyl aromatic rings which may optionally be mono- or di-sus ti tuidos. 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 (carbon bonded to hydrogen, or other carbons in the chain or ring) or can be mono- or poly-substituted. Aralkyl as used herein refers to a substituted alkyl group, -alkyl 1 -aryl, wherein alkyl is lower alkyl and preferably 1-3 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 1-3 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, -OR5, = 0, -CN, -C0R5, perfluoroalkyl of 1-4 carbon atoms, -0- perfluoroalkyl of 1-4 carbon atoms carbon, -CONR5R6, -S (0) "R5, -OPO (OR5) OR6, -PO (OR5) R6, -OC (0) OR5, -OR5NR5R6, -OC (0) NR5R6, -C (0) NR5OR6 , -C00R5, -S03H, -NR5R6, -N [(CH2) 2] 2NR5, -NR5COR6, -NR5COOR6, -S02NR5R6, -N02, -N (R5) S02R6, -NR5CONR5R6, -NR5C (= NR6) NR5R6, -NR5C (= NR6) N (S02R5) R6, -NR5C (= NR6) N (C = 0R5) R6, -tetrazol-5-yl, -S02NHCN, -S02NHCONR5R6, phenyl, heteroaryl or cycloheteroaryl of 4 to 8 carbon atoms carbon; wherein -NR5R6 can form a pyrrolidine, piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine, pyrazolidine, piperazine or azetidine ring; R5 and Re are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or cycloheteroalkyl of 4 to 8 carbon atoms; R7 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, -C (0) -R ?, -S02 -R ?, -C (0) -NHRx, - C (0) -0R ?, -C (NH) -NH2; 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, hydrobromic, phosphoric, nitric acids, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulphonic, phonylphosphonic, and similarly known acceptable acids when a compound of this invention contains a basic portion. The salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium or potassium, when a compound of this invention contains an acidic 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 with 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, which includes 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, scarring 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 proes for producing the compounds of the present invention, which proes comprise one of the following: a) reacting a compound of the formula wherein n, X, Y, A, Ri, R2, R3, Rs, R9, Rio, and R11 are as defined above or a reactive derivative thereof, with a compound of the formula R12NHOH ¿9 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, R 1 R2, R 3, R 8, R 9, R 10, R n and R 2 are as defined above, and R 30 is a suitable protecting group such as t-butyl, benzyl, and tri -alkylsilyl, 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, Ri, R2, R3, R8, R9, Rio, and R11 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 reactive anhydride derivative with the compound of the formula R12NHOH. 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, see for example, Reaction Scheme 16 below. Process c) can be carried out using a strong acid such as TFA to remove the hydroxamate from the resin. With respect to process d) standard separation techniques can be used for the isolation of the particular enantomeric or diastereomeric forms. For example, a racemic mixture can be converted to a mixture of optically active diastereomers by reaction with a simple enantiomer of a "resolving agent" (for example by the formation of the diastereomeric salt or formation of a covalent bond). The resulting mixture of optically active diastereoisomers can be separated by standard techniques (e.g. crystallization or chromatography) and the individual optically active tereoisomer days then treated to remove the "resolving agent" thereby releasing 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 enantomer 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 the process e) the 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 to ester or ether. Reactive sites such as a sulfur atom can be oxidized to SO or S02, (for example as shown in Reaction Scheme 4 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, see Reaction Schemes 4 and 17 below.
PROCESS OF THE INVENTION The compounds of the present invention can be conveniently prepared according to one of the general processes described below. The compounds of the present invention, wherein n = 0, X = O, S or NR7, and R8 and R9 taken with the carbon atom to which they are attached, form a six-membered heterocyclic ring containing N-R7, S or O and A = S, SO or S02 can be prepared according to one of the general processes described below. As described in Reaction Scheme 1, the appropriately substituted mercaptan derivative is alkylated using an ester derivative of a-bromo acetic acid in chloroform which is brought to reflux using N, N-diisopropylethylamine as the 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 in this way can be converted to the corresponding piperidine derivative by reacting it with an amine derivative of bis (2-chloroethyl) N -substituted.
REACTION SCHEME 1 SYMPTOMS I S: to. Derivative of Diisopropylethylamine / CHCl3 / TA / 3 hours; b. Derivative of K2C03 / Acetone / Propargyl Bromide; c. Oxone / MeOH: THF / THF / TA; d. Amine derivative K2C03 / 18-Crown-6 / (C H9) 4NBr / Acetone / Bis-2-chloroethyl or N-substituted / Reflux; and. NaOH / THF: MeOH / TA and (C0C1) 2 / -NH2OH. HCl / Et3N / THF / DMF.
The amines bis-2-chloroethexyl-N-theirs can be prepared from substituted diethanolamine and thionyl chloride. (Reaction Scheme 2). The cyclic product obtained by the operation mentioned above can be hydrolyzed to carboxylic acid and subsequently converted to the hydroxamic acid as described in Reaction Scheme 1.
REACTION SCHEME 2 a: Diisopropylethylamine / R7Br / CHCl3 / Reflux; b: SOCl2 / -CH2Cl2 / Reflux The corresponding sulfides and sulfoxides can be prepared initially from the corresponding saturated heterocyclic carboxylic acid derivative. (Reaction Scheme 3). The isonipecotic acid protected with N-Boc can be lithinated using ter-but-lithium and the resulting anion is reacted with appropriately substituted disulfides. The sulfide derivative can be converted to hydroxamic acids by the process described above.
REACTION MODEL 3 a: tert-Butyl-lithium / -78 ° C / THF / disul furo of bis (4-but-2-ynyloxyphenyl); b: (COCl2 / NH2OH, HCl / Et3N / DMF / CH2Cl2; c: l.HCl / Dioxane; c: 2: R7Br / Et3N; d: MeOH / H202 30% These sulphides can subsequently be converted to the sulfoxides using 30% hydrogen peroxide at room temperature. The required disulfides can be prepared from the appropriately substituted thiol and oxidation of DMSO / HCl. This procedure can be applied to any fused and non-fused heterocyclic carboxylic acid derivative. (Reaction Scheme 4) REACTION SCHEME 4 a: tert-Butyl-lithium / -78 ° C / THF / bis (4-but-2-ynyloxyphenyl) disulfide; b: (COCl2 / NH2OH, CH1 / Et3N / DMF / CH2Cl2, c: CH2Cl2 / HCl / MeOH / R7Br / Et3N, d: MeOH / 30% H202, e: Oxone / MeOH / THF / Rt.
Alternatively, the sulfone derivatives can also be lithinated and carbonylated using either dry ice or C02 gas. (Reaction Scheme 5). The sulfone derivative can be a mono-heterocyclic, bicyclic, benzo-fused or heteroaryl such as fused ring systems of pyridyl, thienyl, furanyl, pyrazinyl, pyrimidyl, thiazolyl.
REACTION SCHEME 5 a: n-But-il-lithium and rapid cooling with C02; b (COCÍ) 2 / DMF / NH2OH. HCl / Et3N The oxygen analogue can be prepared (Reaction Scheme 6) from the appropriately substituted alkynyloxy-benzenesulfonylactocic acid ethyl ester and 2-chloroethyl ether. The corresponding pyran derivative can be hydrolyzed to carboxylic acid, which can be converted to the hydroxamic acid derivative.
REACTION SCHEME 6 a: 2-Chloroethylether / K2C03 / 1.8-Corona-6 / n- (C4H9) 4Br / Acetone / - Ref luj o; b: lON.NaOH / THF / MeOH / TA; c: (COCÍ) 2 / DMF / NH2OH.HCl / Et3N.
The thiols used as intermediates for the synthesis of the compounds of the invention can be made according to Reaction Scheme 7. In this way, the salts of sulfonic acid 1, wherein XR50 is a hydroxy, thiol or substituted amino moiety it 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 reactant compatible with the substituents Ri, R2 and R3 and the acetylene. The sulfonyl chloride 4 can then be reduced to the corresponding thiol using triphenylphosphine in a suitable solvent mixture such as dichloromethane / DMF at a temperature between -20 ° C and 30 ° C.
REACTION SCHEME 7 13 Alternatively, 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, thiophenyl, aniline or protected aniline 8 with 2 to give 9, followed by the reaction with chlorosulfonic acid provides sulfonic acids 10 which is 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 group, the alkylation of XH, where X is O, N or S and the deprotection of sulfur.
Reaction Scheme 8: ^ COORao s R11 The compounds of the invention wherein X is N, O, S, SO or S02, can be synthesized according to Reaction Scheme 8 and the Reaction Scheme 9. The alkylation of the aryl 14 paradisus tideum, or its protected equivalent, with acetylene 2 in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetone or DMF at a temperature of between 20 ° C and 120 ° C. ° 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 are defined as above), in the presence of a base such as potassium t-butoxide in a polar solvent, or a solvent mixture, such as THF or DMF produces the carboxylic acid 16. The conversion of 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 acid anhydride followed by reaction with hydroxylamine. It is understood by those skilled in the art that when A is sulfur, in Reaction Scheme 8 and all relevant subsequent 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 18 are also accessible from the Michael addition of compound 15 for a cyclic acrylate ester, or substituted acrylate ester (substituents are defined above), to provide 18, wherein R 30 is hydrogen or a protecting group of suitable carboxylic acid, which can be converted to the analogous hydroxamic acid. Similarly, the Michael addition of the mono-protected, mono-protected, 1, 4-aryl aryl, wherein XR2s is protected hydroxy or hydroxy, thiol or amine, gives the compound 20. The non-masking of the protecting group gives thiol, aniline or phenol 21 which can be alkylated with a propargyl 2 derivative to provide 18. The protected mono compound 19 can also be reacted with β-propionolactone to provide 22. Alternatively, 22 can be deprotected followed by alkylation to give 16 and 17. 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 which is a chain of one or three carbons can be synthesized according to the Scheme Reaction 9. Compound 19, wherein XR25 is protected hydroxy or hydroxy, thiol or amine, can be reacted with ester 24 or lactone 24a, wherein R30 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 hetero atom X of compound 25 then provides, which can then be alkylated with the propargyl derivative 2 to give acetic acid-ester 27. The ester 27 can be converted to the corresponding hydroxamic acid 28 through conversion of the ester to the carboxylic acid by the hydrolysis of acid or base, followed by conversion to the hydroxamic acid as described in Reaction Scheme 1. Alternatively, compound 15, prepared as shown in Reaction Scheme 8, can be directly alkylated with ester 24 or lactone 24a for give 27 and then 28. Substituents on the alpha to the hydroxamic are defined as above.
REACTION SCHEME 9 (for A = S) 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 10. Esters or carboxylic acids 29, commercially available or known in the literature, can be converting to the corresponding phenols, 30. The alkylation of the phenol with acetylene 2 gives the propargyl ethers, 31, which can be converted to the corresponding carboxylic acids and then to the hydroxamic acids, 33, as described in Reaction Scheme 1 The substituents on the alpha carbon for the hydroxamic are defined as above.
REACTION SCHEME 10 33 32 The compounds of the invention wherein A is -S02-, and R8 and R9 are not hydrogen, are initially available from 4-fluorobenzothiol 34 as shown in Reaction Scheme 11. The deprotonation of the thiol followed by the reaction with • -propiolactone, or an acrylate ester, or 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, in where X is N, 0 or S, then provides sulfone 16. Compound 16 can be converted to the compounds of the invention according to Reaction Scheme 1. Fluoroaryl 35 can also react with a hydroxyl, thiol or amino group masked (HXR40, wherein R 0 is a suitable protecting group) in the presence of a base such as sodium hydride in an aprotic polar solvent such as DMF to provide 36. Deprotection of 36 followed by alkylation with the acetylene derivative 2 then gives 16.
REACTION SCHEME 11 The compounds of the invention wherein X is NH are also available starting from the commercially available nitro-aryl compound, suitable 38 (Reaction Scheme 12). In this way, the anion of compound 38 can be used to alkylate the β-propylactone, or a substituted derivative, or a cyclic acrylate ester to provide 40 and 39 respectively. 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 nitro-ester 40, followed by the reduction to give the corresponding aniline, analogous to the compound 26. of the Reaction Scheme 9.
REACTION SCHEME 12 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 13. These epoxides are available through the oxidation of the corresponding acrylate esters or by the Darzens reaction of an alpha-haloes ter with a ketone. Reaction of the epoxide with thiol, phenol or aniline 19 in the presence of an epoxide ring opening catalyzed with a base or Lewis acid, provides the alpha-hydroxyester ter 42. Deprotection of 42 followed by alkylation with the propargyl derivative 2 da 44. The conversion of ester e 44 to the analogous hydroxamic acid as described in Reaction Scheme 1 then gives 45. Compounds 45, wherein A is sulfur, can be converted to the analogous sulfoxides or sulfones through the Oxidation with hydrogen peroxide, air, Oxona 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 to a suitable leaving group, such as halide or sulfonate ester, followed by displacement with several nucleophiles including amines to provide 44.
E REACTION SYSTEM 13 fifteen Another route for the alpha-hydroxy hydroxamic acids of the invention is shown in Reaction Scheme 14. Compound 15 can be alkylated with alcohol 46 to give 47. Oxidation of the alcohol, with or without concomitant thioether oxidation (for A = S), gives 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 49 into the corresponding carboxylic acid followed by the conversion to the hydroxamic acid as described in Reaction Scheme 1 gives 50.
REACTION SCHEME 14 T SCN The compounds described in the present invention (from Example 30 to 63) were prepared by Reaction Schemes 15 and 16. In reaction scheme 15, the t-Boc-protected ethyl isonipecotate 51 was carefully alkylated using diiodomethane to produce the monobodo compound 52. This was subsequently converted to the different hydroxamic acid derivatives as represented in Reaction Scheme 15. In reaction scheme 16, the N-Boc group was selectively removed using TMSOTf / 2, 6-Lutidine. After derivatization of the nitrogen, O-tBu was removed using TFA in methylene chloride.
Reaction Scheme 15 R = H Reaction Scheme 16 Alternatively, the compounds (wherein A = S02 and n = 0) described in Examples 64 to 74 and 80 were prepared as depicted in Reaction Scheme 17.
Reaction Scheme 17 Example 1 H-droxamide 1- (4-bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid Step 1: To a stirred solution of 4-mercapto phenol (12.6 g, 100 mmol) and N, N-di-sopropylethylamine (13.0 g, 100 mmol) in chloroform (200 ml), ethyl bromoacetate (17.0) was slowly added. g, 100 mmol) in chloroform solution (30 ml) at room temperature. After the addition was complete, the reaction mixture was refluxed for 1 hour and cooled to room temperature. The reaction mixture was washed well with water, dried over anhydrous MgSO.sub.0; it was filtered and concentrated. The oily product obtained was taken for the next step without purification.
Step 2: A mixture of K2C03 (15 g, excess), ethyl ester of (-hydroxy-phenylsulfane) -acetic acid (5 g, 23.6 mmol) and l-bromo-2-but-ina (9.34 g, 35.4 mmol) was carried at reflux with stirring for 8 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous MgSO, filtered and concentrated. The product obtained was taken for the next step without purification. Yield 6.0 g (96%); yellow oil; E.M: 264.0 The (M + H).
Step 3: A stirred solution of (4-but-2-ynyloxy-phenylsulphane) -acetic acid ethyl ester (101 g, 380 mmol) in MeOHrTHF (3: 1) (1000 ml), Oxona ( 670.0 g, excess) in water (1000 ml). The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was then diluted with chloroform (600 ml) and filtered. The organic layer was separated and washed once with a saturated solution of NaHS03 (400 ml). The chloroform layer was washed well with water, dried and concentrated. The oily product was dissolved in MeOH (100 ml) and hexane (600 ml) was added. The solid • colorless separated was filtered and washed with hexane. Yield 108 g (96%); p.f. 91-93 ° C; MS: 297 (M + H) +.
Step 4: A mixture of diethanolamine (22.5 g, 150 mmol), 4-bromobenzyl bromide (25 g, 100 mmol) and N, N-diisopropylethylamine (19.0 g, 150 mmol) was refluxed for 24 hours at sol lution, of clo ro form (500 ml). The reaction mixture was then concentrated and the residue was extracted with chloroform. It was washed well with water, dried over anhydrous MgSO 4, filtered and concentrated. The obtained crude product was taken for the next step without purification. Performance 33.6g (99%); yellow oil: MS: 273.8 (M + H) +.
Et 5: 2- [(4-Bromobenzyl) - (2-hydroxy-ethyl) -amino] -ethanol (33.28 g, 122 mmol) was dissolved in metallic hydrogen chloride (100 ml) at 0 ° C. The methanol was removed in vacuo and the hydrochloride salt was suspended in CH2C12 (300 ml). To a stirred solution of the suspension mentioned above, thionyl chloride (30 g, excess) was slowly added at room temperature. The reaction mixture is conducted at gentle reflux for 3 hours. The reaction mixture was then concentrated and (4-bromo-benzyl) -bis- (2-chloro-ethyl) -amine was used in the next step without purification. Yield: 47 g (99%); solid coffee; p.f. 125 ° C; MS: 309.8 (M + H) +.
Step 6: A stirred mixture of anhydrous K2COa (10 g, excess), 18-crown-6 (1 g), tetrabutylammonium bromide (1.0 g), (4-but-2-ynyloxy-benzenesulfonyl) ethyl ester -acetic (2.8 g, 9.46 mmol) and (4-bromo-benzyl) -bis- (2-chloro-ethyl) -amine (4.9 g, 14.2 mmol) in anhydrous acetone (200 ml) was brought to reflux for 24 hours. hours. The reaction mixture was then cooled and filtered and the filtrate was concentrated. The crude product was extracted with chloroform, washed well with water, dried and concentrated. The brown material was purified by column chromatography on silica gel eluting with 50% ethyl acetate: hexane. Yield 1.35 g (27%); coffee oil; MS: 534 (M + H) +.
Step 7: 1- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid was prepared starting from the ethyl ester of 1- (4-bromo- benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (1.36 g, 2.54 mmole) dissolved in THF: methanol (100: 50 ml) and NaOH ION (15 ml). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then concentrated and the residue was cooled and neutralized with concentrated HCl. The separated solid was extracted with chloroform: methanol (3: 1) (300 ml) and washed with water. The chloroform layer was dried and concentrated. The product was crystallized from methanol. Yield 800 mg (62%); whitish solid; p.f. 197 ° C; MS: 507.9 (M + H) +.
Step 8: To a stirred solution of 1- (4-bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (750 mg, 1.5 mmol) and DMF (1 ml) in CH2C12 (100 ml), oxalyl chloride (508 mg, 4.0 mmol) in methylene chloride (2 ml) was added at 0 ° C. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 hour. The acid chloride formed in this way was concentrated to remove excess oxalyl chloride and redissolved in CH2C12 (30 ml). In a separate flask, hydroxylamine hydrochloride (690 mg, 10 mmol) was dissolved in DMF (10 ml) and triethylamine (10 g, 10 mmol) was added. The reaction mixture was further diluted with acetonitrile (25 ml) and stirred at 0 ° C. Acid chloride was added slowly to the hydroxylamine and after the addition was complete, the reaction mixture was brought to room temperature and stirred for 24 hours. The reaction mixture was concentrated and the residue was extracted with chloroform, washed well with water and dried over Na2SO4. The product was purified by column chromatography on silica gel eluting with 10% methanol: ethyl acetate. 270 mg of l- (4-bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid hydroxamide was isolated as a hydrochloride salt, a white powder. Yield 52%; p.f. 153 ° C; MS: 522.9 (M + H) +; Tti NMR (300 MHz, DMSO-d6): d 1.85 (t, J = 2.04 Hz, 3H), 2.23 (m, 2H), 2.49 (m, 2H), 2.83 (m, 2H), 3.36 (m, 2H) ), 4.28 (s, 2H), 4.89 (d, J = 2.2 Hz, 2H), 7.18 (d, J = 9 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.68 (m, 4H) ), 9.37 (s, 1H), 10.25 (s, 1H).
Example 2 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide 2- [(2-hydroxy-yl) - (4-methoxy-benzyl) -amino] -ethanol according to the general method described in Example 1 (Step 4). Starting from diethanolamine (10.5 g, 100 mmol), and 4-methyl oxybenzyl chloride (15.6 g, 100 mmol). Yield 21 g, (98%); yellow oil; MS: 226 (M + H) +. Bis- (2-chloro-ethyl) - (-methoxy-benzyl) -amine was prepared according to the general method described in Example 1 (Step 5). Starting from 2- [(2-hydroxy-ethyl) - (4-methoxy-benzyl) -amino] -ethanol (11.2 g, 50 mmol). Yield 14 g, (99%); dark coffee solid of low melting; MS: 263 (M + H) +. 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-methoxy-benzyl) piperidin-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1. Starting from ethylester of (-but-2-ynyloxy-benzenesul-fonyl) -acetic acid (2 g, 6.73 mmol) and bis- (2-chloro-yl) - (4-methoxy-benzyl) -amine (2.61 g, 8.75 mmol) ) and following the procedure described in Example 1 (Step 6), 2.5 g of the product was isolated. Performance 2.5 g (77%); yellow oil; MS: 486 (M + H) +. • 4 - (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-methoxy-benzyl) -piperidin-4-carboxylic acid starting from the ethyl ester of 4- (4-but-2) acid was prepared -iniloxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid (2.5 g, 5.15 mmol) dissolved in THF: methanol (3: 1, 200 ml) and 10 N NaOH (15 ml) . The resulting reaction mixture was worked up as described in Example 1 (Step 7). Yield 1.26 g (54%); whitish solid; mp 223 ° C; MS: 458 (M + H) +.
Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -l- (4-methoxy-benzyl) -piperidin-4-carboxylic acid (1 g, 2.19 mmol) and following the procedure described in Example 1 , (Step 8), 350 mg of 4- (4-but-2-ynyloxy-benzenesul-fonyl) -l- (-methoxy-benzyl) -piperidin-4-carboxylic acid hydroxyamide was isolated as a hydrochloride salt, a solid whitish Performance 31%; p.f. 162 ° C; MS: 473 (M + H) +; NMR aH (300 MHz, DMSO-d6): d 1.86 (t, J = 2.13 Hz 3H) 2.23 (m, 2H) 2.49, m, 2H) 2.73, m, 2H), 3. 39 (m, 2H), 3.77 (s, 3H), 4.21 (d, J = 4.26 Hz, 2H), 4.89 (d, J = 2.28 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 9 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 9 Hz, 2H), 9.37 (s, 1H), 10.21 (s, 1H), 11.17 (s, 1H).
Example 3 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-chloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide 2- [(4-chlorobenzyl) - (2 -hydroxyethyl) -amino] -ethanol according to the general method described in Example 1 (Step 4). Starting from diethanolamine (14.3 g, 95 mmol), and 4-chlorobenzyl chloride (10.2 g, 63 mmol). Yield 12.1 g, (84%); yellow oil; MS: 230 (M + H) +. '(4-Chloro-benzyl) -bis- (2-chloro-ethyl) -amine was prepared according to the general method described in Example 1 (Step 5). Starting from 2- [(4-chlorobenzyl) - (2-hydroxy-yl) -amino] -ethanol (12 g, 52.4 mmol). Yield 41.27 g, (90%); yellow powder; p.f. 115 ° C; MS: 303 (M + H) +. 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-chloro-benzyl) -piperidin-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 (Step 6). Starting from (4-but-2-inyloxy-benzenesulfonyl) -acetic acid ethyl ester (4 g, 13.5 mmoles) and (4-chloro-benzyl) -bis- (2-chloro-ethyl) -amine (4.9 g, 16.2 mmol). Yield 3.5 g (53%); white crystals; P.F. 91.8 ° C; MS: 490 (M + H) +. 4 - (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-chloro-benzyl) -piperidin-4-carboxylic acid was prepared starting from the ethyl ester of 4- (4-but-2) acid -iniloxy-benzenesulfonyl) -1- (4-chloro-benzyl) -piperidine-4-carboxylic acid (3.14 g, 6.42 mmol) dissolved in THF: methanol 3: 1 (100 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). Yield 2.37 g (80%); white solid; p.f. 205 ° C; MS: 461.9 (M + H) +.
Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-chloro-benzyl) -piperidine-4-carboxylic acid (2.31 g, 5.11 mmol) and following the procedure described in Example 1 (Step 8), 790 mg of 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-chloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide was isolated as a hydrochloride salt , a yellow solid. Performance 31%; p.f. 130 ° C; MS: 476.9 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6): d 1.856 (s, 3H), 2.23 (m, 2H), 2.73-2.89 (m, 4H), 3.37 (d, 2H), 4.28 (m, 2H), 4.89 (d, 2H), 7.18 (d, J = 8.94 Hz, 2H), 7.54 (s, 4H), (d, J = 8.88 Hz, 2H), 9.40 (s, 1H), 10.3 (s, 1H).
Example 4 l-Benzyl-4- (4-but-2-ynyloxybenzenesulfonyl) -piperidin-4-carboxylic acid hydroxyamide Bis- (2-chloro-ethyl) -benzylamine was prepared according to the general method described in Example 1 (Stage 5). Starting from N-benzyldiethanol-amine (164.6 g, 844 mmol). Performance 178.5 g (79%); solid coffee; MS: 231.9 (M + H) +. L-benzyl-4- (4-but-2-ynyloxy-benzenesul-fonyl) -piperidin-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 (Step 6). Starting from the (4-but-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester (2 g, 6.73 mmoles) and bis- (2-chloro-ethyl) -benzylamine (2.3 g, 8.8 mmol). Yield 3.33 g (99%); yellow oil; MS: 455.9 (M + H) +. L-benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid was prepared starting from the ethyl ester of l-benzyl-4 - (4-but-2-yn-loxi) -benzenesulfonyl) -piperidin-4-carboxylic acid (3 g, 6. 6 mmole) dissolved in THF: methanol (3: 1, 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). Yield 1.65 g (59%); whitish powder; p.f. 191 ° C; MS: 428 (M + H) +. Starting from l-benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (1.55 g, 3.63 mmol) and following the procedure described in Example 1 (Step 8), 1.08 g of l-benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidin-4 hydroxyamide was isolated. -carboxylic acid as a hydrochloride salt, a whitish powder. Yield 62%; p.f. 175 ° C; MS: 443 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.85 (t, J = 2.16 Hz, 3 H), 2.25 (m, 2 H), 2.49 (m, 4 H), 2.77 (m, 2 H), 4.28 (d, J = 4.3 Hz, 2H), 4.89 (d, J = 2.28, 2H), 7.18 (m, 2H), 7.46 (m, 5H), 7.73 (m, 2H), 9.36 (s, 1H), 10.27 (s, 1H), 11.08 (s, 1H).
EXAMPLE 5 1- (4-Bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid hydroxyamide (4-pent-2-ynyloxy-phenylsulphanyl) ethyl ester was prepared -acetic according to the general method described in Example 1 (Step 2). Starting from the ethyl ester of (4-hydroxy-phenylsulfanyl) -acetic acid (5 g, 30 mmol) and 2-pentynyl chloride (3.7 g, 36.6 mmol) 7.15 g of the isolated product. Yield 7.15 g (86%); coffee oil; MS: 278 The (M + H) +. (4-Pent-2-ynyloxy-benzenesul-fonyl) -acetic acid ethyl ester was prepared according to the general method described in Example 1 (Step 3). Starting from the ethyl ester of (4-pent-2-ynyloxy-phenylsulphane) -acetic acid (7.04 g, 25.3 mmoles) and oxone (25 g) was isolated the ethylester of (4-pent-2-ynyloxy-benzenesulfonyl) acid -acetic. Yield 8 g (99%); yellow oil; MS: 310.9 (M + H) +. 1- (4-Bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 (Step 6) . Starting from the ethyl ester of (4 -pent-2-inyloxy-benzenesulfonyl) -acetic acid (4 g, 12.9 mmoles) and (4-bromo-benzyl) -bis- (2-chloro-ethyl) -amine (5.83 g , 16.8 mmoles), 2.85 g of the product was isolated. performance 2. 85 g (31%); white solid of low melting; EM: 549.9 (M + H) +. 1- (4-Bromo-benzyl) -4 - (4-pent-2-ynyloxy-benzenesulfonyl) piperidin-4-carboxylic acid was prepared starting from the ethyl ester of l- (4-bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) piperidine-4-carboxylic acid (2.64 g, 4.8 mmol) dissolved in THF: methanol (100: 50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). performance 1. 6 g (65%); whitish solid; p.f. 217 ° C; MS: 521.9- (M + H) +. Starting from 1- (4-bromo-benzyl) -4- (4-pent-2-ynyloxy-benzenesulfonyl) piperidine-carboxylic acid (1.55 g, 2.98 mmol) following the procedure described in Example 1 (Step 8) , 200 mg of 1- (4-bromo-benzyl) -4- (4 -pent-2-ynyloxy-benzenesulfonyl) piperidin-4-carboxylic acid hydroxyamide was isolated as an HCl salt, a yellow solid. Yield 12%; p.f. 62 ° C; MS: 536.9 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1069 (t, J = 7.47 Hz, 3 H), 2.26 (, 2 H), 2.49 (m, 2 H), 2.73 (m, 2 H), 2.89 (s, 2 H) , 3.40 (d, 2H), 4.26 (d, 2H), 4.9 (m, 2H), 7.18 (m, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.66 (m, 4H), 10.39 ( s, 1H), .11.19 (s, 1H).
Example 6 1- (4-Bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide (4-oct-2-ynyloxy-phenylsulfanyl) ethyl ester was prepared -acetic according to the general method described in Example 1 (Step 2). Starting from the ethyl ester of (4-hydroxy-phenyl-sulfanyl) -acetic acid (5 g, 30 mmol) and l-bromo-2-octine (6.9 g, 36.6 mmol) was isolated 8.9 g of ethyl ester (4 g). -cot-2-ynyloxy-phenyl sulphyl) -acetic. Yield 8.9 g (92%); yellow oil; MS: 320 The (M + H) +. (4-Oct-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester was prepared according to the general method described in Example 1 (Step 3). Starting from the (4-oct-2-ynyloxy-phenylsulfanyl) -acetic acid ethyl ester (8.8 g, 27.5 mmol), 8.45 g of (4-oct-2-ynyloxy-phenylsulfonyl) -acetic acid ethyl ester was isolated. Yield 8.45 g (87%); yellow oil; MS: 352 The (M + H) +. 1- (4-Bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 (Step 6) . Starting from the ethyl ester of (-oct-2-ini-loxy-benzenesul foni 1) -acetic acid (4 g, 11.4 mmol) and (4-bromo-benzyl) -bis- (2-chloro-ethyl) -amine ( 5.13 g, 14.8 mmol) was isolated 1.47 g of l- (4-bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesul-fonyl) -piperidine-4-carboxylic acid ethyl ester. Yield 1.47 g (22%); yellow solid; MS: 591.9 (M + H) +. 1- (4-Bromobenzyl) -4 - (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid was prepared from the ethyl ester of 1- (4-bromobenzyl) -4 - (4 - oct-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid (1.36 g, 2.3 mmol) dissolved in THF: methanol (50:50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). Yield 660 mg (51%); whitish solid; p.f. 199 ° C; E: 562 (M + H) +. Starting from 1- (4-bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (570 mg, 1.01 mmol) and following the procedure described in Example 1 (Step 8), 100 mg of 1- (4-bromo-benzyl) -4 - (4-oct-2-ynyloxybenzenesulfonyl) -piperidin-4-carboxylic acid was isolated as a hydrochloride salt, a white powder. Yield 17%; p.f. 140 ° C; MS: 579 (M + H) +; 1N NMR (300 MHz, DMSO-d6): d 0.828 (t, J = 7.14 Hz, 3H), 1.25 (m, 6H), 1.38 (m, 2H), 2.27 (m, 2H), 2.49 (m, 4H ), 2.73 (m, 2H), 4.03 (m, 2H), 4.91 (s, 2H), 7.18 (d, J = 9 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.68 (m , 4H), 9.43 (s, 1H), 10.25 (s, 1H), 11.19 (s, 1H).
Example 7 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-fluoro-benzyl) -piper.idin-4-carboxylic acid hydroxyamide 2- [(4-Fluoro-benzyl) - (2-hydroxy-ethyl) -amino] -ethanol was prepared according to the general method described in Example 1 (Step 4). Starting from diethanolamine (15.7 g, 150 mmol), and 4-fluoro-benzyl chloride (14.4 g, 100 mmol), 20 g of the product was isolated. Yield 20 g, (93%); yellow oil; MS: 215 (M + H) +. (Fluoro-benzyl) -bis- (2-chloroethyl) -amine was prepared according to the general method described in Example 1 (Step 5). Starting from 2- [(4-fluoro-benzyl) - (2-hydroxy-ethyl) -amino] -ethanol (23.6 g, 110 mmol) was isolated 28 g of the product. Yield 28 g, (96%); solid coffee; p.f. 98-99 ° C; MS: 251 (M + H) +. 4- (4-But-2-ynyloxy-benzenesulfonyl) -l- (4-fluoro-benzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 (Step 6) . Starting from the ethyl ester of (4-but-2-ynyloxy-benzenesulfonyl) -acetic acid (5 g, 16.9 mmol) and (4-fluoro-benzyl) -bis- (2-chloro-ethyl) -amine (5.8 g , 20.1 mmoles) 5.3 g of the product was isolated. Yield 5.3 g (67%); coffee oil; MS: 474 (M + H) +. 4 - (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-fluoro-benzyl) -piperidin-4-carboxylic acid was prepared from 4 - (4-but-2-ynyloxy) ethyl ester -benzenesulfonyl) -1- (4-fluoro-benzyl) -piperidine-4-carboxylic acid (9.5 g, 20 mmol) dissolved in THF: methanol 3: 1 (100 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). performance . 7 g (63%); white solid; p.f. 106-106 ° C; MS: 447 (M + H) + Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-fluoro-benzyl) -piperidine-carboxylic acid (5.7 g, 13 mmol) and following the procedure described in Example 1 (Step 8), 4.1 g of the 4- (4-but-2-ynyloxy-benzenesulfonyl) -l- (4-fluoro-benzyl) -piperidine-carboxylic acid hydroxyamide was isolated as an HCl salt, a yellow solid. Yield: 64%; p.f. 162-4 ° C; MS: 461 (M + H) +; H-NMR (300 MHz CDC13): d 1.92 (s, 3H), 2.02-2.32 (m, 6H), 2.86 (m, 2H), 3.41 (d, 2H), 4.84 (d, 2H), 7.01 (d, J = 8.94 Hz, 2H), 7.15 (d, J = 8.88 Hz, 2H), 7.25 (d, J = 9 Hz, 2H), 7.74 (d, J = 9.0 Hz, 2H), 9.4-9.7 (s broad , 1 HOUR) .
Example 8 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4-carboxylic acid hydroxyamide 4- was prepared. { [bis- (2-hydroxyethyl) 1 -amino] -methyl} benzoni trilo in accordance with the general method described in Example 1 (Step 4) starting from diethanolamine (10.2 g, 97 mmol) and a-bromo-p-toluenonitrile (15.8 g, 81 mmol). Performance, (68%); white solid; p.f. 163 ° C MS: 221.2 (M + H) +. It was prepared 4 -. { [bis- (2-chloroethyl) -amino] -methyl} benzoni trilo in accordance with the general method described in Example 1 (Step 5) starting from 4-. { [bis- (2-hydroxyethyl) -amino] -met il} benzonitrile (33.28 g, 122 mmol). Yield g, (%); solid coffee; p.f. ° C; MS: (M + H) +. The 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 (Step 6). ). Starting from the 4- (4-but-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester (5.86 g, 19.8 mmol) and 4-cyano-benzyl-bis- (2-chloro-ethyl) -amine (5.4 g , 18 mmol) was isolated 4.7 g of the product. Performance (52%); amber oil; MS: 481.0 (M + H) +. 4 - (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidin-4-carboxylic acid was prepared starting from the ethyl ester of 4- (4-but-2-) acid inyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidin-4-carboxylic acid (4 g, 8.3 mmol) dissolved in THF: methanol (60: 30 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). Performance 1.8 g (48%); whitish solid; MS: 441.9 (M + H) +. Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4-carboxylic acid (1.8 g, 4 mmol) and following the procedure described in Example 1 (Step 8), 0.20 g of 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) -piperidine-4-carboxylic acid hydroxamide was isolated as a hydrochloride salt, solid White. Yield 20%; p.f. 109.6 ° C; MS: 468.0 (M + H) +; NMR * H (300 MHz, DMSO-d6): d 1.86 (m, 3H), 2.25 (m, 4H), 2.5 (m, 2H), 2.85 (d, 2H), 4.39 (s, 2H), 4.88 (s, 2H), 7.15-7.19 (d, J = 13.2, 2H), 7.67-7.70 (d, J = 13.5, 2H), 7.78 (m, 2H), 7.96-7.99 (d, J = 9.6, 2H), 9.42 (s, 1H), 10.14 (s, 1H), 11.20 (s, 1H).
Example 9 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-methyl-bensyl) -piperidine-4-carboxylic acid hydroxyamide 2- [(2-hydroxy-yl) - (4-met-il-benzyl) -amino] -ethanol according to the general method described in Example 1 (Step 4). Starting from diethanolamine (4.84 g, 46 mmol) and 4-methybenzyl bromide (8.5 g, 46 mmol), 8.2 g of the product was isolated. Performance, (85%); white solid; MS: 210.1 (M + H) +. 4-Met-il-benzyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method described in Example 1 (Step 5). Starting from 2 - [(2-hydroxy-ethyl) - (4-methyl-yl-benzyl) -amino] -ethanol (6.0 g, 20 mmol) was isolated 5.2 g of the product. Performance: (84%); yellow solid; p.f. 145-147 ° C; MS: 245.9 (M + H) +. 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-methyl-yl-benzyl) -piperidin-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 (Step 6) ). Starting from 4 - (4-but-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester (5.75 g, 19.0 mmol) and 4-methyl-benzyl-bis- (2-chloro-ethyl) -amine (6.04 208 mmoles) 6.47 g of the product was isolated. Performance: (72%); amber oil; MS: 470 (M + H) +. 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidin-4-carboxylic acid starting from the ethyl ester of 4- (4-but-2-) acid was prepared inyloxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid (6.4 g, 13.6 mmol) dissolved in THF: methanol (30: 20 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). Yield 2.3 g (48%); whitish solid; p.f. 213 ° C; MS: 441.9 (M + H) +. Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidine-4-carboxylic acid (2.0 g, 5.0 mmol) and following the procedure described in Example 1 (Step 8), 3.6 g of 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-methyl-benzyl) -piperidin-4-carboxylic acid hydroxamide was isolated as an HCl salt, whitish solid. Yield 1.2 g (28%); p.f. 188 ° C; MS: 457.0 (M + H) +; 1N-NMR (300 MHz, DMSO-d6): d 1.86 (s, 3H), 2.27 (m, 2H), 2.50 (m, 4H), 2.64 (m, 2H), 4.23-4.24 (d, J = 4.5, 2H), 4.89 (d, J = 1.8, 2H), 7.16-7.19 (d, J = 9, 2H), 7.24-7.26 (d, J = 7.5, 2H), 7.37-7.40 (d, J = 8.1, 2H), 9.36 (s, 1H), 10.11 (s, 1H), 11.20 (s, 1H).
Example 10 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (3, -dioloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide 2- [(2-hydroxy-ethyl)) - (3,4-dichloro-benzyl) -amino] -ethanol according to the general method described in Example 1 (Step 4). Starting from diethanolamine (4.84 g, 46 mmol) and 3-dichlorobenzyl chloride (8.97 g, 46 mmol), 9.4 g of the product was isolated. Performance, (78%); white solid; MS: 264.3 (M + H) +. 3,4-Dichloro-benzyl-bis- (2-chloro-ethyl) -amine was prepared according to the general method described in Example 1 (Step 5). Starting from 2 - [(2-hydroxy-ethyl) - (3,4-dichloro-benzyl) -amino] -ethanol (10.7 g, 41 mmol) was isolated 10.7 g of the product. Performance: (84%); yellow solid; p.f. 218-220 ° C; MS: 301.8 (M + H) +. 4- (4-But-2-ynyloxy-benzenesulfonyl) -1- (3,4-dichloro-benzyl) -piperidin-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 (Step 6) ). Starting from the 4- (4-but-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester (6.1 g, 23 mmol) and 3,4-dichloro-benzyl-bis- (2-chloro-ethyl) -amine mmoles) 4.9 g of the product was isolated. Performance: (41%); amber oil; MS: 523.8 (M + H) +. 4 - (4-But-2-ynyloxy-benzenesulfonyl) -1- (3,4-dichloro-benzyl) -piperidine-4-carboxylic acid was prepared starting from the ethyl ester of 4- (4-butyl) acid. 2-ynyloxy-benzenesulfonyl) -1- (3,4-dichloro-benzyl) -piperidine-4-carboxylic acid (8.6 g, 16.4 mmol) dissolved in THF: methanol (40: 30 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7).
Yield 2.1 g (38%); whitish solid; p.f. 232 ° C; MS: 495.9 (M + H) +. Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (3,4-dichloro-benzyl) -piperidine-4-carboxylic acid (2.06 g, 4.0 mmol) and following the procedure described in Example 1 (Step 8), 1.2 g of 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (3,4-dichloro-benzyl) -piperidine-4-carboxylic acid hydroxamide was isolated as a HCl salt, whitish solid. Yield 1.2 g (56%); p.f. 213 ° C; MS: 510.9 (M + H) +; 1 H-NMR (300 MHz, DMSO-d 6): d 1.86 (s, 3 H), 2.30 (m, 2 H), 2.50 (m, 4 H), 2.80 (m, 2 H), 4.40 (s, 2 H), 4.90 ( s, 2H), 7.16-7.19 (d, J = 9, 2H), 7.51-7.54 (d, J = 8.4, 2H), 7.66-7.69 (s, J = 9.0, 2H), 7.75-7.86 (d, J = 11.7, 2H), 7.88 (s, 1H), 9.38 (s, 1H), 10.44 (s, 1H), 11.19 (s, 1H).
Example 11 1- (4-Bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid hydroxyamide Step 1: (4-prop-2-ynyloxy) ethyl ester was prepared phenylsulfonyl) -acetic according to the general method described in Example 1 (Step 2), starting from the ethyl ester of (4-hydroxy-phenylsulfanyl) acetic acid (Example 1, 1st paragraph) (2.12 g, 10 mmol) ) and propargyl bromide (1.8 g, 15 moles) was isolated 2.4 g of the product. Yield: (96%); amber oil; MS: 251 (M + H) +.
Step 2: (4-prop-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester was prepared according to the general method described in Example 1 (Step 3). Starting from the ethyl ester of (4-prop-2-ynyloxy-phenylsulfanyl) -acetic acid (2.5 g, 10 mmol) was isolated 2.8 g of ethyl ester of (4-prop-2-lino-benzenesulfonyl) -acé 'acid. tico Performance: (99%); coffee oil; MS: 283 (M + H) +.
Step 3: 1- (4-Bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid ethyl ester was prepared according to the general method described in Example 1 ( Stage 6). Starting from the ethyl ester of (4-prop-2-ynyloxy-benzenesulfonyl) -acetic acid (21.62 g, 76.7 mmoles) and (4-bromo-benzyl) -bis- (2-chloro-ethyl) -amine (31.9 g , 92 mmoles), 23 g of the ester derivative was isolated. Performance: (58%); yellow oil; MS: 521.9 (M + H) +.
Step 4: 1- (4-Bromo-benzyl) -4 - (4-prop-2-ini-1-oxybenzenesulfonyl) -piperidin-4-carboxylic acid starting from the ethyl ester of 1- (4-bromo) acid was prepared -benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (5 g, 9.59 mmol) dissolved in THF: methanol (150: 50 ml) and 10 N NaOH (15 ml) . The resulting reaction mixture was worked up as described in Example 1 (Step 7). Yield 3.4 g (72%); solid low melting coffee; MS: 491.9 (M-H) -.
Step 5: Starting from 1- (4-bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (3 g, 6.1 mmol) and following the procedure described in Example 1 (Step 8), 580 mg of 1- (4-bro or -benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxamide was isolated as a HCl salt, whitish powder. Yield 18%; p.f. 155 ° C; MS: 508.8 (M + H) +; X H NMR (300 MHz, DMSO-de): 6 2.22 (m, 2H), 2.50 (m, 2H), 2.79 (m, 2H), 3.45 (m, 2H), 4.27 (m, 2H), 4.96 (d , J = 2.3 Hz, 2H), 7.2 (d, J = 9 Hz, 2H), 7.48 (m, 2H), 7.68 (m, 4H), 9.37 (s, 1H), 10.36 (s, 1H), 11.19 (s, 1H).
Example 12 1- (4-Bromo-benzyl) -4- [4- (4-piperidin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidin-4-carboxylic acid hydroxyamide To a stirred solution of piperidine (1.63 g, 19. 2 mmol) diluted in dioxane (100 ml) was added acetic acid (5 ml). The reaction was made gas and stirred for 5 minutes. To the solution of piperidine, 1- (4-bromo-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid ethyl ester was added. (5.0 g, 9.6 mmol), paraformaldehyde (0.29 g, 9.6 mmol) and copper chloride (I) (0.35 g). The reaction turned gray and was heated to reflux for 1 hour and turned brown. It was concentrated and then diluted in ice water, then it was brought to pH 8 with NHOH and extracted into CHCl3. The organic layer was washed 4 times with water then dried over Na 2 SO 4, then concentrated. The product was purified by column chromatography on silica gel eluting with 5% methanol: chloroform solution. Yield 5.15 g (87%); coffee oil; MS: 309.9 (M + 2H) 2+, 618.8 (M + H) +. 1- (4-Bromo-benzyl) -4 - [4 - (4-piperidin-1-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidin-4-carboxylic acid starting from the acid ethyl ester was prepared 1- (4-bromo-benzyl) -4- [4- (4-piperidin-1-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidin-4-carboxylic acid (4.64 g, 7.5 mmol) dissolved in THF methanol (50: 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). Yield 3.35 g (76%); whitish solid; p.f. 180 ° C; MS: 295.9 (M + 2H) 2 + 590.9 (M + H) +. Starting from 1- (4-bromo-benzyl) -4- [4- (4-piperidin-l-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidin-4-carboxylic acid (1.9 g, 3.2 mmoles) and following the procedure described in Example 1 (Step 8), 810 mg of hydroxyamide of 1- (4-bromo-benzyl) -4- [4- (4-piperidin-1-yl-butyl- 2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid as a hydrochloride salt, a pale yellow solid. Performance 40%; p.f. 209 ° C; MS: 303.4 (M + 2 H) 2 + 605.9 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.70 (m, 2 H), 2.29 (m, 2 H), 2.76 (m, 4 H), 3.40 (m, 10 H), 4.14 (s, 2 H), 4.26 (2 H) ), 7.24 (d, J = 9 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.67 (m, 4H), 9.39 (s, 1H), 10.45 (s, 1H).
Example 13 1- (4-Bromo-benzyl) -4- [4- (4-orpholin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid hydroxyamide To a stirred solution of morpholine (1.68 g, 19. 2 mmol) diluted in dioxane (100 ml) was added acetic acid (5 ml). The reaction was made gas and stirred for 5 minutes. Piperidine solution of 1- (4-bromo-benzyl) -4 - (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid ethyl ester was added to the solution. (5.0 g, 9.6 mmol), paraformaldehyde (0.29 g, 9.6 mmol) and copper chloride (I) (0.35 g). The reaction turned gray and was heated to reflux for 1 hour and turned brown. It was concentrated and then diluted in ice water, then it was brought to pH 8 with NH4OH and extracted into CHC13. The organic layer was washed 4 times with water • then dried over Na2SO4, then concentrated. The product, 1- (4-bromo-benzyl) -4 - [4- (4-mor-olin-4-yl-but-2-ynyloxy) -benzenesul-fonyl] -piper idine-carboxylic acid ethyl ester is purified by column chromatography on silica gel eluting with 5% methanol: chloroform solution. Yield 3.0 g (50%); colorless solid; p.f. 110 ° C; MS: 311 (M + 2H) 2 +, 621 (M + H) +. 1- (4-Bromo-benzyl) -4 - [4- (4-morpholin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piper idin-4-carboxylic acid starting from the ethyl ester of 1- (4-Bromo-benzyl) -4- [4- (4-morpholin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidin-4-carboxylic acid (2.87 g, 4.6 mmol) solution in THF: methanol (3: 1, 150 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as described in Example 1 (Step 7). Yield 2.26 g (83%); white powder; p.f. 198 ° C; MS: 593.1 (M + H) +.
Starting from 1- (4-bromo-benzyl) -4- [4- (4-morpholin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidine-4-carboxylic acid (2.1 g, 3.55 mmoles) and following the procedure described in Example 1, 1.8 g of l- (4-bromo-benzyl) -4- [4- (4-morpholin-4-yl-but-2-ynyloxy) hydroxyamide was isolated) -benzenesulfonyl] -piperidin-4-carboxylic acid as a hydrochloride salt, a white solid. Performance 80%; p.f. 94 ° C; MS: 304.4 (M + 2H) 2 + 607.9 (M + H) +; NMR * H (300 MHz, DMSO-d6): d 2.38 (m, 2H), 2.46 (m, 2H), 2.75 (m, 2H), 3.35 (m, 2H), 3.87 (m, 8H), 4.21 ( s, 2H), 4.26 (s, 2H), 5.10 (s, 2H), 7.24 (d, J = 9 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.67 (m, 4H), 9.42 (s, 1H), 10.69 (s, 1H), 11.13 (s, 1H). Examples of the compound where A = S o- S = 0.
Example 14 4- (4-But-2-ynyloxy-phenylsulfanyl) -4-hydroxycarbamoyl-piperidin-1-carboxylic acid tert-butylester To a solution of triphenylphosphine (24.7 g, 94. 2 mmol) and dimethylformamide (0.6 ml) in dichloromethane (25 ml) was added to a solution of 4-but-2-ynyloxy-phenylisulfonyl chloride (7.69 g, 31.4 mmol) in drops of dichloromethane for 30 minutes. After a further 2 hours, IN aqueous hydrochloric acid (20 ml) and water were added. The organic layer was separated and concentrated in vacuo. Aqueous sodium hydroxide (IN, 50 ml) was added and the solid was removed by filtration. The aqueous phase was washed with diethyl ether (3x), treated with IN aqueous hydrochloric acid (50 ml) and extracted with ether (3x). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated to give the thiol as an oil (3.77 g). This material was dissolved in dimethyl sulfoxide (40 ml) and concentrated hydrochloric acid (2 ml) was added. After 18 hours, diethyl ether was added and the organic phase was washed with water (5x) and dried over anhydrous magnesium sulfate. The in va concentration gave a yellow solid which was filtered through silica gel with hexane: ethyl acetate to give bis (4-but-2-inyloxy-phenyl) -sulfur dioxide as a yellow solid (3.0 g, 80%). %). X H NMR (CDC13: 300 MHz): 1.86 (s, -CH 3, 3 H), 4.63 (s, -CH 2, 2 H), 6.90 (d, Ar H, 2 H, J = 9 Hz), 7.40 (d, Ar H, 2 H , J = 9 Hz). To a solution of N-BOC-isonipecotic acid (0.62 g, 2.7 mmoles) in tetrahydrofuran (20 ml) at -78 ° C was added t-butyl-il-li t-thio (3.4 ml)., 1.7M in hexane, 5.7 mmol). After 10 minutes at -78 ° C, the yellow solution was warmed to 0 ° C in an ice bath. After 30 minutes, the colorless solution was cooled to -78 ° C after which bis (4-but-2-ynyloxy-phenyl) disulfide (1.0 g, 2.8 mmol) was added as a solution in tetrahydrofuran (6 ml) . The reaction mixture was allowed to warm to 25 ° C. After 1.5 hours ethyl acetate was added followed by 6 ml of IN aqueous hydrochloric acid in 20 ml of water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography on silica gel (methanol / methylene chloride) gave the product (0.55g). 1H-NMR (DMSO-d6): 1.38 (s, OtBu, 9H), 1.5-1.6 (m, CHH, 2H), 1.84 (s, CH3, 3H), 1.89-1.99 (m, CHH, 2H), 2.95- 3.05 (m, CHH, 2H), 3.6-3.7 (m, CHH, 2H), 4.8 (s, CH2, 2H), 6.95 (d, ArH, 2H, J = 9 Hz), 7.38 (d, ArH, 2H , J = 9 Hz). Dimethylformamide (0.163 ml) was added to a solution of oxalyl chloride (1.06 ml of a 2.0M solution in dichloromethane) in dichloromethane (2 ml) at 0 ° C. After 15 minutes, a solution of the acid in dimethylformamide (5 ml) was added and the reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was added to a mixture of hydroxylamine hydrochloride (0.737 g), triethylamine (2.22 ml), water (5.7 ml) and tetrahydrofuran (22.8 ml) which has been stirring at 0 ° C. 15 minutes. The reaction was maintained at 0 ° C for 18 hours then it was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate (3X), then dried over potassium carbonate and concentrated in va cuo to give 480 mg of tert-butylish 4- (4-But-2-ynyloxy-phenylsulfanyl) -4-hydroxycarbamoyl-piperidine-1-carboxylic acid. X H NMR (DMSO-d 6): 1.37 (s, OtBu, 9H), 1.5-1.6 (m, CHH, 2H), 1.84 (s, CH3, 3H), 1.9-2.0 (m, CHH, 2H), 3.05- 3.15 (m, CHH, 2H), 3.5-3.6 (m, CHH, 2H), 4.8 (s, CH2, 2H), 6.9 (d, ArH, 2H), 7.4 (d, ArH, 2H), 8.8 (s) , NHOH, 1H), 10.7 (d, NHOH, 1H).
Example 15 4- (4-But-2-ynyloxy-phenylsulfanyl) -piperidin-4-carboxylic acid hydroxyamide 4- (4-But-2-ynyloxy-phenyl sulphyl) -4-hydroxycarbamoyl-tert-butyl ester -piperidine-1-carboxylic acid, prepared by the method described in Example 14 (Step 3) (0.175 g, 0.4 mmol), was treated with 4N hydrochloric acid in dioxane (5 ml) at 25 ° C for 1 hour 15 minutes . The reaction mixture was concentrated in vacuo, diethyl ether was added and the resulting precipitate was isolated by filtration to give the 4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidine-4-carboxylic acid hydroxyamide as a white solid (0.12 g). Electroclever Mass Spectrum: ((M + H) + = 321).
Example 16 1- (4-Bromo-benzyl) -4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidin-4-carboxylic acid hydroxyamide The 4- (4-but-2-ynyloxy-phenylsulfanyl) hydroxyamide ) -piperidine-4-carboxylic acid (prepared by the procedure described in Example 15) (0.15 g, 0. 5 mmole) in methanol (5 ml) and dimethylformamide (2.5 ml) was treated with triethylamine (0.15 ml, 1.1 mmol) followed by 4-bromobenzyl bromide (0.13 g, 0. 53 mmoles). After 6 hours, the solution was diluted with ethyl acetate, acidified to pH = 6 with IN aqueous hydrochloric acid, subsequently washed with water, aqueous sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Concentration in vacuo gave the hydroxyamide of 1- (4-bromo-benzyl) -4 - (4-but-2-ylene loxi-phenylsulfanyl) -piperidin-4-carboxylic acid hydroxyamide. 1 H NMR (DMSO-d 6): 1.5-1.6 (m, CHH, 2H), 1.8 (s, CH 3, 3H), 1.9-2.2 (m, CHH, 4H), 2.5-2.6 (m, CHH, 2H), 3.4 (s, CH2Ar, 2H), 4.75 (s, CH2, 2H), 6.9 (d, ArH, 2H), 7.2 (d, ArH, 2H), 7.3 (d, ArH, 2H), 7.5 (d, ArH , 2H), 8.8 (s, NHOH, 1H), 10.6 (d, NHOH, 1H). Mass Spectrum Electrospray: ((M + H) + = 489/491). Examples of compounds, where n = 1 and A = S, S = 0 or S02 Example 17 4- (4-But-2-ynyloxy-disulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide Sodium salt of 4-but-2-ynyloxy-benzenesulonic acid To a solution of 52.35 g (0.225 mole) of sodium salt of 4-hydroxybenzenesulfonate in 1 1 of isopropanol and 225 ml of a solution of 1. ON of hydroxide sodium was added 59.96 g (0.45 moles) of l-bromo-2-butine. The resulting mixture was heated at 70 ° C for 15 hours and then the isopropanol was removed by evaporation in va cuo. The resulting white precipitate was collected by filtration, washed with isopropanol and ether, and dried in vacuo to give 56.0 g (100%) of the butynyl ether as a white solid. 4-But-2-ynyloxy-benzenesulfonyl chloride To a 0 ° solution of 43.8 ml (0.087 mole) of oxalyl chloride in 29 ml of dichloromethane was added in drops 6.77 ml (0.087 mole) of DMF followed by 7.24 g ( 0.029 mole) of the sodium salt of 4-but-2-ynyloxy-benzenesulonic acid.
The reaction mixture was stirred for 10 minutes at 0 ° C, then allowed to warm to room temperature and stirred for 2 days. The reaction was then poured into ice and extracted with 150 ml of hexanes. The organic materials were washed with water and brine, dried over Na 2 SO, filtered and concentrated in vacuo to provide 6.23 g (88%) of the sulfonyl chloride as a yellow solid; p.f. 63-65 ° C. Mass Spectrum: 243.9 (M +).
But-2-ynyloxy-benzene To a solution of 6.14 g (23.40 mmoles) of triphenylphosphine dissolved in 100 ml of benzene and 50 ml of THF was added 1.75 ml (23.40 mmoles) of 2-butyn-1-ol. After five minutes, 2.00 g (21.28 mmol) of the phenol, dissolved in 10 ml of THF, was added to the reaction followed by 3.69 ml (23.40 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 acetate / hexanes (1:10) to give 2.18 g (70 g. %) of the desired propargyl ether as a clear liquid. Mass Spectrum: 146.0 M +. 4-But-2-ynyloxy-benzenesulfonyl chloride To a solution of 0.146 g (1.0 mmol) of but-2-ynyloxy-benzene in 0.3 ml of dichloromethane in an acetone / ice bath under N2 was added dropwise a solution of 0.073 ml (1.1 mmol) of chlorosulfonic acid in 0.3 ml of dichloromethane. After the addition was complete, the ice bath was removed and the reaction was stirred at room temperature for 2 hours. To the reaction was then added dropwise 0.113 ml (1.3 mmol) of oxalyl chloride, followed by 0.015 ml of DMF. The reaction was refluxed for 2 hours and then diluted with hexane and poured into ice water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to provide 0.130 g (53%) of the desired product as a light brown solid. 4-But-2-ynyloxy-benzothiol To a solution of 11.8 g (0.045 mole) of triphenylphosphine dissolved in 10 ml of dichloromethane and 0.3 ml of DMF was added 3.67 g (0.015 mole) of the butyl-2-yl chloride -benzene, fonil, dissolved in 15 ml of dichloromethane and the resulting mixture was stirred for 24 hours at room temperature. After the addition of 5 ml of an IN HCl solution, the reaction was stirred for 0.5 hours followed by the addition of 15 ml of brine. The organic materials were separated and concentrated in vacuo and the residue was diluted with ether and a 2.5N sodium hydroxide solution. The resulting precipitate was removed by filtration and the aqueous layer was acidified to pH 2 and extracted with ether. The combined organic materials were washed with brine, dried over Na 2 SO, filtered through Magnesol® and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes / ether (4: 1) to provide 1.13 g (42%) of the thiol as a yellow oil. Cl Mass Spectrum: 179 (M + H). 4- (4-But-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid To a solution of 0.112 g (2.81 mmol) of 60% sodium hydride in 2 ml of THF, cooled to 0 ° C, a solution of 0.500 g (2.81 mmol) of 4-but-2-ynyloxy-benzothiol, dissolved in 3 ml of THF, was added. The resulting mixture was stirred for 0.5 hour at room temperature, then cooled to 5 ° C, followed by the addition of 0.518 g (3.65 mmoles) of pure 2,7-dioxaespiro [3, 5] nonan-1-one while the reaction temperature is maintained below 10 ° C. The reaction was allowed to warm to room temperature and was stirred for an additional 0.5 hours and then rapidly cooled with 3 ml of a 3N HCl solution and 3 ml of water. The resulting mixture was extracted with dichloromethane and the combined organic materials were washed with water and brine, dried over Na 2 SO, filtered through a plug of silica gel and concentrated in vacuo. The residue was triturated with hexanes and acetonitrile and filtered to give 0.72 g of the carboxylic acid as a semi-solid. Electrospray Mass Spectrum: 319 (M-H) ". 4- (4-But-2-ynyloxy-phenyl-sulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide To a 0 ° C solution of 0.74 g (2.31 mmol) of the 4 - (4 -) acid product but-2-ynyloxy-phenyl sulphonylmethyl) -tetrahydro-pyran-4-carboxylic acid, dissolved in 7 ml of dichloromethane and 0.175 ml of DMF was added 1.27 ml (2.54 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 0.875 ml (14.2 mmol) of a 50% hydroxylamine solution, 5.0 ml of THF and 2.0 ml of t-butanol were then added to the reaction. The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was extracted with dichloromethane and the combined organic materials were washed with water and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane / methanol (92: 8) to provide 0.212 g of the sulfur-hydroxamic acid as a white solid; p.f. 135-137 ° C. Electroclever Mass Spectrum: 336 (M + H) +.
Example 18 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide To a 0 ° C solution of 0.186 g (0.56 mmoles) of the 4- hydroxyamide acid product (4-but-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid, dissolved in 1.2 ml of THF and 4.8 ml of methanol was added dropwise a solution of 0.619 g (1,008 mmoles) of Oxone® in 3 ml of water, while the temperature was kept below 20 ° C.
After the addition was complete, the reaction was stirred at room temperature for 3 hours. The reaction mixture was then poured into a cooled solution of 2.5 ml of toluene and 5 ml of ethyl acetate and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate / toluene and the combined organic layers were washed with water, dried over Na 2 SO 4 and concentrated in vacuo. The residue was triturated with ethyl acetate / toluene (5: 2), filtered and dried in vacuo to provide 0.12 g (55%) of the sulfone-hydroxamic acid as a white solid; p.f. 184-185 ° C. Electrospray Mass Spectrum: 368 (M + H) +.
EXAMPLE 19 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide. To a 0 ° C solution of 0.288 g (0.80 mmoles) of the hydroxyamide acid product. - (4-But-2-ynyloxy-benzenesulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid dissolved in 20 ml of methanol was added 7.0 ml of 30% hydrogen peroxide solution. The reaction was allowed to warm to room temperature and stirred for 24 hours. The reaction mixture was again cooled to 0 ° C, quenched with saturated Na 2 SO 3 and concentrated in vacuo. The residue was diluted with water and dichloromethane. The organic materials were washed with water and brine, dried over Na 2 SO, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane / methanol (95: 5) to provide 0.050 g of the sulfoxide as a white solid. Electroclever Mass Spectrum: 351.9 (M + H) +.
Example 20 4-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-tetrahydro-2H-pyran-4-carboxamide Stage 1: 4-. { [4- (2-Butynyloxy) phenyl] sulfonyl} ethyl tetrahydro-2H-pyran-4-carboxylate (4-But-2-ynyloxy-benzenesulfonyl) -acetic acid ethyl ester (10 g, 33.8 mmol) was added to a stirring solution of potassium carbonate (12 g) , 18-crown-6 (0.5 g), 2-chloroethether (4.75 ml, 40.5 mmol), and tetrabutylammonium bromide (0.5 g) in methyl ethyl ketone (200 ml). The mixture was heated to reflux overnight before the salts were filtered off and the filtrate was concentrated. The residue was dissolved in chloroform and washed with water. The organic layer was dried over Na 2 SO 4, filtered and concentrated. The compound was isolated using column chromatography on silica gel eluting with 20% ethyl acetate: hexane solution. It was isolated 4-. { [4- (2-Butynyloxy) phenyl] sulfonyl} tetrahydro-2H-pyran-4-carboxylate as a yellow oil (10.06 g). Performance 80%; MS: 367.2 (M + H) +. 4 - acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfonyl} tet rahydro-2H-pyran-4-carboxylic acid according to the general method described in Example 1 (Step 7), starting from 4 -. { [4- (2-butyloxy) phenyl] -sulfonyl} ethyl tetrahydro-2H-pyran-4-carboxylate (10 g, 27.3 mmol); 2.7 g, white solid. P.f. 197 ° C; Yield 30%; MS: 337.2 (MH). "Starting from a crude mixture of 4- {[[4- (2-butynyloxy) phenyl] sulfonyl} tetrahydro-2H-pyran-4-carboxylic acid (2.59 g, 7.66 mmoles), and following the procedure described in Example 1 (step 8), 1.51 g of 4 - { [4- (2-butyloxy) -phenyl] sulfonyl] -N-hydroxyetherahydrate was isolated. 2H-pyran-4-carboxamide as off-white crystals, Mp 210 ° C, Yield: 58%, MS: 354.2 (M + H) +; XH NMR (300 MHz, .DMS0-d6): d 1.85 (t, J = 2.28 Hz, 3H), 1.92 (m, 2H), 2.20 (d, J = 13.1 Hz, 2H), 3.15 (t, J = 11.52, 2H), 3.86 (d of d, 2H), 4.88 (d, J = 2.34 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.91 Hz, 2H), 9.16 (s, 1H), 11 (s, 1H).
Example 21 1-Benzyl-4-. { [3- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide [(3-Hydroxyphenyl) sulfani 1] ethyl acetate was prepared according to the general method described in Example 1 (Step 1), starting from ethyl bromoacetate (7.95) g, 47.6 mmoles) and 3-hydroxythiophenol (7.95 g, 47.6 mmoles); 4.21 g of yellow oil. Yield 41%; MS: 211.2 (MH). "{[[3- (2-Butyloxy) phenyl] sulphyl} ethyl acetate was prepared according to the general method described in Example 1 (step 2), initiating from [(3-hydroxyphenyl) sulfanyl] ethyl acetate (3.87 g, 18.3 mmol) and 4-bromo-2-but ina (2.66 g, 20 mmol); 5.16 g of yellow oil. 100% performance; MS (El): 264.1 (M + H) +. It was prepared. { [3- (2-Butyloxy) phenyl] sulphonyl} ethyl acetate according to the general method described in Example 1 (step 3), starting from [(3-butyloxy) phenyl] sulphyl} ethyl acetate (5 g, 18.9 mmol) and oxone (23.3 g, 37.9 mmol); 6.19 g of yellow oil. 100% performance; MS (El): 296.1 (M + H) +. L-benzyl-4 - was prepared. { [3- (2-Butyloxy) -phenyl] sulfonyl} -4-ethylpiperidinecarboxylate according to the general method described in Example 1 (step 6), starting from. { [3- (2-butyloxy) phenyl] sulfonyl} ethyl acetate (3 g, 10.1 mmol) and benzyl-bis- (2-chloro-yl) -amine hydrochloride (2.88 g, 10.7 mmol); 2.91 g of yellow oil. Performance 63%; MS: 456.3 (M + H) +. 1-Benzyl-4 - acid was prepared. { [3- (2-Butynyloxy) phenyl] sulfonyl} -4-pyridinecarboxylic acid according to the general method described in Example 1 (step 7), starting from l-benzyl-4-. { [3- (2-Butynyloxy) phenyl] sulfonyl} Ethyl 4-piperidine carboxylate (2.9 g, 6.37 mmol); 1.10 g of whitish powder; p.f. 171 ° C; 40% yield); MS: 428.4 (M + H) +. Starting from l-benzyl-4- acid. { [3- (2-Butynyloxy) phenyl] sulfonyl} -4-piperidine-carboxylic acid (1 g, 2.34 mmol), and following the procedure described in Example 1 (step 8), 460 mg of l-benzyl-4- was isolated. { [3- (2-butyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide as an off-white solid. P.f. 91.4 ° C; Yield: 41%; MS: 443.4 (M + H) +; 1 H NMR (300 MHz, DMSO-d 6): d 1.83 (t, 3H), 2. 23-2.27 (m, 2H), 2.73-2.89 (m, 2H), 3.29 (m, 2H), 3. 68 (q, 2H), 4.31 m, 1H) 4.39 (d, J = 5 Hz 1H) 4.85 (d, J = 2.25, 2H), 7.25-7.61 (m, 9H), 9.1 1H) 11. 2 (s, 1H) Example 22 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-Hydroxy-1- isopropyl-4-piperidinecarboxamide 4 -. { [4 - (2-Butyloxy) phenyl] -sulfonyl} ethyl-l-isopropyl-4-piperidine carboxylate according to the general method described in Example 1 (step 6), starting from the ethyl ester of (4-but-2-ynyloxy-benzenesulfonyl) 1-acetic acid ( 6 g, 20.3 mmol) and isopropyl [bis (2-chloroethyl)] amine hydrochloride (4.88 g, 22.3 mmol); 5.28 g of brown oil. Yield: 64%; MS: 408.2 (M + H) +. 4 - acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -1-Sipropy-4-piperidinecarboxylic acid according to the general method described in Example 1 (step 7), starting from 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} Ethyl-l-isopropyl-4-piperidine carboxylate (5.25 g, 13 mmol); 2.06 g of yellow solid. P.f. 233 ° C; Yield 42%; MS: 380.1 (M + H) +. Starting from acid 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -l-isopropyl-4-piperidine-carboxylic acid (1.9 g, 5 mmol), and following the procedure described in Example 1 (step 8), 107 mg of 4 - was isolated. { [4 - (2-Butyloxy) phenyl] sulphonyl} -N-hydroxy-l-isopropyl-4-piperidinecarboxamide as a brown solid. P.f. 105 ° C; Yield: 5%; E: 395.2 (M + H) +; 1N-NMR (300 MHz, DMSO-d6): d 1.2 (m, 6H), 1.85 (t, 3H), 2.27 (m, 2H), 2.73 (m, 2H), 3.06 (m, 2H), 3.52 (m , 2H), 3.57 (m, 1H), 4.89 (m, 2H), 7.19 (m, 2H), 7.71 (m, 2H), 9.3 (s, 1H), 11.4 (s, 1H).
Example 23 4-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-1- (3-pyridinylmethyl) -4 -piperidinecarboxamide 4- was prepared. { [4- (2-butynyloxy) phenyl] sulfonyl} Ethyl 1- (3-pyridinylmethyl) -4-piperidine carboxylate according to the general method described in Example 1 (step 6), starting from the ethyl ester of (4-but-2-ynyloxy-benzenesulfonyl) -acetic acid (4 g, 16.9 mmol) and 3-pyridylmethyl [bis (2-chloroethyl)] amine hydrochloride (4.18 g, 18.6 mmol); 370 mg of brown oil. Yield: 5%; MS: 457.4 (M + H) +. 4- acid was prepared. { [4- (2-Butynyloxy) phenyl] -sulfonyl} 1- (3-pyridinylmethyl) -4-piperidinecarboxylic acid according to the general method described in Example 1 (step 6), starting from 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} Ethyl 1- (3-pyridinylmethyl) -4-piperidine carboxylate (320 mg, 0.7 mmol); 150 mg of yellow solid. Yield 50%; MS: 429.2 (M + H) +. Starting from acid 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -l- (3-pyridinylmethyl) -4-piperidinecarboxylic acid (860 mg, 2 mmol), and following the procedure described in Example 1 (step 8), 800 mg of 4- was isolated. { [- (2-Butyloxy) phenyl] -sulfonyl} -N-Hydroxy-1- (3-pyridinylmethyl) -4-piperidinecarboxamide as a white solid. P.f. 115 ° C; Yield: 84%; MS: 444.1 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.96 (t, J = 1.98 Hz, 3H), 2.32 (m, 2H), 2.46 (s, 2H), 2.84 (m, 2H), 3.46 (d, J = 12 Hz, 2H), 4.45 (s, 2H), 4.89 (d, 2.1 Hz, 2H), 7.17 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 8.85 Hz, 2H), 7.9 ( t, J = 5.6 Hz, 1H), 8.0 (s, 1H), 8.51 (d, J = 7.9 Hz, 1H), 8.87 (d, J = 4.6 Hz, 1H), 8.99 (s, 1H), 11.4 ( s, 1H).
Example 24 3-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -1-ethyl-N-hydroxy-3-piperidinecarboxamide Step 1: 1-tert-butyl 3-ethyl ester of piperidin-1,3-dicaboxylic acid To a stirred solution of ethyl nipecotate (5.1 g, 33 mmol) in CH2C12 (75 ml) and triethylamine (3.7 g, 36 mmol) was added in portions of di-t-butyl dicarbonate (7.1 g, 33 mmol). The reaction mixture was stirred at room temperature for 18 hours, quenched with ice water and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, concentrated and chromatographed on a column of silica gel with 20:80 ethylhexane acetate. 1-Tert-butyl ester-3-ethyl ester of piperidin-1,3-dicarboxylic acid was isolated as a waxy solid. Yield 6.86 g (82%). MS (ES): m / z 258.2 (M + H) +.
Stage 2: 3-. { [4 -2-butyloxy) phenyl] sulfonyl} 1, 3-piperidine-dicarboxylate or 1- (tert-butyl) 3-ethyl To a stirred solution of diisopropylamine (7.2 g, 28 mmol) in THF (25 ml) at -78 ° C was added n-butyl -lithium (1.6 ml of solution in hexanes, 19.0 ml, 30.8 mmol). The mixture was stirred for 30 minutes at 0 ° C. The mixture was then cooled to -78 ° C and 1-tert-butyl ester 3-ethyl ester of piperidin-1,3-dicarboxylic acid (5.3 g, 28 mmol) in THF (20 ml) was slowly added. The reaction mixture was stirred for 30 minutes, then 4-but-2-ynyloxy-benzenesulfonyl fluoride was added slowly. { 6 4 g, 28 mmol) in THF (15 ml). The reaction was warmed to room temperature and after 4 hours it was quenched with ice water and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, concentrated and chromatographed on a column of silica gel with 20% ethyl acetate: hexane to yield 3-. { [4 -2-butyloxy) phenyl] -sulfonyl} -1-, 3-piperidine-dicarboxylic acid of l- (tert-butyl) 3-ethyl as a white solid. Yield 9.8 g (76%); p.f. 103.4 ° C; MS (ES): m / z 466.4 (M + H) +. X H NMR (300 MHz, DMSO-d 6): d 1.07 (t, 3H), 1.34 (s, 9H), 3.31 (s, 3H), 3.84 (m, 2H), 4.00 (m, 4H), 4.53 (d , 2H), 4.91 (m, 4H), 7.22 (d, 2H), 7.71 (d, 2H).
Stage 3: To a stirred solution of 3-. { [4-2-butynyloxy) phenyl] sulfonyl} -1, 3-piperidine-di carboxylate of 1 - (tert-butyl) 3-ethyl (5.45 g, 11.7 mmol) in methylene chloride (25 ml) at 0 ° C was added a saturated solution of hydrogen chloride in methylene chloride (25 ml). After 5 hours, the solution was concentrated to produce hydrogen chloride of 3-. { [4- (2-Butynyloxy) phenyl] sulfonyl} Ethyl 3-piperidine carboxylate and stored under nitrogen. White hygroscopic solid; Yield 3.47 g (74%); MS (ES): m / z 366.2 (M + H) +.
Step 4: ethyl (3- {[[4- (2-butynyloxy) phenyl] sulphonyl} -1-etyl-3-piperidinecarboxylate) Hydrogen chloride 3-. { [4 - (2-Butyloxy) -phenyl] sulfonyl} 3-piperidinecarboxylate (2.97 g, 8.0 mmol), ethyl iodide (1.28 g, 8 mmol) and dry potassium carbonate (3.8 g) in dry acetone (60 ml) was heated to reflux for 18 hours. The mixture was allowed to cool and the potassium salts were filtered and concentrated. The residue was extracted with chloroform and washed with H20, dried over sodium sulfate and concentrated to yield 3-. { [4- (2-butynyloxy) phenyl] sulfonyl} ethyl-l-ethyl-3-piperidine carboxylate. This product was used without further purification. Amber rubber, yield 3.47 g (99%); MS (ES): m / z 394 (M + H) +.
Stage 5: Acid 3-. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -l-ethyl-3-piperidinecarboxylic acid 3- was prepared. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -l-ethyl-3-piperidinecarboxylic starting from 3-. { [4 - (2-Butyloxy) phenyl] sulphon 1} Ethyl-ethyl-3-piperidinecarboxylate (3.2 g, 8.0 mmol) dissolved in THF: methanol (15:25 ml) and NaOH (15 ml). The resulting reaction mixture was worked up as described in example 1 (step 7). Yield 2.11 g (71%), white solid: m.p. 159.2 ° C; MS (ES): m / z 366.3 (M + H) +.
Stage 6: 3- { [4 - (2-butynyl loxi) pheny1] sulphon 1} - 1-yt-N-hydroxy-3-piperidinecarboxamide Starting from acid 3-. { [4- (2-butynyloxy) phenyl] sulfonyl} 1-ethyl-3-piperidinecarboxylic acid (2.0 g, 5.5 mmol) and following the procedure described in Example 1 (step 8), 0.193 g of hydrogen chloride of 3- was isolated. { [4 - (2-Butynyloxy) -phenyl] sulfonyl} -l-ethyl-N-hydroxy-3-piperidinecarboxamide as a white solid. Yield 10%; p.f. 190.3 ° C; MS (ES): m / z: 405.3 (M + H) +; X H NMR (300 MHz, DMSO-d 6): d 1.18 (m, 3 H), 1.97 (m, 2 H), 2.55 (m, 2 H), 3.21 (m, 5 H), 3.52 (s, 3 H), 3.82 (d , 1H), 4.91 (m, 2H), 7.19 (d, 2H), 7.51 (s, 5H), 8.67 (s, 1H), 9.48 (s, 1H).
Example 25 3-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -l- (4-chlorobenzyl) -N-hydroxy-3-piperidinecarboxamide Stage 1: 3-. { [4- (2-butyloxy) phenyl] sulfonyl} Ethyl 1- (4-chlorobenzyl) -3-piperidine carboxylate Starting from the hydrogen chloride of 3-. { [4- (2-butynyloxy) phenyl] sulfonyl} Ethyl 3-piperidine carboxylate (1.1 g, 2.7 mmol) and 4-chlorobenzyl chloride (0.485 mg, 3.0 mmol) in dry acetone (50 ml) and following the procedure described in example 24, (step 4), it was isolated 3-. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -! - (4-Chlorobenzyl) -3-piperidinecarboxylic acid ethyl ester as a brown oil. This product was taken for the next step without further purification. Yield 1.66 g (99%); MS (ES): m / z: 491.3 (M + H) +.
Stage 2: Acid 3-. { [4 - (2-Butyloxy) phenyl] sulphonyl} - 1 - (4-chlorobenzyl) -3-piperidinecarboxylic acid 3- was prepared. { [4 - (2-Butynyloxy) phenyl] -sulfonyl} -1- (4-chlorobenzyl) -3-piperidinecarboxylic starting from 3-. { [- (2-Butyloxy) phenyl] -sulfonyl} -1- (4-chlorobenzyl) -3-piperidine-carboxylic acid ethyl ester (1.64 g, 3.3 mmol) dissolved in THF-Methanol (15:50 ml) and NaOH (15 ml). The resulting reaction mixture was worked up as described in example 1 (step 7); Yield 1.11 g (75%), white solid: m.p. 115.2 ° C; MS (ES): m / z 462.1 (M + H) +.
Stage 3: 3-. { [4 - (2-Butyloxy) phenyl] sulfonyl} -1- (4 < chlorobenzyl) -N-hydroxy-3-piperidinecarboxamide Starting from acid 3-. { [4- (2-Butynyloxy) phenyl] sulfonyl) -! - (4-chlorobenzyl) -3-piperidinecarboxylic acid (1.1 g, 2.4 mmol) and following the procedure described in example 1, (step 8), 0.48 was isolated. g of hydrogen chloride of 3-. { [4- (2-butynyloxy) phenyl] sulfonyl} -l- (4-chlorobenzyl) -3-N-hydroxy-3-piperidinecarboxamide as a white solid. Performance 43%; p.f. 124.4 ° C; MS (ES): m / z: 477.1 (M + H) +; NMR * H (300 MHz, DMSO-d6): d 2.0 (m, 2H), 3.39 (m, 5H), 4.27 (d, 2H), 4.89 (m, 2H), 7.14 (d, 2H), 7.15 ( m, 4H), 7.61 (d, 2H), 8.95 (s, 1H), 9.46 (s, 1H).
Example 26 Hydroxyamide of 4-acid. { [4- (2-Butynyloxy) -phenyl] sulfonyl} -l- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid A mixture of diethanolamine (2.1 g, 20 mmol), 4- (2-piperidin-1-yl chloride -ethoxy) benzyl (5.9 g, 20 mmol) and K2CO3 (10 g, excess) was brought to reflux in acetone (100 ml) for 24 hours. At the end, the reaction mixture was cooled to room temperature and filtered. It was concentrated to dryness and redissolved in toluene (200 ml) and thionyl chloride (6.75 g, 50 mmol). It was heated at 80 ° C for 1 hour and the separated brown solid, bis- (2-chloro-yl) - [4- (2-piperidin-1-yl-ethoxy) -benzyl] -amine was filtered and dried. The crude product was taken for the next step without purification. Yield: 7.0 g, (89%). Ethyl ester of 4- acid was prepared. { [4- (2-butynyloxy) phenyl] sulfonyl} -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidin-4-carboxylic acid according to the general method described in example 1 (step 6), starting from. { [4 - (2-Butyloxy) phenyl] -sulfonyl} ethyl acetate (2.9 g, 10.0 mmol) and bis- (2-chloro-ethyl) - [- (2-piperidin-1-yl-ethoxy) -benzyl] -amine dihydrochloride (4.3 g, 10 mmol), isolated 2.8 g of product (brown oil). Performance 48%; MS: 583 (M + H) +. 4- acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidine-4-carboxylic acid according to the general method described in example 1 (step 7), starting from the ethyl ester of acid 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -1- [4- (2-piperidin-1-yl-ethoxy) -benzyl] -pi-eridin-4-carboxylic acid (3.0 g, 5.15 mmol); 2.2 g of white powder. P.f. 172 ° C; Yield 77%; MS: 555 (M + H) +. Starting from acid 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -! - [4- (2-piperidin-1-yl-ethoxy) -benzyl] -piperidin-4-carboxylic acid (5.0 g, 9.0 mmol), and following the procedure described in Example 1 (step 8), isolated 1.8 g of 4 - hydroxyamide. { [4 - (2-Butynyloxy) phenyl] sulfonyl} -1- [4 - (2-piperidin-1-yl-ethoxy) -benzyl] -piperidin-4-carboxylic acid as a yellow fluffy solid. The dihydrochloride salt was prepared by dissolving the free amine with methanolic hydrochloric acid. P.f. 124 ° C; Yield: 1.8 g (32%); MS: 570 (M + H) +.
Example 27 Hydroxyamide of 4-acid. { [4- (2-Butynyloxy) phenyl] -sulfonyl} -l- (3-pentanil) -piperidine-4-carboxylic acid Ethylester of 4- acid was prepared. { [4- (2-butynyloxy) phenyl] sulfonyl} -l- (3-pentanil) -piperidin-4-carboxylic acid according to the general method described in example 1 (step 6), starting from. { [4 - (2-Butyloxy) phenyl] sulfonyl} ethyl acetate (8.8 g, 30.0 mmol) and bis- (2-chloro-ethyl) - (3-pentanil) -amine dihydrochloride (7.4 g, 30 mmol), 3.5 g of product (brown oil) was isolated. Yield 26%; MS: 436 (M + H) +. 4- acid was prepared. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -1- (3-pentanil) -piperidin-4-carboxylic acid according to the general method described in example 1 (step 7, starting from the ethyl ester of 4- {[4- (2-butyloxy)} phenyl] sulphonyl} -l- (3 -pentyl) -piperidine-4-carboxylic acid (3.0 g, 6.8 mmol), 2.5 g of fluffy yellow solid, mp 98 ° C, yield 90%, MS: 408 ( M + H) + Starting from 4- {[[4- (2-butynyloxy) phenyl] sulfonyl} -1- (3-pentanyl) -piperidine-4-carboxylic acid (2.5 g, 6.1 mmoles), and following the procedure described in Example 1 (step 8), 1.8 g of 4- [{(4- (2-butynyloxy) phenyl] sulfonyl] -1- (3-) hydroxyamide was isolated. pentanil) -piperidin-4-carboxylic acid as a yellow fluffy solid The hydrochloride salt was prepared by dissolving the free amine with methanolic hydrochloric acid, mp 101-103 ° C, yield: 1.1 g (42%), MS: 460 (M + H) +. RMN 1H (300 MHz, DMSO-de): d 1.8 (t, 6H), 1.5-1.7 (m, 6H), 1.9 (s, 3H), 2.3-2.7 (m, 8H), 3.0 (m, 2H), 3.4 (s, 3H), 3. 6 (d, 2H), 4.9 (s, 2H), 7.21 (d, 2H), 7.8 (d, 2H), 9. 3 (s, 1H), 9.8 (s, 1H), 11.2 (s, 1H).
Example 28 1- (4-Methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-carboxylic acid hydroxyamide 1- (4-methoxy-benzyl) -4- ethylester was prepared (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid according to the general method described in example 1 (step 6), starting from the ethyl ester of (4-prop-2-ynyloxy-benzenesulfonyl) -acetic acid (prepared as described in example 11, steps 1 and 2) (10.0 g, 35.0 mmol) and (4-methoxy) hydrochloride -benzyl) -bis- (2-chloro-ethyl) -amine (10.5 g, 35 mmol), 6.0 g of product (brown oil) was isolated. Performance 36%; MS: 472 (M + H) +. 1- (4-Methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid was prepared according to the general method described in example 1 (step 7), starting from 1- (4-methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesul-fonyl) -piperidine-4-carboxylic acid ethyl ester (6.0 g, 12.73 mmol); 5.0 g of spongy yellow solid. P.f. 208 ° C; Yield 92%; MS: 444 (M + H) +. Starting from 1- (-methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (6.0 g, 13.5 mmol), and following the procedure described in Example 1 (step 8), 2.0 g of 1- (4-methoxy-benzyl) -4- (4-prop-2-yl loxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide was isolated as a fluffy solid yellow. The hydrochloride salt was prepared by dissolving the free amine with methanolic hydrochloric acid. P.f. 150 ° C; Yield: 2.0 g (29%); MS: 459 (M + H) +. 1 H NMR (300 MHz, DMSO-de): d 2.3-2.8 (m, 6H), 3.3 (d, 2H), 3.5 (s 3H '4.2 2H) 5.0 (s, 2H), 7.3 (d, 2H) 7.5 (d, 2H), 7.6 (d, 2H), 7.7 (d, 2H), 10.9 (s, 1H), 11.2 (s, 1H).
Example 29 1- (4-Chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid hydroxyamide 1- (4-Chloro-benzyl) -acetic acid ester was prepared 4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid according to the general method described in example 1 (step 6), starting from the ethyl ester of (4-prop-2-ynyloxy) -benzenesulfonyl) -acetic (prepared as described in example 11, step 1 and 2) (10.0 g, 35.0 mmol) and (4-chloro-benzyl) -bis- (2-chloro-ethyl) -amine hydrochloride ( 10.5 g, 35 mmol), 8.0 g of product (brown oil) was isolated. Performance 48%; MS: 475 (M + H) +. 1- (4-Chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid was prepared according to the general method described in example 1 (step 7), starting at from 1- (4-chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid ethyl ester (6.0 g, 12.63 mmol); 5.0 g of spongy yellow solid. P.f. 205 ° C; Yield 92%; MS: 448 (M + H) +. Starting from 1- (4-chloro-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid (6.0 g, 13.4 mmol), and following the procedure described in Example 1 (step 8), 2.0 g of 1- (4-chloro-benzyl) -4- (4-prop-2-quinloxy-benzenesul fonyl) -piperidine-4-carboxylic acid hydroxyamide was isolated as a yellow fluffy solid. The hydrochloride salt was prepared by dissolving the free amine with methanolic hydrochloric acid. P.f. 146 ° C; Yield: 4.0 g (59%); MS: 499 (M + H) +. 1 R NMR (300 MHz, DMSO-de): d 2.0-2.5 '(m, 6H), 3.2 (d, 2H), 4.18 (s, 2H), 4.9 (s, 2H), 7.42 (d, 2H), 7.61 (d, 2H), 7.71 (d, 2H), 7.85 (d, 2H), 11.0 (s, 1H), 11.2 (s, 1H).
EXAMPLE 30 4- ( { [4- (2-Butynyloxy) phenyl] sulfanyl} methyl) -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxylic acid tert-butyl Step 1: tert-butyl-ester-ether-ethyl ester of piperidin-1,4-dicarboxylic acid To a solution of ethyl isonipecotate (4.72 g, 0.03 mmol) in 30 ml of THF was slowly added di-tert-butyl dicarbonate (7.2 g, 0.03 mmol) at room temperature. The resulting mixture was stirred for two hours and diluted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate: hexanes (1: 9) to provide 7.52 g (97%) of the desired product as a colorless oil. Electrospray Mass Spectrum: 258.3 (M + H) +.
Stage 2: 4- (iodomethyl) piperidin-1,4-dicarboxylic acid ester of 1- (tert-butyl) To a solution of tert-butyl ester ethyl ester and piperldin-1,4-dicarboxylic acid (12.8 g, 49.74 mmol) in 73 ml of dry THF under an N2 atmosphere at -42 ° C was added 24.87 ml (49.74 mmoles) of 2M lithium diisopropylamine in heptane / THF / and ilbenzene in droplets not to exceed -40 ° C. After one hour, 4.0 ml (49.74 mmoles) of diiodomethane was added and the solution was warmed to room temperature overnight. The resulting solution was diluted with H20 and extracted with ethyl acetate. The organic materials were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 18.84 g (95%) of the desired product as a brown oil. Electrospray Mass Spectrum: 398.2 (M + H) +.
Step 3: Sodium salt of 4-but-2-ynyloxy-benzenesulfonic acid: To a solution of sodium salt of 4-hydroxybenzenesulfonate (52.35 g, 0.225 mmoles) in 1 1 of isopropanol and 225 ml of a 1.0 N solution. of sodium hydroxide was added 59.96 g (0.45 moles) of l-bromo-2-but-ina. The resulting mixture was heated at 70 ° for 15 hours and then the propanol was removed by evaporation in vacuo. The resulting white precipitate was collected by filtration, washed with isopropanol and ether, and dried to yield 45.08 g (81%) of the desired product as a white solid.
Step 4: 4-But-2-ynyloxy-benzenesulfonyl chloride To a stirred solution of oxalyl chloride (47.8 ml, 0.545 moles) at 0 ° in 240 ml of CH2C12 was added a solution of DMF (43.0 ml) of sodium salt of 4-but-2-ynyloxy-benzenesulonic acid in a dropwise form. The reaction mixture was stirred at 0 ° C for 30 minutes and then allowed to warm to room temperature and stirred for 18 hours. The reaction was then poured into ice and extracted with hexanes. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 42.0 g (95%) of the desired product as a yellow solid.
Step 5: 4-But-2-ynyloxy-benzothiol To a solution of 11.8 g (0.045 mole) of triphenylphosphine in 10 ml of CH2C12 and 0.3 ml of DMF was added dropwise a solution of 4-but-2-ynyloxy chloride. -benzenesulfonyl in 15 ml of CH2C12. It was stirred at room temperature for two hours, added 5 ml in IN HCl, stirred for 30 minutes, and then 15 ml of brine was added. The organic materials were separated and concentrated in a vacuum. The residue was diluted with ether and the insolubles were filtered. The filtrate was washed with 2.5N NaOH and the separated aqueous solution, acidified and extracted with ether. The organics were washed with H20, brine, dried over MgSO4, filtered and concentrated in vacuo to give 1.54 g (58%) of the desired product as a pale yellow oil.
Step 6: 4 - ( { [4 - (2-Butyloxy) phenyl] sulfanyl} methyl) -1,4-piperidinedicarboxylic acid ester of 1- (tert-butyl) 4-ethyl A mixture of 0.294 g ( 0.74 mmoles) of 4- (iodomethyl) -piperidin-1,4-dicarboxylic acid 1- (tert-butyl) 4-ethyl ester, 0.145 g (0.814 mmol) of 4-but-2-ynyloxy-benzyl-iol and 0.204 g (1.48 mmol) of K2C03 in 2.0 ml of DMF was stirred at room temperature for 18 hours. The resulting mixture was diluted with EtOAc, washed with H20, brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc: Hexanes (1:19) to provide 0.328 g (99%) of the desired product as a colorless oil. Electrospray Mass Spectrum: 448.3- (M + H) +.
Step 7: 4- (4-but-2-ynyloxy-phenylsulfanylmethyl) -piperidine-1,4-dicarboxylic acid mono-tert-butyl ester A mixture of 0.288 g (0.0643 mmol) of 4- ( { [4- (2-Butynyloxy) phenyl] sulfanyl} methyl) -1,4-piperidine dicarboxylate of 1- (tert-butyl) 4 ethyl, 3.25 ml of IN NaOH, 3.25 of THF and 3.25 of MeOH was heated to reflux for 3 hours. The organic materials were removed and the residue was diluted with H20, acidified and extracted with EtOAC. The organics were washed with H20, brine, dried over MgSO4, filtered and concentrated in vacuo to provide 0.241 g (89%) of the desired product as an off-white gum. Electrospray Mass Spectrum: 464.3 (M + FA-H) " Step 8: WAY 173665 4 - ( { [4 - (2-Butynyl) phenyl] -sulfanylmethyl) -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxylate tert -butyl To a solution of 0.204 g ( 0.49 mmole) of mono-tert-butyl ester of 4- (4-but-2-ynyloxyphenylsulfanylmethyl) -piperidin-1,4-dicarboxylic acid, 0.079 g (0.58 mmoles) of 1-hydroxybenzothiazole in 2.5 ml of DMF was added 0.112 g (0.84 mmol) of 1- (3-dimethylaminopropyl-1) -3-ylcarbodiimide hydrochloride, and stirred at room temperature for 1 hour. Then 0.3 ml of 50% aqueous hydroxylamine was added and stirred for 18 hours. The resulting mixture was diluted with EtOAc, washed with H20, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1.5% MeOH / CH2Cl2 to provide 0.077 g (36%) of the desired product as a white solid. Electrospray Mass Spectrum: 435.2 (M + H) +.
Example 31 4- ( { [4- (But-2-ynyloxy) enyl] thio.} Methyl) -N-hydroxy-piperidin-4-carboxamide To a solution of 0.143 g, (0.033 mmol) of 4- ( { [4- (2-Butynyloxy) phenyl] sulfanyl} methyl) -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxylic acid tert-butyl ester in 5 ml of CH2C12 and 1 ml of MeOH are added 5 ml of 4M HCl in dioxane and stirred for 1 hour. The reaction was concentrated in vacuo and the residue was triturated with ether and filtered to give 0.093 g (76%) of the desired product as a pale orange solid. Electrospray Mass Spectrum: 335.3 (M + H) +.
Example 32 4- ( { [4- (2-Butynyloxy) phenyl] sul ini1.} Methyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid tert -butyl ester To a suspension of 4- ( { [4- (2-Butyloxy) -phenyl] sulfanyl.} Methyl) -4- [(hydroxyamino) carbonyl] -1-piperidine-carboxylic acid tert-butyl ester (0.24 g, 0.55 mmol) at 0 ° C in 7 ml of MeOH was added dropwise 3.5 ml of 30% hydrogen peroxide. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The reaction was cooled to 0 ° C and quenched with 3.5 ml of saturated Na 2 SO 3 solution.
The organic materials were removed and the aqueous solution was extracted with CH2C12. The organics were washed with H20, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether to provide 0.166 g (67%) of the desired product as an off-white solid. Electrospray Mass Spectrum: 451.3 (M + H) +.
Example 33 4- [[[4- (2-Butynyloxy) phenyl] sulfinyl] methyl] -N-hydroxy-4-piperidinecarboxamide 4- ( { [4- (2-Butynyloxy) phenyl] sulfinyl was prepared. .methyl) -N-hydroxy-4-piperidinecarboxamide according to the general method described in Example 31. Starting from 4- ( { [4- (2-Butynyloxy) phenyl] -sulfinyl Jmethyl) -4 - [(Hydroxyamino) carbonyl] -1-tert-butylpiperidinecarboxylate (0.082g, 0.18mmol), 0.066g (95%) of the desired product was isolated as a white solid. Mass Spectrum Electropu.lveri zador: 351.2 (M + H) +.
The solution is 4- ( { [4- (Bu t-2-ynyloxy) phenyl] sulfonyl} methyl) -4- [(hydroxy amino) carbonyl] piperidin-1-tert-butylcarboxylate A a solution of 4- ( { [4- (2-Butyloxy) phenyl] -sulfanyl}. methyl) -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxylic acid tert -butyl ester (0.422 g, 0.97 mmol. ) in 8 ml of MeOH, 4 ml of CH2C12 and 2 ml of THF was added a solution of 1.79 g (2.91 mmoles) of OXONE in 8 ml of H20 and stirred at room temperature for 18 hours. The solid was filtered and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc, washed with H20, brine, dried over MgSO4, filtered, and concentrated to provide 0.351 g (77%) of the desired product as a white solid. Electrospray Mass Spectrum: 467.3 (M + H) +.
Example 35 4- ( { [4- (2-Buyloyloxy) phenyl] sulfonyl} methyl) -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxylic acid tert-butyl 4- ( { [4- (2-Butynyl-oxy) -phenyl] -sulfonyl-methyl) -4- [(hydroxyamino) carbonyl] -1-tert-butyl-piperidinecarboxylate according to the general method described in Example 31. Starting from 4 - ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -4- [(hydroxyamino) carbonyl] -piperidine-1-carboxylic acid tert -butyl ester (0.10 g, 0.214 mmol), 0.074 was isolated g (86%) of the desired product as a white solid. Electrospray Mass Spectrum: 367.3 (M + H) +.
Example 36 l-Acetyl-4- [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -N-hydroxy-4-piperidinecarboxamide Step 1: 1-tert-butyl 4-ethyl ester of 4 - [[[ 4- (2-Butynyloxy) phenyl] sulfonyl] methyl] -1,4-piperidine-dicarboxylic acid To a solution of 4- ( { [4- (2-Butyloxy) -phenyl] sulfanyl-Jmethyl) -1, 4 tert-butylpiperidicarboxylate (1.66g, 3.7mmol) (prepared in Example 30, step 6) in 20ml of CH2C12 was added tetrabutylammonium oxone (17.38g, 14.7mmol) and stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the residue was diluted with EtOAc, washed with H20, 5% KHS04, brine, dried over MgSO4, filtered and concentrated to give 1.69 g (95%) of the desired product as a gum. pale yellow. Electrospray Mass Spectrum: 480.3 (M + H) +.
Step 2: 4 - [[[4- (2-Butynyloxy) -phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid ethyl ester 4 - [[4- (2-butynyl-oxy) phenyl] ethyl ester was prepared ] sulfonyl] methyl] -4-piperidinecarboxylic acid according to the general method described in Example 31. Starting from 1 - tert -butyl 4-ethyl ester of 4 - [[[4- (2-butyloxy) phenyl]] -sulfonyl] methyl] -1,4-piperidinedicarboxylic acid (1.62 g, 3.4 mmol), 1335 g (95%) of the desired product was isolated as a brown solid. Electrospray Mass Spectrum: 380.2 (M + H) +.
Step 3: 1-Acetyl-4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] -methyl] -4-iperidinecarboxylic acid ethyl ester To a solution of 4 - [[[4- (2-but loxi) phenyl] sulfonylmethyl] -4-piperidinecarboxylic acid (0.24 g, 0.576 mmole), triethylamine (0.32 ml) and a catalytic amount of 4-dimethylaminopyridine in 6.0 ml of CH2C12 was added a solution of acetyl chloride (0.068 ml , 0.864 mmole) in 1.0 ml of CH2C12. The reaction was stirred at room temperature for 4 hours and washed with H20, brine, dried over MgSO4, filtered through a pad of silica gel and concentrated to provide 0.242 g (100%) of the desired product as a colorless rubber. Electrospray Mass Spectrum: 422.2 (M + H) +.
Step 4: 1-Acetyl-4 - (4-but-2-ynyloxy-benzenesulfonylmethyl) -piperidin-4-carboxylic acid The acid 1-acetyl-4 - (4-but-2-ynyloxy-benzenesul fonilmet was prepared il) -piperidin-4-carboxylic acid according to the general method described in Example 30, (step 7). Starting from the ethyl ester of 1-acet-il-4- [[[4- (2-butyloxy) -phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid, (0.22 g, 0.524 mmol), 0.141 was isolated g of the desired product as a pale yellow solid. Electrospray Mass Spectrum: 438.2 (M + Fa-H) ".
Step 5: 1-Acetyl-4 - [[[4- (2-butyloxy) phenyl] -sulfonyl] methyl] -N-hydroxy-4-piperidinecarboxamide The l-acetyl-4- [[[4- (2-Butyloxy) -phenyl] sulphon-1] methyl] -N-hydroxy-4-piperidinecarboxamide according to the general method described in Example 30 (step 8). Starting from 1-acetyl-4- (4-but-2-ynyloxy-benzenesul fonyl-methyl) piperidine-4-carboxylic acid (0.122 g, 0.31 mmol), 0.048 g (38%) of the desired product was isolated as a pale yellow solid. Electrospray Mass Spectrum: 409.2 (M + H) +.
Example 37 1- (2-Butynyl) -4- ( { [4- (2-Butynyloxy) -phenyl] -sulfonyl Jethyl) -N-hydroxy-4-piperidinecarboxamide hydrochloride Step 1: Ethyl ester of 1- ( 2-butyl) -4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic A mixture of 4 - [[[4- (2-butynyloxy) phenyl] ethyl ester ] sulfonyl] methyl] -4-piperidinecarboxylic acid (0.208 g, 0.5 mmol), l-bromo-2-but-ine (0.044 ml, 0.53 mmol) and K2C03 (0.138 g, 1.0 mmol) in 5.0 ml of DMF was stirred at room temperature for 6 hours. The reaction was diluted with EtOAc and washed with H20, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc: hexanes (1: 1) to give 0.183 g (85%) of the desired product as a pale yellow gum. Electrospray Mass Spectrum: 432.2 (M + H) +.
Step 2: 1- (2-Butyl) -4- [4 - (2-butyloxy) -benzenesul-phenylmethyl] -piperidine-4-carboxylic acid 1- (2-butyl) -4- [ 4- (2-Butynyloxy) benzenesulfonylmethyl] -piperidine-4-carboxylic acid according to the general method described in Example 30 (step 7). Starting from the ethyl ester of 1- (2-butynyl) -4- [[[4- (2-butyloxy) -phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid, (0.153 g, 0.354 mmole), isolated 0.12 g (85%) of the desired product as a white solid. Electrospray Mass Spectrum: 404.2 (M + H) +.
Step 3: 1- (2-Butyl) -4 - ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-4-piperidinecarboxamide Hydrochloride 1- (2- Hydrochloride was prepared butyl) -4 - ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-4-piperidinecarboxamide according to the general method described in Example 30 (step 8). Starting from 1 - (2-butyl) -4 - [4 - (2-butyloxy) -benzenesulfonylmethyl] -piperidine-4-carboxylic acid (0.15 g, 0.34 mmol), 0.05 g of the desired product, which was dissolved in 1.0 ml of CH2Cl2 and treated with 0.225 ml of 1M HCl in CH2C12. The solution was stirred for 1 hour, and concentrated in vacuo. The residue was triturated with ether to provide 0.044 g (28%) of the hydrochloride of the desired product as a beige solid. Electrospray Mass Spectrum: 419.2 (M + H) +.
EXAMPLE 38 Nl- (tert-Butyl) -4- ( { [4- (2-butynyloxy) phenyl] sulfonyl.] - methyl) -N-4-hydroxy-1, 4- [4- (2 - butynyloxy) phenyl] -sulfonyl} methyl) -N-4-hydroxy-1, 4-1] sulfonyl} methyl) -N- 4-hydroxy-l, 4-piperidinedicarboxamide Stage 1: 1-tert-butylcarbamoyl-4 - (4-but-2-ynyloxy-benzenesulfonylmethyl) -piperidine-4-carboxylic acid ethyl ester To one solution of tert-butyl isocyanate (0.097 ml, 0.85 mmoles) in 8.0 ml of CH2C12 was added 4- [[[4- (2-butynyloxy) phenyl] -sulfonyl] methyl] -4-piperidinecarboxylic acid ethyl ester (prepared from Example 36, Step 2) (0.337 g, 0.81 mmol) and triethylamine (0.135 mL, 0.97 mmol) and stirred at room temperature for 2 hours. The reaction was diluted with CH2C12 and washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ether: hexanes (1: 1) to give 0.28'4 g (73%) of the desired product as a white solid. Electrospray Mass Spectrum: 479.2 (M + H) +.
Step 2: 1- [(tert-butylamino) carbonyl] -4 - ( { [4 - (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -4-onyl] -4- ( { [4- (2-Butynyloxy) phenyl] sulfonylmethyl) -4-piperidinecarboxylic acid 1- [(tert-butylamino) carbonyl] -4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -4-onyl] -4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -4-picididin-carboxylic acid according to the general method described in Example 30 (step 7). Starting from the ethyl ester of 1-tert-butylcarbamoyl-4- (4-but-2-ynyloxy-benzenesulfonylmethyl) -piperidine-carboxylic acid (0.259 g, 0.54 mmol), 0.169 g, (69%) of the desired product as a white solid. Electrospray Mass Spectrum: 451.4 (M + H) +.
Step 3: Nl - (tert-Butyl) -4 - ( { [4 - (2-Butynyloxy) phenyl] -sulfonyl.} Methyl) -N-4-hydroxy-l, 4- [4- (2 -butynyloxy) -phenyl] sulfonyl} methyl) -N-4-hydroxy-1, 4-1] sulfonyl} -methyl) -N-4-hydroxy-1,4-piperidinedicarboxamide Nl- (tert-Butyl) -4 - ( { [4- (2-Butynyloxy) phenyl] sulfonyl} methyl) -N was prepared -4-hydroxy-l, 4- [4- (2-butynyloxy) phenyl] -sulfonyl} methyl) -N-4-hydroxy-l, 4-1] -sulfonylmethyl) -N-4-hydroxy-l, 4-piperidinedicarboxamide according to the general method described in Example 30 (step 8). Starting from 1- [(tert-butylamino) carbonyl] -4- ( { [4- (2-Butynyloxy) -phenyl] sulfonyl Jmethyl) -4 -onyl] -4- ( { [4- (2-Butynyloxy) -phenyl] sulfonyl-Jethyl) -4-piperidinecarboxylic acid (0.149 g, 0.33 mmol), 0.077 g of the desired product was isolated as a pale yellow solid. Electrospray Mass Spectrum: 466.3 (M + H) +.
Example 39 4- ( { [4- (2-Binylinoxy) phenyl] sulfonyl} methyl] -4- [(hydroxyamino) carbonyl] -1-methyl piperidinearboxylate Step 1: Ethylester 4- ( 4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidine-1,4-dicarboxylic acid To a solution of 4 - [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid ethyl ester ( 0.354 g, 0.85 mmoles) in 1.0 ml of CH2C12 under an N2 atmosphere was added dropwise a solution of N, 0-bis (trimethylsilyl) acetamide (0.462 ml, 1.87 mmoles) in 0.5 ml of CH2C12 and stirred for 1 hour . The reaction was cooled to 0 ° C and a solution of 0.079 ml (1.02 mmol) of methyl chloroformate in 0.5 ml of CH2C12 was added dropwise. The reaction was allowed to stir at room temperature for 1 hour and cooled to 0 ° C, quenched with buffer solution of pH 7 and extracted with EtOAc. The organics were washed with H20, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc: hexanes (1: 2) to provide 0.315 g (85%) of the desired product as a colorless oil. Electrospray Mass Spectrum: 438.3 (M + H) +.
Step 2: 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidin-1,4-dicarboxylic acid monomethyl ester 4- (4-but-2-ynyloxy-benzenesulfonylmethyl) - monometic acid ester was prepared piperidin-1,4-dicarboxylic acid according to the general method described in Example 30 (step 7). Starting from 4- (4-but-2-ynyloxy-benzenesulfonylmethyl) piperidine-1,4-dicarboxylic acid methyl ester (0.277 g, 0.633 mmol), 0.175 g (67%) of the desired product was isolated as a solid White. Electrospray Mass Spectrum: 410.2 (M + H) +.Step 3: 4 - ( { [4 - (2-Butynyloxy) phenyl] sulfonyl.] Methyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylate or methyl. 4- ( { [4- (2-Butyloxy) phenyl] sulfonyl] .methyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid methyl ester according to the general method described in Example 30 (step 8). Starting from 4- (4-but-2-yn-loxi-benzenesulfonyl-methyl) -piperidin-1,4-dicarboxylic acid (4-15-, 0.366 mmol) monomethane, 0.053 g (34 g) was isolated. %) of the desired product as a white solid. Electrospray Mass Spectrum: 425.3 (M + H) +.
Example 40 4- ( { [4- (2 -Butynyloxy) phenyl] sulfonyl} .me.-yl) -4- [(hydroxyamino) carbonyl] -1-benzyl piperidinecarboxylate Stage 1: Benzyl ester ethyl ester 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidin-1,4-dicarboxylic acid 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) yl) -piperidine-1,4-dicarboxylic acid benzylester according to the general method described in Example 39 (step 1). Starting from the ethyl ester of 4- [[[4- (2-butynyloxy) -phenyl] sulphonyl] methyl] -4-piperidinecarboxylic acid (0.312 g, 0.75 mmol), was isolated, 0.337 g (87%) of the desired product as a colorless oil. Electrospray Mass Spectrum: 514.2 (M + H) +.
Step 2: 4- (4-But-2-ynyloxy-benzenesulfonylmethyl) -piperidin-1,4-dicarboxylic acid monobenzyl ester 4- (4-but-2-inyloxy-benzenesul fonylmethyl) monobenzyl ester) -I, 4 -dicarboxylic-piperidin-1 according to the general method described in Example 30 (step 7). Starting from the 4- (4-but-2-ynyloxy-benzenesulfonylmethyl) piperidine-1,4-dicarboxylic acid benzyl ester ethyl ester (0.32 g, 0.623 mmoles), 0.2 g of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 484.2 (M + H) +.
Step 3: 4 - ( { [4 - (2-Butyloxy) phenyl] sulphonylmethyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylate benzyl 4- ( { [4 - (2-Butyloxy) phenyl] -sulfonyl.} Methyl) -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxylic acid benzyl according to the general method described in Example 30, (step 8). Starting from the monobenzyl ester of 4- (4-but-2-ynyloxy-benzenesulfonylmethyl) -piperidin-1,4-dicarboxylic acid (0.18 g, 0.37 mmol), 0.106 g (57%) of the desired product was isolated as a whitish solid. Electrospray Mass Spectrum: 501.3 (M + H) +.
Example 41 l-Benzyl-4- ( { [4- (2-butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-butynyloxy) phenyl] sulyl onyl Jmethyl) -N-hydroxy-4 - piperidinecarboxamide Step 1: l-benzyl-4- ( { [4- (2-Butyloxy) phenyl] sulphonyl} -methyl) -4-4- (2-butynyloxy) phenyl] sulfonyl Jmethyl) -4 ethyl ethylpiperidinecarboxylate L-benzyl-4- ( { [4- (2-Butynyloxy) -phenyl] sulfonylmethyl) -4-4- (2-butynyloxy) phenyl] -sulfonylmethyl) -4-piperidinecarboxylate was prepared of ethyl ester according to the general method described in Example 37 (step 1). Starting from the 4- [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidinecarboxylic acid ethyl ester? (prepared, in Example 36, step 2) (0.312 g, 0.75 mmole), 0.265 g of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 470.2 (M + H) +.
Step 2: L-benzyl-4 - ( { [4- (2-butynyl-loxi) phenyl] -sulfonyl} -methyl) -4-piperidinecarboxylic acid-benzyl-4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -4-piperidinecarboxylic acid L-benzyl-4 - ( { [4 - (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -4-piperidinecarboxylic acid-benzyl-4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl-methyl-4-piperidinecarboxylic acid according to the general method described in Example 30 (step 7). Starting from l-benzyl-4- ( { [4- (2-Butynyloxy) phenyl] -sul-fonyl} -methyl) 4-4- (2-butyloxy) phenyl] sulfonyl-Jmethyl) -4 ethyl ethylpiperidine carboxylate (0.25 g, 0.53 mmole), 0.227 g (90%) of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 442.2 (M + H) +.
Step 3: l-Benzyl-4- ( { [4- (2-butynyloxy) phenyl] sulfonyl] -methyl) -N-hydroxy-4-butyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-4-piperidinecarboxamide L-Benzyl-4- ( { [4- (2-Butyloxy) -phenyl] sulfonyl-Jethyl) -N-hydroxy-4-butynyloxy) phenyl] -sulfonyl was prepared Jmethyl) -N-hydroxy-4-piperidinecarboxamide according to the general method described in Example 30 (step 8). Starting from 1-benzyl-4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -4-piperidinecarboxylic acid-benzyl-4 ( { [4- (2-butynyloxy) phenyl] -sulfonyl.} - methyl) -4-piperidinecarboxylic acid (0.211 g, 0.44 mmol), 0.108 g of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 457.2 (M + H) +.
Example 42 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- [(2,2,5-trimethyl-1,3-dioxan-5-yl) ) carbonyl] -4- piperidinecarboxamide Step 1: 4 - ( { [4 - (2-Butynyloxy) phenyl] sulphonyl} methyl) -1- [(2, 2, 5-trimethyl-1,3) -dioxan-5-yl) carbonyl] -4-ethylpiperidinecarboxylate The 4 - ( { [4 - (2-Butyloxy) phenyl] -sulfonylmethyl) -1- [(2, 2, 5-trimethyl) ethyl -l, 3-dioxan-5-yl) -carbonyl] -4-piperidinecarboxylate according to the general method described in Example 30 (step 8). Starting from 4- [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidine-carboxylic acid ethyl ester (0.333 g, 0.8 mmol) and 2,2,5-trimethyl-1 acid , 3) dioxan-5-carboxylic acid (0.168 g, 0.96 mmole), 0.339 g (79%) of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 536.1 (M + H) +.
Step 2: 4 - ( { [4 - (2-Butyloxy) phenyl] sulphonyl} -methyl) -l - [(2,2,5-rimet-1, 3-dioxan- 5-yl) carbonyl] -4-piperidinecarboxylic acid 4- ( { [4 - (2-Butyloxy) -phenyl] sulfonylj-methyl) -1- [(2, 2, 5-trimethyl-1, 3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylic acid according to the general method described in Example 30 (step 7). Starting from 4 - ( { [4 - (2-Butynyloxy) -phenyl] sulfonyl Jmethyl) -1- [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] - 4-ethylpiperidine carboxylate (0.299g, 0.558mmol), 0.235g (83%) of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 506.2 (M-H) ".
Step 3: 4 - ( { [4 - (2-Butyloxy) phenyl] sulfoni 1.] Methyl) -N-hydroxy-1- [(2, 2, 5-trimethyl-1,3-dioxan- 5-yl) carbonyl] -4-piperidinecarboxamide 4- ( { [4 - (2-Butynyloxy) -phenyl] sulfonyl-methyl) -N-hydroxy-1 - [(2,2,5-trimethyl- 1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxamide according to the general method described in Example 30 (step 8). Starting from 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -1- [(2, 2, 5-trimethyl-1,3-dioxan-5-yl) carbonyl] - 4-piperidinecarboxylic acid (0.22 g, 0.433 mmol), 0.16 g of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 523.2 (M + H) +.
Example 43 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl.} - methyl) -N-hydroxy-1- [3-hydroxy-2- (hydroxymethyl) -2-methylpropanoyl] -4 - piperidinecarboxamide A mixture of 4 - ( { [4 - (2-Butyloxy) -phenyl] sulfonylmethyl) -N-hydroxy-1- [(2,2,5-trimethyl-1,3-dioxan-5-yl ) carbonyl] -4-piperidinecarboxamide (0.106 g, 0.2 mmol) and 2 ml of IN HCl in 2 ml of THF was stirred at room temperature for 4 hours. The reaction was diluted with EtOAc, washed with H20, saturated NaHCO3, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ether to provide 0.67 g (71%) of the desired product as an off-white solid. Electrospray Mass Spectrum: 483.2 (M + H) +.
Example 44 1- [Amino (imino) methyl] -4- ( { [4- (2-Butynyloxy) -phenyl] -sulfonyl.} Methyl) -N-hydroxy-4-1] -4- ( { [4- (2-Butynyloxy) -enyl] sulfonyl} methyl) -N-hydroxy-4-oxy) phenyl] sulfonyl} - methyl) -N-hydroxy-4-piperidinecarboxamide Stage 1: Thiourea protected with N, N'-t-Boc: To a stirred solution of thiourea (0.57 g, 7. 5 mmoles) in 150 ml of. THF under N2 at 0 ° C was added 60% NaH (1.35 g, 33.8 mmol) in mineral oil. After 5 minutes, the ice bath was removed and the reaction mixture was allowed to stir at room temperature for 10 minutes. The reaction mixture was cooled to 0 ° C and 3.6 g (16.5 mmol) of di-tert-butyl dicarbonate was added. After 30 minutes, the ice bath was removed and the reaction was stirred for 2 hours. The reaction was then quenched with saturated NaHC03 solution, poured into water and extracted with 3x EtOAc. The organics were washed with H20, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with hexane to provide 1.72 g (83%) of the desired product as a white solid.
Step 2: 4 - [(tert-Butoxyamino) carbonyl] -4- ( { [4- (2-yloxy) -phenyl] sulfonylmethyl) -1-piperidinecarboxylate tert -butyl 4 - [(tert-butoxyamino ) carbonyl] -4 - ( { [4- (2-yloxy) phenyl] sulfonyl Jethyl) -1-piperidine-carboxylic acid tert-butyl ester according to the general method described in Example 30 (step 8). Starting from the mono-tert-butyl ester of 4 - (4-but-2-ini loxi-benzenesul fonylmet i 1) -piperidin-1,4-dicarboxylic acid (2.53 g, 5.6 mmoles) and O-hydrochloride ter-butyl-hydroxylamine (1.4 g, 11.2 mmol), 2.31 g (79%) of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 523.2 (M + H) +.
Step 3: N- (tert-But oxy) -4- ( { [4 - (2-butynyloxy) pheny1] sulfonylmethyl) -4- [4- (2-butynyloxy) phenyl] sulfonylj-mer. il) -4-piperidinecarboxamide To a solution of 4 - [(tert-butoxyamino) carbonyl] -4- ( { [4- (2-yloxy) phenyl] sulfonylmethyl) -1-piperidinecarboxylic acid tert -butyl ester (3.0 5.5 mmoles) in 6 ml of CH2C12 was added rimet ilsilyl-trifluoromethylsulfonate (1.1 ml, 6.05 mmol) followed by 0.7 ml of 2,6-lut idine. The reaction was stirred for 1 hour and diluted with CH2C12. The organic materials were washed with H20, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to provide 2.01 g (86%) of the desired product as an off-white solid. Electrospray Mass Spectrum: 423.2 (M + H) +.
Step 4: tert-but i ter of butoxycarboni 1) -amino] methylene] carbamic acid of [[4- [(tert-butoxyamino) -carbonyl] -4- [[[4- (2- [4- ( 2-butynyloxy) phenyl] -sulfonyl.} - methyl) -4-piperidinecarboxamide To a mixture of N- (tert-butoxy) -4 - ( { [4- (2-Butynyloxy) phenyl] sulfonylmethyl) -4 - [4- (2-Butynyloxy) -phenyl] sulfonyl Jmethyl) -4-piperidinecarboxamide (0.127 g, 0. 3 mmoles), thiourea protected with di-t-boc (obtained from step 1) (0.091 g, 0.33 mmol) and triethylamine (0.092 ml) in 3 ml of DMF was added mercury (II) chloride (0.09 g, 0.33 mmol) and stirred for 1 hour at 0 ° C. The reaction was diluted with EtOAc and filtered through a pad of celite. The organics were washed with H20, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with hexanes to provide the desired product as a white solid. Electrospray Mass Spectrum: 665.5 (M + H) +.
Step 5: 1- [Amino (imino) met il] -4 - ( { [4 - (2-butyloxy) -phenyl] sulfonylmethyl) -N-hydroxy-4-1] -4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-4-oxy) -phenyl] sulfonyl Jmethyl) -N-hydroxy-4-piperidinecarboxamide A mixture of tert-butylester of butoxycarbonyl) -amino] methylene ] [[4- [(tert-butoxyamino) carbonyl] -4 - [[[4- (2- [4- (2-butynyloxy) phenyl] -sulfonyl] -methyl) -4-piperidinecarboxamide ( 0.135 g, 0.2 mmol) and 3 ml of trifluoroacetic acid in 2 ml of CH2C12 was heated at 60 ° C for 24 hours. The reaction was concentrated in vacuo and subjected to preparative CLAP to provide 0.032 g (31%) of the desired product as a beige solid. Electrospray Mass Spectrum: 409.3 (M + H) +.
Example 45 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- (4-hydroxy-2-butynyl) -henyl] sulfonyl} methyl) -N-hydroxy- 1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide Step 1: 4 - ( { [4 - (2-Butyloxy) phenyl] sulphonyl} metil) 1- (4 - { [ 3-chloroanilino) carbonyl] oxy} -2-butynyl) -4-ethylpiperidinecarboxylate. 4 - ( { [4- (2-Butyloxy) phenyl] -sulfonylmethyl) -1- (4- {[3-chloroanilino) carbonyl]] oxy } Ethyl -2-butyl) -4-piperidinecarboxylate according to the general method described in Example 37 (step 1). Starting from the ethyl ester of 4- [[[4- (2-butynyloxy) phenyl] sulfonyl] methyl] -4-piperidine-carboxylic acid (0.291 g, 0.7 mmoles) and 4-chloro-2-butyl- (3-chlorophenyl) carbamate (0.19 g, 0.735 mmoles), 0.27 g (64%) of the desired product was isolated as a pale yellow oil. Electrospray Mass Spectrum: 601.3 (M + H) +.
Step 2: 4 - ( { [4 - (2-Butyloxy) pheny1] sulfonyl} methyl) -1- (4-hydroxy-2-butynyl) -4-ynyloxy) phenyl] sulfonyl} methyl) -1- (4-hydroxy-2-butynyl) -4-ethylpiperidinecarboxylate A solution of 4- ( { [4- (2-Butynyloxy) phenyl] -sulfonylmethyl) -1- (4 - { [3-Chloroanilino) carbonyl] oxy} -2-butyl) -4-ethylpiperidinecarboxylate (from step 1) (0.22g, 0.366mmol) and lithium hydroxide hydrate (0.019g, 0.44mmol) in 4ml of MeOH was heated to reflux by 3 hours. The reaction was concentrated, diluted with H20, acidified to pH3 and extracted with CH2C12. The organic materials were washed with H20, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 3% MeOH / CH2Cl2 to provide 0.12 g (73%) of the desired product as a yellow oil. Electrospray Mass Spectrum: 448.3 (M + H) +.
Step 3: 4 - ( { [4 - (2-Butyloxy) phenyl] sulfonyl} - methyl) -1- (4-hydroxy-2-butynyl) -4-ynyl] sulfonyl Jmethyl) -1 - (4-Hydroxy-2-butynyl) -4-piperidinecarboxy 1 i co 4- ( { [4- (2-Butyloxy) phenyl] -sulfonyl Jmethyl) -1- (-hydroxy-2- butynyl) -4-inyl] sulfonyl} -methyl) -1- (4-hydroxy-2-butyl) -4-piperidinecarboxylic acid according to the general method described in Example 30 (step 7). Starting from 4 - ( { [4- (2-Butynyloxy) phenyl] sulfonylmethyl) -1- (4-hydroxy-2-butyl) -4-ethylpiperidinecarboxylate (0.115g, 0.257mmol), was isolated 0.08 g (74%) of the desired product as a white solid. Electrospray Mass Spectrum: 420.4 (M + H) +.
Step 4: 4- ( { [4- (2-Butynyloxy) phenyl] sulf onyl Jmethyl) -N-hydroxy-1- (-hydroxy-2-butyl) -henyl) sulfonyl-Jmethyl) -N-hydroxy- 1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide It was prepared - ( { [4 - (2-Butyloxy) phenyl] -sulfonyl Jmethyl) -N-hydroxy-1- (4-hydroxy) -2 butynyl) -henyl) -sulfonyl Jmethyl) -N-hydroxy-1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide according to the general method described in Example 30 (step 8). Starting from 4- ( { [4- (2-Butynyloxy) phenyl] -sulfoni 1.} - methyl) -1- (4-hydroxy-2-butyl) -4-nyl] sulfonyl} -methyl) -1- (4-hydroxy-2-butynyl) -4-piperidinecarboxylic acid (0.073 g, 0.174 mmole), 0.026 g (34%) of the desired product was isolated as a white solid. Electrospray Mass Spectrum: 435.3 (M + H) +.
The methods for the synthesis of the solution phase of the compounds of the present invention is as shown in the following reaction scheme.
EXAMPLE 46 Trifluoroacetic acid salt of 4- ( { [4-but-2-ynyloxy) phenyl] sulfonyl Jethyl) -1-ethyl-N-hydroxypiperidin-4-carboxamide Step A: A solution of N- ( tert-butoxy) -4- ( { [4- (2-but ini-loxi) phenyl] sulfonyl} methyl) -4- [4- (2-butynyloxy) phenyl] sulfonyl} methyl-4-piperidinecarboxylamide (0.097 g, 0.23 mmol), ethyl iodide (0.019 ml, 0.24 mmol) and triethylamine (0.096 ml, 0.69 mmol) in 2 ml of CH2C12 was stirred at room temperature for 18 hours and then concentrated in va c uo Step B: A solution of the residue from Step A in 1 ml of CH2C12 and 1 ml of trifluoroacetic acid was heated at 50 ° C for 2 hours and then concentrated in vacuo to provide the desired product. The following hydroxamic acids were synthesized according to the processes of the trifluoroacetic acid salt of 4- ( { [4 - (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -1-ethyl-N-hydroxypiperidin-4 - carboxamide using appropriate reagents.
Example 47: Reagent - 0.029 ml (0.24 mmol) of the trifluoroacetic acid salt of 2-chloro-5- (chloro-meth i-) thiophen-4- ( { [4- (but-2-ynyloxy) phenyl ] sulfonylj-methyl) -1- [(5-chlorothien-2-yl) methyl] -N-hydroxypiperidin-4-carboxamide.
Example 48: Reagent - 0.0496 g (0.24 mmoles) of the tl-fluoroacetic acid salt of 4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (pyridin-4 -ylmethyl) -piperidine-4-carboxamide of 4-picolyl chloride hydrochloride.
Example 49: 4- ( { [4- (But-2-ynyloxy) phenyl] -sulfonyl Jmethyl) -N-hydroxy-1- (pyridin-3-ylcarbonyl) piperidine-4-carboxamide acid salt Step A : a solution of N- (tert-butoxy) -4- ( { [4 - (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -4- [4- (2-butynyloxy) -phenyl] sulfoni 1 Jmet il-4-piperidinecarboxyamide (0.097 g, 0.23 mmole), triethylamine (0.064 ml, 0.64 mmole), nicotinoyl chloride hydrochloride (0.061 g, 0.34 mmole), and -dimet ilaminopyridine (0.002 g) in 2 ml of CH2C12 was stirred at room temperature for 18 hours and then concentrated in vacuo. Step B: same as in Step B of Example 46. The following hydroxamic acids were synthesized according to the procedures of the trifluoroacetic acid salt of 4 - ( { [4 - (but-2-ynyloxy) phenyl] sulfonyl.] methyl) -N-hydroxy-1- (pyridin-3-ylcarbonyl) piperidin-4-carboxamide using the appropriate reagents.
Example 50 Reagent - 0.04 ml (0.276 mmol) of l-benzoyl-4- ( { [4-but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-piperidine-4-carboxamide of benzoyl chloride Example 51 Reagent - 0.037 ml (0.276 mmoles) of 4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (thien-2-ylcarbonyl) piperidin-4 -carboxamide of 2-thiophenecarbonyl chloride Example 52 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -Nl-ethyl-N-4-hydroxypiperidin-1,4-dicarboxamide Stage A: A solution of N- (ter- butoxy) -4 - ( { [4 - (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -4- [4- (2-butynyloxy) -phenyl] sulphonyl} met il-4-piperidinecarboxyamide (0.097 g, 0.23 mmol), triethylamine (0.064 mL, 0.64 mmol) and ethyl isocyanate (0.02 mL, 0.253 mmol) in 2 mL of CH2C12 was stirred at room temperature for 18 hours and then concentrated in va cu o. Step B: same as Step B of Example 46. The following hydroxamic acids were synthesized according to the procedures of Example 52, using the appropriate reagents.
Example 53 Reagent - 0.275 ml (0.253 mmol) of 4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl-methyl) -N-4-hydroxy-N-l-enylpiperxdin-1,4-dicarboxamide of phenyl isocyanate Example 54 Reagent - 0.32 ml (0.253 mmol) of 4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -Nl-, N-1-diethyl-N- - hydroxypiperidin-1, 4 -dicarboxamide of diethylcarbamoyl chloride Example 55 Reagent - 0.0295 ml (0.253 mmoles) of 4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (morpholin-4-ylcarbonyl) piperidin-4- carboxamide of morpholinecarbonyl chloride Example 56 Reagent - 0.043 g (0.253 mmol) of 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-4-hydroxy-N-methyl-Nl-phenylpiperidin-1,4 methylphenylcarbamoyl chloride -dicarboxamide Example 57 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl-methyl) -4- [(hydroxyamino) carbonyl] piperxdin-1-carboxylic acid octyl Stage A: A solution 0.097 g (0.23 mmoles) of N- (tert-butoxy) -4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl.} - methyl) -4- [4- (2-butynyloxy) phenyl] sulfonyl} methyl) -4-piperidinecarboxyamide (0.097 g, 0.23 mmole), octyl chloroformate (0.0495 ml, 0.253 mmole) and diisopropylethylamine (0.08 ml, 0.46 mmole) in 2 ml of CH2C12 was stirred at room temperature for 18 hours and then He concentrated in va cuo. Step B: same as Step B of Example 46.
The following hydroxamic acids were synthesized according to the procedures of Example 57 using the appropriate reagents.
Example 58 Reactive - 0. 038 ml (0.253 mmoles) of 4 - ( { [4 - (but-2-ynyloxy) phenyl] sulfonyl-methyl) -4- [(hydroxyamino) -carbonyl] piperidine-1-carboxylate of 4-methoxyphenyl of 4-methoxyphenyl chloroformate Example 59 Reagent-0. 0323 ml (0.253 mmoles) of 4 - ( { [4- (but-2-ynyloxy) phenyl] sulfonyl-methyl) -N-hydroxy-1- (f-enylsulfonyl) -piperidin-4 -carboxamide chloride of benzenesulf onyl EXAMPLE 60 Reagent - 0.0457 g (0.253 mmol) of 4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- [(1-methyl-1H-imidazole-4 -yl) sulfonyl] piperidine-4-carboxamide of l-methylimidazole-4-sulfonyl chloride Example 61 1- [2- (Benzylamino) acetyl] -4- ( { [4- (but-2-ynyloxy) -phenyl] sulfonylmethyl) -N-hydroxypiperidine-4-carboxamide Stage A: A solution of N - (tert-butoxy) -4 - ( { [4 - (2-Butynyloxy) phenyl] sulfonylmethyl) -4- [4- (2-butynyloxy) -phenyl] sulfonyl-Jmet-il-4-piperidinecarboxyamide (0.097 g, 0.23 mmole), triethylamine (0.064 ml, 0.64 mmole), chloroacetyl chloride (0.064 ml, 0.64 mmole), and 4-dimethylaminopyridine (0.002 g) in 2 ml of CH2C12 was stirred at room temperature for 18 hours. The solution was then treated with benzylamine (0.075 ml, 0.69 mmol) and stirred for 18 hours and then concentrated in vacuo. Step B: same as Step B of Example 46.
The following hydroxamic acids were synthesized according to the procedure of Example 61 using the appropriate amine reagents.
Example 62 Reagent - 0.060 ml (0.69 mmol) of 4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (2-morpholin-4-ylace) iperidin - 4-morpholine carboxamide Example 63 Reagent - 0.076 ml (0.69 mmoles) of 4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- [2- (4-methylpiperazin-1- il) asethyl] piperidine-4-carboxamide of N-methylpiperazine LC Conditions: Hewlett Packard 1100;; YMC ODS-A column of 4.6 mm x 50 mm 5 u at 23 ° C; injection 10 ul; Solvent A: TFA / 0.05% water; Solvent B: TFA / acetonitrile 0.05%; Gradient: Time 0: 98% A; 1 minute: 98% A; 7 minutes: .10% A, 8 minutes: 98% A; After 1 minute of time. Flow rate 2.5 ml / minute; Detection: DDA of 220 and 254 nm.
Mass Spectrum Conditions: API. electrospray Example 64 Hydroxamide of l-acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid Stage 1: 4-But-2-ynyloxybenzenesulphonyl fluoride: To a solution of 4-chloride but-2-inyloxybenzenesul fonyl (prepared from Example 30, step 4) (2.0 g, 8.18 mmol) in acetonitrile (10 ml) was added KF-CaF2 (2.85 g, 16.3 mmol) and the resulting mixture was stirred for 4 hours. hours at room temperature. The reaction mixture was filtered and the filtrate was concentrated. The crude product was dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous Na2SO4 and the solvent was removed to obtain 1.5 g (80%) of the product as a solid.
Step 2: 4- (4-but-2-ynyloxybenzenesulfonyl) -piperidin-1,4-dicarboxylic acid methyl ester 4- to 4-diisopropylamine (1.58 ml, 11.3 mmol) in THF (25 ml) at 0 ° C n-BuLi 2.5M (4.68 ml, 11.7 mmol) was added and the resulting mixture was stirred for 15 minutes at that temperature. The reaction mixture was cooled to -78 ° C and a solution of 1- (tert-butyl) -4-methyl 1,4-piperidinecarboxylate (prepared from example 30, step 1) (2.67 g, 11.0 mmol) in THF (40 ml). The resulting mixture was stirred for 1 hour and added into a solution of 4-but-2-ynyloxy-benzenesulfonyl fluoride (2.5 g, 11.0 mmol) in THF (25 mL). After stirring for 4 hours at room temperature, the reaction was quenched with aqueous, saturated NH 4 Cl solution and extracted with EtOAc, dried over anhydrous Na 2 SO 4. The crude product was purified by silica gel chromatography to obtain 2.6 g (53%) of the product as a solid; H-NMR (300 MHz, CDC13) d 1.44 (s, 9H), 1.87 (m, 3H), 1.98 (m, 2H), 2.32 (m, 2H), 2.62 (m, 2H), 3.74 (s, 3H) , 4.17 (m, 2H), 4.74 (m, 2H), 7.09 (d, 2H, J = 7.2 Hz), 7.71 (d, 2H, J = 7.2 Hz).
Step 3: 4- (4-But-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester: To a solution of the product from step 2 (500 mg, 1.11 mmol) in methylene chloride (10 ml) was added 4M HCl (2 ml) and the resulting mixture was stirred for 2 hours at room temperature. The solid was filtered, washed with ether to obtain 410 mg (95%) of the product as a solid. X H NMR (300 MHz, CDC13): d 1.86 (m, 3 H), 2.52 (m, 4 H), 2.89 (m, 2 H), 3.52 (m, 2 H), 3.74 (s, 3 H), 4.74 (m, 2 H) ), 7.10 (d, 2H, J = 8.7 Hz), 7.69 (d, 2H, J = 8.7 Hz).
Step 4: 1-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid methyl ester To a solution of the product from step 3 (105 mg, 0.23 mmol) in methylene chloride (1 ml) triethylamine (93 mg, 0.92 mmol), acetyl chloride (18 mg, 0.23 mmol) was added followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 8 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 75 mg (80%) of the product as a solid.
Step 5: 1-Acetyl-4 - (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid: A solution of the ester, from step 4 (240 mg, 0.61 mmol)) and lithium hydroxide 18 mg, 0.75 mmol) in mixture with tetrahydrofuran / -methanol / water (3: 3: 2) was stirred at room temperature. 15 hours. The mixture was concentrated, acidified to pH 3-5 with IN aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave the acid. Yield: 200 mg, (87%). X H NMR (300 MHz, acetone-de): d 1.84 (t, 3H, J = 2.8 Hz), 1.90-2.05 (m, 2H), 2.06 (s, 3H), 2.25-2.51 (m, 3H), 3.06 (m, 1H), 4.04 (m, 1H), 4.63 (m, 1H), 4.86 (q, 1H, J = 2.0).
Step 6: 1-Acetyl-4 - (4-but-2-ynyloxybenzenesulfonyl) piperidinecarboxylic acid hydroxyamide To a solution of 1-acetyl- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-acid Carboxylic (180 mg, 0.48 mmol) in dimethylformamide was added hydroxy-benzotriazole (77 mg, 0.57 mmol) followed by 1- (3-dimethylaminopropyl) -3-yl-carbodiimide hydrochloride (127 mg, 0.66 mmol) and N-methylmorpholine (0.078 ml, 0.71 mmol). The resulting mixture was stirred for 1 hour at room temperature when the 50% aqueous hydroxylamine solution (0.145 ml, 2.37 mmol) was added and the mixture was stirred for 15 hours at that temperature. The solvent was removed and the ethyl acetate / water was added to the crude product. The organic layer was separated and washed successively with IN aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to obtain 100 mg (53%) of the product as a solid. H-NMR (300 MHz, CDC13): d 1.64 (m, 1H), 1.85 (m, 3H), 1.99 (s, 3H), 2.31 (m, 4H), 2.83 (m, 1H), 3.88 (m, 1H) ), 4.41 (m, 1H), 4.88 (m, 2H), 7.16 (d, 2H, J = 9.0 Hz), 7.66 (d, 2H, J = 9.0 Hz), 9.20 (m, - 1H), 11.00 ( m, 1H); ES-MS: m / z 395.2 (M + H) +.
Example 65 l-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid hydroxyamide Step 1: l-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-methyl ester carboxylic acid To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (416 mg, 4.12 mmol), benzoyl (144 μl, 1.24 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 375 mg (80%) of the product as a solid. ESMS: m / z 456.1 (M + H) +.
Step 2: L-Benzoyl-4- (4-but-2-inyloxybenzenesulfonyl) piperidin-4-carboxylic acid L-benzoyl-4- (4-but-2-inyloxybenzenesulfonyl) piperidin-4 acid was prepared carboxylic acid, starting from the methyl ester of l-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid (300 mg, 0.66 mmol) and lithium hydroxide (18 mg, 0.75 mmol). The resulting reaction mixture was worked up as described in Example 64, (step 5). Yield: 250 mg (86%) of the acid. HR-MS: m / z Calculated for C23H23N06S 442.1319; . Found 442.1317.
Step 3: 1-Benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid hydroxyamide The general procedure for step 6 (Example 64) was followed using l-benzoyl-4- (4 -but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid (100 mg, 0.23 mmole) in dimethylformamide (2 ml), 1-hydroxybenzot riazole (36 mg, 0.27 mmol), 1- [3- (dimethylamino) propyl] -3-ylcarbodiimide hydrochloride (62 mg, 0.32 mmol), N -methylmorpholine (0.038 ml, 0.35 mmol), and hydroxylamine (0.083 ml, 1.15 mmol) to obtain 40 mg (38%) of the product as a solid. ES-MS: m / z 457.2 (M + H) +.
Example 66 1- (4-Methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid hydroxyamide Step 1: 1- (4-methoxybenzoyl) -4- (4-buty) methyl ester -2-ini loxibencenesulfonyl) piperidin-4-carboxylic acid To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) piperidin-4-carboxylic acid methyl ester (260 mg, 0.77 mmol) in chloroform (7 ml) was added triethylamine (311 mg, 3.08 mmol), 4-methoxybenzoyl chloride (158 mg, 0.92 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 280 mg (75%) of the product as a solid. HR - MS: m / z Ca l cu l a do ra C25H27N07 S 4 8 6. 158 1; Finding 4 8 6. 157 6.
Step 2: 1- (4-Methoxybenzoyl) - - (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid 1- (4-methoxybenzoyl) -4 - (4-but-2-inyloxybenzenesulfonyl) acid was prepared piperidin-4-carboxylic following the procedure of Example 64 (step 5). Starting from the methyl ester of l- (4-methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulphonyl) -piperidine-4-carboxylic acid methyl ester (250 mg, 0.52 mmol) in 4 ml of tetrahydrofuran: methanol (1: 1) and 1N sodium hydroxide (1.03 ml, 1.03 mmole), 150 mg (62%) of the acid was isolated. HR-MS: m / z Calculated for C24H25N07S 472.1425; Found 472.1426.
Step 3: 1- (4-Methoxybenzoyl) -4 - (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid hydroxyamide: 1- (4-methoxybenzoyl) -4- (4-hydroxyamide was prepared -but-2-ynyloxybenzenesulfonyl) -piperidine-4-carboxylic acid following the procedure of Example 64 (step 6). Starting from 1- (4-methoxybenzoyl) -4- (4-but-2-ynyloxybenzenesulfonyl) piperidine-4-carboxylic acid (90 mg, 0.19 mmol) in dimethylformamide (2 ml), 1-hydroxybenzotriazole ( 31 mg, 0.23 mmol), 1- [3- (dimethylamino) -propyl] -3-ethyl-carbodiimide hydrochloride (51 mg, 0.27 mmol), N-methylmorpholine (0.031 mL, 0.28 mmol), and hydroxylamine (0.068 mL) , 0.95 mmole), 70 mg (76%) of the product was isolated as a solid. HR-MS: m / z Calculated for C24H26N 07S 487.1534; Found 487.1531.
Example 67 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyrrolidin-1-carbonyl) -4-piperidinecarboxamide Step 1: 4- (4-But-2-ynyloxy-benzenesulfonyl) methyl ester -1- (pyrrolidin-1-carbonyl) piperidine-4-carboxylic acid To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added triethylamine (208 mg, 2.06 mmol), pyrrolidincarbonyl chloride (206 mg, 1.54 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 400 mg (87%) of the product as a solid; ES-MS: m / z 449.3 (M + H) +.
Step 2: 4 - (4-But-2-ynyloxybenzenesulfonyl) -1 - (pyrrolidin-1-carbonyl) -? Iperidin-4-carboxylic acid: 4- (4-But-2-ynyloxybenzenesulfonyl) acid was prepared 1- (pyrrolidin-1-carbonyl) piperidine-4-carboxylic following the procedure of Example 64 (step 5). Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -1- (pyrrolidin-1-carbonyl) piperidin-4-carboxylic acid methyl ester (250 mg, 0.52 mmoles) in 4 ml of tetrahydrofuran: methanol (1: 1) and IN sodium hydroxide (1.03 ml, 1.03 mmol), 150 mg (62%) of the acid was isolated. HR-MS: m / z Calculated for C24H25N07S 472.1425; Found 472.1426.
Step 3: 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyrrolidine-1-carbonyl) piperidinecarboxamide was prepared following the procedure of Example 64 (step 6). Starting from 4- (4-but-2-ynyloxybenzenesulphonyl) -N-hydroxy-1- (pyrrolidin-1-carbonyl) piperidinecarboxylic acid (255 mg, 0.23 mmole) in dimethylformamide (6 ml), 1-hydroxybenzotriazole (96 mg, 0.71 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol), N-methylmorpholine (0.099 mL, 0.84 mmol), and hydroxylamine (0.181 mL, 2.8 mmoles), 150 mg (60%) of the product was isolated as a solid. HRMS: m / z Calculated for C2? H27N306S 450.1693; Found 450.1692.
Example 68 Ethyl 4- (4-But-2-ynyloxy-benzensulfonyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylate Stage 1: 4- (4-but-2-ynyloxy-benzenesulfonyl) -l, 4 1-ethyl 4-methyl piperidine-dicarboxylate To a solution of 4- (4-but-2-ynyloxy-benzenesulfone 1) -piperidine-4-carboxylic acid methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added sodium bicarbonate (865 mg, 10.3 mmol), ethyl chloroformate (0.147 ml, 1.54 mmol). The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 425 mg (98%) of the product as a solid. ES-MS: m / z 424.4 (M + H) +.
Step 2: 1- (Ethylcarbonyl) -4 - (4-but-2-ynyloxy-benzenesulfonyl) -1-piperidinecarboxylic acid 1- (Ethylcarbonyl) -4 - (4-but-2-ynyloxybenzenesulfonyl) acid ) -1-piperidinecarboxylic following the procedure of Example 64 (step 5).
Starting from 4 - (4-but-2-ynyloxybenzenesulfonyl) -1,4-piperidine-dicarboxylic acid 1-ethyl 4-methyl (400 mg, 0.95 mmol) in 8 ml of tetrahydrofuran: methanol; water (1: 1: 0.5) and lithium hydroxide (50 mg, 2.04 mmol), 340 mg (88%) of the acid was isolated. HR-MS: m / z Calculated for C? 9H23N07S 408.1122; Found 408.1126.
Step 3: 4- (4-but-2-yn-loxibencensul foni 1) -4 - [(hydroxy-amino) carbonyl] -1-piperidinecarboxylate ethyl 4- (4-but-2-ynyloxybenzenesulfonyl) -4- was prepared [(hydroxyamino) carbonyl] -1-ethylpiperidinecarboxylate following the procedure of Example 64 (step 6). Starting from 1- (ethylcarbonyl) -4- (4-but-2-ynyloxybenzenesulfonyl) -1-piperidinecarboxylic acid (225 mg, 0.55 mmole) in dimethylformamide (6 ml), 1-hydroxybenzothiazole (89 mg , 0.66 mmoles), 1- [3- (dimethylamino) -propyl] -3-ethylcarbodiimide hydrochloride (148 mg, 0.77 mmol), N-methylmorpholine (0.091 mL, 0.86 mmol), and hydroxylamine (0.168 mL, 2.75 mmoles), 150 mg (64%) of the product was isolated as a solid. HR-MS: m / z Calculated for C? 9H2 N207S 425.1377; Found 425.1375.
Example 69- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(trifluoromethyl) sulfonyl] -4-piperidinecarboxamide Stage 1: 4 - (4-but-2-inyloxybenzenesul foni 1) -1 - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxylate methyl To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (350 mg, 0.90 mmol) in chloroform (10 ml) was added triethylamine (182 mg, 1.81 mmol). , trifluoromethanesulfonyl chloride (0.125 ml, 1.17 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 245 mg (56%) of the product as a solid. HR-MS: m / z Calculated for C? 8H20F3NO7S2 484.0706; Found 484.0700.
Step 2: 4- (4-But-2-ynyloxybenzenesulfonyl) -l- [(trifluoromethyl) sulfonyl] -4-piperidinecarboxylic acid 4- (4-But-2-ynyloxybenzenesulfonyl) -1- [(trifluoromethyl) acid was prepared ) sulfonyl] -4-piperidinecarboxylic following the procedure of Example 64 (step 5). Starting from methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(trifluoromethyl) sulfonyl] -4-piperidinecarboxylate (225 mg, 0.47 mmole) in 8 ml of tetrahydrofuran: methanol; water (1: 1: 0.5) and lithium hydroxide (24 mg, 0.98 mmol), 175 mg (80%) of the acid was isolated. ES-MS: m / z 468.1 (M-H). " Step 3: 4- (4-but-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(trifluoromethyl) -sulfonyl] -4-piperidinecarboxamide. 4 - (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(trifluoromethyl) -sulfonyl] -4-piperidinecarboxamide was prepared following the procedure of Example 64 (step 6). Starting from 4- (4-but-2-ynyloxybenzenesulfonyl) -l- [(trifluoromethyl) -sulfonyl] -4-piperidinecarboxylic acid (145 mg, 0.31 mmol) in dimethylformamide (3 ml), 1-hydroxybenzothiazole ( 50 mg, 0.37 mmol), 1- [3- (dimethylamino) -propyl] -3-ethylcarbodiimide hydrochloride (83 mg, 0.47 mmol), N-methylmorpholine (0.051 ml, 0.47 mmol), and hydroxylamine (0.095 ml, 1.55 mM). mmoles), 90 mg (60%) of the product was isolated as a solid. HR-MS: m / z Calculated for C? 7H19F3N207S2 485.0659; Found 485.0666.
Example 70 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (3-pyridinylcarbonyl) -4-piperidinecarboxamide Step 1: 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) Methyl) -4-piperidinecarboxylate To a solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -piperidin-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added triethylamine ( 443 mg, 4.39 mmol), nicotinyl chloride (276 ml, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 460 mg (78%) of the product as a solid. HR -EM: m / z Calculated for C23H24N206S 457.1428; Found 457.1428.
Step 2: 4 - (4-But-2-ynyloxybenzenesulphonyl) -1- (3-pyridinylcarbonyl) -4-piperidinecarboxylic acid 4 - (4-But-2-ynyloxybenzenesulfonyl) -1- ( 3-pyridinyl carbonyl) -4-piperidinecarboxylic acid following the procedure of Example 64 (step 5). Starting from methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -4-piperidinecarboxylate (430 mg, 0.94 mmole) in 8 ml of tetrahydrofuran: methanol (1: 1), and sodium hydroxide IN (1.89 ml, 1.89 mmol) to obtain 235 mg (57%) of the acid. HR - MS: m / z Calculated for C22H22N20fiS 443.1271; Found 443.1270.
Step 3: 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (3-pyridinylcarbonyl) -4-piperidinecarboxamide was prepared following the procedure of Example 64 (step 6). Starting from 4- (4-but-2-ynyloxybenzenesulfonyl) -1- (3-pyridinylcarbonyl) -4-piperidinecarboxylic acid (195 mg, 0.44 mmole) in dimethylformamide (4 ml), 1-hydroxybenzotriazole (72 mg, 0.53 mmoles), 1- [3- (dimethylamino) -propyl] -3-yl-carbodiimide hydrochloride (119 mg, 0.62 mmol), N-methylmorpholine (0.072 ml, 0.66 mmol) and hydroxylamine (0.135 ml, 2.2 mmoles), 65 mg (32%) of the product was isolated as a solid. HR-MS: m / z Calculated for C22H23N306S 458.1380; Found 458.1373.
EXAMPLE 71 4- (4-But-2-ynyloxybenzenesulfonyl) ~ N-hydroxy-1- (2-thienylcarbonyl) -4-piperidinecarboxamide Step 1: 4- (4-but-2-ini loxybenzenesulphonyl) -1- (2 methyl-thienylcarbonyl) -4-methylpiperidinecarboxylate To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) triethylamine (261 mg, 2.58 mmol), t-phenoylcarbonyl chloride (227 mg, 1.55 mmol) was added followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 480 mg (81%) of the product as a solid. HR-MS: m / z Calculated for C22H23N06S2 462.1040; Found 462.1039.
Step 2: 4 - (4-But-2-ynyloxybenzenesul foni 1) -1- (2-thienylcarbonyl) -4-piperidinecarboxylic acid. 4- (4-But-2-ynyloxy-benzenesulfonyl) -1 acid was prepared. - (2-thienylcarbonyl) -4-piperidinecarboxylic following the procedure of Example 64 (erapa 5). Starting from methyl 4 - (4-but-2-ynyloxy-benzenesulfonyl) -1- (2-thienylcarbonyl) -4-piperidinecarboxylate (435 mg, 0.94 mmole) in 8 ml of tetrahydrofuran: methanol (1: 1) , and 1N sodium hydroxide (1.89 ml, 1.89 mmol) to obtain 360 mg (86%) of the acid. HR-MS: m / z Calculated for C21H2? N06S2 448.0883; Found 448.0882.
Step 3: 4- (4-but-2-ynyloxybenzenesulfonyl) 1) -N-hydroxy-1- (2-thienylcarbonyl) -4-piperidinecarboxamide 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy- 1- (2-thienylcarbonyl) -4-piperidinecarboxamide following the procedure of Example 64 (step 6). Starting from 4 - (4-but-2-ynyloxy-benzenesulfonyl) -1- (2-thienyl carbonyl) -4-piperidinecarboxylyl (335 mg, 0.75 mmole) in dimethylformamide (7 ml), 1-hydroxybenzotriazole (121 mg, 0.90 mmol), 1- [3- (dimethylamino) propyl] -3-ethyl-carbodiimide hydrochloride (201 mg, 1.05 mmol), N-methymorpholine (0.124 mL, 1.13 mmol), and hydroxylamine (0.229 mL, 3.75 mmol), 216 mg (62%) of the product was isolated as a solid. HR-MS: m / z Calculated for C2? H22N206S2 463.0992; Found 463.0988.
Example 72 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(4-methoxyphenyl) sulfonyl] -4-piperidinecarboxamide Step 1: 4 - (4-but-2-ynyloxybenzenesulfonyl) - 1 - [ Methyl (4-methoxyphenyl) sulfonyl] -4-piperidincarboxylate To a solution of 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added triethylamine (261 mg, 2.58 mmole), 4-methoxyphenylsulfonyl chloride (320 mg, 1.55 mmole) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 590 mg (88%) of the product as a solid. HR-MS: m / z Calculated for C24H72N08S2 522.1251; Found 522.1252.
Step 2: 4 - (4-But-2-yn-loxybenzenesulfonyl) -1 - [(4-methoxy phenyl) sulfonyl] -4-piperidinecarboxylic acid 4 - (4-But-2-ynyloxy-benzenesulfonyl) - 1- [(4-methoxyphenyl) sulfonyl] -4-piperidinecarboxylic following the procedure of Example 64 (step 5). Starting from methyl 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(4-methoxy phenyl) -sulfonyl] -4-piperidinecarboxylate (545 mg, 1.04 mmol) in 8 ml of tetrahydrofuran: methanol (1 : 1), and 1N sodium hydroxide (2.09 ml, 2.09 mmol) to obtain 446 mg (85%) of the acid. HR - MS: m / z Ca l cu l to do c ra C23H25N08 S2 50 8. 10 94; Found 0 8. 1073 Step 3: 4- (4-but-2-ynyloxybenzenesulfonyl) 1-N-hydroxy-1- [(4-methoxy phenyl) -sulfonyl] -4-piperidinecarboxamide 4- (4-but-2-ynyloxybenzenesulfonyl) was prepared -N-hydroxy-1- [(4-methoxy phenyl) sulfonyl] -4-piperidinecarboxamide following the procedure of Example 64 (step 6). Starting from 4- (4-but-2-ynyloxybenzenesulfonyl) -1 - [(4-methoxy phenyl) sulfonyl] -4-piperidinecarboxylic acid (402 mg, 0.79 mmole) in dimethylformamide (8 ml), 1-hydroxybenzot riazole (128 mg, 0.95 mmol), l- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (212 mg, 1.11 mmol), N-methylmorpholine (0.130 ml, 1.19 mmol), and hydroxylamine (0.242 ml, 3.95 mmoles), 396 mg (96%) of the product was isolated as a solid. HR -EM: m / z Calculated for C23H26N208S2 523.1203; Found 523.1198.
Example 73 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidi-carboxamide Stage 1: 4 - (4-But-2-ynyloxybenzenesulfonyl) -1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylic acid methyl ester 4- (4 methyl-but-2-inyloxybenzenesulfonyl) -1- [2, 2, 5-trimethyl-l, 3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylate following the procedure of Example 64 (step 6). Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in dimethylformamide (10 ml), acid (2,2,5-trimethyl) -1, 3-dioxan-5-yl) carboxylic acid (224 mg, 1.29 mmol), 1-hydroxybenzotriazole (209 mg, 1.56 mmol), 1- [3- (dimethylamino) propyl] -3-et i hydrochloride 1-carbodiimide (346 mg, 1.81 mmol), and N-methyl-morpholine (0.212 ml, 1.94 mmol), to obtain 385 mg (59%) of the product as a solid. HR-MS: m / z Calculated for C25H33N08S 508.2000; Found 508.1998.
Step 2: 4 - (4-But-2-ini-loxybenzenesulfonyl) -1- [(2, 2, 5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylic acid The acid was prepared 4 - (4-But-2-ynyloxy-benzenesulfonyl) -1 - [(2, 2, 5-trimethyl-1,3-dioxan-5-yl) -carbonyl] -4-piperidinecarboxylic acid following the procedure of Example 40 (stage 5) Starting from methyl 4- (4-but-2-ynyloxy-benzenesulfonyl) -1 - [(2,2,5-trimethyl-l, 3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylate (335 mg, 0.66 mmol) in 4 mL of tetrahydrofuran: methanol (1: 1), and IN sodium hydroxide (1.3 mL, 1.3 mmol) to obtain 315 mg (97%) of the acid. HR-MS: m / z Calculated for C24H3? N08S 494.1843; Found 494.1835.
Step 3: 4- (4-but-2-ynyloxybenzenesul foni 1) -N-hydroxy-1- [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxamide: 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1 - [(2,2,5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxamide was prepared following the procedure of Example 64 (step 6). Starting from 4- (4-but-2-ynyloxy-benzenesulfonyl) -1 - [(2, 2, 5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxylic acid ( 280 mg, 0.57 mmol) in dimethylformamide (6 ml), 1-hydroxybenzotriazole (92 mg, 0.57 mmol), 1- [3- (dimethylamino) propyl] -3-ethyl-carbodiimide hydrochloride (153 mg, 0.80 mmol), N-methylmorpholine (0.094 ml, 0.85 mmole), and hydroxylamine (0.174 ml, 2.85 mmole), 180 mg (62%) of the product was isolated as a solid. HR-MS: m / z Calculated for C2 H32N208S 531.1771; Found 531.1768.
Example 74 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [3-hydroxy-2- (hydroxymethyl) -2-methylpropanoyl] -4-piperidinecarboxamide To a solution of the product of Example 73 (150 mg 0.29 mmole) in tetrahydrofuran (2 ml) was added 1N aqueous hydrochloric acid (2 ml) and the resulting mixture was stirred for 4 hours. The organic layer was washed with sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The solvent was removed to obtain 40 mg (29%) of the product. HR -EM: m / z Calculated for C21H28N208S 469.1639; Found 469.1537.
Example 75 4-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -4- [(hydroxy-amino.} -4- [(hydroxyamino) carbonyl] -1- tert-butyl piperidinecarboxalate Step 1: 1- (tert-butoxycarbonyl) -4- { [4- (2 -butynyloxy) phenyl] sulfonyl, 4-pyridinecarboxylic acid A solution of 4- (4-but-2-ynyloxybenzenesulfonyl) -piperidine-1,4-dicarboxylic acid tert-butylester methyl ester (from example 64, stage 2) (15 g, 33.2 mmol) in water (100 ml), methanol (50 ml) and tetrahydrofuran (50 ml) was treated with lithium hydroxide hydrate (2.73 g, 66.4 mmol) and heated to reflux for 8 hours The reaction mixture was concentrated in vacuo and filtered through celite, IN aqueous hydrochloric acid was added to the filtrate, a thick gum was obtained which was dissolved in dichloromethane and washed with water. a foam (14.9 g) The trituration with diethylether gave 1- (tert-butoxy-carbonyl) -4 - { [4 - (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylic acid as a powder white EM Electrospray m / z 482 (M-H) ~.
Stage 2: 4 -. { [4 - (2 -But ini loxi) pheny1] sulphonyl} -4 - [(hydroxyamino) carbonyl] -1-piperidinecarboxalate tert -butyl dimethylformamide (3.53 ml, 46 mmol) was added to a solution of oxalyl chloride (22.9 ml of a 2.0M solution in dichloromethane) in dichloromethane (25 ml ) at 0 ° C. After 15 minutes a solution of 1- (tert-butoxycarbonyl) -4- acid was added. { [4- (2-butynyloxy) phenyl] sulfonyl} -4-piperidinecarboxylic acid (10 g, 22.9 mmol) in dimethylformamide and the reaction mixture was allowed to warm to room temperature. After 1 hour, the reaction mixture was added to a mixture of hydroxylamine hydrochloride (16 g, 229 mmol), triethylamine (48 ml, 344 mmol), water (123 ml) and tetrahydrofuran (500 ml) which has been stirred at 0 ° C for 15 minutes. The reaction was allowed to warm to room temperature. After 18 hours it was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (3X), then dried over potassium carbonate and concentrated in vacuo. Trituration with diethyl ether gave 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -4- [(hydroxyamino) carbonyl] -1-tert-butylpiperidinecarboxalate as a white powder (6.3 g). 1 H NMR (dmso-d 6, 300 MHz) d 1.38 (s, 9 H, t-butyl), 1.6-1.7 (m, 2 H, CH H), 1.85 (t, 3 H, CH 3, J = 2.2 Hz), 2.2-2.3 (m, 2H, CHH), 2.5-2.7 (m, 2H, NCHH), 3.9-4.0 (m, 2H, NCHH), 4.87 (q, 2H, 0CH2, J = 2.2 Hz), 7.1-7.7 (m, 4H, ArH). EM Electrosprayer m / z 453 (M + H) +.
Example 76 Hydrochloride of 4-. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide A 4-. { [4- (2-butynyl oxy) phenyl] sulfonyl} -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxalate tert -butyl (prepared from Example 75) (6.3 g13.9 mmoles) 4N hydrochloric acid in dioxane was added. After 6 hours, the reaction mixture was concentrated in vacuo. Methanol was added and the resulting mixture was concentrated in vacuo. Dichloromethane was added and i n va cuo (2X) was removed. Trituration with diethyl ether gave 4- hydrochloride. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide as a white powder (5.14 g). 1 H NMR (dmso d6, 300 MHz) d 1.86 (t, 3H, CH3, J = 2.2 Hz), 2.0-2.7 (m, 8H, CH2), 4.89 (q, 2H, 0CH2, J = 2.2 Hz), 7.1-7.8 (m, 4H, ArH), 8.8-11.0 (m, 4H, NH2, NHOH). EM Electropulverizer m / z 353 (M + H) +.
Example 77 Methyl (. {4 -. {[4- (2-butynyloxy) phenyl] sulfonyl} - 4- (hydroxyamino) carbonyl] -1-piperidinyl} methyl] benzoate hydrochloride 4 - hydrochloride. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -N-hydroxy-4-piperidinecarboxamide (prepared from Example 76) (2.5 g, 6.43 mmol) and methyl 4- (bromomethyl) benzoate (1.62 g, 7.07 mmol) in methanol (100 ml) at 50 ° C were added. added triethylamine (2.25 ml, 16.1 mmol). After 30 minutes additional methanol (50 ml) was added. After 18 hours, the reaction mixture was concentrated in vacuo and INN aqueous hydrochloric acid (10 ml) and water were added. The resulting solid was isolated and methanol (20 ml) and IN hydrochloric acid in diethyl ether (15 ml) were added. Diethyl ether was added to the resulting solution. Trituration of the precipitate gave (. {4- {4- [2 (butynyloxy) phenyl] sulfonyl} -4- ([(hydroxyamino) -carbonyl] -1-piperidinyl-Jmet-yl) -benzoate hydrochloride. methyl as a white powder (2.4 g) 1NMRI (dmso d6, 300 MHz) d 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.1-3.5 (m, 8H, CH2), 3.87 (S, 3H) , OCH3), 4.40 (broad s, 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J = 2.2 Hz), 7.1-8.1 (m, 8H, ArH), 9.3-11.2 Cm, 3H, NH, NHOH) . EM Electrospray m / z 501.5 (M + H) +.
EXAMPLE 78 4- (. {4- {[4- (2-Butynyloxy) phenyl] -sulfonyl} -4- [(hydroxyamino) carbonyl] -1- piperidinyl} methyl) benzoic acid hydrochloride ( { 4- { [4- (2-b.utyloxy) -phenyl] sulfonyl} -4- [(hydroxyamino) -carbonyl] -1-piperidinyl} methyl) benzoate hydrochloride. methyl (prepared from Example 77) (0.072 g, 0.134 mmol) in methanol (1 ml) was added aqueous sodium hydroxide IN (0.5 ml). After 18 hours IN aqueous hydrochloric acid (0.5 ml) was added and the reaction mixture was concentrated in vacuo. Water was added and the precipitate was triturated to give 4- (. {4- [{[4- (2-Butynyloxy) phenyl] sulfonyl} -4- [(hydroxyamino) -carbonyl] -1-hydrochloride. -piperidinyl.} methyl) benzoic acid as a whitish solid (0.040 g). X H NMR (dmso dβ, 300 MHz) d 1.85 (t, 3 H, CH 3, J = 2.2 Hz), 2.1-3.5 (m, 8 H, CH 2), 4.37 (broad s, 2 H, NCH 2 Ar), 4.89 (q, 2 H) , OCH2, J = 2.2 Hz), 7.0-8.1 (m, 8H, ArH), 9.3-11.2 (m, 3H, NH, NHOH), 13.1 (broad s, 1H, COOH). EM Electropulverizer m / z 487.1 (M + H) +. 1- [4- (aminocarbonyl) benzyl] -4- hydrochloride. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide A (. {4 - { [4 - (2-Butyloxy) -phenyl] sulfonyl} -4- [(hydroxyamino) -carbonyl] -1-piperidinyl hydrochloride Jmethyl) methyl benzoate (from example 77) (0.20 g) in methanol (10 ml) was added concentrated aqueous ammonium hydroxide (4 ml). After several weeks, the reaction mixture was concentrated in vacuo and chromatographed on silica gel (methanol / dichloromethane) to give a white powder which was dissolved in dichloromethane and methanol. IN hydrochloric acid was added in diethyl ether followed by additional diethyl ether. Trituration gave 1- [4 - (aminocarbonyl) benzyl] -4- hydrochloride. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide as a white powder (0.106 g). 1 H NMR (Dmso d6, 300 MHz) d 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.2-3.5 (m, 8H, CH2), 4.33 (s broad, 2H, NCH2Ar), 4.89 (q, 2H, OCH2 , J = 2.2 Hz), 7.1-8.0 (m, 8H, ArH), 7.47 (s, 1H, CONH), 8.04 (s, 1H, CONH), 9.35 (broad s, 1H, NHOH), 10.44 (s broad , 1H, NHOH), 11.1 (s, 1H, NH). EM Electrospray m / z 486.3 (M + H) +.
Example 80 4-. { [4- (but-2-ynyloxy) phenyl] sulfinyl} -4- [(hydroxyamino) carbonyl] piperidine-1-carboxalate tert-butyl A 4-. { [4- (but-2-linoxy) phenyl] sulfanil} -4- [(hydroxyamino) carbonyl] piperidine-1-carboxy-tert-butyl ester (0.30 g) (obtained from example 14) in methanol (10 ml) was added 30% aqueous hydrogen peroxide (3 ml) . After 3 days water and dichloromethane were added, and the organic phase was washed with aqueous Na 2 SO 3. Concentration of the organic phase gave material which was dissolved in methanol (8 ml) and treated with 30% aqueous hydrogen peroxide. After several days of processing as in the previous gave 4 -. { [4 - (but-2-ynyloxy) phenyl] sulfinyl} -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxalate as a colorless foam (0.26 g). 1 H NMR (dmso d6, 300 MHz) d 1.38 (s, 9H, t-butyl), 1.5-1.7 (m, 2H, CHH), 1.85 (t, 3H, CH3, J = 2.2 Hz), 2.1-2.2 ( m, 2H, CHH), 2.5-2.7 (m, 2H, NCHH), 3.8-4.0 (m, 2H, NCHH), 4.81 (q, 2H, 0CH2, J = 2.2Hz), 7.1-7.4 (m, 4H , ArH), 9.1 (s, 1H, NHOH), 10.8 (s, 1H, NHOH). EM Electrosprayer m / z 437.2 (M + H) +.
EXAMPLE 81 4- (4- (But-2-ynyloxy-benzenesulfinyl) -piperidinecarboxylic acid hydroxamide A 4- { [4- (But-2-ynyloxy) phenyl] sulfinyl] -4 - [(hydroxyamino) carbonyl] piperidine-1-carboxylate or tert-butyl (prepared from example 80) (0.26 g) was added 4N hydrochloric acid in dioxane (4 ml) After 1 hour, the reaction mixture Concentrate in va cuo Methanol was added and in vacuo removed, dichloromethane was added, and 3X in vacuo was removed to give 4- (4-but-2-ynyloxy-benzenesulfinyl) -piperidin-4-hydroxamide hydrochloride. carboxylic acid as a yellow solid (0.19 g). 1 H NMR (dmso d6, 300 MHz) d 1.86 (t, 3 H, CH 3, J = 2.2 Hz), 1.7-2.8 (m, 8 H, CH 2), 4.82 (q, 2H, OCH2, J = 2.2 Hz), 7.1-7.5 (m, 4H, ArH), 8.4-11.0 (m, 4H, NH2, NHOH) EM Electrospray m / z 337.2 (M + H) +.
Example 82 Hydroxamide hydrochloride 1- (4-bromobenzyl) -4- (4-but-2-xnxloxy-benzenesulfinyl) -pxperidin-4-carboxxlxco hydrochloride To a solution of hydroxamide hydrochloride of 4- (4 - (but-2-inyloxy-benzenesul finyl) -piperidine-4-carboxylic acid (prepared from Example 81) (0.162 g, 0.434 mmol) and 4-bromobenzyl bromide (0.120 g, 0.478 mmol) in methanol was added triethylamine (0.13 ml, 0.91 mmol) After 4 hours, the reaction mixture was concentrated in vacuo and chromatographed on silica gel (methanol / dichloromethane) to give an oily solid which was dissolved in dichloromethane. The solution was added with IN hydrochloric acid in ether (1 ml) The concentration in va c uo gave hydroxamide hydrochloride of 1- (4-bromo-benzyl) -4 - (4-but-2-inyloxy-benzenesulfinyl) -piperidine hydrochloride. -4-carboxylic acid as a brown solid (0.102 g) XH NMR (dmso d6, 300 MHz) d 1.85 (t, 3H, CH3, J = 2.2 Hz), 1.9-3.5 (m, 8H, CH2), 3.87 ( S, 3H, OCH3), 4.3 (broad s, 2H, NCH2Ar), 4.82 (q, 2H, OCH2, J = 2.2 Hz), 7.0-7.8 (m, 8H, ArH), 9.2-11.1 (m, 3H, NH, NHOH). EM Electrospray m / z 505.1 / 507.2 (M + H) +.
Pharmacology The 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 - methyl-pentanoyl) Leu-Gly-OEt by the matrix metalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9 (gelatinase), which results in the release of a substrate product that reacts colorimetrically with DTNB (acid 5, 5 '-dithiobis (2-nor tro-benzoic)). The activity of the enzyme is measured by the speed of the color increase. The thiopeptide substrate becomes cooler as a 20 mM deposit 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 being used. The enzyme deposit 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 / their treatment 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 hours. minutes at 405 nm on a reading plate and the increase in color for a time is plotted as a linear line or stroke. 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, Ca * 2 5 mM, Brij at 0.02%, Cysteine at 0.5%), 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 of 340 nm, emission of 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 (r >; 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 the Measurement of TACE Inhibition Using dark 96-well 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 10% glycerol (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 of 5 x 10 ~ 5 M 2 (medium THP-1). Each vial of cells is grown for approximately two weeks before being used and then used for a trial for only 4 to 6 weeks for protection compounds. Cells 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 / ml reservoir of Lipopolysaccharide (LPS) (Calbiochem Lot # B13189) at 37 ° C in C02 5% at a concentration of 1091 x 106 cells / ml (1.1 ml / well) for a total of 24 hours. At the same time, 50 ml / well of drug, vehicle or THP-1 medium was placed in appropriate wells to give a final volume of 1.2 ml / well. The test and standard compounds are dissolved 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, 10 mM, 3 mM, 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 agonizing) can absorb Pl. The percentage of live cells is calculated by the number of cells not stained with Pl, 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 soluble p55 / 60 TNF-R and IL-8 in TCS of THP-1 cell cultures are obtained with the commercially available ELISA tests of R &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: % Ca ± ao = pgnl (peripterated) - pg / ml (vehicle positive control) x 100 pgtnl (vehicle positive control) - pg / ml (vehicle negative caitrol 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: % of Carbium = pg (native control of caprus) - pgml (ccnt-riL of celabrail) x 100 pg ml (negative vehicle control) 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, expression of the membrane 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 previous section, the inhibition of TACE and the standard pharmacological test procedures of THP are given in Tables 1 below.
Table 1 : a = nM or% inhibition b =% inhibition c = μM or% inhibition, unless indicated otherwise Based on the results obtained in the standard pharmacological test procedures described above, 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-a (TACE) and are therefore useful in the treatment of disorders such as arthritis, tumor metastasis, tissue ulceration, scarring of abnormal wounds, periodontal disease, 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 articular disease, demyelinating diseases of the nervous system, liver cirrhosis, glomerular disease of the kidney, premature rupture of the fetal membranes, inflammatory bowel disease, age-related macular degeneration, diabetic retinopathy, vit reorret proliferative inopathy a, retinopathy due to prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis / neovascularization and corneal graft rejection. 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 carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for 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 intravenously. 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. 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 may be in packaged compositions, for example packaged powders, vials, ampoules, pre-filled 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 (7)

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 by: Ri is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms or cycloheteroalkyl with 4 to 8 carbon atoms; R2 and R3 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, -CN, _ or -CCH; R7 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, -C (0) -R ?, -S02-R ?, -C (0) -NHR ?, -C (0) NR5R6, -C (O) R? NR5R6, -C (0) -OR ?, -C ( NH) -NH2; R5 and Re are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or cycloheteroalkyl of 4 to 8 carbon atoms; . R8, R9, io and Rn are each, independently, hydrogen, aryl, or heteroaryl, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl of 4 to 8 carbon atoms, alkyl of 1-18 carbon atoms, alkenyl of 2 -18 carbon atoms, alkynyl of 2-18 carbon atoms; with the proviso that one of the pairs R8 and R9, R9 and RIO or RIO and Rll, together with the carbon atom or atoms to which they are attached, form a cycloalkyl ring of 3-6 carbon atoms, or a ring cycloheteroalkyl of 4 to 8 carbon atoms; R 2 is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6 carbon atoms, cycloheteroalkyl of 4 to 8 carbon atoms, 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; Y 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 or triazolyl or thiadiazolyl. 3. A compound according to claim 1, characterized in that it is selected from the group consisting of: 1- (4-bromo-benzyl) -4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidin-4- hydroxyamide carboxylic; 4 - (4-But-2-ynyloxy-benzenesul fonyl) -1- (4-methoxy-benzyl) -piperidine-4-carboxylic acid hydroxyamide i-Co; Hydroxyamide 4 - (4-but-2-ynyloxy-benzenesul fonyl) -1- (4-chloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide of l-benzyl-4- (4-but-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4 - (4 -pent-2-ini-loxi-benzenesul-fonyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4- (4-oct-2-ynyloxy-benzenesul fonyl) piperidin-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-fluoro-benzyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-benzenesulfonyl) -1- (4-cyano-benzyl) piperidine-4-carboxylic acid hydroxyamide; 4 - (4-But-2-ynyloxy-benzenesulfonyl) -1- (4-methyl-yl-benzyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-benzenesulfonyl) -1- (3,4-dichloro-benzyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4 - (4-prop-2-ynyloxy-benzenesul fonyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4 - [4- (4-piperidin-4-yl-but-2-ynyloxy) -benzenesulfonyl] -piperidin-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4 - [4- (4-morpholin-4-yl-but-2-ynyloxy) benzenesulfonyl] -piperidin-4-carboxylic acid hydroxyamide; Ter-Butyl ester of 4- (4-but-2-ynyloxy-phenylsulphyl) -4-hydroxycarbamoyl-piperidin-1-carboxylic acid; Hydroxyamide 4- (4-but-2-ynyloxy-phenylsulfanyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-bromo-benzyl) -4- (4-but-2-yl loxyphenylsulphyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-phenylsulfanylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-benzenesulphonylmethyl) -tetrahydro-pi-4-carboxylic acid hydroxyamide; Hydroxyamide 4 - (4-but-2-ynyloxy-benzenesulfinylmethyl) -tetrahydro-pyran-4-carboxylic acid hydroxyamide; 4- . { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxytetrahydro-2H-pyran-4-carboxamide; l-Benzyl-4-. { [3- (2-Butynyloxy) phenyl] -sulfonyl} -N-hydroxy-4-piperidinecarboxamide; 4-. { [4- (2-Butyloxy) phenyl] sulfonyl} -N-hydroxy-l-isopropyl-4-piperidinecarboxamide; 4-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -N-hydroxy-1- (3-pyridinylmethyl) -4 -piperidinecarboxamide; 3-. { [4- (2-Butynyloxy) phenyl] sulfonyl} -l-ethyl-N-hydroxy-3-piperidinecarboxamide;
3- . { [4- (2-Butynyloxy) phenyl] sulfonyl} -l- (4-chlorobenzyl) -N-hydroxy-3-piperidinecarboxamide; Hydroxyamide of 4 - acid. { [- (2-Butyloxy) -phenyl] sulfonyl} -1- [4- (2-piperidin-yl-ethoxy) -benzyl] -piperidin-4-carboxylic acid; Hydroxyamide of 4 - acid. { [4 - (2-Butyloxy) -phenyl] sulfonyl} -1- (3-pentanil) -piperidin-4-carboxylic; Hydroxyamide 1- (4-methoxy-benzyl) -4- (4-prop-2-ynyloxy-benzenesulfonyl) -piperidine-4-carboxylic acid hydroxyamide; Hydroxyamide 1- (4-chloro-benzyl) -4 - (4-prop-2-ynyloxy-benzenesulfonyl) -piperidin-4-carboxylic acid hydroxyamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfanyl-Jethyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid tert -butyl ester; 4- ( { [4- (But-2-ynyloxy) phenyl] thio.} Methyl) -N-hydroxypiperidin-4-carboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfinyl] methyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid tert-butyl ester; 4- [[[4- (2-Butynyloxy) phenyl] sulfinyl] methyl] -N-hydroxy-4-piperidinecarboxamide; 4- ( { [4- (2-But-2-ynyloxy) phenyl] sulfonyl-Jethyl} -4- [(hydroxyamino) -carbonyl] -piperidine-1-carboxylic acid tert -butyl ester; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jethyl) -4 - [(hydroxyamino) -carbonyl] -1-piperidinecarboxylate or tert-butyl; l-Acetyl-4- [[[4- (2-butynyloxy) phenyl] -sul-fonyl] methyl] -N-hydroxy-4-piperidinecarboxamide; 1- (2-butyl) -4 - ( { [4 - (2-Butynyloxy) phenyl] sulfonyl} -methyl) -N-hydroxy-4-piperidinecarboxamide hydrochloride; Nl- (tert-Butyl) -4- ( { [4- (2-Butynyloxy) phenyl] -sulfonyl Jmethyl) -N-4-hydroxy-l, 4- [4- (2-butynyloxy) -phenyl] sulfonylmethyl) -N-4-hydroxy-l, 4-1] sulfonyl} -methyl) -N-4-hydroxy-1,4-piperidinecarboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl] methyl] -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylate; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl-methyl) -4- [(hydroxyamino) -carbonyl] -1-piperidinecarboxylic acid benzyl ester; 1-Benzyl- 4- ( { [4- (2-Butynyloxy) phenyl] -sulfonyl.} Methyl) -N-hydroxy-4-butynyloxy) phenyl] -sulfonyl Jmethyl) -N-hydroxy-4-piperidine -carboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- [(2, 2, 5-trimethyl-l, 3-dioxan-5-yl) -carbonyl] - 4-piperidinecarboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- [3-hydroxy-2- (hydroxymethyl) -2-methyl-propanoyl] -4-piperidinecarboxamide; 1- [Amino (imino) methyl] -4- ( { [4- (2-Butynyloxy) -phenyl] sulfonyl Jmethyl) -N-hydroxy-4-1] -4- ( { [4- ( 2-butynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-4-oxy) -phenyl] sulfonyl Jmethyl) -N-hydroxy-4-piperidinecarboxamide; 4- ( { [4- (2-Butynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (4-idroxy-2-butynyl) -henyl] sulfonyl} -methyl) -N-hydroxy-1- (4-hydroxy-2-butynyl) -4-piperidinecarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl-methyl) -l-ethyl-N-hydroxypiperidin-4-carboxamide of the trifluoroacetic acid salt; 2-Chloro-5- (chloromethyl) thiophen-4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl} methyl) -1- [(5-chlorothien-2-yl) -methyl) ] -N-hydroxypiperidine-4-carboxamide of the trifluoroacetic acid salt; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl.] Methyl) -N-hydroxy-1- (pyridin-4-ylmethyl) piperidine-4-carboxamide of the trifluoroacetic acid salt; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jethyl) -N-hydroxy-1- (pyridin-3-ylcarbonyl) piperidine-4-carboxamide of the trifluoroacetic acid salt; l-Benzoyl-4- ( { [4- (but-2-ynyloxy) phenyl] -sulfonyl-J-methyl) -N-hydroxy-piperidin-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (thien-2-ylcarbonyl) piperidine-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl.] Methyl) -N-l-ethyl-N-4-hydroxy-piperidin-1,4 -dicarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonylmethyl) -N-4-hydroxy-N-l-phenyl-1-piperidin-1,4-dicarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl} ethyl) -N-l-, N-l-diethyl-N-4-hydroxypiperidin-1,4-dicarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (morpholin-4-ylcarbonyl) piperidine-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-4-hydroxy-N-l-methyl-N-l-phenylpiperidin-1,4-dicarboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl-Jethyl} -4- [(hydroxyamino) -carbonyl] piperidine-1-carboxylic acid octyl ester; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl-Jethyl} -4- [(hydroxy-amino) carbonyl] piperidine-1-carboxylic acid 4-methoxyphenyl ester; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (phenylsul fonyl) piperidin-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- [(1-met yl-lH-imidazol-4-yl) sulfonyl] -piperidine- 4 - carboxamide; 1- [2- (Benzylamino) acetyl] -4- ( { [4- (but-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxypiperidine-4-carboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl Jmethyl) -N-hydroxy-1- (2-morpholin-4'-ylacetyl) piperidin-4-ca rboxamide; 4- ( { [4- (But-2-ynyloxy) phenyl] sulfonyl} methyl) -N-hydroxy-1- [2- (4-methyl-piperazin-1-yl) acetyl] -piperidine -4 -carboxamide; 1-Acetyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid hydroxyamide; L-benzoyl-4- (4-but-2-ynyloxybenzenesulfonyl) piperidin-4-carboxylic acid hydroxyamide; 1 - (4-Methoxybenzoi 1) -4 - (4-but-2-yl loxybenzenesulonyl) piperidin-4-carboxylic acid hydroxyamide;
4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (pyrrolidin-1-carbonyl) -4-piperidinecarboxamide; 4- (4 -But-2-ynyloxybenzenesulfonyl) -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxyl ethyl ester; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(trifluoromethyl) sulfonyl] -4 -piperidinecarboxamide; 4- (4-But-2-inyloxybenzenesulfonyl) -N-hydroxy-1- (3-pyridinylcarbonyl) -4-piperidinecarboxamide; 4- (4 -But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- (2-thienylcarbonyl-1) -4-piperidinecarboxamide; 4- (4 -But-2-inyloxybenzenesulfonyl) -N-hydroxy -1 - [(4-methoxyphenyl) -sulfonyl] -4-piperidinecarboxamide; 4- (4-But-2-ynyloxybenzenesulfonyl) -N-hydroxy-1- [(2, 2,
5-trimethyl-1,3-dioxan-5-yl) carbonyl] -4-piperidinecarboxamide; 4- . { [4- (2-Butynyloxy) phenyl] sulfonyl} -4- [(hydroxyamino) carbonyl] -1-piperidinecarboxylate tert -butyl; Hydrochloride of 4 -. { [4 - (2-Butyloxy) phenyl] -sulfonyl} -N-hydroxy-piperidinecarboxamide; ( { 4 - { [4 - (2-Butynyloxy) phenyl] -sulfonyl} -4- [(hydroxyamino) carbonyl] -1-piperidinyl-J-methyl) benzoate methyl chloride; Acidic hydrochloride ({4- {[4- (2-butynyloxy) -phenyl] sulfonyl} -4- [(hydroxyamino) carbonyl] -1-piperidinylmethyl) benzoic acid; 1- [4 - (aminocarbonyl) benzyl] -4- hydrochloride. { [4- (2-butynyloxy) phenyl] sulfonyl} -N-hydroxy-4-piperidinecarboxamide; 4-. { [4- (But-2-ynyloxy) phenyl] sulfinyl} -4- [(hydroxyamino) carbonyl] piperidine-1-carboxalate of tert-butyl; 4- (4- (But-2-ynyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid hydroxamide hydrochloride and l- (4-bromo-benzyl) -4- (4-buty) hydroxamide hydrochloride -2-inyloxy-benzenesulfinyl) -piperidine-4-carboxylic acid, and pharmaceutical salts thereof. 4. A method for the inhibition of pathological changes mediated by the enzyme (TACE) that converts to TNF-a, in a mammal that needs it, characterized in that it comprises administering to the mammal, a therapeutically effective amount, of a compound having the formula I according to claim 1; or a pharmaceutically acceptable salt thereof. 5. The method according to claim 4, 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 infection, by HIV.
6. A pharmaceutical composition, characterized in that it comprises a compound having the formula I according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
7. A process for the preparation of a compound of the formula I according to claim 1, characterized in that it comprises one of the following: a) reacting a compound of the formula wherein n, X, Y, A, Rx, R2, R3, R8, R9, Rio, and Rn are as defined in claim 1 or a reactive derivative thereof, with a compound of the formula R12NHOH where R? 2 is as defined in the claim 1, to give a compound of the formula I; or b) deprotect a compound of the formula: wherein n, X, Y, A, RX, R2, R3, R8, R9, R10, Rn 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 c) separating a supported hydroxamate derivative with resin containing the group wherein n, X, Y, A, Ri, R2, R3, R8, R9, Rio, and R11 are as defined in claim 1 to give a compound of the formula I; wherein R 2 is hydrogen; or d) separating a mixture (e.g., racemate) from optically active isomers of a compound of the formula I to isolate one enantiomer or diastereomer substantially free of the other enantiomer or diastere; 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/2001/007573A 1999-01-27 2001-07-26 Alkynyl containing hydroxamic acid derivatives, their preparation and their use as matrix metalloproteinase (mmp) inhibitors/tnf-alpha converting enzyme (tace) inhibitors MXPA01007573A (en)

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US09/238,038 1999-01-27

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MXPA01007573A true MXPA01007573A (en) 2002-05-09

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