U.S. patent application number 10/977962 was filed with the patent office on 2005-05-26 for acetylenic alpha-amino acid-based sulfonamide hydroxamic acid tace inhibitors.
This patent application is currently assigned to WYETH HOLDINGS CORPORATION. Invention is credited to Chen, James M., Cole, Derek C., Du, Mila T., Laakso, Leif M., Levin, Jeremy I..
Application Number | 20050113346 10/977962 |
Document ID | / |
Family ID | 26852148 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050113346 |
Kind Code |
A1 |
Levin, Jeremy I. ; et
al. |
May 26, 2005 |
Acetylenic alpha-amino acid-based sulfonamide hydroxamic acid tace
inhibitors
Abstract
Compounds of the formula: 1 are useful in treating disease
conditions mediated by TNF-.alpha., such as rheumatoid arthritis,
osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple
sclerosis, Crohn's disease and degenerative cartilage loss.
Inventors: |
Levin, Jeremy I.; (New City,
US) ; Chen, James M.; (US) ; Cole, Derek
C.; (New City, NY) ; Du, Mila T.; (Suffern,
NY) ; Laakso, Leif M.; (New City, NY) |
Correspondence
Address: |
WYETH
PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
WYETH HOLDINGS CORPORATION
|
Family ID: |
26852148 |
Appl. No.: |
10/977962 |
Filed: |
October 29, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10977962 |
Oct 29, 2004 |
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10377008 |
Feb 27, 2003 |
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6812227 |
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10377008 |
Feb 27, 2003 |
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09748912 |
Dec 27, 2000 |
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09748912 |
Dec 27, 2000 |
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09492691 |
Jan 27, 2000 |
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6225311 |
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60155249 |
Jan 27, 1999 |
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Current U.S.
Class: |
514/114 ;
514/357; 514/408; 514/459; 514/575; 546/336; 548/561; 558/185;
562/621 |
Current CPC
Class: |
A61K 31/5375 20130101;
C07D 213/68 20130101; C07C 2601/04 20170501; A61K 31/54 20130101;
C07D 309/12 20130101; C07D 279/12 20130101; C07C 311/29 20130101;
C07D 279/10 20130101; C07F 9/36 20130101 |
Class at
Publication: |
514/114 ;
514/459; 514/575; 514/357; 514/408; 546/336; 548/561; 562/621;
558/185 |
International
Class: |
A61K 031/66; A61K
031/44; A61K 031/40 |
Claims
1-18. (canceled)
19. A process for preparing a compound of formula B having the
formula: 65B wherein: X is SO.sub.2 or --P(O)--R.sub.10; Y is aryl
or heteroaryl, with the proviso that X and Z may not be bonded to
adjacent atoms of Y; Z is O, NH, CH.sub.2 or S; R.sub.1 is
hydrogen, aryl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, alkynyl of 2-6 carbon atoms; R.sub.2 is hydrogen, aryl,
aralkyl, heteroaryl, heteroaralkyl, cycloalkyl of 3-6 carbon atoms,
C.sub.4-C.sub.8 cycloheteroalkyl, alkyl of 1-6 carbon atoms,
alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms; or
R.sub.1 and R.sub.2, together with the atom to which they are
attached, may form a ring wherein R.sub.1 and R.sub.2 represent a
divalent moiety of the formula: 66wherein Q=a carbon-carbon single
or double bond, O, S, SO, SO.sub.2, --N--R.sub.11, or
--CONR.sub.14; m=1-3; r=1 or 2, with the proviso that when Q is a
bond, r is equal to 2; R.sub.3 is hydrogen, alkyl of 1-6 carbon
atoms, cycloalkyl of 3-6 carbon atoms, C.sub.4-C.sub.8
cycloheteroalkyl, aralkyl, or heteroaralkyl; or R.sub.1 and
R.sub.3, together with the atoms to which they are attached, may
form a 5 to 8 membered ring wherein R.sub.1 and R.sub.3 represent
divalent moieties of the formulae: 67wherein Q and m are as defined
above; A is aryl or heteroaryl; s is 0-3; u is 1-4; R.sub.4 and
R.sub.5 are each, independently, hydrogen or alkyl of 1-6 carbon
atoms, --CN, or --CCH; R.sub.6 is hydrogen, aryl, heteroaryl, alkyl
of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, cycloalkyl of 3-6 carbon atoms, or
--C.sub.5-C.sub.8cycloheteroalkyl; R.sub.8 and R.sub.9 are each,
independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6
carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon
atoms, aryl, aralkyl, heteroaryl, heteroaralkyl, or
--C.sub.4-C.sub.8-cycloheteroalkyl; R.sub.10 is alkyl of 1-6 carbon
atoms, cycloalkyl of 3-6 carbon atoms, aryl or heteroaryl; R.sub.11
is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon
atoms, aryl, heteroaryl, --S(O).sub.nR.sub.8, --COOR.sub.8,
--CONR.sub.8R.sub.9, --SO.sub.2NR.sub.8R.sub.9 or --COR.sub.8;
R.sub.12 and R.sub.13 are independently selected from H,
--OR.sub.8, --NR.sub.8R.sub.9, alkyl of 1-6 carbon atoms, alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6
carbon atoms, aryl, heteroaryl, --COOR.sub.8; --CONR.sub.8R.sub.9;
or R.sub.12 and R.sub.13 together form a
--C.sub.3-C.sub.6-cycloalkyl of 3-6 carbon atoms or a
--C.sub.5-C.sub.8-cycloheteroalkyl ring; or R.sub.12 and R.sub.13,
together with the carbon to which they are attached, form a
carbonyl group; with the proviso that R.sub.10 and R.sub.12 or
R.sub.11 and R.sub.12 may form a cycloheteroalkyl ring when they
are attached to adjacent atoms; R.sub.14 is hydrogen, aryl,
heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon
atoms; and n is 0-2; or a pharmaceutically acceptable salt thereof,
which comprises one of the following steps: a) reacting a compound
of formula V: 68wherein R.sub.1 R.sub.2, R.sub.3, R.sub.4, R.sub.6,
X, Y and Z are defined above, or a reactive derivative thereof,
with hydroxylamine to give a corresponding compound of formula B;
or b) deprotecting a compound of formula VI: 69wherein R.sub.1
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, X, Y and Z are defined
above, and R.sub.30 is a suitable protecting group to give a
corresponding compound of formula B or c) cleaving a resin
supported hydroxamate derivative containing the group: 70to give a
compound of formula B as defined above; or d) resolving a mixture
of optically active isomers of a compound of formula B to isolate
one enantiomer or diastereomer substantially free of the other
enantiomer or diastereomers; or e) converting a compound of formula
B into a pharmaceutically acceptable salt; or f) converting a
compound of formula B having a reactive substituent group or site
to give a compound of formula B having a different substituent
group or site.
20. The process according to claim 19, further comprising the
optional steps in which formula V is prepared by: 1a) reacting an
amino acid derivative having the formula 71wherein R.sub.1 and
R.sub.2 are as defined in claim 19; and R.sub.40 is hydrogen or a
suitable carboxylic acid protecting group, with a compound having
the formula 72wherein R.sub.4, R.sub.5, R.sub.6, X and Z are as
defined in claim 19, with the proviso that R.sub.6 is not hydrogen;
and J is fluorine, bromine or chlorine to form an amino derivative;
2a) alkylating the amino derivative with R.sub.3J, wherein R.sub.3
is as defined in claim 19 and J is defined above, and a base in a
polar aprotic solvent to form a sulfonamnide derivative; and 3a)
converting the sulfonamide to the compound of formula V; or 1b)
reacting an N-substituted amino acid derivative having the formula
73wherein R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 19,
with the proviso that R.sub.3 is not hydrogen; and R.sub.40is
hydrogen or a suitable carboxylic acid protecting group, with the
above compound having the formula 74wherein R.sub.4, R.sub.5,
R.sub.6, X, Z and J are as defined above to form a sulfonamide
derivative; and 2b) converting the sulfonamide to the compound of
formula V.
21. The process according to claim 20, wherein R.sub.30 is t-butyl,
benzyl, trialkylsilyl and R.sub.40is hydrogen or methyl.
22. The process according to claim 20, wherein the base is
potassium carbonate or sodium hydride.
23. The process according to claim 20, wherein the polar aprotic
solvent is acetone, N,N-dimethylformamide (DMF) or tetrahydrofuran
(THF).
24. The process according to claim 20, wherein Y is a phenyl ring
substituted at the 1- and 4-positions by X and Z, respectively, or
a pharmaceutically acceptable salt thereof.
25. The process according to claim 24, wherein X is SO.sub.2.
26. The process according to claim 25, wherein Z is oxygen.
27. The process according to claim 26, wherein R.sub.4 and R.sub.5
are hydrogen.
28. The process according to claim 27, wherein R.sub.6 is
--CH.sub.2OH or methyl.
29. The process according to claim 28, wherein R.sub.1 and R.sub.3,
together with the atoms to which they are attached, form a
piperazine, piperidine, tetrahydroisoquinoline, morpholine,
thiomorpholine or diazepine ring.
30. The process according to claim 29, wherein R.sub.1, R.sub.2 or
R.sub.3 is hydrogen.
31. The process according to claim 26, further comprising the
optional steps of: 1a) alkylating a compound of formula I, or a
salt or solvate thereof: 75into a compound of formula II 76wherein
R.sub.4, R.sub.5 and R.sub.6 are as defined in claim 26, with the
proviso that R.sub.6 is not hydrogen; or 1b) alkylating phenol, or
a salt or solvate thereof, into a compound of formula IV: 77wherein
R.sub.4, R.sub.5 and R.sub.6 are as defined in claim 26, with the
proviso that R.sub.6 is not hydrogen; and 2b) reacting the compound
of formula IV, or the salt or solvate thereof, with chlorosulfonic
acid to prepare the above compound of formula II.
32. The process according to claim 31, further comprising the step
of reacting the compound of formula II, or the salt or solvate
thereof, with a halogenating agent to give a compound of formula
III: 78wherein R.sub.4, R.sub.5 and R.sub.6 are as defined in claim
31, with the proviso that R.sub.6 is not hydrogen; and J is
fluorine, bromine or chlorine.
33. The process according to claim 32, wherein the halogenating
agent is selected from the group consisting of thionyl chloride,
chlorosulfonic acid, oxalyl chloride, phosphorus pentachloride,
fluorosulfonic acid and thionyl bromide.
34. The process according to claim 33, wherein the resultant
sulfonyl chloride, fluoride or bromide, is optionally converted
into a triazolide derivative, an imidazolide derivative or a
benzothiazolide derivative by reacting the sulfonyl chloride,
fluoride or bromide compound with 1,2,4-triazole, imidazole or
benzotriazole to provide a compound of formula III in which J is
1,2,4-triazolyl, imidazol-yl or benzotriazolyl, respectively.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/155,249, filed Jan. 27, 1999.
FIELD OF INVENTION
[0002] This invention relates to acetylenic aryl sulfonamide
hydroxamic acids which act as inhibitors of TNF-.alpha. converting
enzyme (TACE). The compounds of the present invention are useful in
disease conditions mediated by TNF-.alpha., such as rheumatoid
arthritis, osteoartis, sepsis, AIDS, ulcerative colitis, multiple
sclerosis, Crohn's disease and degenerative cartilage loss.
BACKGROUND OF THE INVENTION
[0003] TNF-.alpha. converting enzyme (TACE) catalyzes the formation
of TNF-.alpha. from membrane bound TNF-.alpha. precursor protein.
TNF-.alpha. is a pro-inflammatory cytokine that is believed to have
a role in rheumatoid arthritis [Shire, M. G.; Muller, G. W. Exp.
Opin. Ther. Patents 1998, 8(5), 531; Grossman, J. M.; Brahn, E. J.
Women's Health 1997, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Med
1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613.]
septic shock [Mathison, et. al. J. Clin. Invest. 1988, 81, 1925;
Miethke, et. al. J. Exp. Med. 1992, 175, 91.], graft rejection
[Piguet, P. F.; Grau, G. E.; et. al. J. Exp. Med. 1987, 166,
1280.], cachexia [Beutler, B.; Cerami, A. Ann. Rev. Biochem. 1988,
57, 505.], anorexia, inflammation [Ksontini, R.; MacKay, S. L. D.;
Moldawer, L. L. Arch Surg. 1998, 133, 558.], congestive heart
failure [Packer, M. Circulation, 1995, 92(6), 1379; Ferrari, R.;
Bachetti, T.; et. al. Circulation, 1995, 92(6), 1479.],
post-ischaemic reperfusion injury, inflammatory disease of the
central nervous system, inflammatory bowel disease, insulin
resistance [Hotamisligil, G. S.; Shargill, N. S.; Spiegelman, B.
M.; et. al. Science, 1993, 259, 87.] and HIV infection [Peterson,
P. K.; Gekker, G.; et. al. J. Clin. Invest. 1992, 89, 574;
Pallares-Trujillo, J.; Lopez-Soriano, F. J. Argiles, J. M. Med.
Res. Reviews, 1995, 15(6), 533.]], in addition to its
well-documented antitumor properties [Old, L. Science, 1985, 230,
630.]. For example, research. with anti-TNF-.alpha. ntibodies and
transgenic animals has demonstrated that blocking the formation of
TNF-.alpha. inhibits the progression of arthritis [Rankin, E. C.;
Choy, E. H.; Kassimos, D.; Kingsley, G. H.; Sopwith, A. M.;
Isenberg, D. A.; Panayi, G. S. Br. J. Rheumatol. 1995, 34, 334;
Pharmaprojects, 1996, Therapeutic Updates 17 (October),
au197-M2Z.]. This observation has recently been extended to humans
as well as described in "TNF-.alpha. in Human Diseases", Current
Pharmaceutical Design, 1996, 2, 662.
[0004] It is expected that small molecule inhibitors of TACE would
have the potential for treating a variety of disease states.
Although a variety of TACE inhibitors are known, many of these
molecules are peptidic and peptide-like which suffer from
bioavailability and pharmacokinetic problems. In addition, many of
these molecules are non-selective, being potent inhibitors of
matrix metalloproteinases and, in particular, MMP-1. Inhibition of
MMP-1 (collagenase 1) has been postulated to cause joint pain in
clinical trials of MMP inhibitors [Scrip, 1998, 2349, 20] Long
acting, selective, orally bioavailable non-peptide inhibitors of
TACE would thus be highly desirable for the treatment of the
disease states discussed above.
[0005] U.S. Pat. Nos. 5,455,258, 5,506,242, 5,552,419, 5,770,624,
5,804,593, and 5,817,822 as well as European patent application
EP606,046A1 and WIPO international publications WO9600214 and
WO9722587 disclose non-peptide inhibitors of matrix
metalloproteinases and/or TACE of which the aryl sulfonamide
hydroxamic acid shown below is representative. Additional
publications disclosing sulfonamide based MMP inhibitors which are
variants of the sulfonamide-hydroxamate shown below, or the
analogous sulfonamide-carboxylates, are European patent
applications EP-757037-A1 and EP-757984-A1 and WIPO international
publications WO9535275, WO9535276, WO9627583, WO9719068, WO9727174,
WO9745402, WO9807697, WO9831664, WO9833768, WO9839313, WO9839329,
WO9842659 and WO9843963. The discovery of this type of MMP
inhibitor is further detailed by MacPherson, et. al. in J. Med.
Chem., 1997, 40, 2525 and Tamura, et. al. in J. Med. Chem. 1998,
41, 640. 2
[0006] Publications disclosing .beta.-sulfonamide-hydroxamate
inhibitors of MMPs and/or TACE in which the carbon alpha to the
hydroxamic acid has been joined in a ring to the sulfonamide
nitrogen, as shown below, include U.S. Pat. No. 5,753,653, WIPO
international publications WO9633172, WO9720824, WO9827069,
WO9808815, WO9808822, WO9808823, WO9808825, WO9834918, WO9808827,
Levin, et. al. Bioorg. & Med. Chem. Letters 1998, 8, 2657 and
Pikul, et. al. J. Med. Chem. 1998, 41, 3568. 3
[0007] The patent applications DE19,542,189-A1; WO9718194, and
EP803505 disclose additional examples of cyclic sulfonamides as MMP
and/or TACE inhibitors.
[0008] In this case the sulfonamide-containing ring is fused to a
aromatic or heteroaromatic ring. 4
[0009] Examples of sulfonamide hydroxamic acid MMP/TACE inhibitors
in which a 2 carbon chain separates the hydroxamic acid and the
sulfonamide nitrogen, as shown below, are disclosed in WIPO
international publications WO9816503, WO9816506, WO9816514 and
WO9816520 and U.S. Pat. No. 5,776,961. 5
[0010] Analogous to the sulfonamides are the phosphinic acid amide
hydroxamic acid MMP/TACE inhibitors, exemplified by the structure
below, which have been disclosed in WIPO international publication
WO9808853. 6
[0011] Sulfonamide MMP/TACE inhibitors in which, a thiol is the
zinc chelating group, as shown below, have been disclosed in WIPO
international application 9803166. 7
[0012] It is an object of this invention to provide aryl
sulfonamide hydroxamic acid MMP/TACE inhibitors in which the
sulfonyl aryl group is para-substituted with a substituted butynyl
moiety or a propargylic ether, amine or sulfide.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The invention provides TACE and MMP inhibitors having the
formula: 8
[0014] wherein:
[0015] X is SO.sub.2 or --P(O)--R.sub.10;
[0016] Y is aryl or heteroaryl, with the proviso that X and Z may
not be bonded to adjacent atoms of Y;
[0017] Z is O, NH, CH.sub.2 or S;
[0018] R.sub.1 is hydrogen, aryl, alkyl of 1-6 carbon atoms,
alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms;
[0019] R.sub.2 is hydrogen, aryl, aralkyl, heteroaryl,
heteroaralkyl, cycloalkyl of 3-6 carbon atoms, C.sub.4-C.sub.8
cycloheteroalkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, alkynyl of 2-6 carbon atoms;
[0020] or R.sub.1 and R.sub.2, together with the atom to which they
are attached, may form a ring wherein R.sub.1 and R.sub.2 represent
a divalent moiety of the formula: 9
[0021] wherein
[0022] Q=a carbon-carbon single or double bond, O, S, SO, SO2,
--N--R.sub.11, or --CONR.sub.14;
[0023] m=1-3;
[0024] r=1or 2, with the proviso that when Q is a bond, r is equal
to 2;
[0025] R.sub.2 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl
of 3-6 carbon atoms, C4-C8 cycloheteroalkyl, aralkyl, or
heteroaralkyl;
[0026] or R.sub.1 and R.sub.3, together with the atoms to which
they are attached, may form a 5 to 8 membered ring wherein R.sub.1
and R.sub.3 represent divalent moieties of the formulae: 10
[0027] wherein Q and m are as defined above;
[0028] A is aryl or heteroaryl;
[0029] s is 0-3;
[0030] u is 1-4;
[0031] R.sub.4 and R.sub.5 are, each, independently, hydrogen or
alkyl of 1-6 carbon atoms, --CN, or --CCH;
[0032] R.sub.6 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon
atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,
cycloalkyl of 3-6 carbon atoms, or
--C.sub.5-C.sub.8-cycloheteroalkyl;
[0033] R.sub.9 and R.sub.9 are each, independently, hydrogen, alkyl
of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, aralkyl,
heteroaryl, heteroaralkyl, or --C4-C8-cycloheteroalkyl;
[0034] R.sub.10 is allyl of 1-6 carbon atoms, cycloalkyl of 3-6
carbon atoms, aryl or heteroaryl;
[0035] R.sub.11 is hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl
of 3-6 carbon atoms, aryl, heteroaryl, --S(O).sub.nR.sub.8,
--COOR.sub.8, --CONR.sub.8R.sub.9, --SO.sub.2NR.sub.8R.sub.9 or
--COR.sub.8;
[0036] R.sub.12 and R.sub.13 are independently selected from H,
--OR.sub.8, --NR.sub.8R.sub.9, alkyl of 1-6 carbon atoms, alkenyl
of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6
carbon atoms, aryl, heteroaryl, --COOR.sub.8; --CONR.sub.8R.sub.9;
or R.sub.12 and R.sub.13 together form a
--C.sub.3-C.sub.6-cycloalkyl of 3-6 carbon atoms or a
--C.sub.5-C.sub.8-cycloheteroalkyl ring; or R.sub.12 and R.sub.13
together with the carbon to which they are attached, form a
carbonyl group;
[0037] with the proviso that R.sub.10 and R.sub.12 or R.sub.11 and
R.sub.12 may form a cycloheteroalkyl ring when they are attached to
adjacent atoms;
[0038] R.sub.14 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon
atoms or cycloalkyl of 3-6 carbon atoms;
[0039] and n is 0-2;
[0040] or a pharmaceutically acceptable salt thereof.
[0041] Preferred compounds of this invention are those of structure
B in which Y is a phenyl ring substituted at the 1- and 4-positions
by X and Z, respectively, or a pharmaceutically acceptable salt
thereof.
[0042] More preferred compounds of this invention are those of
structure B in which Y is a phenyl ring substituted at the 1- and
4-positions by X and Z, respectively, X is SO.sub.2, or a
pharmaceutically acceptable salt thereof.
[0043] More preferred compounds of this invention are those of
structure B in which Y is a phenyl ring substituted at the 1- and
4-positions by X and Z, respectively, X is SO.sub.2, Z is
oxygen.
[0044] More preferred compounds of this invention are those of
structure B in which Y is a phenyl ring substituted at the 1- and
4-positions by X and Z, respectively, X is SO.sub.2, Z is oxygen
and R.sub.4 and R.sub.5 are hydrogen.
[0045] More preferred compounds of this invention are those of
structure B in which Y is a phenyl ring substituted at the 1- and
4-positions by X and Z, respectively, X is SO.sub.2, Z is oxygen,
R.sub.4 and R.sub.5 are hydrogen, and R.sub.6 is --CH.sub.2OH or
methyl.
[0046] More preferred compounds of this invention are those of
structure B in which R.sub.1 and R.sub.3, together with the atoms
to which they are attached, form a piperazine, piperidine,
tetrahydroisoquinoline, morpholine, thiomorpholine or diazepine
ring.
[0047] More preferred compounds of this invention are those of
structure B in which R.sub.1 and R.sub.3, together with the atoms
to which they are attached, form a piperazine, piperidine,
tetrahydroisoquinoline, morpholine, thiomorpholine or diazepine
ring, and Y is a phenyl ring substituted at the 1- and 4-positions
by X and Z, respectively, X is SO.sub.2, and Z is oxygen, or a
pharmaceutically acceptable salt thereof. 11
[0048] More preferred compounds of this invention are those of
structure B in which R.sub.1 and R.sub.3, together with the atoms
to which they are attached, form a piperazine, piperidine,
tetrahydroisoquinoline, morpholine, thiomorpholine or diazepine
ring, Y is a phenyl ring substituted at the 1- and 4-positions by X
and Z, respectively, X is SO.sub.2, Z is oxygen, and R.sub.2 is
hydrogen, such that structure B has the absolute stereochemistry
shown above, or a pharmaceutically acceptable salt thereof.
[0049] More preferred compounds of this invention are those of
structure B in which R.sub.1 is hydrogen, such that these compounds
have the D-configuration, as shown below: 12
[0050] More preferred compounds of this invention are those of
structure B in which R.sub.1 is hydrogen, such that these compounds
have the D-configuration, as shown above, and R.sub.3 is hydrogen,
or a pharmaceutically acceptable salt thereof. Still more preferred
compounds of this invention are those of structure B in which
R.sub.1 is hydrogen, such that these compounds have the
D-configuration, as shown above, R.sub.3 is hydrogen, Y is a phenyl
ring substituted at the 1- and 4-positions by X and Z,
respectively, X is SO.sub.2, Z is oxygen, or a pharmaceutically
acceptable salt thereof.
[0051] Most preferred compounds of the present invention are
[0052]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-3-meth-
yl-butyramide;
[0053]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-acetam-
ide
[0054]
N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-methyl-amino]-3-methyl-but-
yramide;
[0055]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hy-
droxy-acetamide hydrochloride;
[0056]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-acetamide;
[0057]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-methyl-butyram-
ide;
[0058]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-propionamide;
[0059]
2-[(4-But-2ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hyd-
roxy-propionamide hydrochloride;
[0060] 2-(4-But-2-ynyloxy
benzenesulfonylamino)-N-hydroxy-2-methylpropiona- mide;
[0061]
4-(4-But-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-c-
arboxylic acid hydroxyamide;
[0062]
4-(4-Hept-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3--
carboxylic acid hydroxyamide;
[0063]
2-(4-But-2-ynyloxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoline-
-3-carboxylic acid hydroxyamide;
[0064]
4-Benzoyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-[1,4]diazepane-2-carb-
oxylic acid hydroxyamide;
[0065]
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-methyl-piperazine-2-carboxyli-
c acid hydroxyamide hydrochloride;
[0066]
4-[4-(4-Hydroxy-but-2-ynyloxy)benzenesulfonyl]-2,2-dimethyl-thiomor-
pholine-3-carboxylic acid hydroxyamide;
[0067]
4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1-
-carboxylic acid tert-butyl ester;
[0068]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-2-methylpropiona-
mide;
[0069]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-5-guanidino-pentanoic acid
hydroxyamide;
[0070]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-5-(4-methylbenzenesulfonyl-
-guanidino)-pentanoic acid hydroxyamide;
[0071]
3-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-succinamic acid
cyclohexyl ester;
[0072]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-3-cyclohexyl-N-hydroxy-pro-
pionamide;
[0073]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-2-cyclohexyl-N-hydroxy-ace-
tamide
[0074]
3-tert-Butylsulfanyl-2-(4-but-2-ynyloxy-benzenesulfonylamino)-N-hyd-
roxy-propionamide;
[0075]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-(4-methoxy-ben-
zylsulfanyl)-propionamide;
[0076]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N1-hydroxy-succinamide;
[0077]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-3-cyclohexyl-N-hydroxy-pro-
pionamide;
[0078]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-2-cyclohexyl-N-hydroxy-ace-
tamide;
[0079] 2-(4-But-2-ynyloxy-benzenesulfonylamino)-4-methyl-pentanoic
acid hydroxyamide;
[0080]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-4-methylsulfanyl-
-butyramide;
[0081]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-phenyl-propion-
amide;
[0082] 1-(4-But-2-ynyloxy-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid hydroxyamide;
[0083]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-(1H-indol-3-yl-
)-propionamide;
[0084]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-(4-hydroxy-phe-
nyl)-propionamide;
[0085]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-methyl-butyram-
ide;
[0086] 2-(4-But-2-ynyloxy-benzenesulfonylamino)-4-methyl-pentanoic
acid hydroxyamide;
[0087]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-6-(2-chloro-benzylamino)-h-
exanoic acid hydroxyamide;
[0088] 2-(4-But-2-ynyloxy-benzenesulfonylamino)-hexanoic acid
hydroxyamide;
[0089]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-2-phenyl-acetami-
de;
[0090]
3-Benzyloxy-2-(4-but-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-prop-
ionamide;
[0091]
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-acetamide;
[0092]
(2R,3S)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-met-
hyl-pentanamide;
[0093]
(2R)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3,3-dime-
thyl-butanamide;
[0094]
(2S)-2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-p-
ropionamide;
[0095]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-ethyl-amino]-N-hydroxy-3-methy-
l-butyramide;
[0096]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-N-hydroxy-3-
-methylbutanamide;
[0097]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-propyl-amino]-N-hydroxy-3-meth-
yl-butyramide;
[0098]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-(3-phenyl-propyl)-amino]-N-hyd-
roxy-3-methyl-butyramide;
[0099]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-cyclopropylmethyl-amino]-N-hyd-
roxy-3-methyl-butyramide;
[0100]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-isobutyl-amino]-N-hydroxy-3-me-
thyl-butyramide;
[0101]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hy-
droxy-3-methyl-butyramide;
[0102]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-2-cyclohexyl-N-h-
ydroxy-acetamide;
[0103]
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-2-cy-
clohexyl-N-hydroxy-acetamide;
[0104]
2-{(4-But-2-ynyloxy-benzenesulfonyl)-[4-(2-piperidin-1-yl-ethoxy)-b-
enzyl]-amino}-2-cyclohexyl-N-hydroxy-acetamide;
[0105]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(diethylamino)propyl]amino}-
-N-hydroxy-3-methylbutanamide;
[0106]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(4-morpholinyl)propyl]amino-
}-N-hydroxy-3-methylbutanamide;
[0107]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(4-methyl-1-piperazinyl)pro-
pyl]amino}-N-hydroxy-3-methylbutanamide hydrochloride;
[0108]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(diethylamino)butyl]amino}--
N-hydroxy-3-methylbutanamide;
[0109]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)but-
yl]amino}-N-hydroxy-3-methylbutanamide;
[0110]
2-[[[4-(2-Butynyloxy)phenyl]sulfonyl][2-(4-morpholinyl)ethyl]amino]-
-N-hydroxy-3-methylbutanamide;
[0111]
2-[{[4-(But-2-ynyloxy)phenyl]sulfonyl}(2-morpholin-4-ylethyl)amino]-
-N-hydroxyacetamide hydrochloride;
[0112]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)-2--
butynyl]amino}-N-hydroxy-3-methylbutanamide;
[0113]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(diethylamino)-2-butynyl]am-
ino}-N-hydroxy-3-methylbutanamide;
[0114]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(methylamino)-2-butynyl]ami-
no}-N-hydroxy-3-methylbutanamide;
[0115]
((2R)-{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino)[(4-diethylam-
ino)cyclohexyl]-N-hydroxyethamide;
[0116]
(2R)-{[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-hydrox-
ycyclohexyl)ethanamide;
[0117]
(2R)-{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino)-N-hydroxy-2-(-
4-hydroxycyclohexyl)-ethanamide;
[0118]
2-[(6-But-2-ynyloxy-pyridine-3-sulfonyl)-methyl-amino]-N-hydroxy-ac-
etamide;
[0119]
2-[[(4-{[3-(4-Chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)-
amino]-N-hydroxyacetamide;
[0120] N-Hydroxy-2-(methyl
{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)ace- tamide;
[0121]
2-[(4-But-2-ynylthiophenylsulfonyl)methylamino]-N-hydroxyacetamide;
[0122]
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)-2--
yl}[4-(4-methyl-1-piperazinyl)-2-butynyl]amino}-N-hydroxypropanamide;
[0123]
1-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-sulfonyl}(met-
hyl)amino]-N-hydroxycyclohexanecarboxamide;
[0124]
1-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(3-pyridinylmethyl)amino]N-hyd-
roxycyclohexanecarboxamide;
[0125]
1-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxycyclohexanecar-
boxamide;
[0126]
1-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxycyclopentaneca-
rboxamide;
[0127]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-met-
hyl-3-[(2-(4-morpholinylethyl)sulfanyl]-butanamide
hydrochloride;
[0128]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-met-
hyl-3-{[2-(4-methyl-1-ethyl-1-piperazinyl)ethyl]sulfanyl}butanamide;
[0129]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-met-
hyl-3-{[2-(diethylamino)ethyl]sulfanyl}butanamide;
[0130]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-met-
hyl-3-{[2-(1-pyrrolidinyl)ethyl]sulfanyl}butanamide;
[0131]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-met-
hyl-3-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}butanamide;
[0132] Methyl
1-[2-({2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)]amino]--
3-(hydroxyamino)-1,1-dimethyl-3-oxopropyl}sulfanyl)ethyl]-2-pyrrolidinecar-
boxylate;
[0133]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-met-
hyl-3-[(2(4-morpholinylpropyl)sulfanyl]butanamide;
[0134]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-met-
hyl-3-{[2(4-methyl-1-ethyl-1-piperazinyl)propyl]sulfanyl}butanamide;
[0135]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-met-
hyl-3-{[2-(diethylamino)propyl]sulfanyl}butanamide;
[0136]
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methy-
l-3-methylsulfanyl-butyramide;
[0137]
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-ethyl-
sulfanyl-butyramide;
[0138]
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methy-
l-3-propylsulfanyl-butyramide;
[0139]
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methy-
l-3-(pyridin-3-ylmethylsulfanyl)-butyramide;
[0140]
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methy-
l-3-benzylsulfanyl-butyramide;
[0141]
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-(meth-
ylsulfanyl)-butyramide;
[0142]
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-(pyri-
din-3-ylmethylsulfanyl)-butyramide;
[0143]
3-(Benzylthio)-2-[[[4-(2-butynyloxy)phenyl]sulfonyl]methylamino]-N--
hydroxypropanamide;
[0144]
3-(Benzylthio)-2-[[[4-(2-butynyloxy)phenyl]sulfonyl]pyridin-3-ylmet-
hylamino]-N-hydroxypropanamide;
[0145]
2-[[[4-(2-Butynyloxy-phenyl]sulfonyl]amino]-N-hydroxy-3-methyl-(3-m-
ethylthio)-butyramide;
[0146]
2-[(4-But-2-ynyloxy-benenesulfonyl)-amino]-N-hydroxy-3-methyl-3-eth-
ylsulfanyl-butyramide;
[0147]
2-[(4-But-2-ynyloxy-benenesulfonyl)-amino]-N-hydroxy-3-methyl-3-pro-
pylsulfanyl-butyramide;
[0148]
2-[(4-Butynyloxy-phenylsulfonyl)-amino]-N-hydroxy-3-methyl-[(3-pyri-
dinylmethyl)thio]butyramide;
[0149]
2-[(4-Butynyloxy-phenyl)sulfonyl)-amino]-N-hydroxy-3-methyl-(3-benz-
ylsulfanyl) butyramide;
[0150]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-3-{[(-methyl-1-
H-imidazol-2-yl]methylsulfanyl}butanamide;
[0151]
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-3-methyl-3-{[2-
-(4-morpholinyl)ethyl]sulfanyl}butanamide;
[0152]
tert-Butyl{[2-({[4-2-butynyloxy)phenyl]sulfonyl}amino)-3-(hydroxyam-
ino)-1,1-dimethyl-3-oxopropyl]sulfanyl}acetate;
[0153]
tert-Butyl{[2-({[4-2-butynyloxy)phenyl]sulfonyl}amino)-3-(hydroxyam-
ino)-1,1-dimethyl-3-oxopropyl]sulfanyl acetic acid, sodium
salt;
[0154]
2-[(4-Butynyloxy-phenylsulfonyl)-amino]-N-hydroxy-3-(methylthio)-pr-
opanamide;
[0155]
2-[[4-Butynyloxy-phenylsulfonyl]-amino]-N-hydroxy-3-(benzylthio)-pr-
opanamide;
[0156]
2-[[4-Butynyloxy-phenylsulfonyl]-amino]-N-hydroxy-3-(pyridinylthio)-
-propanamide;
[0157]
2-({[4-(2-Butnyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(Z)-11-tetr-
adecenylsulfanyl]propanamide;
[0158]
(2S)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hy-
droxypropyl)sulfanyl]-3-methylbutanamide;
[0159]
(2S)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hy-
droxypropyl)sulfanyl]-3-propanamide;
[0160]
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-1-
,4-thiazepane-3-carboxamide;
[0161]
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepane-
-3-carboxamide;
[0162]
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepane-
-3-carboxamide 1,1-dioxide;
[0163]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-hydroxyp-
henyl)acetamide;
[0164]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-[4-(2-propy-
nyloxy)phenyl]acetamide;
[0165]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-(4--
methoxyphenyl)acetamide;
[0166]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4--
[2-(4-morpholinyl)ethoxy]phenyl}acetamide;
[0167] tert-Butyl
2-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino-
]-2-(hydroxyamino)-2-oxoethyl]phenoxy}ethylcarbamate;
[0168]
2-[4-(2-Aminoethoxy)phenyl]-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(m-
ethyl)amino]-N-hydroxyacetamide;
[0169]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-}4-[2-(dimeth-
ylamino)ethoxy]phenyl}-N-hydroxyacetamide;
[0170]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4--
[2-(1-pyrrolidinyl)ethoxy]phenyl}acetamide;
[0171]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4--
[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}acetamide;
[0172] tert-Butyl
4-(2-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)am-
ino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}ethyl)-1-piperazinecarboxylate;
[0173]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4--
[2-(1-piperazinyl)ethoxy]phenyl}acetamide;
[0174] tert-Butyl
3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino-
]-2-(hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate;
[0175]
2-[4-(3-Aminopropoxy)phenyl]-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(-
methyl)amino]-N-hydroxyacetamide;
[0176] tert-Butyl
(3S)-3-{4-[(1R)-1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(me-
thyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}-1-pyrrolidinecarboxylate;
[0177]
(2R)-2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy--
2-(4-[(3S)-pyrrolidinyloxy]phenyl}ethanamide;
[0178] tert-Butyl
(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amin-
o)-2-(hydroxyamino)-2-oxoethyl)phenoxy]ethyl)-(methyl)carbamate;
[0179]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino)-N-hydroxy-2-{4--
[2-(methylamino) ethoxy]phenyl}acetamide;
[0180] Ethyl
3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(-
hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate;
[0181]
2-{4-[3-(Acetylamino)propoxy]phenyl}-2-[{[4-(2-butynyloxy)phenyl]su-
lfonyl}(methyl)amino]-N-hydroxyacetamide;
[0182]
Butyl-3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(-
hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate;
[0183]
Benzyl-3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2--
(hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate;
[0184]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-(4--
{3-[(methylsulfonyl)amino]propoxy}phenyl)acetamide;
[0185]
2-(4-{3-[(Anilinocarbonyl)amino]propoxy}phenyl)-2-[{[4-(2-butynylox-
y)phenyl]sulfonyl}(methyl)amino]-N-hydroxyacetamide;
[0186] tert-Butyl
2-{4-[(1R)-1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-
-(hydroxyamino)-2-oxoethyl]phenoxy}ethylcarbamate;
[0187]
(2R)-2-[4-(2-Aminoethoxy)phenyl]-2-({[4-(2-butynyloxy)phenyl]-sulfo-
nyl}amino)-N-hydroxyethanamide;
[0188]
(2R)-2-{4-[2-(Acetylamino)ethoxy]phenyl}-2-({[4-(2-butynyloxy)pheny-
l]sulfonyl}amino)-N-hydroxyethanamide;
[0189] tert-Butyl
4-(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(-
hydroxyamino)-2-oxoethyl)phenoxy]ethyl)-1-piperazinecarboxylate;
[0190] tert-Butyl
4-(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(-
hydroxyamino)-2-oxoethyl)phenoxy]ethyl)-(methyl)carbamate;
[0191]
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(methy-
lamino)ethoxy]phenyl})acetamide;
[0192]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(1-py-
rrolidinyl)ethoxy]phenyl}acetamide;
[0193]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(4-mo-
rpholinyl)ethoxy]phenyl}acetamide;
[0194]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino){4-[2-(dimethylamino)eth-
oxy]phenyl}-N-hydroxyacetamide;
[0195]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(4-me-
thyl-1,3-thiazol-5-yl)ethoxy]phenyl}acetamide;
[0196]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-{2-[2-(2-
-thoxyethoxy)ethoxy]ethoxy}phenyl)acetamide;
[0197]
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(2-me-
thoxyethoxy)ethoxy]phenyl}acetamide;
[0198]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-phe-
nyl-acetamide;
[0199]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophen-
yl)-N-hydroxyacetamide;
[0200]
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-[(4-chlorophe-
nyl)sulfanyl]-N-hydroxypentanamide;
[0201] 1-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic
acid hydroxyamide;
[0202]
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piper-
azine-2-carboxylic acid hydroxyamide;
[0203]
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 1-diethylamide 3-hydroxyamide;
[0204]
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(pyrrolidine-1-carbonyl)-pipe-
razine-2-carboxylic acid hydroxyamide;
[0205]
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 1-diisopropylamide 3-hydroxyamide;
[0206] Benzyl
4-{[4-(2-butylyloxy)phenyl]sulfonyl}-3-[(hydroxyamino)carbon-
yl]-1-piperazinecarboxylate;
[0207]
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 3-hydroxyamide 1-(methyl-phenyl-amide);
[0208]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-3-hydroxy-N-1-(4-methoxyphen-
yl)-1,3-piperazinedicarboxamide;
[0209]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-1-(4-fluorophenyl)-N-3-hydro-
xy-1,3-piperazinedicarboxamide;
[0210]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-1-(3,5-dichlorophenyl)-N-3-h-
ydroxy-1,3-piperazinedicarboxamide;
[0211]
4-Acetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxyli-
c acid hydroxyamide;
[0212]
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-propionyl-piperazine-2-carbox-
ylic acid hydroxyamide;
[0213]
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(thiophene-2-carbonyl)-pipera-
zine-2-carboxylic acid hydroxyamide;
[0214]
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-methanesulfonyl-piperazine-2--
carboxylic acid hydroxyamide;
[0215]
4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1-
-carboxylic acid methyl ester;
[0216]
{2-[4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazi-
n-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester;
[0217]
4-Aminoacetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carb-
oxylic acid hydroxyamide;
[0218]
1-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-[(2,2,5-trimethyl--
1,3-dioxan-5-yl)carbonyl]-2-piperazinecarboxamide;
[0219]
1-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-[3-hydroxy-2-(hydr-
oxy-methyl)-2-methylpropanoyl-2-piperazinecarboxamide;
[0220]
4-(4-Bromo-benzyl)-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-
-carboxylic acid hydroxyamide;
[0221]
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-pyridin-3-ylmethyl-piperazine-
-2-carboxylic acid hydroxyamide;
[0222]
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorphol-
ine-3-carboxylic acid hydroxyamide;
[0223]
9-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-6-thia-9-azaspiro[4-
,5]-decane-10-carboxamide;
[0224]
9-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4-azaspiro[5-
,5]-undecane-5-carboxamide;
[0225]
4-({[4-(2-Butynyloxy)phenyl]sulfonyl)-2,2-diethyl-thiomorpholine-3--
carboxylic acid hydroxyamide;
[0226]
4-({[4-(2-Butynyloxy)phenyl]sulfonyl)-N-hydroxy-thiomorpholine-3-ca-
rboxamide;
[0227]
4-([4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-3-morpholinecarboxam-
ide;
[0228]
9-Benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4,9--
diazaspiro[5.5]undecane-5-carboxamide;
[0229]
9-Methyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4,9--
diazaspiro[5.5]undecane-5-carboxamide;
[0230]
N-Hydroxy-2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pe-
ntynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide;
[0231]
N-Hydroxy-4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dim-
ethyl-3-thiomorpholine carboxamide;
[0232] tert-Butyl
5-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomor-
pholinyl}sulfonyl)phenoxy]-3-pentynylcarbamate;
[0233]
4-({4-[(5-Amino-2-pentynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimet-
hyl-3-thiomorpholine carboxamide;
[0234]
4-[(4-{[4-(Benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-N-hydroxy-2,2--
dimethyl-3-thiomorpholine carboxamide;
[0235]
N-Hydroxy-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-he-
xynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide;
[0236]
N-Hydroxy-4-({4-[(6-hydroxy-2-hexynyl)oxy]phenyl}sulfonyl)-2,2-dime-
thyl-3-thiomorpholine carboxamide;
[0237] tert-Butyl
6-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiom-
rorpholinyl}sulfonyl)phenoxy]-4-hexynylcarbamate;
[0238]
(3S)-4-({4-[(6-Amino-2-hexynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-d-
imethyl-3-thiomorpholine carboxamide;
[0239] tert-Butyl
7-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiom-
orpholinyl}sulfonyl)phenoxy]-5-heptynylcarbamate;
[0240]
(3S)-4-({4-[(7-Amino-2-heptynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2--
dimethyl-3-thiomorpholine carboxamide;
[0241]
(3S)-N-Hydroxy-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl}-
sulfonyl)-3-thiomorpholine carboxamide;
[0242]
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3--
thiomorpholine carboxamide (1S)-oxide;
[0243]
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3--
thiomorpholine carboxamide (1)-oxide;
[0244]
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3--
thiomorpholine carboxamide 1,1-dioxide;
[0245]
(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-
-thiomorpholine carboxamide;
[0246]
(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2-pentynyloxy)phenyl]sulfonyl}-3-
-thiomorpholine carboxamide;
[0247]
(3S)-N-Hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-
-dimethyl-3-thiomorpholine carboxamide;
[0248]
4-[4-({(3S)-3-[(Hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}-
sulfonyl)phenoxy]-2-butynyl acetate;
[0249]
(3S)-N-Hydroxy-4-({4-[(6-hydroxy-2,4-hexadiynyl)oxy]phenyl}sulfonyl-
)-2,2-dimethyl-3-thiomorpholine carboxamide;
[0250]
(3S)-N-Hydroxy-2,2-dimethyl4-{[4-(2,4-pentadiynyloxy)phenyl]sulfony-
l}-3-thiomorpholine carboxamide;
[0251]
(3S)-4-({4-[(4-Fluoro-2-butynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2--
dimethyl-3-thiomorpholine carboxamide;
[0252]
4-({4-[(4-Amino-2-butynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimeth-
yl-3-thiomorpholine carboxamide;
[0253] tert-Butyl
4-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomor-
pholinyl}sulfonyl)phenoxy]-2-butynylcarbamate;
[0254] tert-Butyl
4-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomor-
pholinyl}sulfonyl)phenoxy]-2-butynyl(methyl)carbamate;
[0255]
7-[4-({(3S)-3-[(Hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}-
sulfonyl)phenoxy]-5-heptynyl acetate;
[0256]
(3S)-N-Hydroxy-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,-
2-dimethyl-3-thiomorpholinecarboxamide;
[0257]
(3S,5S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,5-trimet-
hyl-3-thiomorpholinecarboxamide;
[0258]
(3S,5R)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,5-trimet-
hyl-3-thiomorpholinecarboxamide;
[0259]
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,6-trimet-
hyl-3-thiomorpholinecarboxamide;
[0260]
tert-Butyl{(2R,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxy-
amino)carbonyl]-6,6-dimethylthiomorpholinyl}methylcarbamate;
[0261]
tert-Butyl{(2S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxy-
amino)carbonyl]-6,6-dimethylthiomorpholinyl}methylcarbamate;
[0262]
(3S,6R)-Trans-6-(aminomethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}--
N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide
hydrochloride;
[0263]
(3S,6S)-Cis-6-(aminomethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N--
hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide hydrochloride;
[0264]
tert-Butyl{(2S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxy-
amino)carbonyl]-6,6-dimethylthiomorpholinyl)acetate;
[0265]
{(2S,5S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)carb-
onyl]-6,6-dimethylthiomorpholinyl}acetic acid;
[0266]
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-6-[2-(hydrox-
yamino)-2-oxoethyl]-2,2-dimethyl-3-thiomorpholinecarboxamide;
[0267]
(3S,6S)-6-(2-Amino-2-oxoethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-
-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
[0268]
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-6-[2-(dimethylamino)-2-
-oxoethyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide;
[0269]
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-
-6-[2-(4-morpholinyl)-2-oxoethyl]-3-thiomorpholinecarboxamide;
[0270]
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-
-6-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-3-thiomorpholinecarboxamide
hydrochloride;
[0271]
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-6-(2-{[2-(dimethylamin-
o)ethyl]amino}-2-oxoethyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxam-
ide;
[0272] Methyl
(3S,6S)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-{[4-(2-buty-
nyloxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate;
[0273]
(4S)-3-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-5,5-dimethyl-1,-
3-thiazolidine-4-carboxamide;
[0274] tert-Butyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(hydroxya-
mino)carbonyl]-1-piperidinecarboxylate;
[0275]
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-4-piperidinec-
arboxamide;
[0276]
1-Benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazep-
ane-5-carboxamide;
[0277]
1-Benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepa-
ne-5-carboxamide;
[0278] tert-Butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)ca-
rbonyl]-1,4-diazepane-1-carboxylate;
[0279]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-5-carb-
oxamide;
[0280]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-methyl-1,4-diazepa-
ne-5-carboxamide;
[0281]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepine-5-car-
boxamide;
[0282]
(2R)-5-(Acetylamino)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-
-hydroxypentanamide;
[0283]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]thiophene-2-carboxamide;
[0284]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[(ethylamino)c-
arbonyl]amino}-N-hydroxypentanamide;
[0285]
(2R)-5-[(Anilinocarbonyl)amino]-2-({[4-(but-2-ynyloxy)phenyl]sulfon-
yl}amino)-N-hydroxypentanamide;
[0286] Octyl
(4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxya-
mino)-5-oxopentylcarbamate;
[0287] 4-Methoxyphenyl
(4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-
-(hydroxyamino)-5-oxopentylcarbamate;
[0288]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[(diethylamino-
)carbonyl]amino}-N-hydroxypentanamide;
[0289]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[(me-
thylanilino)carbonyl]amino}pentanamide;
[0290]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[(1--
methyl-1H-imidazol-4-yl)sulfonyl]amino}pentanamide;
[0291]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(2-m-
orpholin-4-ylacetyl)amino]pentanamide;
[0292]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[2-(-
4-methylpiperazin-1-yl)acetyl]amino}pentanamide;
[0293]
(2R)-5-{[2-(Benzylamino)acetyl]amino}-2-({[4-(but-2-ynyloxy)phenyl]-
sulfonyl}amino)-N-hydroxypentananide;
[0294]
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3,-
4-dihydro-2H-1,4-thiazine-3-carboxamide;
[0295]
(2R)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(imin-
o{[(4-{[4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino}methyl)amino]pentan-
amide;
[0296]
(2R)-2-(4-But-2-ynyloxy-benzenesulfonylamino)-5-guanidino-pentanoic
acid hydroxyamide;
[0297]
(2R)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(imin-
o{[(4-methylphenyl)sulfonyl]amino}methyl)amino]pentanamide;
[0298]
(3R)-3-({[4-(But-2-ynlyoxy)phenyl]sulfonyl}amino)-4-(hydroxyamino)--
4-oxobutanoic acid;
[0299]
(2S)-3-(tert-Butylthio)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino-
)-N-hydroxypropanamide;
[0300]
(2S)-3-{[(Acetylamino)methyl]thio}-2-({[4-(but-2-ynyloxy)phenyl]sul-
fonyl}amino)-N-hydroxypropanamide;
[0301]
(2S)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(4-m-
ethylbenzyl)thio]propanamide;
[0302]
(2S)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(4-m-
ethoxybenzyl)thio]propanamide;
[0303]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxypentaned-
iamide;
[0304]
(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)--
5-oxopentanoic acid;
[0305]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-4-pheny-
lbutanamide;
[0306]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-(1H-i-
midazol-5-yl)propanamide;
[0307]
(2R,4S)-1-{[4-(But-2-ynyloxy)phenyl]sulfonyl}-N,4-dihydroxypyrrolid-
ine-2-carboxamide;
[0308]
(2R)-6-Amino-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-
hexanamide;
[0309] Benzyl
(5R)-5-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxy-
amino)-6-oxohexylcarbamate;
[0310]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-(1-na-
phthyl)propanamide;
[0311]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-(2-na-
phthyl)propanamide;
[0312]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxyhexanami-
de;
[0313]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxypentanam-
ide;
[0314]
(2R)-5-Amino-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-
pentanamide;
[0315]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-3-(3,4-difluoroph-
enyl)-N-hydroxypropananide;
[0316]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-3-(4-fluorophenyl-
)-N-hydroxypropanamide;
[0317]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-(4-ni-
trophenyl)propanamide;
[0318]
(2R)-1-({[4-(But-2-ynyloxy)phenyl]sulfonyl}-N-hydroxypiperidine-2-c-
arboxamide;
[0319]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxyprop-
anamide;
[0320]
(2R)-3-(Benzyloxy)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-h-
ydroxypropanamide;
[0321]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-thien-
-2-ylpropanamide;
[0322]
(2R,3S)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N,3-dihydroxyb-
utanamide;
[0323]
(2R,3S)-3-(Benzyloxy)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)--
N-hydroxybutanamide;
[0324]
(4S)-3-{[4-(But-2-ynyloxy)phenyl]sulfonyl}-N-hydroxy-1,3-thiazolidi-
ne-4-carboxamide;
[0325]
(3R)-2-{[4-(But-2-ynyloxy)phenyl]sulfonyl}-N-hydroxy-1,2,3,4-tetrah-
ydroisoquinoline-3-carboxamide;
[0326]
(2R)-3-[4-(Benzyloxy)phenyl]-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}-
amino)-N-hydroxypropanamide;
[0327]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-pheny-
lethanamide;
[0328]
(2R)-5-(Acetylamino)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-
-hydroxypentanamide;
[0329]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]-1-benzimidazole-5-carboxamide;
[0330]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]benzamide;
[0331]
4-Bromo-N-[(4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hyd-
roxyamino)-5-oxopentyl]benzamide;
[0332]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(butyrylamino)--
N-hydroxypentanamide;
[0333]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]-3-chlorothiophene-2-carboxamide;
[0334]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]-4-chlorobenzanide;
[0335]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]cyclohexanecarboxamide;
[0336]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{([2-(3,4-dichl-
orophenyl)acetyl]amino)-N-hydroxypentanamide;
[0337]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]-2,5-dimethyl-3-furamide;
[0338]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]-3,5-dimethylisoxazole-4-carboxamide;
[0339]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(3-p-
henylpropanoyl)amino]pentanamide;
[0340]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]isonicotinamide;
[0341]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]nicotinamide;
[0342]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]-2-methoxybenzamide;
[0343]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]-4-methoxybenzamide;
[0344]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[2-(-
4-nitrophenyl)acetyl]amino}pentanamide;
[0345]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(2-p-
henylacetyl)amino]pentanamide;
[0346]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]quinoline-3-carboxamide;
[0347]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]thiophene-3-carboxamide;
[0348]
(E)-N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl)}amino)-5-(hydrox-
yamino)-5-oxopentyl]-3-phenylprop-2-enamide;
[0349]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamyn-
o)-6-oxohexyl]-1H-benzimidazole-5-carboxamide;
[0350]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]benzamide;
[0351]
4-Bromo-N-[(5R)-5-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hyd-
roxyamino)-6-oxohexyl]benzamide;
[0352]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]-3-chlorothiophene-2-carboxamide;
[0353]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]-4-chlorobenzamide;
[0354]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]-cyclohexanecarboxamide;
[0355]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-{[2-(3,4-dichlo-
rophenyl)acetyl]amino}-N-hydroxyhexanamide;
[0356]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]-2,5-dimethyl-3-furamide;
[0357]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]-3,5-dimethylisoxazole-4-carboxamide;
[0358]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-6-[(3-p-
henylpropanoyl)amino]hexanamide;
[0359]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]isonicotinamide;
[0360] N-[(5R)-5-({[4
(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]-2-methoxybenzamide;
[0361]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]-4-methoxybenzamide;
[0362]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-6-{[2-(-
4-nitrophenyl)acetyl]amino}hexanamide;
[0363]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-6-[(2-p-
henylacetyl)amino]hexanamide;
[0364]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]quinoline-3-carboxamide;
[0365]
N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxyamin-
o)-6-oxohexyl]thiophene-3-carboxamide;
[0366]
(E)-N-[(5R)-5-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-6-(hydroxy-
amino)-6-oxohexyl]-3-phenylprop-2-enamide;
[0367]
(Z)-N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxa-
mino)-5-oxopentyl]octadec-9-enamide;
[0368]
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamin-
o)-5-oxopentyl]thiophene-2-carboxamide;
[0369] (2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-
{[(ethylamino)carbonyl]amino)-N-hydroxypentanamide;
[0370]
(2R)-5-[(Anilinocarbonyl)amino]-2-({[4-(but-2-ynyloxy)phenyl]sulfon-
yl}amino)-N-hydroxypentanamide;
[0371] Octyl
(4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxya-
mino)-5-oxopentylcarbamate;
[0372] 4-Methoxyphenyl
(4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-
-(hydroxyamino)-5-oxopentylcarbamate;
[0373]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[(diethylamino-
)-carbonyl]amino)-N-hydroxypentanamide;
[0374]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[(me-
thylanilino)carbonyl]amino)pentanamide;
[0375]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[(1--
methyl-1H-imidazol-4-yl)sulfonyl]amino}pentanamide;
[0376]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(2-m-
orpholin-4-ylacetyl)amino]pentanamide;
[0377]
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[2-(-
4-methylpiperazin-1-yl)acetyl]amino}pentanamide; and
[0378]
(2R)-5-{[2-(Benzylamino)acetyl]amino}-2-({[4-(but-2-ynyloxy)phenyl]-
sulfonyl}amir hydroxypentanamide;
[0379] or a pharmaceutical salt thereof.
[0380] Heteroaryl, as used throughout, is a 5-10 membered mono- or
bicyclic ring having from 1-3 heteroatoms selected from N, NR14, S
and O. Heteroaryl is preferably 13
[0381] wherein K is O, S or --NR14 and R14 is hydrogen, aryl,
heteroaryl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon
atoms. Preferred heteroaryl rings include pyrrole, furan,
thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole,
pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole,
indole, isoindole, benzofuran, benzothiophene, quinoline,
isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole,
benzimidazole, benzothiazole, benzisoxazole, and benzoxazole.
Heteroaryl groups may optionally be mono or di substituted.
[0382] C4-C8 cycloheteroalkyl as used herein refers to a 5 to 9
membered saturated or unsaturated mono or bi-cyclic ring having 1
or 2 heteroatoms selected from N, NR14, S or O. Heterocycloalkyl
rings of the present invention are preferably selected from; 14
[0383] wherein K is NR14, O or S and R14 is a bond, hydrogen, aryl,
heteroaryl, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-6 carbon
atoms.
[0384] Preferred heterocycloalkyl rings include piperidine,
piperazine, morpholine, tetrahydropyran, tetrahydrofuran or
pyrrolidine. Cycloheteroalkyl groups of the present invention may
optionally be mono- or di- substituted.
[0385] Aryl, as used herein refers to a phenyl or napthyl rings
which may, optionally be mono-, di- or tri-substituted.
[0386] Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both
straight chain as well as branched moieties. Alkyl, alkenyl,
alkynyl, and cycloalkyl groups may be unsubstituted unsubstituted
(carbons bonded to hydrogen, or other carbons in the chain or ring)
or may be mono- or poly-substituted. Lower alkyl moieties contain
from 1 to 6 carbon atoms.
[0387] Aralkyl as used herein refers to a substituted alkyl group,
-alkyl-aryl, wherein alkyl is lower alkyl and preferably from 1 to
3 carbon atoms, and aryl is as previously defined.
[0388] Heteroaralkyl as used herein refers to a substituted alkyl
group, alkyl-heteroaryl wherein alkyl is lower alkyl and preferably
from 1 to 3 carbon atoms, and heteroaryl is as previously
defined.
[0389] Halogen means bromine, chlorine, fluorine, and iodine.
[0390] Suitable substituents of aryl, aralkyl, heteroaryl,
heteroaralkyl, alkyl, alkenyl, alkynyl, and cycloalkyl include, but
are not limited to hydrogen, halogen, alkyl of 1-6 carbon atoms;
alkenyl of 2-6 carbon atoms; alkynyl of 2-6 carbon atoms,
cycloalkyl of 3-6 carbon atoms, --OR.sub.8, --[[O(CH2)p]q]--OCH3,
CN, --COR.sub.8, perfluoroalkyl of 1-4 carbon atoms,
--O-perfluoroalkyl of 1-4 carbon atoms, --CONR.sub.8R.sub.9,
--S(O).sub.nR.sub.8, --S(O).sub.nR.sub.18C(O)OR.sub.-
8--S(O).sub.nR.sub.18OR.sub.9, --S(O).sub.nR.sub.18NR.sub.8R.sub.9,
--S(O).sub.nR.sub.18NR.sub.8R.sub.9COOR.sub.8,
--S(O)NR.sub.18NR.sub.8COR- .sub.9, --OPO(OR.sub.8)OR.sub.9,
--PO(OR.sub.8)R.sub.9, --OC(O)NR.sub.8R.sub.9,
--C(O)NR.sub.8OR.sub.9, --C(O)R.sub.18NR.sub.8R.s- ub.9,
--COOR.sub.8, --SO.sub.3H, --NR.sub.8R.sub.9,
--N[(CH.sub.2).sub.2].sub.2NR.sub.8, --NR.sub.8COR.sub.9,
--NR.sub.8C(O)CH.dbd.CHaryl,
--NR.sub.8C(O)(CH.sub.2).sub.nNR.sub.8R.sub.- 9,
--NR.sub.8C(O)CH.sub.2NHCH.sub.2aryl, NR.sub.8C(O)R.sub.18,
--NR.sub.8COOR.sub.9, --SO.sub.2NR.sub.8R.sub.9, --NO.sub.2,
--N(R.sub.8)SO.sub.2R.sub.9, --NR.sub.8CONR.sub.8R.sub.9,
--NR.sub.8C(.dbd.NR.sub.9)NR.sub.8R.sub.9,
--NR.sub.8C(.dbd.NR.sub.9)N(SO- 2R.sub.8)R.sub.9,
NR.sub.8C(.dbd.NR.sub.9)N(C.dbd.OR.sub.8)R.sub.9-tetrazo- l-5-yl,
--SO.sub.2NHCN, --SO.sub.2NHCONR.sub.8R.sub.9,
--(OR18)NR.sub.8S(O)R.sub.9, --(OR18)NR.sub.8C(O)R.sub.9,
--(OR18)NR.sub.8C(O)NR.sub.8R.sub.9, --(OR18)NR.sub.8COOR.sub.9,
--(OR18)NR.sub.8R.sub.9, phenyl, heteroaryl, or
--C.sub.4-C.sub.8-cyclohe- teroalkyl;
[0391] wherein --NR.sub.8R.sub.9 may form a heterocyclic group as
previously defined, such as pyrrolidine, piperidine, morpholine,
thiomorpholine, oxazolidine, thiazolidine, pyrazolidine,
piperazine, and azetidine ring; p is 1 or 2, q is 1 through 3
and
[0392] R.sub.18 is alkyl of 1-20 carbon atoms.
[0393] In some preferred embodiments of the present invention R8
and R18 may be further substituted with halogen, C1-C3 alkyl, C1-C3
alkoxy and OH, and NO.sub.2.
[0394] When a moiety contains more than substituent with the same
designation (i.e., phenyl tri-substituted with R.sub.1) each of
those substituents (R.sub.1 in this case) may be the same or
different.
[0395] Pharmaceutically acceptable salts can be formed from organic
and inorganic acids, for example, acetic, propionic, lactic,
citric, tartaric, succinic, fumaric, maleic, malonic, mandelic,
malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric,
sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic,
toluenesulfonic, camphorsulfonic, and similarly known acceptable
acids when a compound of this invention contains a basic moiety.
Salts may also be formed from organic and inorganic bases,
preferably alkali metal salts, for example, sodium, lithium, or
potassium, when a compound of this invention contains an acidic
moiety.
[0396] The compounds of this invention may contain an asymmetric
carbon atom and some of the compounds of this invention may contain
one or more asymmetric centers and may thus give rise to optical
isomers and diastereomers. While shown without respect to
stereochemistry, the present invention includes such optical
isomers and diastereomers; as well as the racemic and resolved,
enantiomerically pure R and S stereoisomers; as well as other
mixtures of the R and S stereoisomers and pharmaceutically
acceptable, salts thereof. It is recognized that one optical
isomer, including diastereomer and enantiomer, or stereoisomer may
have favorable properties over the other. Thus when disclosing and
claiming the invention, when one racemic mixture is disclosed, it
is clearly contemplated that both optical isomers, including
diastereomers and enantiomers, or stereoisomers substantially free
of the other are disclosed and claimed as well.
[0397] The compounds of this invention are shown to inhibit the
enzymes MMP-1, MMP-9, MMP-13 and TNF-.alpha. converting enzyme
(TACE) and are therefore useful in the treatment of arthritis,
tumor metatasis, tissue ulceration, abnormal wound healing,
periodontal disease, graft rejection, insulin resistance, bone
disease and HIV infection. In particular, the compounds of the
invention provide enhanced levels of inhibition of the activity of
TACE in vitro and in cellular assay and/or enhanced selectivity
over MMP-1 and are thus particularly useful in the treatment of
diseases mediated by TNF.
[0398] The invention is further directed to a process for making
compounds of structure B involving one or more reactions as
follows:
[0399] 1) alkylating a compound of formula I, or a salt or solvate
thereof, 15
[0400] into a compound of formula II 16
[0401] 2) reacting a compound of formula II above, or a salt or
solvate thereof, with a chlorinating agent such as thionyl
chloride, chlorosulfonic acid, oxalyl chloride, phosphorus
pentachloride, or other halogenating agents such as fluorosulfonic
acid or thionyl bromide to a compound of formula III: 17
[0402] wherein J is fluorine, bromine, chlorine.
[0403] The resultant sulfonyl chloride, fluoride or bromide, may be
further converted into triazolide, imidazolide or benzothiazolide
derivatives, where J is 1,2,4-triazolyl, benzotriazolyl or
imidazol-yl, by reacting the compound with 1,2,4-triazole,
imidazole or benzotriazole, respectively. R.sub.4, R.sub.5 and
R.sub.6 are as defined above.
[0404] The invention is still further directed to a process for
making compounds of structure B involving one or more reactions as
follows:
[0405] 1) alkylating phenol, or a salt or solvate thereof, into a
compound of formula IV: 18
[0406] 2) reacting a compound of formula IV above, or a salt or
solvate thereof with chlorosulfonic acid to prepare acompound of
formula II above.
[0407] Particularly preferred intermediates are compounds of
formulae II and III, with the proviso that R6 is not hydrogen.
[0408] Compounds of the present invention are prepared using
conventional techniques known to those skilled in the art of
organic synthesis. The starting materials used in preparing the
compounds of the invention are known, made by known methods or are
commercially available.
[0409] Compounds of the following general structures (FIG. 1;
V-XX), and the methods used to prepare them, are known and
references are given herein below.
[0410] Compounds V-XII:
[0411] a) U.S. Pat. No. 5,753,653.
[0412] b) Kogami, Yuji; Okawa, Kenji. Bull. Chem. Soc. Jpn. 1987,
60(8), 2963.
[0413] Compound XII:
[0414] Auvin, S.; Cochet, O.; Kucharczyk, N.; Le Goffic, F.; Badet,
B. Bioorganic Chemistry, 1991, 19, 143.
[0415] Compounds XIII-XIV:
[0416] a) Angle, S. R.; Breitenbucher, J. G.; Arnaiz, D. O. J. Org.
Chem. 1992, 57, 5947.
[0417] b) Asher, Vikrain; Becu, Christian; Anteunis, Marc J. O.;
Callens, Roland Tetrahedron Lett. 1981, 22(2), 141.
[0418] Compounds XV;
[0419] Levin, J. I.; DiJoseph, J. F.; Killar, L. M.; Sung, A.;
Walter, T.; Sharr, M. A.; Roth, C. E.; Skotnicki, J. S.; Albright,
J. D. Bioorg. & Med. Chem. Lett. 1998, 8, 2657.
[0420] Compounds XVI:
[0421] U.S. Pat. No. 5,770,624
[0422] Compounds XVII:
[0423] Pikul, S.; McDow Dunham, K. L.; Almstead, N. G.; De, B.;
Natchus, M. G.; Anastasio, M. V.; McPhail, S. J.; Snider, C. E.;
Taiwo, Y. O.; Rydel, T.; Dunaway, C. M.; Gu, F.; Mieling, G. E. J.
Med. Chem. 1998, 41, 3568.
[0424] Compounds XVIII:
[0425] U.S. Pat. Nos. 5,455,258, 5,506,242, 5,552,419 and
5,770,624
[0426] MacPherson, et. al. in J. Med Chem, 1997, 40, 2525.
[0427] Compounds XIX:
[0428] U.S. Pat. Nos. 5,455,258 and 5,552,419
[0429] Compounds XX:
[0430] U.S. Pat. No. 5,804,593
[0431] Tamura, et. al. in J. Med. Chem. 1998, 41, 640.
[0432] Those skilled in the art will recognize that certain
reactions are best carried out when other potentially reactive
functionality on the molecule is masked or protected, thus avoiding
undesirable side reactions and/or increasing the yield of the
reaction. To this end, those skilled in the art may use protecting
groups. Examples of these protecting group moieties may be found in
T. W. Greene, P. G. M. Wuts "Protective Groups in Organic
Synthesis", 2.sup.nd Edition, 1991, Wiley & Sons, New York.
Reactive side chain functionalities on amino acid starting
materials are preferably protected. The need and choice of
protecting groups for a particular reaction is known to those
skilled in the art and depends on the nature of the functional
group to be protected (hydroxy, amino, carboxy, etc.), the
structure and stability of the molecule of which the substituent is
part and the reaction conditions.
[0433] When preparing or elaborating compounds of the invention
containing heterocyclic rings, those skilled in the art recognize
that substituents on that ring may be prepared before, after or
concomitant with construction of the ring. For clarity,
substituents on such rings have been omitted from the schemes
herein below.
[0434] Those skilled in the art will recognize that the nature and
order of the synthetic steps presented may be varied for the
purpose of optimizing the formation of the compounds of the
invention.
[0435] The hydroxamic acid compounds of the invention, 1, are
prepared according to Scheme 1 by converting a carboxylic acid, 2,
into the corresponding acid chloride or anhydride, or by reacting
it with a suitable peptide coupling reagent, followed by reaction
with hydroxylamine to give 1, or with a protected hydroxylamine
derivative to give 3. Compounds 3, wherein R.sub.30 is a t-butyl,
benzyl, trialkylsilyl or other suitable masking group may then be
deprotected by known methods to provide the hydroxamic acid 1.
19
[0436] Carboxylic acids 2 may be prepared as shown in Scheme 2.
Amino acid derivative 4, in which R.sub.40 is hydrogen or a
suitable carboxylic acid protecting group, may be sulfonylated or
phosphorylated by reacting with compounds 6, in which J is a
suitable leaving group including, but not limited to chlorine. The
N--H compound 7 may then be alkylated with R.sub.3J and a base such
as potassium carbonate or sodium hydride in a polar aprotic solvent
such as acetone, N,N-dimethylformamide (DMF), or tetrahydrofuran
(THF) to provide sulfonamide 8. Compound 8 is also available
through direct reaction of 6 with an N-substituted amino acid
derivative, 5. Conversion of 8 into the carboxylic acid is
performed by acid, base hydrolysis, or other method consistent with
the choice of protecting group R.sub.40 and the presence of a
carbon-carbon triple bond. 20
[0437] Compounds of formula 2 are also available without starting
from an amino acid derivative 4. As shown in Scheme 2A, a compound
of formula I is reacted with a compound of formula II (J is bromo
or chloro, n is equal to 0 to 3, and R" is phenyl substituted
phenyl or arylthio) in the presence of an acid scavenger such as
ethyldiisopropylamine, potassium carbonate, sodium carbonate,
sodium diisopropylamide in a solvent such as isopropyl alcohol,
acetonitrile, N,N-dimethylformamide in the temperature range
0.degree. to 100.degree. C. to give a compound of formula III,
equivalent to compound 8. 21
[0438] Compounds 1 of the invention containing a heteroaryl
sulfonamide may be prepared as shown in Scheme 2B. The
6-chloropyridine 3-sulfonyl chloride is available from the
corresponding amino-pyridine. Sulfonylation of the appropriate
amino acid with this pyridyl sulfonyl chloride then provides the
6-chloropyridine sulfonamide. Base mediated displacement of the
chloro substituent of the 6-chloropyridine sulfonamide with the
desired propargylic alcohol, amine or thiol with concomitant ester
hydrolysis gives carboxylic acid 2. Conversion of the acid into the
corresponding hydroxamic acid as described in Scheme 1 then gives
the pyridyl sulfonamide 1. 22
[0439] Methods of preparation of sulfonylating agents 6 are shown
in Scheme 3. Thus, sulfonic acid salts 9, where ZR.sub.50 is a
hydroxy, thiol or substituted amino moiety may be alkylated with
acetylenes 10, where J is a suitable leaving group such as halogen
mesylate, tosylate, or triflate to give 11. Acetylenes 10 are
commercially available or known compounds, or they may be
synthesized by known methods by those skilled in the art. The
sulfonic acid salts 11 may be converted into the corresponding
sulfonyl chloride or other sulfonylating agent 6 by known methods,
such as reaction with oxalyl chloride or other reagent compatible
with substituents R.sub.4, R.sub.5 and R.sub.6 and the acetylene.
Alternatively, the disulfide 12 may be converted into di-acetylene
13 by reaction with compounds 10, followed by reduction of the
disulfide bond to provide the analogous thiols which may be
converted into 6 by known methods. Alkylation of the phenol,
thiophenol, aniline or protected aniline 14 with 10 to give 15,
followed by reaction with chlorosulfonic acid provide sulfonic
acids 16 which are readily converted into 6 with oxalyl chloride or
similar reagents. Thiophenols 17 are also precursors to 6 via
protection of the thiol, alkylation of ZH, where Z is O, N or S,
and deprotection of the sulfur followed by oxidation to the
sulfonic acid 16. 23
[0440] The phosphorus containing analogs of 8 may be prepared using
similar methodology, as shown in Scheme 4. 24
[0441] The acetylenic side chain may also be appended after
sulfonylation or phosphorylation of the amino acid derivative, as
shown in Scheme 5. Thus, the amino acid derivatives 4 and 5 can be
sulfonylated or phosphorylated with compounds 20, where ZR.sub.50
is hydroxy or protected hydroxy, thiol or amine, and, if necessary
alkylated as in Scheme 2, to give 21. Removal of the R.sub.50
masking group to give 22 and subsequent alkylation of the resulting
phenol, thiol or amine with 10 provide 8. In the case where
ZR.sub.50 is equal to OH, no deprotection step is required to give
22. 25
[0442] The propargylic amine analogs of 8 can be synthesized as
shown in Scheme 6 starting from the amino acid derivatives 4 and/or
5. Sulfonylation or phosphorylation with para-nitro aryl compound
23, for example 4-nitrobenzenesulfonyl chloride, followed by
alkylation with R.sub.3J (for 5) using a base such as potassium
carbonate or sodium hydride in DMF provides 24. Reduction of the
nitro moiety with hydrogen and palladium on carbon, tin chloride or
other known method to give aniline 25 and subsequent alkylation
with 10 then provides 8. Aniline 25 may be derivatized (26) prior
to alkylation with 10 and then deprotected after the alkylation
step. 26
[0443] Acetylenic derivatives 8 are also accessible via the fluoro
compounds 28, readily prepared from the amino acid derivatives 4
and/or 5 by reaction with fluoroaryl 27, as shown in Scheme 7.
Displacement of the fluorine of 28 in the presence of a base such
as sodium hydride with a masked hydroxy, thiol, or amino group
(HZR.sub.70, where R.sub.70 is a suitable protecting group) in a
polar aprotic solvent such as DMF, followed by deprotection gives
29, which can then be alkylated with 10 to provide 8. Conversion of
28 to 29, where Z is sulfur, might also be accomplished with
Na.sub.2S, K.sub.2S, NaSH or KS(C.dbd.S)OEt. Disulfide obtained as
a result of this displacement followed by oxidation can be reduced
to the desired thiol using triphenylphosphine or a similar reducing
agent. The fluorine of 28 can also be displaced in a polar aprotic
solvent with the propargylic derivative 30, where Z is O, S or NH,
in the presence of a base such as sodium hydride, to give 8
directly. 27
[0444] Compound 8, wherein Z is a methylene group, is available via
31, as shown in Scheme 8. Benzylic bromination of 31 with
N-bromosuccinimide in a chlorinated hydrocarbon solvent provides
bromide 32. This is followed by displacement of the bromide with
the appropriate propynyl cuprate to provide sulfonamide 8. 28
[0445] Methods for the solid phase synthesis of the compounds of
the invention are shown in Scheme 9 and Scheme 10. In Scheme 9 an
Fmoc protected amino acid, or any suitably N-protected amino acid,
is bound to a resin using peptide coupling reagent such as
1,3-diisopropylcarbodiimid- e (DIC) and 1-hydroxybenzotriazole
(HOBT) in a polar, aprotic solvent such as DMF at room temperature.
An amine such as piperidine in an inert solvent such as DMF at room
temperature then removes the Fmoc masking moiety and the resulting
free amine, 33, can be sulfonylated with compound 6 in the presence
of a tertiary amine base or pyridine. The carboxylic acid 2
(R.sub.3=H) is then released from the resin with TFA or other
strong acid. The resulting carboxylic acids can be converted into
the corresponding hydroxamic acids 1 (R.sub.3=H) as in Scheme 1.
29
[0446] In Scheme 10 a hydroxylamine linked resin is constructed
following known methods (Rickter, L. S.; Desai, M. C. Tetrahedron
Lett. 1997, 38, 321) and a suitably protected amino acid is bound
to the resin and deprotected as in Scheme 9 to give 34.
Sulfonylation of the free amine may be followed by alkylation of
the NH-sulfonamide with R.sub.3J and a base, wherein J is a leaving
group such as halide sulfonate or triflate, or via a Mitsonobu
protocol. Cleavage of the hydroxamate from the resin is then
accomplished using a strong acid such as trifluoroacetic acid to
provide 1. Alternatively, the NH-sulfonamide is cleaved from the
resin without alkylating to give the NH-sulfonamide hydroxamic
acids (1, R.sub.3=H). 30
[0447] In Scheme 11 commercially available piperazine-2-carboxylic
acid (35) or its ester (Demaine, D. A; Smith, S.; Barraclough, P.
Synthesis 1992, 1065; Rissi, E.; Jucker, E. Helv. Chim. Acta 1962,
45, 2383.) may be functionalized predominantly at the N-4 position,
as described in U.S. Pat. No. 5,753,653 and in Synthesis 1992, 1065
and references cited therein, to give 36 or 37. Sulfonylation or
phosphorylation at N-1 followed by the requisite functional group
manipulations as described in Schemes 2-8, provides compounds of
structure 2, wherein R.sub.1 and R.sub.3 together with the atoms to
which they are attached form a piperazine ring. The t-butyl
carbamate of compound 36 can be removed after sulfonylation or
phosphorylation of N-1, followed by derivatization of N-4 with a
variety of functional groups. Conversion to the hydroxamic acids is
as shown in Scheme 1. 31
[0448] The preparation of intermediates for the synthesis of the
diazepine or diazocine analogs of 1 is described in Scheme 12. An
ester derivative 38 such as ethyl 1,4-dibromobutyrate, bearing two
leaving groups, J, can react with a protected diamine; 39, such as
N,N'-dibenzylethylenediamine in the presence of a tertiary amine
base in a non-polar solvent such as benzene, to provide the 7 or
8-membered ring 40. Deprotection of 40 using hydrogen and a
palladium catalyst gives the cyclic diamine 41. Functionalization
of 41 predominantly at N-5 provides 42. Compound 42 may then be
sulfonylated followed by removal of R.sub.17, if desired, and
subsequent alkylation, acylation or sulfonylation of N-5.
Conversion into compound 1 is then accomplished according to
Schemes 1-8. Alternatively, N-5 alkyl compounds can be prepared by
carrying through the N-5 t-butyl carbamate through to the
hydroxamic acid stage, followed by removal of the carbamate and N-5
alkylation with an alkyl halide and tertiary amine base in the
presence of the hydroxamic acid. 32
[0449] Piperidine, morpholine and piperazine derivatives of
compound 1 are available according to Scheme 13. Amino-ketone 43,
wherein Q is O, S or NR.sub.17 undergoes removal of protecting
group R.sub.10, wherein R.sub.10 is a benzyl, t-butoxycarbonyl,
benzyloxycarbonyl or other suitable masking group, followed by
intramolecular reductive amination to give the cyclic imine 44.
Imine 44 reacts in ethereal solvents with a nucleophile, R.sub.15M,
in which M is lithium, magnesium halide or cerium halide to provide
the saturated 6-membered ring 45. A variety of protecting groups
may be required for functionality in R.sub.15 prior to metallation.
Compounds 45 may then be converted into compounds of structure 1
according to Schemes 1-8. 33
[0450] Thiomorpholines, thiazepines and thiazocines of the
invention may be constructed according to Scheme 14. An ester 46
such as 1,3-dibromopropionate, containing two leaving groups, J,
can react with an amino-thiol to provide thiazepine 47 which can
then be converted into compounds of structure 1 according to
Schemes 1-8. Alternatively, cysteine or homocysteine derivative 48,
in the amino acid or amino-ester form, can be alkylated with alkyl
halides such as 2-bromoethanol or 3-bromo-1-propanol to give
alcohol 49 (R.dbd.OH) after sulfonylation or phosphorylation of the
free amine group. The moiety R.sub.90 of compound 49 is consistent
with the methods disclosed in Schemes 2-8 for subsequent conversion
into compounds 1 of the invention and includes nitro, fluoro,
methoxy, hydroxy and --ZCR.sub.4R.sub.5CCR.sub.6 where Z is O,
NR.sub.17, or S. Alcohol-sulfonamide 49 can be ring-closed using
standard Mitsonobu conditions to afford thiomorpholine or
thiazepine 50 which can be converted into compounds of structure 1
according to Schemes 1-8. The acyclic intermediate 49 can also be
carried forward to the desired hydroxamic acids 49A and 49B via
ester hydrolysis and hydroxamate formation, with or without prior
alkylation of the sulfonamide nitrogen. The R moiety of compound 49
can be manipulated prior to conversion into 49B. For example, when
R is a hydroxyl group, conversion of the --OH group into a leaving
group followed by displacement with amines and subsequent ester
hydrolysis and, hydroxamate formation gives compounds 49B where R
is a secondary amine. 34
[0451] Diazepines or diazocines may be constructed according to
Scheme 15, as described in Bioorg. & Med. Chem. Lett. 1998, 8,
2657, and modified according to Schemes 1-8 to provide diazepines
of structure 1. 35
[0452] Morpholines, oxazepines and oxazocines of the invention are
prepared as shown in Scheme 16. A serine derivative, 51a (x=1), is
sulfonylated or phosphorylated to give 51b and then converted into
the aziridine 51c. Nucleophilic ring opening of the aziridine with
a bifunctional alcohol species, such as 2-bromoethanol,
1,3-propanediol or 3-chloro-1-propanol, then provides 52 (n=0,1)
which is ring-closed via intramolecular alkylation or Mitsonobu
reaction to form 53. Compound 53 can be converted into compounds of
structure 1 according to Schemes 1-8. The homoserine derivative 51a
(x=2) can also be sulfonylated to give 51b, followed by
O-alkylation to give 52, with protection of the sulfonamide-NH as
required, and subsequent ring closure as before to give 53.
Alternatively, the homoserine derivative 51b can be N-alkylated to
provide 51d, followed by intramolecular etherification to give 53.
36
[0453] Methodology for preparing additional heterocyclic compounds
of the invention are shown in Schemes 17 and 18. Aspartic acid
derivatives may be accessed by direct sulfonylation or
phosphorylation of aspartic acid to give 54, followed by functional
group manipulation as shown in Scheme 17. Alternatively, 58.
Sulfonylation or phosphorylation of 58 then provides 54. Peptide
coupling of a primary amine and compound 54 gives carboxamide 59
which can be cyclized using 1,3,5-trioxane to give heterocycle 60.
Seven and eight-membered ring analogs of 60 can be prepared by
coupling the appropriate secondary amine, in which one of the amine
substituents bears a n alcohol or leaving group, to carboxylic acid
54. Intramolecular alkylation or Mitsonobu reaction then provides
the cyclic structure. Compound 60 can be converted into compounds
of structure 1 according to Schemes 1-8. 37
[0454] In Scheme 18 the construction of compounds of the invention
containing heterocyclic rings with a 1,3-orientation of the
sulfonamide or phosphinic acid amide nitrogen and a heteroatom is
described. Compound 61, such as a diamine, an amino-alcohol or an
amino-thiol , is sulfonylated or phosphorylated to give 62.
Addition of a pyruvate or glyoxylate group under standard
conditions then forms the heterocycle 63. Compound 63 can be
converted into compounds of structure 1 according to Schemes 1-8.
38
[0455] Compounds 1 of the invention derived from the amino acid
D-4-hydroxyphenylglycine can be made as shown in Scheme 19.
Esterification of the amino acid followed by protection of the
amine as the t-butyl or fluorenylmethyl carbamate gives compound
64. Alkylation of the phenol via Mitsunobu reaction with the
desired alcohol gives 65. Cleavage of the t-butyl or
fluorenylmethyl carbamate using HCl or a secondary amine,
respectively, then provides amino-ester 66. Compound 66 can then be
sulfonylated to give NH-sulfonamide 67. At this point the
NH-sulfonamide can be alkylated, or the amino acid side chain can
be manipulated. Hydrolysis of the ester and subsequent conversion
into the hydroxamic acid then provides compounds 1. 39
[0456] The N-alkyl sulfonamides derived from the amino acid
D-4-hydroxyphenylglycine can be made as shown in Scheme 20 via
sulfonylation of the ester of D-4-hydroxyphenyl glycine to give 68.
R.sub.8 is as previously defined, or is a protecting group known to
those skilled in the art. Protection of the phenol with a
trialkylsilyl, or other suitable protecting group, followed by
N-alkylation with an alkyl halide in the presence of sodium hydride
or potassium carbonate provides 69. Removal of the silyl protecting
group and functionalization of the unmasked phenol via Mitsunobu or
base-catalyzed alkylation then provides 70. Conversion of the ester
into the desired hydroxamic acid then gives compounds 1 of the
invention. 40
[0457] Compounds of the invention in which R.sub.1 and R.sub.3
together form a thiomorpholine ring can be made according to Scheme
2, in which the thiomorpholine ring is constructed prior to
sulfonylation of the amine, or according to Scheme 14. The
thiomorphohine ring may be manipulated after sulfonylation as shown
in Scheme 21 (Shown for the thiomorpholine derived form
D-penicillamine). Thus, sulfonylation of the thiomorpholine 71,
gives 72. Oxidation of the thioether with m-chloroperbenzoic acid
or other suitable oxidizing agent gives a mixture of diastereomeric
sulfoxides 73. Pummerer rearrangement of the sulfoxides in acetic
anhydride with subsequent elimination of the resulting acetate
gives 74. Ester hydrolysis of 74 followed by hydroxamate formation
then gives 75. Alternatively, 72 can be converted into the
corresponding hydroxamic acid 76 which can be oxidized to the
sulfoxide or sulfone with m-chloroperbenzoic acid or peracetic
acid, respectively. 41
[0458] Spiro-fused thiomorpholines are available as shown in Scheme
22. Reaction of a cyclic ketone 78 (X=S, SO, SO2, NR) with
isocyanate 55 (Scheme 17) in the presence of a base such as sodium
hydride gives formamide 79 after acid work-up. Use of an acyclic
ketone in this reaction provides a route to other geminally
disustituted 2-substituted thioimorpholines. Michael addition of
2-mercaptoethanol to 79 provides alcohol 80. Hydrolysis of the
formamide then gives amino-ester 81. Sulfonylation of 81 gives
hydroxy-sulfonamide 82 which can be cyclized to the thiomorpholine
under Mitsunobu conditions to provide 83. Ester hydrolysis and
hydroxamate formation then gives 84. 42
[0459] The preparation of 6-substituted thiomorpholines of the
invention is shown, starting from D-penicillamine derivatives, in
Schemes 23-26. Thus, in Scheme 23 D-penicillamine disulfide or
other S-protected penicillamine is esterified and sulfonylated to
give 85. Alkylation of the sulfonamide with an allylic bromide
gives 86. Deprotection of the thiol using tributylphosphine in the
case of the disulfide gives the thiol-olefin 87 which can be
cyclized in the presence of benzoyl proxide or other radical
initiator to give a mixture of 6-methyl thiomorpholines 88. Base
hydrolysis followed by hydroxamate formation gives the cis-6-alkyl
thimorpholine 89. 43
[0460] In the case where R of compound 86 is a t-butyl ester
deprotection of the thiol occurs with concomitant cyclization via
an intramolecular Michael addition to give 88 as the major
diastereomer (.about.10:1) with the 6-substituent cis to the
3-substituent. As shown in Scheme 24, lithium iodide ester cleavage
of 88 provides a mixture of mono and diacids, 90 and 91. The
diacid, 91, can be directly converted into the dihydroxamic acid
92. Monoacid 90 can be converted into the O-benzyl protected
hydroxamic acid 93. Deprotection of the t-butyl ester with TFA or
HCl then gives the acid 94. Derivatization of the acid with amines
using standard peptide coupling reagents (EDC, HOBT, etc.) to form
amides 95, followed by deprotection of the benzyl protecting group
with boron tris(trifluoroactetate) and TFA provides compounds 96.
Alternatively, the t-butyl ester of compound 88 can be selectively
cleaved with TFA or HCl to give a monoacid. This acid can be
converted into a variety of amides followed by cleavage of the C-3
ester and its conversion to the corresponding hydroxamic acid,
compound 96. 44
[0461] In Scheme 25, compound 87 (R=H) is cyclized in the presence
of bromine to give 97 as a mixture of diastereomers. The bromine of
97 may be displaced with a variety of nucleophiles to give 98,
followed by ester hydrolysis and hydroxamate formation to give
derivatives of structure 99. For the specific example wherein 97 is
reacted with sodium azide in DMF to give a mixture of azides 98
(X=N.sub.3), the azides can be reduced and carbamoylated to give a
separable mixture of t-butyl carbamates, 100a and 100b. Ester
cleavage with lithium iodide in ethyl acetate followed by
hydroxamate formation gives either diastereomer 101a or 101b
(R=BOC). Removal of the BOC protecting group at the hydroxamate
stage provides either amine 101a or 100b (R=H). Alternatively, the
BOC protecting group of 100 can be removed and the resulting amine
acylated, alkylated or sulfonylated prior to hydroxamate formation
In this manner, compounds 101 bearing a variety of functional
groups at R may be obtained. 45
[0462] In Scheme 26 an alternative preparation of BOC-carbamate
100a is shown. Thus, selective cleavage of the t-butyl ester of
compound 88 with TFA or HCl provides the acid 102. Curtius
rearrangement of this acid using diphenylphosphoryl azide
triethylamine and t-butanol gives BOC-carbamate 100a as a single
diastereomer. Cleavage of the C-3 ester of 100a with lithium iodide
(for R.sub.40=Me) followed by conversion of the resulting acid into
the O-benzyl protected hydroxamic acid, using O-benzylhydroxylamine
and BOP-Cl gives 103. Deprotection of the t-butyl carbamate of 103
provides primary amine 104 which can be derivatized via alkylation,
acylation or sulfonylation, followed by removal of the hydroxamate
protecting group to provide analogs of structure 105. 46
[0463] Compounds of the invention can also be prepared by modifying
substituents on the acetylenic side chain at any stage after
sulfonylation or phosphorylation of the starting amino acid
derivatives 4 or 5. Functional groups such as halogen, hydroxy,
amino, aldehyde, ester, ketone, etc. may be manipulated by standard
methods to form the moieties defined by R.sub.1, R.sub.2, R.sub.3
and R.sub.6 of compounds 1. It is recognized by those skilled in
the art of organic synthesis that the successful use of these
methods is dependent upon the compatibility of substituents on
other parts of the molecule. Protecting groups and/or changes in
the order of steps described herein may be required.
[0464] Scheme 27 describes some of the routes that may be used to
append substituents onto the acetylenic side chain. Thus,
selectively protected propargylic alcohols 108 are available from
the known terminal alkynes 106 via reaction with dihydropyran or
other suitable alcohol protecting group to give 107. Metallation of
107 with n-butyllithium and subsequent quenching of the anion with
paraformaldehyde then gives 108. The phenolic coupling partner for
alcohols 108 is made by silylating 4-hydroxybenzenesulfonyl
chloride in situ with bis(trimethylsilyl)acetami- de and then
adding the thiomorpholine and a tertiary amine base. The resulting
sulfonamide is desilylated in methanol to give 110. Alkylation of
110 with 108 using Mitsunobu conditions provides propargylic ethers
111. Removal of the THP protecting group of 111 with pyridinium
para-toluenesulfonate in methanol gives the corresponding alcohol
that is converted into a leaving group by sulfonylation or reaction
with carbon tetrabromide and triphenylphosphine. Displacement of
the leaving group with sodium azide followed by reduction and
acylation, hydrolysis of the C-3 ester and hydroxamate formation
gives 113. Alternatively, 111 can be hydrolyzed directly to the
carboxylic acid and converted into hydroxamic acid 114. Removal of
the THP protecting group at this stage then gives alcohol 115. The
alcohol 115, where n is equal to 1, can be made by alkylating 110
directly with 2-butyne-1,4-diol using Mitsunobu conditions to
provide 116. Compound 116 can then be converted into 113, where n
is equal to 1, in the same manner as for alcohol 112. Compound 116
can be converted into hydroxamic acid 115 via acetylation of 116,
followed by selective hydrolysis of the C-3 ester, hydroxamate
formation and cleavage of the acetate with an aqueous base such as
ammonium hydroxide. In a similar manner, ester derivatives of
alcohols 115 and amide, sulfonamide and urea derivatives of 113 can
be prepared. 47
[0465] Additional methods available for the derivatization of
compounds of structure 116A (equivalent to compound 8 wherein
R.sub.6 is hydrogen) are shown in Scheme 28. Metallation of the
terminal acetylene 116A followed by addition of an aldehyde or
alkyl halide, sulfonate or triflate provides derivatives 117 and
118. Reaction of 116A with formaldehyde and an amine provides the
Mannich addition product 119. Cyanogen bromide addition to 119
gives the propargylic bromide 120 which may be displaced with a
variety of nucleophiles to give, for example, ethers, thioethers
and amines, 121. Palladium catalyzed coupling reactions of 116A
provide the aryl or heteroaryl acetylenes 122. It is recognized by
those skilled in the art of organic synthesis that the successful
use of these methods is dependent upon the compatibility of
substituents on other parts of the molecule. Protecting groups
and/or changes in the order of steps described herein may be
required. The variables are described previously. R.sub.6, R.sub.7
and R.sub.8 are as defined previously and may also include suitable
protecting groups known to those skilled in the art. 48
[0466] The following specific examples illustrate the preparation
of representative compounds of this invention. The starting
materials, intermediates, and reagents are either commercially
available or can be readily prepared following standard literature
procedures by one skilled in the art of organic synthesis.
EXAMPLE 1
4-But-2-ynyloxy-benzenesulfonic Acid Sodium Salt
[0467] To a solution of 52.35 g (0.225 mol) of
4-hydroxybenzenesulfonate sodium salt in 1 L of isopropanol and 225
mL of a 1.0N solution of sodium hydroxide was added 59.96 g (0.45
mol) of 1-bromo-2-butyne. The resulting mixture was heated to
70.degree. for 15 h and then the isopropanol was removed by
evaporation in vacuo. 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.
EXAMPLE 2
4-But-2-ynyloxy-benzenesulfonyl Chloride
[0468] To a 0.degree. solution of 43.8 mL (0.087 mol) of 2M oxalyl
chloride/dichloroethane solution in 29 mL of dichloromethane was
dropwise added 6.77 mL (0.087 mol) of DMF followed by 7.24 g (0.029
mol) of the product of Example 1. The reaction mixture was stirred
for 10 minutes at 0.degree. then let warm to room temperature and
stirred for 2 days. The reaction was then poured into ice and
extracted with 150 mL of hexanes. The organics were washed with
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to provide 6.23 g (88%) of the sulfonyl
chloride as a yellow solid; m.p. 63-65.degree. C. EI Mass Spec:
243.9 (M.sup.+).
EXAMPLE 3
But-2-ynyloxy-benzene
[0469] To a solution of 6.14 g (0.023 mol) of triphenylphosphine
dissolved in 100 mL of benzene and 40 mL of THF was added 1.75 mL
(0.023 mol) of 2-butyn-1-ol. After five minutes 2.00 (0.023 mol)
phenol, dissolved in 10 mL of THF, was added to the reaction
followed by 3.69 mL (0.023 mol) of diethyl azodicarboxylate. The
resulting reaction mixture was stirred for 18 h at room temperature
and then concentrated in vacuo. The residue was chromatographed on
silica gel eluting with ethyl acetate/hexanes (1:10) to provide
2.18 g (70%) of the butynyl ether as a clear liquid. EI Mass Spec:
146.0 MH+
EXAMPLE 4
4-But-2-ynyloxy-benzenesulfonyl Chloride
[0470] To a solution of 0.146 g (1.0 mmol) of the product of
Example 3 in 0.3 mL of dichloromethane in an acetone/ice bath under
N.sub.2 was dropwise added 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 h. To the reaction was then
dropwise added 0.113 mL (1.3 mmol) of oxalyl chloride, followed by
0.015 mL DMF. The reaction was heated to reflux for 2 h 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 mg (53%) of the desired product as a
light brown solid.
EXAMPLE 5
2-[(4-Methoxy-benzenesulfonyl)-methyl-amino]-3-methyl-butyric Acid
tert-butyl Ester
[0471] To a solution of 1.00 g (2.915 mmol) of
N-[(4-methoxyphenyl)sulfony- l]-D-valine tert-butyl ester (J. Med
Chem 1997, 40, 2525) in 10 mL of DMF was added 0.128 g (3.207 mmol)
of 60% sodium hydride. After 30 minutes at room temperature 0.45 mL
(7.289 mmol) of iodomethane was added and the reaction was stirred
for 15 h. The reaction mixture was then diluted with ether and
washed with water. The organic layer was dried over MgSO.sub.4,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel eluting with ethyl acetate/hexanes (1:10) to provide
0.993 g (95%) of the N-methyl sulfonamide as a colorless oil.
Electrospray Mass Spec: 357.9 (M+H)+
EXAMPLE 6
(2R)-2-[(4-Hydroxy-benzenesulfonyl)-methyl-amino]-3-methyl-butyric
Acid
[0472] To a 0.degree. solution of 0.707 g (1.980 mmol) of the
product of Example 5 in 50 mL of dichloromethane was added 9.4 mL
(9.395 mmol) of a 1.0M solution of boron tribromide in
dichloromethane. The resulting mixture was stirred at 0.degree. for
0.5 h and then warmed to room temperature and stirred for an
additional 4 h. The reaction mixture was then poured into a
saturated sodium bicarbonate solution and extracted with
dichloromethane. The aqueous layer was acidified with 5% HCl
solution and extracted with dichloromethane. The combined organics
were dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was chromatographed on silica gel eluting with
ethyl acetate/hexanes (1:1) to provide 0.271 g (48%) of the
phenol-carboxylic acid as a colorless oil. Electrospray Mass Spec:
287.9 (M+H)+
EXAMPLE 7
(2R)-2-[(4-Hydroxy-benzenesulfonyl)-methyl-amino]-3-methyl-butyric
Acid Methyl Ester
[0473] To a solution of 0.240 g (0.836 mmol) of the product of
Example 6 in 5.0 mL of DMF was added 0.211 g (2.509 mmol) of sodium
bicarbonate followed by 0.104 mL (1.672 mmol) of iodomethane. The
resulting mixture was stirred at room temperature for 4 h and then
diluted with water and extracted with ether. The combined organics
were washed with saturated sodium bicarbonate solution, dried over
MgSO.sub.4, filtered and concentrated in vacuo to provide 0.210 g
(83%) of the methyl ester as a colorless oil. Electrospray Mass
Spec: 300.3 (M-H)-
EXAMPLE 8
2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-3-methyl-butyric
Acid
[0474] To a solution of 0.187 g (0.714 mmol) of triphenylphosphine
in 3 mL of benzene was added 0.053 mL (0.714 mmol) of neat
2-butyn-1-ol followed by a solution of 0.172 g (0.571 mmol) of the
product of Example 7 dissolved in 1.0 mL of THF. To the resulting
reaction mixture was added 0.112 mL (0.714 mmol) of diethyl
azodicarboxylate and the reaction was stirred for 15 h at room
temperature and then concentrated in vacuo. The residue was
chromatographed on silica gel eluting with ethyl acetate/hexanes
(1:10) to provide 0.159 g (79%) of the butynyl ether-methyl
ester.
[0475] To a solution of 0.159 g (0.450 mmol of the butynyl
ether-methyl ester dissolved in 6.0 mL of methanol/THF (1:1) was
added 0.5 mL of a 5.0N solution of sodium hydroxide. The resulting
mixture was stirred at room temperature overnight and then
acidified with 10%. HCl solution and extracted with
dichloromethane. The combined organics were dried over MgSO.sub.4,
filtered and concentrated in vacuo to provide 0.138 g (90%) of the
carboxylic acid as a white solid. Electrospray Mass Spec: 338.0
(M-H)-
EXAMPLE 9
2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-buty-
ramide
[0476] To a 0.degree. solution of 0.48 mL (0.965 mmol) of a 2.0M
solution of oxalyl chloride in dichloromethane, diluted with 4.1 mL
of dichloromethane, is added 0.075 mL (0.965 mmol) of DMF and the
reaction is stirred for 15 minutes at 0.degree.. A solution of
0.109 g (0.322 mmol) of the carboxylic acid product of Example 8,
dissolved in 1 mL of DMF, was added to the reaction and the
resulting mixture is stirred for 1 at room temperature and then
poured into a 0.degree. mixture of 1.0 mL of water, 4 mL of THF and
1.0 mL of a 50% aqueous solution of hydroxylamine. The reaction is
allowed to warm to room temperature overnight and the organics are
then concentrated in vacuo. The residue is diluted with ethyl
acetate, washed with 5% HCl solution, water and saturated sodium
bicarbonate, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo to provide 0.102 g (89%) of the hydroxamic acid as a white
solid. Electrospray Mass Spec 354.9 (M+H)+
EXAMPLE 10
2-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-3-methyl-butyric Acid
Methyl Ester
[0477] To a solution of 6.00 g (0.051 mol) of D, L-valine in 380 mL
of THF/water (1:1) was added 10.9 mL (0.077 mol) of triethylamine
followed by 9.94 g (0.051 mol) of 4-fluorobenzenesulfonyl chloride
and the resulting mixture was stirred for 15 h at room temperature.
The THF was then removed in vacuo and the resulting solution was
extracted with ethyl acetate. The combined organics were washed
with 10% HCl solution and water, dried over MgSO.sub.4, filtered
and concentrated in vacuo to provide 4.8 g of the sulfonamide as a
white solid.
[0478] To a solution of 4.8 g (0.017 mol) of the sulfonamide in 30
mL of DMF was added 14.5 g (0.105 mol) of potassium carbonate
followed by 4.35 mL (0.070 mol) of iodomethane. The reaction was
stirred at room temperature for 5 h and then diluted with water and
extracted with ether. The combined organics were washed water,
dried over MgSO.sub.4, filtered and concentrated in vacuo. The
residue was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:10) to provide 2.8 g (53%) of the methyl ester
as a colorless oil. Electrospray Mass Spec 303.9 (M+H)+
EXAMPLE 11
2-[(4-Fluoro-benzenesulfonyl)-methyl-amino]-3-methyl-butyric
Acid
[0479] To a solution of 2.7 g (8.910 mmol) of the product of
Example 10 in 90 mL of THF/methanol (1:1) was added 45 mL of a 1.0N
sodium hydroxide solution and the reaction was stirred at room
temperature for 24 h. The reaction mixture was then acidified with
10% HCl solution and extracted with ethyl acetate. The combined
organics were dried over MgSO.sub.4, filtered and concentrated in
vacuo to provide 2.5 g (97%) of the carboxylic acid as a white waxy
solid. Electrospray Mass Spec 287.9 (M-H)-
EXAMPLE 12
2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-3-methyl-butyric
Acid
[0480] To a solution of 3.17 mL (0.042 mol) of 2-butyn-1-ol in 60
ml of DMF at room temperature was added 1.70 g (0.040 mol) 60%
sodium hydride. The resulting mixture was stirred for 0.5 h and
then a solution of 2.45 g (8.478 mmol) the product of Example if
dissolved in 20 mL of DMF was added to the reaction. The reaction
mixture was then heated to reflux for 24 h, cooled to room
temperature and then acidified to pH 2 with 10% HCl solution. After
stirring for 1 h the resulting mixture was diluted with water and
extracted with ethyl acetate. The combined organics were then dried
over MgSO.sub.4, filtered and concentrated in vacuo. The residue
was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:2) to provide 1.67 g (58%) of the desired
carboxylic acid product as a white solid identical to the product
of Example 8.
EXAMPLE 13
(4-Fluoro-benzenesulfonylamino)-acetic Acid Ethyl Ester
[0481] To a solution of 4.00 g (0.029 mol) of glycine ethyl ester
hydrochloride in 40 mL of chloroform and 7.0 mL of pyridine was
added 5.58 g (0.029 mol) of 4-fluorobenzenesulfonyl chloride and
the reaction was stirred at room temperature for 15 h. The reaction
mixture was then washed with water and 5% HCl solution and the
organics were dried over MgSO.sub.4, filtered and concentrated in
vacuo. The resulting white solid was washed with ether/hexanes
(1:1) and dried in vacuo to provide 4.72 g (63%) of the sulfonamide
as a white solid. Electrospray Mass Spec 261.8 (M+H)+
EXAMPLE 14
[(4-Fluoro-benzenesulfonyl)-methyl-amino]-acetic Acid Ethyl
Ester
[0482] To a solution of 3.00 g (0.011 mol) of the product of
Example 13 in 30 mL of DMF was added 4.76 g. (0.034 mol) of
potassium carbonate followed by 1.43 mL (0.023 mol) of iodomethane.
The reaction was stirred at room temperature for 5 h and then
diluted with water and extracted with ether. The combined organics
were washed water, dried over MgSO.sub.4, filtered and concentrated
in vacuo. The residue was chromatographed on silica gel eluting
with ethyl acetate/hexanes (1:3) to provide 3.0 g (95%) of the
N-methyl sulfonamide as a colorless oil. Electrospray Mass Spec
275.9 (M+H)+
EXAMPLE 15
[(4-Fluoro-benzenesulfonyl)-methyl-amino]-acetic Acid
[0483] According to the procedure of Example 11, 3.0 g (0.011 mol)
of the product of Example 14 provided 2.32 g (86%) of the
carboxylic acid as a white solid. Electrospray Mass. Spec 245.9
(M-H)-
EXAMPLE 16
[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic Acid
[0484] According to the procedure of Example 12, 0.350 g (1.417
mmol) of the product of Example 15 provided 0.164 g (39%) of the
butynyl ether-carboxylic acid as a white solid. Electrospray Mass
Spec 297.9 (M+H)+
EXAMPLE 17
2-[(4-But2-ynyloxy-benzenesulfonyl)methyl-amino]-N-hydroxy-acetamide
[0485] According to the procedure of Example 9, 0.139 g (0.468
mmol) of the product of Example 16 provided 0.118 g (81%) of the
hydroxamic acid as a white solid. Electrospray Mass Spec 312.9
(M+H)+
EXAMPLE 18
2-[(4-Methoxy-benzenesulfonyl)-methyl-amino]-3-methyl-butyric
Acid
[0486] To a solution of 0.250 g (0.700 mmol) of the product of
Example 5 in 1.0 mL of dichloromethane was added 0.5 mL of
trifluoroacetic acid and the resulting mixture was stirred for 2 h
at room temperature and then concentrated in vacuo. The residue was
chromatographed on silica gel eluting with a gradient of ethyl
acetate/hexanes (1:3) to (1:1) to provide 0.211 g (100%) of the
carboxylic acid as a colorless oil. Electrospray Mass Spec 300.0
(M-H)-
EXAMPLE 19
N-Hydroxy-2-[(4-methoxy-benzenesulfonyl)-methyl-amino]-3-methyl-butyramide
[0487] According to the procedure of Example 9, 0.179 g (0.595
mmol) of the product of Example 18 provided 0.156 g (83%) of the
hydroxamic acid as a colorless oil. Electrospray Mass Spec 316.9
(M+H)+
EXAMPLE 20
(4-But-2-ynyloxy-benzenesulfonylamino)-acetic Acid Ethyl Ester
[0488] To a solution of 1.00 g (7.163 mmol) of glycine ethyl ester
in 10 mL of chloroform and 2.0 mL of pyridine was added 1.75 g
(7.163 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride and the
reaction was stirred at room temperature for 15 h. The reaction
mixture was then diluted with ether and the organics were washed
with 5% HCl solution and water, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The resulting brown solid was washed with
ether to provide 0.96 g (43%) of the sulfonamide as a white solid.
Electrospray Mass Spec 311.8 (M+H)+
EXAMPLE 21
[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-acetic
Acid Ethyl Ester
[0489] To a solution of 0.300 g (0.965 mmol) of the product of
Example 20 in 5.0 mL of DMF was added 0.419 g (3.038 mmol) of
potassium carbonate followed by 0.166 g (1.013 mmol) of 3-picolyl
chloride hydrochloride. The resulting mixture was stirred at room
temperature for 15 h and then diluted with ether and water. The
organics were washed with water, dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give a pale yellow solid. The
solid was washed with ether/hexanes (1:1) and dried in vacuo to
provide 0.334 g (86%) of the N-picolyl sulfonamide as a tan solid.
Electrospray Mass Spec 402.9 (M+H)+
EXAMPLE 22
[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-acetic
Acid
[0490] To a solution of 0.282 g (0.701 mmol) of the product of
Example 21 in 7.0 mL of THF/methanol (1:1) was added 3.5 mL of a
1.0N solution of sodium hydroxide and the reaction was stirred
overnight at room temperature. The reaction was then neutralized
with 5% HCl solution and extracted with dichloromethane. The
combined organics were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to provide 0.216 g (82%) of the carboxylic
acid as a pale yellow solid. Electrospray Mass Spec 375.0
(M+H)+
EXAMPLE 23
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hydroxy-a-
cetamide Hydrochloride
[0491] To a 0.degree. solution of 0.71 mL (1.412 mmol) of a 2.0M
solution of oxalyl chloride in dichloromethane, diluted with 6.2 mL
of dichloromethane, is added 0.109 mL (1.412 mmol) of DMF and the
reaction is stirred for 15 minutes at 0.degree.. A solution of
0.176 g (0.471 mmol) of the carboxylic acid product of Example 22,
dissolved in 1 mL of DMF, was added to the reaction and the
resulting mixture is stirred for 1 h at room temperature and then
poured into a 0.degree. mixture of 1.4 mL of water, 7.0 mL of THF
and 1.4 mL of a 50% aqueous solution of hydroxylamine. The reaction
is allowed to warm to room temperature overnight and the organics
are then concentrated in vacuo. The residue is diluted with ethyl
acetate, washed with water and saturated sodium bicarbonate, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
provide 0.123 g (67%) of the hydroxamic acid as a white solid.
[0492] To a solution of 0.119 g (0.306 mmol) of the
amino-hydroxamic acid dissolved in 5.0 mL of dichloromethane and
5.0 mL of methanol was added 0.61 mL (0.61 mmol) of a 1.0M solution
of HCl in ether. The resulting mixture was stirred for 1 h at room
temperature and then concentrated in vacuo. The residue was
dissolved in 1.0 mL of dichloromethane and 10 mL of ether was
added. The resulting precipitate was filtered, washed with ether
and dried in vacuo to provide 0.096 g (74%) of the hydrochloride
salt of the amino-hydroxamic acid as a brown solid. Electrospray
Mass Spec 389.9 (M+H)+
EXAMPLE 24
(4-But-2-ynyloxy-benzenesulfonylamino)-acetic Acid
[0493] To a solution of 0.30 g (0.965 mmol) of the product of
Example 20 in 10 mL of THF/methanol (1:1) was added 4.8 mL of a
1.0N sodium hydroxide solution and the reaction was stirred
overnight at room temperature and then acidified to pH 2 with 10%
HCl solution. The resulting mixture was extracted with
dichloromethane and the combined organics were dried over
MgSO.sub.4, filtered and concentrated in vacuo to provide 0.238 g
(83%) of the sulfonamide as a white solid. Electrospray Mass Spec
281.9 (M-H)-
EXAMPLE 25
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-acetamide
[0494] To a solution of 0.150 g (0.505 mmol) of the product of
Example 24 dissolved in 2.7 mL of DMF was added 0.082 g (0.606
mmol) of 1-hydroxybenzotriazole hydrate (HOBT) followed by 0.129 g
(0.672 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC). The resulting mixture was stirred at room
temperature for 1 h and then 0.15 mL of a 50% aqueous hydroxylamine
solution was added. The reaction was then stirred overnight and
then diluted with ethyl acetate. The organics were washed with 5%
HCl solution, water and saturated sodium bicarbonate solution and
then dried over MgSO.sub.4, filtered and concentrated in vacuo to
provide 0.086 g (54%) of the hydroxamic acid as a white solid.
Electrospray Mass Spec 298.9 (M+H)+
EXAMPLE 26
2-(4-But-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric Acid
[0495] To a solution of 0.500 g (4.255 mmol) D,L-valine in 40 mL of
THF/water (1:1) was added 5.0 mL of triethylamine followed by 1.144
g (4.681 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride and the
reaction was stirred overnight at room temperature. The reaction
mixture was then diluted with ethyl acetate and the organic layer
was washed with water and 5% HCl solution, dried over MgSO.sub.4,
filtered and concentrated in vacuo. The solid residue was washed
with ether/hexanes (1:1) to provide 0.383 g (28%) of the
sulfonamide as a white solid. Electrospray Mass Spec 323.9
(M-H)-
EXAMPLE 27
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-3-methyl-butyramide
[0496] According to the procedure of Example 25, 0.189 g (0.583
mmol) of the product of Example 26 provides 0.110 g (56%) of the
desired hydroxamic acid as a white solid. Electrospray Mass Spec
341.0 (M+H)+
EXAMPLE 28
2-(4-But-2-ynyloxy-benzenesulfonylamino)-propionic Acid Ethyl
Ester
[0497] According to the procedure of Example 20, 1.00 g (6.51 mmol)
of D,L-alanine ethyl ester hydrochloride reacted with 1.75 g (7.16
mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride to provide 1.22 g
(58%) of the sulfonamide as a white solid. Electrospray Mass Spec:
325.9 (M+H)+
EXAMPLE 29
2-(4-But-2-ynyloxy-benzenesulfonylamino)-propionic Acid
[0498] According to the procedure of Example 24, 0.500 g (1.538
mmol) of the product of Example 28 provided 0.457 g (100%) of the
carboxylic acid as a tan solid. Electrospray Mass Spec: 295.9
(M-H)-
EXAMPLE 30
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-propionamide
[0499] According to the procedure of Example 25, 0.410 g (1.38
mmol) of the product of Example 29 provided 0.287 g (67%) of the
hydroxamic acid as a white solid. Electrospray Mass Spec: 313.4
(M+H)+
EXAMPLE 31
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-propionic
Acid Ethyl Ester
[0500] According to the procedure of Example 21, 0.500 g (1.538
mmol) of the product of Example 28 provided 0.461 g (72%) of the
N-3-picolyl sulfonamide as a pale yellow oil. Electrospray Mass
Spec: 416.9 (M+H)+
EXAMPLE 32
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-propionic
Acid
[0501] According to the procedure of Example 22, 0.419. g (1.007
mmol) of the product of Example 31 provided 0.39 g (1005) of the
carboxylic acid as a white foam. Electrospray Mass Spec: 388.9
(M+H)+
EXAMPLE 33
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hydroxy-p-
ropionamide Hydrochloride
[0502] According to the procedure of Example 23, 0.364 g (0.938
mmol) of the product of Example 32 provided 0.149 g of the
hydroxamic acid N-3-picolyl hydrochloride salt as a light brown
solid. Electrospray Mass Spec: 403.9 (M+H)+
EXAMPLE 34
4-Amino-2,6-dimethyl-pyrimidine-5-carboxylic Acid Ethyl Ester
[0503] To a solution of 0.65 g (6.31 mmol) of 2-aminoisobutyric
acid, 0.077 g of 4-dimethylaminopyridine and 7.4 mL of
triethylamine in 20 mL of THF and 20 mL of water was added 1.68 g
(6.87 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride and the
resulting mixture was stirred overnight at room temperature. The
mixture was then diluted with ethyl acetate and washed with 5% HCl
solution and water, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with ethyl acetate/hexanes (1:1) to provide 0.396 g
(20%) of the sulfonamide as a white solid. Electrospray Mass Spec:
309.9 (M-H)-
EXAMPLE 35
2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-2-methyl-propionamide
[0504] According to the procedure of Example 25, 0.359 g (1.154
mmol) of the product of Example 34 provided 0.193 g (51%) of the
hydroxamic acid as a clear glass. Electrospray Mass Spec: 327.3
(M+H)+
EXAMPLE 36
(3S)-4-(4-Fluoro-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic
Acid
[0505] To a 0.degree. solution of 1.00 g (3.155 mmol) of
3-(S)-dimethylthexylsilyl-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carbo-
xylate (prepared as described in PCT patent application WO9720824)
in 20 mL of dichloromethane was added 0.693 mL (6.85 mmol) of
4-methylmorpholine followed by 0.606 g (3.114 mmol) of
4-fluorobenzenesulfonyl chloride. The reaction was allowed to warm
to room temperature and then stirred overnight The reaction mixture
was then poured into water and the organic layer was washed with
water, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The residue was dissolved in 20 mL of methanol and the
solution was heated to reflux for 1 h and then concentrated in
vacuo. The residue was then chromatographed on silica gel eluting
with ethyl acetate/hexanes (1:3) to provide 0.385 g (40%) of the
sulfonamide as a white foam. Electrosptay Mass Spec 331.8
(M-H)-
EXAMPLE 37
4-(4-But-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxyl-
ic Acid
4-(4-Hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic
Acid
[0506] To a solution of 3.07 mL (0.041 mol) of 2-butyn-1-ol in 75
ml of DMF at room temperature was added 1.64 g (0.041 mol) 60%
sodium hydride. The resulting mixture was stirred for 0.5 h and
then a solution of 2.50 g (8.197 mmol) the product of Example 36
dissolved in 10 mL of DMF was added to the reaction. The reaction
mixture was stirred overnight at room temperature and then
acidified to pH 2 with 10% HCl solution and extracted with ether.
The combined organics were then dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with ethyl acetate/hexanes (1:3) to provide 1.2 g (42%)
of the butynyl ether-carboxylic acid product as a tan solid
(Electrospray Mass Spec 383.9 (M+H)+) and 0.947 g of the
phenol-carboxylic acid as a pale yellow oil (Electrospray Mass Spec
329.9 (M-H)-)
[0507]
Alternatively,4-(4-But-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thio-
morpholine-3-carboxylic acid may be prepared in 31% yield according
to the procedure of Example 36 using
4-but-2-ynyloxy-benzenesulfonyl chloride as the sulfonylating
agent.
EXAMPLE 38
4-(4-But-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxyl-
ic Acid Hydroxyamide
[0508] To a 0.degree. solution of 0.75 mL (1.504 mmol) of a 2.0M
solution of oxalyl chloride in dichloromethane, diluted with 6.4 mL
of dichloromethane, is added 0.116 mL (1.504 mmol) of DMF and the
reaction is-stirred for 15 minutes at 0.degree.. A solution of
0.176 g (0.501 mmol) of the butynyl ether-carboxylic acid product
of Example 37, dissolved in 1 mL of DMF, was added to the reaction
and the resulting mixture is stirred for 1 h at room temperature
and then poured into a 0.degree. mixture of 1.5 mL of water, 7.4 mL
of THF and 1.5 mL of a 50% aqueous solution of hydroxylamine. The
reaction is allowed to warm to room temperature overnight and the
organics are then concentrated in vacuo. The residue is diluted
with ethyl acetate, Washed with 5% HCl solution, water and
saturated sodium bicarbonate, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo to provide 0.168 g (91%) of the
hydroxamic acid as a tan solid. Electrospray Mass Spec 398.9
(M+H)+
EXAMPLE 39
4-(4-Hept-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxy-
lic Acid
[0509] According to the procedure of Example 37, 0.350 g (1.051
mmol) of the product of Example 36 and 0.730 mL (5.738 mmol) of
2-heptyn-1-ol provides 0.306 g (63%) of the heptynyl
ether-carboxylic acid as a white solid. Electrospray Mass Spec
424.0 (M-H)-
EXAMPLE 40
4-(4-Hept-2-ynyloxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxy-
lic Acid Hydroxyamide
[0510] According to the procedure of Example 38, 0.257 g (0.605
mmol) of the product of Example 39 provides 0.214 g (80%) of the
hydroxamic acid as a white solid. Electrospray Mass Spec 440.9
(M+H)+
EXAMPLE 41
2-(4-But-2-ynyloxy-benzenesulfonyl)-1,2,3,4-tetrahydro-isoquinoline-3-carb-
oxylic Acid Hydroxyamide
[0511] To a solution of 2.00 g (9.359 mmol) of
1,2,3,4-tetrahyro-3-isoquin- olinecarboxylic acid hydrochloride in
70 mL of THF/water (1:1) was added 10.0 mL of triethylamine
followed by 2.30 g (9.407 mmol) of 4-but-2-ynyloxy-benzenesulfonyl
chloride and the reaction was stirred overnight at room
temperature. The reaction mixture was then diluted with ethyl
acetate and the organic layer was washed with water and 5% HCl
solution, dried over MgSO4, filtered and concentrated in vacuo. The
solid residue was washed with ether/hexanes (1:1) to provide 2.73 g
(76%) of the sulfonamide as a pale yellow solid. Electrospray Mass
Spec 385.9 (M+H)+
[0512] According to the procedure of Example 38, 0.736 g (1.912
mmol) of the sulfonamide provides 0.503 g (66%) of the hydroxamic
acid as a white solid. Electrospray Mass Spec 400.9 (M+H)+
EXAMPLE 42
Methyl 3-Hydroxy-2-(4-methoxybenzenesulfonylamino)propionate
Reference Example 13 in Case# 33,315
3-Hydroxy-2-(4-methoxy-benzenesulfonylamino)-propionic Acid Methyl
Ester
[0513] To a mixture of 5.0 g (32.14 mmol) of D, L-serine methyl
ester and 15.7 mL (0.012 mol) of triethylamine in 100 mL of
dichloromethane, cooled to 0.degree. C., was added 6.64 g (32.14
mmol) of 4-methoxybenzenesulfony- l chloride. The mixture was then
stirred under argon at room temperature for two days. The mixture
was diluted with 100 mL of dichloromethane and then washed with 60
mL each of water, 2N citric acid and brine and than dried over
Na.sub.2SO.sub.4. The solvent was removed under vacuum to give a
solid which was recrystallized from ethyl acetate to give 5.0 g
(54%) of the product as white crystals, m.p. 92-94.degree. C.
[0514] Anal for C.sub.11H.sub.15NO.sub.6S:
[0515] Calc'd: C, 45.7; H, 5.2; N, 4.8; S, 11.1;
[0516] Found: C, 45.6; H, 5.2; N, 4.8; S, 11.1;
EXAMPLE 43
2-[(3-Chloro-propyl)-(4-methoxy-benzenesulfonyl)-amino]-3-hydroxy-propioni-
c Acid Methyl Ester and
2-[(3-Chloro-propyl)-(4-methoxy-benzenesulfonyl)-amino]-acrylic
Acid Methyl Ester
[0517] To a solution of 0.25 g (0.865 mmol) of the sulfonamide of
Example 42 in 4.5 mL of DMF was added 0.042 g (1.038 mmol) of 60%
sodium hydride. The resulting mixture was stirred for 30 min at
room temperature and then 0.26 mL (2.595 mmol) of
1,3-dibromopropane was added and the reaction was stirred overnight
at room temperature.
[0518] The reaction mixture was diluted with water and extracted
with ether. The combined organics were washed with water and brine,
dried over MgSO.sub.4, filtered and concentrated in vacuo. The
residue was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:1) to give 0.148 g (47%) of the chloro-alcohol
and 0.049 g (16%) of the acrylic acid methyl ester. Electrospray
Mass Spec: 382.9 (M+NH.sub.4.sup.+) chloro-alcohol; 348.1
(M+H).sup.+ acrylic acid methyl ester.
EXAMPLE 44
2-[(3-Chloro-propyl)-(4-methoxy-benzenesulfonyl)-amino]-acrylic
Acid Methyl Ester
[0519] To a solution of 1.213 g (3.319 mmol) of the chloro-alcohol
product of Example 43 in 60 mL of dichloromethane was added 2.31 mL
(16.59 mmol) of triethylamine followed by 0.31 mL (3.982 mmol) of
methanesulfonyl chloride. The resulting mixture was stirred at room
temperature for 1 h and an additional 0.31 mL (3.982 mmol) of
methanesulfonyl chloride was then added and the reaction was
stirred overnight.
[0520] The reaction was then diluted with ether, washed with 2N
citric acid solution, water and brine, dried over MgSO.sub.4,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel eluting with ethyl acetate/hexanes (1:3) to give
0.989 g (86%) of the chloro-olefin. Electrospray Mass Spec: 348.1
(M+H).sup.+
EXAMPLE 45
4-Benzyl-1-(4-methoxy-benzenesulfonyl)-[1,4]diazepane-2-carboxylic
Acid Methyl Ester
[0521] To a solution of 0.910 g (0.2.619 mmol) of the product of
Example 44 in 30 mL of DMF was added 0.432 g (0.2.881 mmol) of
sodium iodide. The reaction was stirred for 30 min at room
temperature and then 0.590 mL (5.499 mmol) of benzylamine and 0.96
mL (5.499 mmol) of diisopropylethylamine was added and the
resulting mixture was heated at 80 degrees for 3 h and then cooled
to room temperature.
[0522] The reaction was diluted with ether, washed with water and
then extracted with 10% HCl solution. The combined acid extracts
were then basified with 1N NaOH solution and extracted with ether.
The ether layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with ethyl acetate/hexanes (1:3) to give 0.835 g (76%)
of the diazepane. Electrospray Mass Spec: 418.9 (M+H)+
EXAMPLE 46
1-(4-methoxy-benzenesulfonyl)-[1,4]diazepane-2-carboxylic Acid
Methyl Ester
[0523] To a solution of 11.0 g (0.026 mol) of the product of
Example 45 in 50 mL of ethanol was added 4.40 g of 20% palladium
hydroxide on carbon (Pearlman's catalyst) and the resulting
suspension was shaken at room temperature in a Parr reactor under
44 psi of hydrogen for 4 h. The reaction mixture was then filtered
through Celite and the filter cake was washed with 100 mL of
methanol. The filtrate was concentrated in vacuo and the residue
was diluted with ethyl acetate. The solution was washed with water,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The resulting oil was pure enough for use in the next step.
Electrospray Mass Spec: 328.9 (M+H).sup.+
EXAMPLE 47
4-Benzoyl-1-(4-hydroxy-benzenesulfonyl)-[1,4]diazepane-2-carboxylic
Acid Methyl Ester
[0524] To a solution of 2.576 g (7.854 mmol) of the product of
Example 46 in 60 mL of dichloromethane was added 3.28 ml (0.024
mol) of triethylamine followed by 2.74 mL (0.024 mol) of benzoyl
chloride and the resulting mixture was stirred at room temperature
for 18 h. The reaction mixture was then diluted with ether and
washed with 5% citric acid solution, water and saturated sodium
bicarbonate solution. The organics were dried over MgSO.sub.4,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel eluting with ethyl acetate/hexanes (2:1) to provide
2.35 g (69%) of the carboxamide-ester as a colorless oil.
[0525] To a 0.degree. solution of 1.88 g (4.352 mmol) of the
carboxamide-ester in 100 mL of dichloromethane was added 17.4 mL
(17.4 mmol) of a 1.0M solution of boron tribromide in
dichloromethane. The reaction was stirred at room temperature for 2
h and then poured into an ice cold solution of saturated sodium
bicarbonate. The resulting mixture was extracted with
dichloromethane and the combined organics were dried over
MgSO.sub.4, filtered and concentrated in vacuo to provide 0.645 g
(35%) of the phenol as a white foam. Electrospray Mass Spec: 419.0
(M+H).sup.+
EXAMPLE 48
4-Benzoyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-[1,4]diazepane-2-carboxylic
Acid
[0526] To a solution of 0.096 g (0.368 mmol) of triphenylphosphine
in 3 mL of benzene was added 0.028 mL (0.368 mmol) of neat
2-butyn-1-ol followed by a solution of 0.123 g (0.294 mmol) of the
phenol product of Example 47 dissolved in 1.0 mL of THF. To the
resulting reaction mixture was added 0.058 mL (0.368 mmol) of
diethylazodicarboxylate and the reaction was stirred for 15 h at
room temperature and then concentrated in vacuo. The residue was
chromatographed on silica gel eluting with ethyl acetate/hexanes
(1:1) to provide the butynyl ether-methyl ester.
[0527] The methyl ester was then dissolved in 6.0 mL of
THF/methanol (1:1) and 1.5 mL of 1N sodium hydroxide solution was
added. The reaction was stirred overnight at room temperature and
then the THF/methanol was removed in vacuo. The residue was diluted
with 1N sodium hydroxide solution and washed with ether, ethyl
acetate and dichloromethane. The aqueous layer was acidified with
10% HCl solution and extracted with dichloromethane and these
extracts were dried over MgSO4, filtered and concentrated in vacuo
to provide 0.093 g (70%) of the butynyl ether-carboxylic acid as a
colorless oil. Electrospray Mass Spec: 457.0 (M+H).sup.+
EXAMPLE 49
4-Benzoyl-1-(4-but-2ynyloxy-benzenesulfonyl)-[1,4]diazepane-2-carboxylic
Acid Hydroxyamide
[0528] According to the procedure of Example 38, 0.108 g (0.238
mmol) of the product of Example 48 provides 0.067 g (60%) of the
hydroxamic acid as a white foam. Electrospray Mass Spec: 472.0
(M+H).sup.+
EXAMPLE 50
Piperazine-1,3-dicarboxylic Acid 1-tert-butyl Ester 3-ethyl
Ester
[0529] To a solution of 1.00 g (6.329 mmol) of ethyl
piperazine-2-carboxylate [Rissi, E.; Jucker, E. Helv. Chim. Acta
1962, 45, 2383.]in 25 mL of chloroform was added 1.66 g (7.595
mmol) of di-t-butyl dicarbonate followed by 0.168 g of
4-dimethylaminopyridine. The reaction was stirred at room
temperature for 15 h and then concentrated in vacuo. The residue
was chromatographed on silica gel eluting with ethyl acetate to
provide 1.63 g (100%) of the t-butyl carbamate as a colorless oil.
Electrospray Mass Spec: 258.9 (M+H).sup.+
EXAMPLE 51
4-(4-Fluoro-benzenesulfonyl)-piperazine-1,3-dicarboxylic Acid
1-tert-butyl Ester 3-ethyl Ester
[0530] To a solution of 1.35 g (5.233 mmol) of the product of
Example 50 dissolved in 20 mL of chloroform and 1.5 mL of pyridine
was added 1.02 g (5.233 mmol) of 4-fluorobenzenesulfonyl chloride
and the resulting mixture was stirred overnight at room
temperature. The chloroform was removed in vacuo and the residue
was diluted with ether and washed with water, 5% HCl solution and
saturated sodium bicarbonate solution and then dried over MgSO4,
filtered and concentrated in vacuo. The residue was triturated with
ether/hexanes (1:1) and the solid was collected by filtration and
dried in vacuo to provide 1.50 g (69%) of the sulfonamide as a
white solid. Electrospray Mass Spec: 416.9 (M+H).sup.+
EXAMPLE 52
1-(4-Fluoro-benzenesulfonyl)-piperazine-2-carboxylic Acid Ethyl
Ester
[0531] To a solution of 0.75 g (1.803 mmol) of the product of
Example 51 in 5 mL of dichloromethane was added was added 2.0 mL of
trifluoroacetic acid and the resulting mixture was stirred for 2 h
at room temperature. The reaction mixture was then concentrated in
vacuo and the residue was diluted with ether. The organics were
washed with saturated sodium bicarbonate solution, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to provide
0.515 g (90%) of the amine as a colorless oil pure enough for use
in the next step. Electrospray Mass Spec: 316.9 (M+H).sup.+
EXAMPLE 53
1-(4-Fluoro-benzenesulfonyl)-4-methyl-piperazine-2-carboxylic Acid
Ethyl Ester
[0532] To a solution of 0.469 g (1.484 mmol) of the product of
Example 52 dissolved in 10 mL of DMF was added 0.614 g (4.452 mmol)
of potassium carbonate followed by 0.092 mL (1.484 mmol) of
iodomethane and the resulting mixture was stirred at room
temperature for 3 h. The reaction mixture was then diluted with
ether and washed with water. The organics were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to provide
0.446 g (91%) of the N-methyl amine as a colorless oil.
Electrospray Mass Spec: 330.9 (M+H).sup.+
EXAMPLE 54
1-(4-Fluoro-benzenesulfonyl)-4-methyl-piperazine-2-carboxylic
Acid
[0533] To a solution of 0.390 (1.182 mmol) of the product of
Example 53 dissolved in 12 mL of methanol/THF (1:1) was added 5.9
mmol of 1.0N sodium hydroxide solution and the resulting mixture
was stirred for 15 h at room temperature. The reaction was then
brought to pH 6 with 5% HCl and extracted with dichloromethane. The
organics were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to provide 0.265 g (74%) of the carboxylic
acid as a pale yellow solid. Electrospray Mass Spec: 302.9
(M+H).sup.+
EXAMPLE 55
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-methyl-piperazine-2-carboxylic
Acid
[0534] To a solution of 0.302 mL (4.04 mmol) of 2-butyn-1-ol in 5.5
mL of DMF at room temperature was added 0.162 g (4.04 mmol) of 60%
sodium hydride. The resulting mixture was stirred for 0.5 h and
then a solution of 0.244 g (0.808 mmol) of the product of Example
54 dissolved in 2.0 mL of DMF was added to the reaction. The
reaction mixture was then stirred at room temperature for 3 h and
then neutralized with 5% HCl and extracted with dichloromethane.
The combined organics were then dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel eluting with ethyl acetate to provide 0.118 g (42%)
of the desired butynyl ether-carboxylic acid product as a tan
solid. Electrospray Mass Spec: 352.9 (M+H)+
EXAMPLE 56
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-methyl-piperazine-2-carboxylic
Acid Hydroxyamide Hydrochloride
[0535] According to the procedure of Example 38, 0.095 g (0.270
mmol) of the product of Example 55 provides 0.080 g (81%) of the
amino-hydroxamic acid.
[0536] To a solution of 0.070 g (0.191 mmol) of the
amino-hydroxamic acid dissolved in 2.0 mL-of dichloromethane was
added 0.38 mL (0.38 mmol) of a 1.0M solution of HCl in ether. The
resulting mixture was stirred for 1 h at room temperature and then
diluted with ether. The precipitate was filtered, washed with ether
and dried in vacuo to provide 0.064 g (83%) of the hydrochloride
salt of the amino-hydroxamic acid as a tan solid. Electrospray Mass
Spec 367.9 (M+H)+
EXAMPLE 57
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3dicarboxylic Acid
1-tert-butyl Ester 3-ethyl Ester
[0537] According to the procedure of Example 51, 1.55 g (5.99 mmol)
of the product of Example 50 and 1.61 g (6.59 mmol) of
4-but-2-ynyloxy-benzenesu- lfonyl chloride provided 1.96 g (72%) of
the sulfonamide as a white solid. Electrospray Mass Spec 467.0
(M+H)+
EXAMPLE 58
4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine1-carboxy-
lic Acid tert-butyl Ester
[0538] According to the procedure of Example 54, 0.400 g (0.858
mmol) of the product of Example 57 provided 0.376 g (100%) of the
carboxylic acid as a clear glass.
[0539] According to the procedure of Example 25, 0.472 g (1.078
mmol) of the carboxylic acid provided 0.342 g (70%) of the
hydroxamic acid as a white foam. Electrospray Mass Spec 454.0
(M+H)+
EXAMPLE 59
4-(4-Hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic
Acid Methyl Ester
[0540] To a solution of 0.919 g (2.776 mmol) of
4-(4-hydroxy-benzenesulfon-
yl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid in 20 mL of DMF
was added 0.764 g (9.099 mmol) of sodium bicarbonate and 0.19 mL
(3.03 mmol) of iodomethane. The resulting mixture was stirred for 5
h at room temperature and then diluted with ether, washed with
water, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to provide 0.743 g (78%) of the methyl ester as a pale yellow
solid. Electrospray Mass Spec 345.8 (M+H)+
EXAMPLE 60
2,2-Dimethyl-4-{4-[4-(tetrahydro-pyran-2-yloxy)-but-2-ynyloxy]-benzenesulf-
onyl}-thiomorpholine-3-carboxylic Acid Methyl Ester
[0541] To a solution of 0.633 g (2.415 mmol) of triphenylphosphine
in 10 mL of benzene/THF (3:1) was added 0.410 g (2.415 mmol) of
4-tetrahydropyran-2-butyn-1,4-diol followed by 0.38 mL (2.415 mmol)
of diethyl azodicarboxylate and 0.696 g (2.017 mmol) of the product
of Example 59. The resulting mixture was stirred at room
temperature for 24 h and then concentrated in vacuo. The residue
was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:10) to provide 0.56 g (56%) of the butynyl ether
as a colorless oil. Electrospray Mass Spec 497.9 (M+H)+
EXAMPLE 61
4-[4-(4-Hydroxy-but-2-ynyloxy)-benzenesulfonyl]-2,2-dimethyl-thiomorpholin-
e-3-carboxylic Acid Hydroxyamide
[0542] To a solution of 0.413 g (0.831 mmol) of the product of
Example 60 in 10 mL of methanol/THF (1:1) was added 4.2 mL (4.20
mmol) of a 1.0N sodium hydroxide solution and the resulting mixture
was heated to reflux for 5 h and concentrated in vacuo. The residue
was diluted with water and neutralized with 5% HCl solution. The
mixture was extracted with ethyl acetate and washed with water,
dried over MgSO4, filtered and concentrated in vacuo to provide
0.335 g (84%) of the carboxylic acid as a colorless oil.
[0543] To a solution of 0.270 g (0.559 mmol) of the carboxylic acid
dissolved in 3.0 mL of DMF was added 0.091 g (0.671 mmol) of
1-hydroxybenzotriazole hydrate (HOBT) followed by 0.143 g (0.743
mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC). The resulting mixture was stirred at room
temperature for 1 h and then 0.17 mL of a 50% aqueous hydroxylamine
solution was added. The reaction was then stirred overnight and
then diluted with ethyl acetate. The organics were washed with 5%
HCl solution, water and saturated sodium bicarbonate solution and
then dried over MgSO4, filtered and concentrated in vacuo.
[0544] The residue was dissolved in 10 mL of methanol and 20 mg of
pyridinium p-toluenesulfonate was added and the mixture was heated
to reflux for 18 h. After cooling to room temperature, the reaction
mixture was diluted with ethyl acetate and the organics were washed
with 5% HCl solution, water, and saturated sodium bicarbonate
solution. The organics were then dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel eluting with ethyl acetate/hexanes (4:1) to provide
0.073 g (32%) of the hydroxamic acid alcohol as a pale yellow
solid. Electrospray Mass Spec 414.9 (M+H)+
EXAMPLE 62A
[(4-Hydroxy-benzenesulfonyl)-methyl-amino]-acetic Acid Ethyl
Ester
[0545] To a solution of 1.00 g (6.51 mmol) of sarcosine ethyl ester
hydrochloride in 10 mL of chloroform was added 2.0 mL of pyridine
followed by 1.25 g.(6.51 mmol) of 4-hydroxybenzenesulfonyl
chloride. The reaction was stirred at room temperature for 15 h and
then concentrated in vacuo. The residue was diluted with ethyl
acetate and washed with 5% HCl solution and water, dried over
MgSO.sub.4, filtered and concentrated in vacuo to provide 1.47 g
(83%) of the sulfonamide-phenol as a white solid Electrospray Mass
Spec 273.8 (M+H)+
EXAMPLE 62B
L-2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-propionamide
[0546] Step A: Coupling of N-(9-Fluorenylmethoxycarbonyl)-L-alanine
to Hydroxylamine Resin
[0547]
4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenz-
ene)-resin.sup.1 (0.9 g, 1.1 meq/g) was placed in an empty SPE
column (Jones Chromatography USA, Inc. Part # 120-1024-H) and
suspended in DMF (4 mL). N-(9-Fluorenylmethoxycarbonyl)-L-alanine
(560 mg, 2.0 eq.) HOBt (730 mg, 6.0 eq.) and DIC (454 uL, 4.0 eq.)
were added. The reaction was shaken on an orbital shaker at room
temperature for 2-16 hours. The reaction was filtered and washed
with DMF (3.times.20 mL). A sample of resin was removed and
subjected to the Kaiser test. If the test showed the presence of
free amine (resin turned blue) the coupling described above was
repeated, otherwise the resin was washed with DCM (3.times.20 mL),
MeOH (2.times.20 mL), and DCM (2.times.20 mL). (A wash consisted of
addition of the solvent and agitation either by nitrogen bubbling
or shaking on the orbital shaker for 1-5 minutes, then filtration
under vacuum). The resin was dried in vacuo at room
temperature.
[0548] Step B: Removal of the N-(9-Fluorenylmethoxycarbonyl)
Protecting Group
[0549] The N-(9-fluorenylmethoxycarbonyl)amino hydroxamate resin
prepared in. Step A (0.9 g) was suspended in 20% piperidine in DMF
(4 mL). The reaction was shaken at room temperature for 15 minutes,
then the resin was filtered and washed with DMF (1.times.4 mL) and
the deprotection repeated for 30 minutes. The reaction was filtered
and washed with DMF (2.times.2 mL), MeOH (2.times.2 mL), and DCM
(2.times.2 mL). The resin was dried in vacuo at room
temperature.
[0550] Step C: Sulfonamide Formation
[0551] The amino hydroxamate resin prepared in Step B (0.9 g) was
suspended in DCM (3.0 mL) and pyridine (142 .quadrature.L, 2.0 eq.)
and 4-but-2-ynyloxy-benzenesulfonyl chloride (220 mg, 1.1 eq.) were
added. The reaction mixture was shaken on an orbital shaker at room
temperature for 12-24 hours. The reaction was filtered and washed
with DCM (2.times.2 mL), DMF (2.times.2 mL), MeOH (2.times.2 mL),
and DCM (2.times.2 mL). The resin was dried in vacuo at room
temperature.
[0552] Step D: Cleavage of the 4-but-2-ynyloxybenzenesulfonyl Amino
Hydroxamate from Resin
[0553] The 4-but-2-ynyloxybenzenesulfonyl amino hydroxamate resin
prepared in Step C (300 mg) was suspended in DCM (1.0 mL) and TFA
(1.0 mL) was added. The reaction was shaken for 1 hour at room
temperature. The reaction was filtered and the resin washed with
DCM (2.times.1 mL). The filtrate and the washing were combined and
concentrated to dryness on a Savant SpeedVac Plus. MEOH (1 mL) was
added and the mire concentrated.
[0554] The crude product was purified by reverse phase HPLC under
the following conditions:
[0555] Column: ODS-AM, 20 mm.times.50 mm, 5 .mu.m particle size
(YMC, Inc. Wilmington, N.C.)
[0556] Solvent Gradient: 5-95% acetonitrile (0.05% TFA) in water
(0.05% TFA) over 16 minutes.
[0557] Flow Rate: 22.5 mL/minute.
[0558]
L-2-(4-But-2-ynyloxy-benzenesulfonylamino)-N-hydroxy-propionamide
(22.5 mg, 24%) had HPLC retention time.sup.2 3.59 min. and Ms.sup.3
313 (M+H).
[0559] The hydroxamic acids compounds shown in Table 1 are
synthesized according to the procedures of Example 62B using the
following Fmoc protected amino acids as starting materials:
Fmoc-.alpha.-Me-Ala, Fmoc-Abu, Fmoc-Ala, Fmoc-Arg, Fmoc-Arg(Ts),
Fmoc-Asn, Fmoc-Asp(All), Fmoc-Asp(Chx), Fmoc-.beta.-Ala,
.alpha.-Fmoc-.gamma.-Boc-Diaminobutyric acid, Fmoc-Cha, Fmoc-Chg,
Fmoc-Cys(Bu-t), Fmoc-Cys(Mob), Fmoc-D-Asn, Fmoc-D-Orn(Boc),
Fmoc-D-Cha, Fmoc-D-Chg, Fmoc-D-Leu, Fmoc-D-Met, Fmoc-D-Phe,
Fmoc-D-Pro, Fmoc-D-Trp, Fmoc-D-Tyr(Bu-t), Fmoc-D-Val,
Fmoc-Glu(Bu-t), Fmoc-His(Boc), Fmoc-Hyp(Bn), Fmoc-Ile, Fmoc-Leu,
Fmoc-Lys(2-Cl-Bn), Fmoc-Lys(Boc), Fmoc-Nle, Fmoc-Phe,
Fmoc-Cys(Acm), Fmoc-Ser(Ac), Fmoc-Ser(Bn), Fmoc-Ser(Bu-t),
Fmoc-Thr(Bn), Fmoc-Thr(Bu-t), Fmoc-Trp(Boc), Fmoc-Tyr(Bu-t),
Fmoc-Tyr(Bn), Fmoc-Val, Fmoc-Phg, Fmoc-Gly, Fmoc-D-Arg(Mtr),
Fmoc-D-Arg(Pbf), Fmoc-D-Arg(Mtr), Fmoc-D-Asp, Fmoc-D-Cys(t-Bu),
Fmoc-D-Cys(Acm), Fmoc-D-Cys(Mbzl), Fmoc-D-Cys(Mob), Fmoc-D-Gln,
Fmoc-D-Glu, Fmoc-D-Hfe, Fmoc-D-His, Fmoc-D-Hyp, Fmoc-D-Lys,
Fmoc-D-Lys(Cbz), Fmoc-D-1-Nal, Fmoc-D-2-Nal, Fmoc-D-Nle,
Fmoc-D-Nve, Fmoc-D-Orn, Fmoc-D-3,4-diF-Phe, Fmoc-D4-F-Phe,
Fmoc-D4-nitro-Phe, Fmoc-D-Pip, Fmoc-D-Ser, Fmoc-D-Ser(Bn),
Fmoc-D-2-Thi, Fmoc-D-Thr, Fmoc-D-Thr(Bn), Fmoc-D-Thz, Fmoc-D-Tic,
Fmoc-D-Tyr(Bn), Fmoc-D-Phg.
1TABLE 1 HPLC retention time.sup.2 Example Amino acid.sup.4 (min.)
MS.sup.3 (M + H) 62B L-Ala 3.59 313 63 L-Abu 3.73 327 64 L-Arg 3.21
398 65 L-Arg(Ts) 4.30 552 66 L-Asn 4.00 356 67 L-Asp 4.00 357 68
L-Asp(Chx) 4.73 439 69 .beta.-Ala 3.63 313 70 L-A.sub.2bu 3.12 342
71 L-Cha 4.75 395 72 L-Chg 4.41 381 73 L-Cys(t-Bu) 4.49 401 74
L-Cys(Mob) 4.76 465 75 D-Asn 3.99 356 76 D-Orn 3.10 356 77 D-Cha
4.70 395 78 D-Chg 4.43 381 79 D-Leu 4.20 355 80 D-Met 4.00 373 81
D-Phe 4.36 389 82 D-Pro 3.90 339 83 D-Trp 4.64 428 84 D-Tyr 3.83
405 85 D-Val 3.89 341 86 L-Glu 3.92 371 87 L-His 3.06 379 88
L-Hyp(Bn) 4.67 445 89 L-Ile 4.13 355 90 L-Leu 4.21 355 91
L-Lys(2-Cl- 4.91 495 Bn) 92 L-Lys 4.22 370 93 L-Nle 4.25 355 94
L-Phe 4.37 389 95 L-Phg 4.24 375 96 L-Cys(Acm) 3.56 416 97
L-Ser(Bn) 4.57 419 98 L-Ser 3.38 329 99 L-Thr(Bn) 4.69 433 100
L-Thr 3.45 343 101 L-Trp 4.33 428 102 L-Tyr 3.80 405 103 L-Tyr(Bn)
5.14 495 104 L-Val 3.87 341 295 D-Arg(Mtr) 4.72 610 296 D-Arg 3.24
398 297 D-Arg(Ts) 4.34 552 298 D-Asp 4.02 357 299 D-Cys(t-Bu) 4.54
401 300 D-Cys(Acm) 3.61 416 301 D-Cys(Mbzl) 5 449 302 D-Cys(Mob)
4.76 465 303 D-Gln 3.94 370 304 D-Glu 3.94 371 305 D-Hfe 4.63 403
306 D-His 3.11 379 307 D-Hyp 3.43 355 308 D-Lys 3.18 370 309
D-Lys(Cbz) 4.75 504 310 D-1-Nal 4.78 439 311 D-2-Nal 4.83 439 312
D-Nle 4.3 355 313 D-Nva 4.05 341 314 D-Orn 3.15 356 315
D-3,4-diF-Phe 4.58 425 316 D-4-F-Phe 4.48 407 317 D-4-NO2-Phe 4.44
434 318 D-Pip 4.26 353 319 D-Ser 3.42 329 320 D-Ser-(Bn) 4.62 419
321 D-Thi 4.33 395 322 D-Thr 3.5 343 323 D-Thr(Bn) 4.75 433 324
D-Thz 4.17 357 325 D-Tic 4.63 401 326 D-Tyr(Bn) 5.19 495 327 D-Phg
4.29 375 .sup.2LC conditions: Hewlett Packard 1100; YMC ODS-A 4.6
mm .times. 50 mm 5 u column at 23.degree. C.; 10 uL injection;
Solvent A: 0.05% TFA/water; Solvent B: 0.05% TFA/acetonitrile;
Gradient: Time 0: 98% A; 1 min: 98% A; 7 min: 10% A, 8 min: 10% A;
8.9 min: 98% A; Post time 1 min. Flow rate 2.5 mL/min; Detection:
220 and 254 nm DAD. .sup.3MS conditions: API-electrospray
.sup.4Amino acid refers to the amino acid portion of the molecule,
for example in Example 62B the amino acid is D-Ala.
EXAMPLE 62B
[0560] 49
EXAMPLE 105
(2R,3S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-methylpent-
anamide
[0561] According to the procedure of Example 26, 0.5 g (3.811 mmol)
of D-isoleucine and 1.025 g (4.192 mmol) of
4-but-2-ynyloxy-benzenesulfonyl chloride provided 0.378 g of the
NH-sulfonamide carboxylic acid as a white solid. Electrospray Mass
Spec 338.2 (M-H)
[0562] According to the procedure of Example 25, 0.345 g (1.018
mmol) of the carboxylic acid provided 0.191 g of the hydroxamic
acid,
(2R,3S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-methylpen-
tanamide, as a white solid. Electrospray Mass Spec 355.2
(M+H).sup.+
EXAMPLE 106
(2R)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3,3-dimethylbut-
anamide
[0563] According to the procedure of Example 26, 0.422 g (3.216
mmol) of D-tert-leucine and 0.865 g (3.538 mmol) of
4-but-2-ynyloxy-benzenesulfony- l chloride provided 0.532 g of the
NH-sulfonamide carboxylic acid as a white solid. Electrospray Mass
Spec 338.3 (M-H).sup.-
[0564] According to the procedure of Example 25, 0.472 g (1.392
mmol) of the carboxylic acid provided 0.131 g of the hydroxamic
acid,
(2R)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3,3-dimethylbu-
tanamide, as a white solid. Electrospray Mass Spec 355.2
(M+H).sup.+
EXAMPLE 107
(2S)-2-[(4-But-2-ynyloxy-benzenesulfonyl)-methyl-amino]-N-hydroxy-propiona-
mide
[0565] According to the procedure of Example 20, 0.500 g (3.58
mmol) of D-alanine methyl ester hydrochloride and 0.877 g (3.58
mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride provided 0.532 g
of the NH-sulfonamide ester,
(2R)-2-(4-but-2-ynyloxy-benzenesulfonylamino)-propi- onic acid
methyl ester, as a white solid. Electrospray Mass Spec 312.1
(M+H).sup.+
[0566] According to the procedure of Example 21, 0.30 g (0.971
mmol) of (2R)-2-(4-but-2-ynyloxy-benzenesulfonylamino)-propionic
acid methyl ester provided 0.31 g of
(2R)-2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino- ]-propionic
acid methyl ester as a colorless oil. Electrospray Mass Spec 326.2
(M+H).sup.+
[0567] To a solution of 0.273 g (0.840 mmol) of
(2R)-2-[(4-but-2-ynyloxy-b- enzenesulfonyl)-methyl-amino]-propionic
acid methyl ester in 6 mL of THF/methanol (1/1) was added 0.123 g
(2.94 mmol) of lithium hydroxide monohydrate and the resulting
solution was stirred at room temperature for 3 h. The reaction was
then acidified with 5% HCl solution and extracted with chloroform.
The combined organics were dried over MgSO4, filtered and
concentrated in vacuo to give 0.256 g of
2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-propionic acid
as a white solid. Electrospray Mass Spec 310.2 (M-H).sup.-
[0568] According to the procedure of Example 25, 0.220 g (0.707
mmol) of of
2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-propionic acid
provided 0.172 g of
(2S)-2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amin-
o]-N-hydroxy-propionamide as a white solid: Electrospray Mass Spec
327.2 (M+H).sup.+
EXAMPLE 108
2-[(4-But-2-ynyloxy-benzenesulfonyl)-ethyl-amino]-N-hydroxy-3-methyl-butyr-
amide
[0569] According to the procedure of Example 20, 1.500 g (8.95
mmol) of D,L-valine methyl ester hydrochloride and 2.19 g (8.95
mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride provided 2.15 g
of the NH-sulfonamide ester,
2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-b- utyric acid
methyl ester, as a white solid.
[0570] According to the procedure of Example 5, 0.350 g (1.032
mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric
acid methyl ester and 0.25 mL (3.097 mmol) of iodoethane provided
0.334 g of
2-[(4-but-2-ynyloxy-benzenesulfonyl)-ethyl-amino]-3-methyl-butyric
acid methyl ester as a white solid. Electrospray Mass Spec 368.4
(M+H).sup.+
[0571] According to, the procedure of Example 11, 0.304 g (0.828
mmol) of
2-[(4-but-2-ynyloxy-benzenesulfonyl)-ethyl-amino]-3-methyl-butyric
acid methyl ester provided 0.273 g of
2-[(4-but-2-ynyloxy-benzenesulfonyl)-eth-
yl-amino]-3-methyl-butyric acid as a white solid. Electrospray Mass
Spec 352.2 (M-H).sup.-
[0572] According to the procedure of Example 9, 0.232 g (0.657
mmol) of
2-[(4but-2-ynyloxy-benzenesulfonyl)-ethyl-amino]-3-methyl-butyric
acid provided 0.235 g of
2-[(4-but-2-ynyloxy-benzenesulfonyl)-ethyl-amino]-N-h-
ydroxy-3-methyl-butyramide as an off-white solid. Electrospray Mass
Spec 369.3 (M+H).sup.+
EXAMPLE 109
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-N-hydroxy-3-methyl-
butanamide
[0573] According to the procedure of Example 108, starting from D,
L-valine methyl ester hydrochloride and propargyl bromide,
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-N-hydroxy-3-methy-
lbutanamide was obtained as a white foam. Electrospray Mass Spec
379.4 (M+H).sup.+
EXAMPLE 110
2-[(4-But-2-ynyloxy-benzenesulfonyl)-propyl-amino]-N-hydroxy-3-methyl-buty-
ramide
[0574] According to the procedure of Example 108, starting from D,
L-valine methyl ester hydrochloride and propyl iodide,
2-[(4-but-2-ynyloxy-benzenesulfonyl)-propyl-amino]-N-hydroxy-3-methyl-but-
yramide was obtained as a white solid. Electrospray Mass Spec 383.2
(M+H).sup.+
EXAMPLE 111
2-[(4-But-2-ynyloxy-benzenesulfonyl)-(3-phenyl-propyl)-amino]-N-hydroxy-3--
methyl-butyramide
[0575] According to the procedure of Example 108, starting from D,
L-valine methyl ester hydrochloride and 1-bromo-3-phenylpropane,
2-[(4-but-2-ynyloxy-benzene-ulfonyl)-(3-phenyl-propyl)-amino]-N-hydroxy-3-
-methyl-butyramide was obtained, as a white solid. Electrospray
Mass Spec 459.2 (M+H).sup.+
EXAMPLE 112
2-[(4-But-2-ynyloxy-benzenesulfonyl)-cyclopropylmethyl-amino]-N-hydroxy-3--
methyl-butyramide
[0576] According to the procedure of Example 108, starting from D,
L-valine methyl ester hydrochloride and (bromomethyl)cyclopropane,
2-[(4-but-2-ynyloxy-benzenesulfonyl)-cyclopropylmethyl-amino]-N-hydroxy-3-
-methyl-butyramide was obtained as a white, solid. Electrospray
Mass Spec 395.3 (M+H).sup.+
EXAMPLE 113
2-[(4-But-2-ynyloxy-benzenesulfonyl)-isobutyl-amino]-N-hydroxy-3-methyl-bu-
tyramide
[0577] According to the procedure of Example 108, starting from D,
L-valine methyl ester hydrochloride and 2-methyl-1-iodopropane,
2-[(4-but-2-ynyloxy-benzenesulfonyl)-isobutyl
-amino]-N-hydroxy-3-methyl-- butyramide was obtained as a white
solid. Electrospray Mass Spec 397.2 (M+H).sup.+
EXAMPLE 114
2-[(4-But-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-amino]-N-hydroxy-3-
-methyl-butyramide
[0578] According to the procedure of Example 108, starting from D,
L-valine methyl ester hydrochloride and 3-picolyl chloride
hydrochloride,
2-[(4-but-2-ynyloxy-benzensesulfonyl)-pyridin-3-ylmethyl-amino]-N-hydroxy-
-3-methyl-butyramide was obtained as a white solid. Electrospray
Mass Spec 432.2 (M+H).sup.+
EXAMPLE 115
2[(4-But-2-ynloxy-benzensulfonyl)-methyl-amino]-2-cyclohexyl-N-hydroxy-ace-
tamide
[0579] According to the procedure of Example 107, starting from
D-cylcohexylglycine methyl ester hydrochloride and iodomethane,
2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-2-cyclohexyl-N-hydroxy-
-acetamide was obtained as a white solid. Electrospray Mass Spec
395.2 (M+H).sup.+
EXAMPLE 116
2-[(4But-2-ynyloxy-benzenesulfonyl)-pyridin3-ylmethyl-amino]-2-cyclohexyl--
N-hydroxy-acetamide
[0580] According to the procedure of Example 107, starting from
D-cyclohexlglycine methyl ester hydrochloride and 3-picolyl
chloride hydrochloride,
2-[(4-but-2-ynyloxy-benzenesulfonyl)-pyridin-3-ylmethyl-am-
ino]-2-cyclohexyl-N-hydroxy-acetamide was obtained as a tan solid.
Electrospray Mass Spec 472.3 (M+H).sup.+
EXAMPLE 117
2-{(4-But-2-ynyloxy-benzenesulfonyl)-[4-(2piperidin-1-yl-ethoxy)-benzyl]-a-
mino}-2-cyclohexyl-N-hydroxy-acetamide
[0581] According to the procedure of Example 107, starting from
D-cyclohexylglycine methyl ester hydrochloride and
4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (U.S. Pat. No.
5,929,097),
2-{(4-but-2-ynyloxy-benzenesulfonyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-
-amino}-2-cyclohexyl-N-hydroxy-acetamide was obtained as a white
solid. Electrospray Mass Spec 598.3 (M+H).sup.+
EXAMPLE 118
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(diethylamino)propyl]amino}-N-hydr-
oxy-3-methylbutanamide
[0582] According to the procedure of Example 5, 1.00 g (2.95 mmol)
2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid
methyl ester and 0.88 mL (8.849 mmol) of 1-bromo-3-chloropropane
provided 0.92 g of
methyl2-[{[4-(2-butynyloxy)penyl]sulfonyl}(3-chloropropyl)amino]-3-met-
hylbutanoate as a white solid. Electrospray Mass Spec 416.2
(M+H).sup.+
[0583] To a solution of 0.45 g (1.08 mmol) of methyl
2-[{[4-(2-butynyloxy)-phenyl]sulfonyl}(3-chloropropyl)amino]-3-methylbuta-
noate in 5.0 mL of DMF was added 0.163 g (1.08 mmol) of sodium
iodide and 0.34 mL (3.24 mmol) of diethylamine. The reaction was
heated to 80.degree. C. for 3 h and then cooled to room
temperature. The mixture was then diluted with water and extracted
with ethyl acetate. The combined organics were washed with water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo to provide 0.441 g of methyl
2-{{[4-(2-butynyloxy)-phenyl]sulfonyl}[3-(diethylamino)propyl]a-
mino}-3-methylbutanoate as a brown oil. Electrospray Mass Spec
453.5 (M+H).sup.+
[0584] According to the procedure of Example 11, 0.412 g (0.912
mmol) of methyl
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[3-(diethylamino)propyl]amino-
}-3-methyl-butanoate provided 0.368 g of
N-{[4-(2-butynyloxy)phenyl]sulfon-
yl}-N-[3-(diethylamino)propyl]valine as a tan foam. Electrospray
Mass Spec 439.4 (M+H).sup.+
[0585] According to the procedure of Example 9, 0.338 g (0.772
mmol) of of
N-}[4-(2-butynyloxy)phenyl]sulfonyl}-N-[3-(diethylamino)propyl]valine
provided 0.223 g of
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[3-(diethylamino-
)propyl]amino}-N-hydroxy-3-methylbutanamide as a brown foam.
Electrospray Mass Spec 369.3 (M+H).sup.+
EXAMPLE 119
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(4-morpholinyl)propyl]amino}-N-hyd-
roxy-3-methylbutanamide
[0586] According to the procedure of Example 118, using morpholine
instead of diethylamine,
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(3-chloropropyl)ami-
no]-3-methylbutanoate was converted into
2-{{[4-(2-butynyloxy)phenyl]sulfo-
nyl}[3-(4-morpholinyl)propyl]amino}-N-hydroxy-3-methylbutanamide,
obtained as a white foam. Electrospray Mass Spec 468.4
(M+H).sup.+
EXAMPLE 120
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[3-(4-methyl-1-piperazinyl)propyl]ami-
no}-N-hydroxy-3-methylbutanamide Hydrochloride
[0587] According to the procedure of Example 118, using
1-methylpiperazine instead of diethylamine,
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(3-chloropr-
opyl)amino]-3-methylbutanoate was converted into
2-{{[4-(2-butynyloxy)phen-
yl]sulfonyl}-[3-(4-methyl-1-piperazinyl)propyl]amino}-N-hydroxy-3-methylbu-
tanamide, which was converted into the corresponding hydrochloride
salt with ethereal HCl solution to provide an off-white solid.
Electrospray Mass Spec 481.4 (M+H).sup.+
EXAMPLE 121
2-{{[4-(2-Butynyloxy)phenyl[sulfonyl}[4-(diethylamino)butyl]amino}-N-hydro-
xy-3-methylbutanamide
[0588] According to the procedure of Example 118, using
1-bromo-4-chlorobutane instead of 1-bromo-3-chlorobutane,
2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid
methyl ester was converted into
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(diethyl-
amino)butyl]amino}-N-hydroxy-3-methylbutanamide, which was
converted into the corresponding hydrochloride salt with ethereal
HCl solution to provide a brown solid. Electrospray Mass Spec 468.2
(M+H).sup.+
EXAMPLE 122
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)butyl]amin-
o}-N-hydroxy-3-methylbutanamide
[0589] According to the procedure of Example 118, using
1-bromo-4-chlorobutane instead of 1-bromo-3-chlorobutane and
1-methylpiperazine instead of diethylamine,
2-(4-but-2-ynyloxy-benzenesul- fonylamino)-3-methyl-butyric acid
methyl ester was converted into
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)butyl]ami-
no}-N-hydroxy-3-methylbutanamide, which was converted into the
corresponding hydrochloride salt with ethereal HCl solution, to
provide a brown solid. Electrospray Mass Spec 495.2 (M+H).sup.+
EXAMPLE 123
2-[[[4-(2-Butynyloxy)phenyl]sulfonyl][2-(4-morpholinyl)ethyl]amino]-N-hydr-
oxy-3-methylbutanamide
[0590] According to the procedure of Example 21, 0.419 g (1.236
mmol) of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric
acid methyl ester and 0.408 g (2.20 mmol) of
4-(2-chloroethyl)morpholine hydrochloride provided 0.506 g of
2-[(4-but-2-ynyloxy-benzenesulfonyl)-(2-
-morpholin-4-yl-ethyl)-amino]-3-methyl-butyric acid methyl ester as
a colorless oil. Electrospray Mass Spec 453.0 (M+H).sup.+
[0591] According to the procedure of Example 11, 0.469 g (1.04
mmol) of
2-[(4-but-2-ynyloxy-benzenesulfonyl)-(2-morpholin-4-yl-ethyl)-amino]-3-me-
thyl-butyric acid methyl ester provided 0.245 g of
2-[(4-but-2-ynyloxy-ben-
zenesulfonyl)-(2-morpholin-4-yl-ethyl)-amino]-3-methyl-butyric acid
as a white solid. Electrospray Mass Spec 438.9 (M+H).sup.+
[0592] According to the procedure of Example 9, 0.243 g (0.554
mmol) of,
2-[(4-but-2-ynyloxy-benzenesulfonyl)-(2-morpholin-4-yl-ethyl)-amino]-3-me-
thyl-butyric acid provided 0.105 g of
2-[[[4-(2-butynyloxy)phenyl]sulfonyl-
][2-(4-morpholinyl)ethyl]amino]-N-hydroxy-3-methylbutanamide, which
was converted into the corresponding hydrochloride salt with
etheral HCl solution to give 0.105 g of
2-[[[4-(2-butynyloxy)phenyl]sulfonyl][2-(4-mo-
rpholinyl)ethyl]amino]-N-hydroxy-3-methylbutanamide hydrochloride
as a white solid. Electrospray Mass Spec 454.0 (M+H).sup.+
EXAMPLE 124
2-[{[4-(But-2-ynyloxy)phenyl]sulfonyl}(2-morpholin-4-ylethyl)amino]-N-hydr-
oxyacetamide Hydrochloride
[0593] According to the procedure of Example 123,
(4-but-2-ynyloxy-benzene- sulfonylamino)-acetic acid ethyl ester
provided 2-[{[4-(but-2-ynyloxy)phen-
yl]sulfonyl}(2-morpholin-4-ylethyl)amino]-N-hydroxyacetamide
hydrochloride as an off-white sold. Electrospray Mass Spec 412.3
(M+H).sup.+
EXAMPLE 125
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)-2-butynyl-
]amino}-N-hydroxy-3-methylbutanamide
[0594] According to the procedure of Example 5, 0.800 g (2.36 mmol)
of 2-(4-but-2-ynyloxy-benzenesulfonylamino)-3-methyl-butyric acid
methyl ester and 0.53 g (4.72 mmol) of 80% propargyl bromide gave
0.89 g of methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-3-methylbu-
tanoate as a colorless oil. Electrospray Mass Spec 378.2
(M+H).sup.+
[0595] To a solution of 0.500 g (1.326 mmol) of methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(2-propynyl)amino]-3-methylbutanoate
in 4.0 mL of dioxane was added 0.099 g (3.316 mmol) of
paraformaldehyde, 5 mg of cuprous chloride, 0.5 mL of acetic acid
and 0.294 ml (2.652 mmol) of 1-methylpiperazine. The resulting
mixture was stirred at room temperature for 15 minutes after which
the reaction had turned green. The reaction was then heated to
reflux for 2 h, after which the reaction had turned brown. The
reaction mixture was cooled to room temperature and extracted with
ether. The combined organics were washed with saturated sodium
bicarbonate solution, dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give 0.649 g of methyl
2-{{[4-(2-butynyloxy)phen-
yl]sulfonyl}-4-(4-methyl-1-piperazinyl)-2-butynyl]amino}-3-methylbutanoate
as a brown oil. Electrospray Mass Spec 490.3 (M+H).sup.+
[0596] According to the procedures of Examples 11 and 9
methyl2-{{[4-(2-butynyloxy)phenyl]sulfonyl}-4-(4-methyl-1-piperazinyl)-2--
butynyl]amino}-3-methylbutanoate provided the hydroxamic acid
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)-2-butyny-
l]amino}-N-hydroxy-3-methylbutanamide as a white solid. This was
converted into
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)-2-b-
utynyl]amino}-N-hydroxy-3-methylbutanamide hydrochloride with
ethereal HCl solution to give the product as a brown powder.
Electrospray Mass Spec 491.3 (M+H).sup.+
EXAMPLE 126
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(diethylamino)-2-butynyl]amino}-N--
hydroxy-3-methylbutanamide
[0597] To a solution of 1.00 g (2.653 mmol) of methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(2propynyl)amino]-3-methylbutanoate
in 8.0 mL of dioxane was added 0.198 g (6.632 mmol) of
paraformaldehyde, 10 mg of cuprous chloride, 1.0 mL of acetic acid
and 0.55 ml (5.305 mmol) diethylamine. The resulting mixture was
stirred at room temperature for 15 minutes after which the reaction
had turned green. The reaction was then heated to reflux for 2 h,
after which the reaction had turned brown. The reaction mixture was
cooled to room temperature and extracted with ether. The combined
organics were washed with saturated sodium bicarbonate solution,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give 1.23 g of methyl 2-{{[4-(2-butynyloxy)pheny-
l]sulfonyl}[4-(diethylamino)-2-butynyl]amino}-3-methylbutanoate as
a brown oil.
[0598] Methyl
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(diethylamino)-2-but-
ynyl]amino}-3-methylbutanoate was converted into
2-{{[4-(2-butynyloxy)phen-
yl]sulfonyl}[4-(diethylamino)-2-butynyl]amino}-N-hydroxy-3-methylbutanamid-
e hydrochloride, isolated as a brown foam, according to the
procedures of Examples 11 and 9. Electrospray Mass Spec 464.5
(M+H).sup.+
EXAMPLE 127
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(methylamino)-2-butynyl]amino}-N-h-
ydroxy-3-methylbutanamide
[0599] To a 0.degree. solution of 0.689 g (1.491 mmol) of methyl
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(diethylamino)-2-butynyl]amino}-3-
-methylbutanoate in 12 mL of diethyl ether was added 0.60 mL of a
3.0M solution of cyanogen bromide in dichloromethane. The reaction
was allowed to warm to room temperature and stirred overnight. The
resulting mixture was diluted with ether, washed with 5% HCl and
brine, dried over Na2SO4, filtered and concentrated in vacuo to
provide the crude propargylic bromide.
[0600] The bromide was dissolved in 7.0 mL of THF and 7.0 mL of
a2.0M solution of methylamine in THF was added. The resulting
mixture was stirred at room temperature overnight and then diluted
with ethyl acetate and saturated sodium bicarbonate solution. The
organics were dried over Na2SO4, filtered and concentrated in
vacuo. The residue was then dissolved in 10.0 mL of DMF and 0.39 g
of di-t-butyldicarbonate and 0.039 g of 4-dimethylaminopyridine was
added. The reaction was again stirred overnight at room temperature
and then diluted with water and extracted with ether. The combined
organics were washed with water, dried over Na2SO4, filtered and
concentrated in vacuo to provide methyl
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(methylamino)-2-butynyl]amino}-3--
methylbutanoate.
[0601] The carbarmate was dissolved in 3.2 mL of THF/MeOH (1:1) and
1.6 mL of a 1.0N NaOH solution was added. The reaction was heated
to reflux for 15 h and then cooled, neutralized with 5% HCl
solution and extracted with dichloromethane. The organics were
dried over Na2SO4, filtered and concentrated in vacuo to provide
0.157 g of 2-{{[4-(2-butynyloxy)phenyl]s-
ulfonyl}[4-(methylamino)-2-butynyl]amino}-3-methylbutanoic
acid.
[0602] According to the procedure of Example 25, 0.143 g (0.283
mmol) of
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(methylamino)-2-butynyl]amino}-3--
methylbutanoic acid was converted into 0.079 g of the hydroxamic
acid,
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(methylamino)-2-butynyl]amino}-N--
hydroxy-3-methylbutanamide, obtained as a brown solid. Electrospray
Mass Spec 422.3 (M+H).sup.+
EXAMPLE 128
((2R)-}[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino)[(4-diethylamino)cyc-
lohexyl]-N-hydroxyethamide
[0603] To a solution of D-4-hydroxy phenylglycine dissolved in 3N
NaOH was added Raney nickel (6.75 g) and water (45 mL )and the
mixture was then hydrogenated on a Parr hydrogenator at
50-80.degree. C. for 24 h at 40 psi of hydrogen. The reaction
mixture was filtered through Celite, washed with dioxane, filtered
and concentrated to 20 mL. An additional 20 mL of dioxane was added
and the reaction was cooled to 0.degree. C. and triethylamine (2.72
mL, 19.4 mmol ) was added, followed by
4-(2-butynyloxy)-benzenesulfonyl chloride (3.21 g, 13.2 mmol). The
mixture was stirred at room temperature overnight and then
concentrated in vacuo. The residue was dissolved in water and
neutralized with 1N HCl to pH 2-3. The precipitated white solid was
filtered to provide 2.8 g of
(2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-hydroxycyclo-hexyl)ethano-
ic acid. mp 90-100.degree. C. Electrospray Mass Spec 382.1
(M+H).sup.+
[0604] To a solution of
(2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-hy-
droxy-cyclohexyl)ethanoic acid (0.39 g, 1.0 mmol) in 3 mL of DMF
was added iodomethane (0.14 mL, 2.2 mmol) and potassium carbonate
(0.69 g, 5 mmol) and the resulting mixture was stirred at room
temperature overnight. The reaction was then diluted with ethyl
acetate and the organic layer was washed with water and brine,
dried over sodium sulfate, filtered, and concentrated.
Chromatography on silica gel eluting with hexane:ethyl acetate
(3:7) provided 0.05 g of the cis-isomer as an oil, Electrospray
Mass Spec410.2 (M+H ).sup.+; and 0.28 g of the trans-isomer as a
white solid. mp 94-96.degree. C. Electrospray Mass Spec 410.3 (M+H
).sup.+.
[0605] To a solution of a 1:5 mixture of (cis)- and (trans)-methyl
(2R)-){[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino)(4-hydroxycyclohexy-
l)ethanoate (0.65 g, 0.159 mmol) in dichloromethane (2 mL) was
added Dess-Martin periodinane (0.75 g, 1.77 mmol) and the reaction
was stirred at room temperature for 1 h. The mixture was diluted
with 50 mL of ether and poured into 1N NaOH (20 mL) and stirred
until the solid disappeared. The ether was washed with 20 mL of 1N
NaOH, water and brine, dried over sodium sulfate, filtered, and
concentrated to obtain 0.61 g of methyl
(2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino)(4-oxocyclohexyl)eth-
anoate. Electrospray-Mass Spec 408.2 (M+H ).sup.+.
[0606] To a solution of methyl
(2R)-{4-(2-butynyloxy)phenyl]sulfonyl}(meth-
yl)amino)(4-oxocyclohexyl)ethanoate (0.54 g, 1.32 mmol) dissolved
in 4 mL of 1,2 dichloroethane was added diethylamine (0.097 mL,
0.93 mmol) and the reaction was stirred at room temperature
overnight. Sodium triacetoxyborohydride (0.49 g, 2.32 mmol) was
then added, followed by acetic acid (0.078 g, 1.32 mmol). The
mixture was stirred at room temperature overnight. The reaction was
then concentrated in vacuo and the residue was diluted with ethyl
acetate and washed with saturated NaHCO.sub.3. The ethyl acetate
was washed with 1N HCL and the aqueous layer was neutralized with
5N NaOH to pH .about.8-9, and then extracted with CH.sub.2Cl.sub.2.
The organic layer was washed with water and brine, dried over
sodium sulfate, filtered, and concentrated to provide 0.18 g of
methyl
((2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino)[(4-dieth-
ylamino)cyclohexyl]ethanoate. Electrospray Mass Spec 465.5 (M+H
).sup.+.
[0607] To a solution of methyl
((2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}(me-
thyl)amino)[(4-diethylamino)cyclohexyl]ethanoate (0.15 g, 0.32
mmol) in 2.0 mL of THF was added 1N NaOH (0.40 mL) and 2 mL of
methanol and the mixture was heated to .about.55.degree. C.
overnight. The reaction was concentrated in vacuo to give 0.17 g of
((2R)-{[4-(2-butynyloxy)phenyl]su-
lfonyl}(methyl)amino)[(4-diethylamino)cyclohexyl]-ethanoicacid,
sodium salt. Electrospray Mass Spec 451.4 (M+H ).sup.+.
[0608] According to the procedure of Example 9,
((2R)-{[4-(2-butynyloxy)ph-
enyl]sulfonyl}(methyl)-amino)[(4-diethylamino)cyclohexyl]-ethanoicacid,
sodium salt was converted into the hydroxamic acid,
((2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino)[(4-diethylamino)cy-
clohexyl)]-N-hydroxyethamide. Electrospray Mass Spec 466.4
(M+H).sup.+.
EXAMPLE 129
(2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-2-(4-hydroxycyclohe-
xyl)ethanamide
[0609] To a mixture of (cis)- and
(trans)-(2R)-{[4-(2-butynyloxy)phenyl]su-
lfonyl}amino)(4-hydroxycyclohexyl)ethanoic acid from Example 128
(0.57 g, 1. 5mmol) was added t-butyldimethylsilyl chloride (0.56 g,
3.6 mmol), imidazole (0.5 g 7.5 mmol) and DMF (4 mL) and the
mixture was stirred at room temperature overnight. After removing
the solvent, the resulting oil was extracted with ether and water.
The ether layer was washed with water and brine, dried over sodium
sulfate, filtered and concentrated to provide 0.78 g of
tert-butyl(dimethyl)silyl(2R)-{[4-(2-butynyloxy)phenyl]-
sulfonyl}amino)(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)ethanoate.
Yield 85.2%. Electrospray Mass Spec 610.2 (M+H ).sup.+.
[0610] To a solution of
tert-butyl(dimethyl)silyl(2R)-){[4-(2-butynyloxy)p-
henyl]sulfonyl}amino)(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)ethanoa-
te (0.76 g, 1.24 mmol) in 8 mL of THF/methanol (1:1) was added 1N
NaOH (1.25 mL, 1.25 mmol) and the reaction was stirred at room
temperature overnight. Reducing the solvent to one quarter volume,
then adding brine, the aqueous layer was neutralized with 1M KHSO4
to pH .about.4 and then extracted with ethyl acetate. The combined
organics were washed with water and brine, dried over sodium
sulfate, filtered, and concentrated to obtain 0.68 g of
(2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-{[tert-b-
utyl-(dimethyl)silyl]oxy}cyclohexyl) ethanioic acid. Electrospray
Mass Spec 494.2 (M-H).sup.-.
[0611] To a solution of
(2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-{[-
tert-butyl(dimethyl)silyl]oxy}cyclohexy) ethanoic acid (0.62 g 1.25
mmol) and 1-(3-dimethyl aminopropyl) 3-ethyl carbodimide (0.39 g,
1.67 mmol) in DMF (7 mL), was added 1-hydroxybenzotriazole (0.23 g,
1.50 mmol) and the reaction was stirred at room temperature for 2
h. Hydroxylamine (0.54 mL of 50% in water, 8.75 mmol) was added and
the reaction was stirred overnight. The solvent was removed in
vacuo and the residue was diluted with ethyl acetate and water. The
organic layer was washed with saturated NaHCO.sub.3 and water,
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by using preparative TLC to obtain 0.3 g of
(2R)-){[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-{[tert-butyl(dimethyl)si-
lyl]oxy}cyclohexyl)-N-hydroxythanamide as an off-white solid mp
125.degree. C. (d). Electrospray Mass Spec 511.2 (M+H).sup.+.
[0612] To a solution of
(2R)-{[4-(2-butynyloxy)phenyl]sufonyl}amino)(4-{[t-
ert-butyl(dimethyl)silyl]oxy}-N-hydroxyethanamide (0.11 g, 0.21
mmol) in 2.5 mL of acetonitrile, cooled in an ice bath, was added 1
mL of 8% HF in acetonitrile. After a couple of minutes, a solid
precipitated. The reaction was diluted with dichloromethane and
water and filtered to give a white solid 0.06 g. The
dichloromethane layer was washed with water and brine, dried over
sodium sulfate, filtered, and concentrated to provide an additional
0.02 g of (2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}amino-N-hy-
droxy-2-(4-hydroxycyclohexyl)ethanamide. mp 180-182.degree. C.
Electrospray Mass Spec 397.2 (M+H ).sup.+.
EXAMPLE 130
(2R)-{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino)-N-hydroxy-2-(4-hydro-
xycyclohexyl)-ethanamide
[0613] According to the procedure in Example 129, (trans)-methyl
(2R)-{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino)(4-hydroxycyclohexyl-
)ethanoate (from Example 128) was converted into
(2R)-{[4-(2-butynyloxy)ph-
enyl]sulfonyl}(methyl)amino)-N-hydroxy-2-(4-hydroxycyclohexyl)-ethanamide.
Mp 195-197.degree. C. Electrospray Mass Spec 411.2 (M+H
).sup.+.
EXAMPLE 131
2-[(6-But-2-ynyloxy-pyridine-3sulfonyl)-methyl-amino]-N-hydroxy-acetamide.
[0614] In a 250 mL three neck round bottom flask equipped with an
overhead stirrer was charged 27 mL water, and cooled to -3.degree.
C. (ice/NaCl). Thionyl chloride (4.52 mL, 61.96 mmol, 4.5 eq) was
added slowly so the temperature did not exceed 7.degree. C. The ice
bath was removed, allowed to warm to room temperature, then 0.07 g
(0.69 mmol, 0.05 eq) of copper (I) chloride was added. The mixture
was then recooled to -5.degree.
[0615] 5-Amino-2-chloropyridine (1.77 g, 13.67 mmol) was dissolved
in 14 mL of concentrated HCl and cooled to -5.degree. C. to which a
solution of 1.04 g (15.14 mmol, 1.1 eq) NaNO2 in 12 mL of water was
added slowly so the temperature was maintained between -5 and
0.degree. C. This mixture was then added to the thionyl
chloride/water/CuCl mixture. A frothing precipitate resulted and
was allowed to stir for another 30 min. The product was filtered
and air dried. Solids were taken up in ethyl acetate, washed with
brine, dried over MgSO4 and concentrated in vacuo to afford 1.7 g
(62%) of 6-chloro-pyridine-3-sulfonyl chloride as a light tan
solid. Electrospray Mass Spec 210.9 (M+H).sup.+
[0616] To a solution of 6-chloro-pyridine-3-sulfonylchloride (5.15
g, 24.3 mmol) in 50 mL of anhydrous chloroform, 7.4 mL of pyridine
and 8.82 g (48.6 mmol, 2 eq) of sarcosine hydrochloride were added
and the reaction proceeded overnight at room temperature. The
solvent was removed in vacuo, diluted with water, neutralized with
sodium bicarbonate and extracted with ethyl acetate which was then
washed with brine, dried over MgSO4, directly preadsorbed onto
silica gel and purified via flash chromatography using 5:1
Hex:EtOAc to afford 3.97 g (51%) of
[(6-chloro-pyridine-3-sulfonyl)-methyl-amino]-acetic acid
tert-butyl ester. Electrospray Mass Spec 321.1 (M+H).sup.30
[0617] To a solution of 0.77 mL (19.3 mmol) of 2-butynl-ol and 0.18
g (4.37 mmol) of sodium hydroxide were heated at 100.degree. C. for
one hour. [(6-chloro-pyridine-3-sulfonyl)-methyl-amino]-acetic acid
tert-butyl ester (1.0 g, 3.12 mmol) was added to this solution.
Additional butynol was added to facilitate stirring, and the
reaction was stirred at 100.degree. C. overnight. The reaction was
cooled, diluted with water, and washed with ethyl acetate. The
aqueous layer was acidified with 2N HCl, and extracted with ethyl
acetate (2.times.). The combined organics were washed with brine,
dried over MgSO4, concentrated to solids which were slurried in
1:1:1 dichloromethane: hexane:ethyl acetate to afford 0.41 g (45%)
of [(6-but-2-ynyloxy-pyridine-3-sulfonyl)-- methyl-amino]-acetic
acid as an off-white solid. Electrospray Mass Spec 299.0
(M+H).sup.+
[0618] In an oven dried 50 mL round bottom flask was combined 0.228
g (0.579 mmol))
[(6-but-2-ynyloxy-pyridine-3-sulfonyl)-methyl-amino]-acetic acid in
5 mL of anhydrous dichloromethane and 0.22 mL DMF and the mixture
was cooled to 0 .degree. C. Oxalyl chloride (1.45 mL, 2.9 mmol, 3.5
eq) was slowly added to the cold solution, the ice bath was removed
and the reaction let warm to room temperature for 45 min. The
solvent was then removed in vacuo and the residue was dissolved in
5 mL of dichloromethane and dropwise added to a solution of 0.46 g
hydroxylamine hydrochloride, 1.2 mL DMF, 1.2 mL triethylamine, 8 mL
dichloromethane and 8 mL acetonitrile. After stirring overnight at
room temperature, the solvent was removed in vacuo, diluted with
water and neutralized. The solids in the mixture were filtered and
dried in vacuo. Reverse phase HPLC afforded 0.084 g (39%) of
2-[(6-but-2-ynyloxy-pyridine-3-sulfonyl)-methyl-amino]-N-
-hydroxy-acetamide. Electrospray Mass Spec 314.3 (M+H).sup.+
EXAMPLE 132
2-[[(4-{[3-(4-Chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino]--
N-hydroxyacetamide
[0619] To a solution of 4-(3-bromo-prop-1-ynyl)-phenol (5.0 g,
30.12 mmol) dissolved in dichloromethane, 8.3 g (31.63 mmol, 1.05
eq) of triphenylphosphine was added and the solution was cooled to
0.degree. C. Bromine (1.55 mL, 30.12 mmol 1.0 eq) was added
dropwise and the reaction was warmed to room temperature. The
reaction was then diluted with dichloromethane, washed with sodium
hydrosulfite pentahydrate, washed with brine, dried over MgSO4 and
concentrated. The residue was purified via flash chromatography
using 4:1 hexane:ethyl acetate to afford 5.56 g (80%) of
1-(3-bromo-prop-1-ynyl)-4-chloro-benzene as an amber oil.
Electrospray Mass Spec 280.4 (M+H)+
[0620] To a solution of 4-hydroxybenzenesulfonic acid sodium salt
(2.81 g, 12.11 mmol) in 50 mL of isopropyl alcohol, 11.8 mL 2N NaOH
and 5.56 g (24.2 mmol, 2 eq) of
1-(3bromo-prop-1-ynyl)-4-chloro-benzene was added. The solution was
heated to 70.degree. C. overnight. The reaction was cooled,
concentrated in vacuo, filtered and air dried to afford 2.8 g (67%)
of 4-[3-(4-chloro-phenyl)prop-2-ynyloxy]-benzenesulfonic acid,
sodium salt. Electrospray Mass Spec 321.3 (M-H)-
[0621] To a solution of the crude
4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-b- enzenesulfonic acid
sodium salt (2.81 g, 8.7 mmol) was added 2.8 g of phosphorous
pentachloride and 50 mL of dichloromethane. The reaction warmed to
40.degree. followed by dissolution of the reagents. The reaction
was then quenched with ice, extracted with dichloromethane, washed
with water, brine, dried over magnesium sulfate, filtered and
concentrated in vacuo. The resulting oil was purified via flash
chromatograhpy using 20:1 Hex:EtOAc to afford 0.5 g (17%) of
4-[3-(4-chlorophenyl)-prop-2-ynyloxy]-benzenesulfonyl chloride.
[0622] A solution of 0.57 g (1.67 mmol) of
4-[3-(4-chloro-phenyl)-prop-2-y- nyloxy]-benzenesulfonyl chloride
and 0.61 g (3.34 mmol, 2 eq) of sarcosine t-butyl ester
hydrochloride in 0.51 mL of pyridine and 15 mL of chloroform was
allowed to react overnight at room temperature. The reaction was
concentrated in vacuo, diluted with water/ethyl acetate,
neutralized with NaHCO3 and extracted with EtOAc (2.times.). The
combined organics, were washed with brine, dried over MgSO4,
filtered and concentrated to afford a yellow oil which was purified
via flash chormatography using 6:1 hexane: ethyl acetate to afford
0.396 g (53%) of tert-butyl
[[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](meth-
yl)amino]acetate as a white solid. Electrospray Mass Spec 450.4
(M+H)+
[0623] To a solution of tert-butyl
[[(4-{[3-(4-chlorophenyl)-2-propynyl]ox-
y}phenyl)-sulfonyl](methyl)amino]acetate (0.331 g, 0.736 mmol in
methanol/THF was added 1.23 mL (3.5 eq) of a 1.0N solution of LiOH
and the reaction was stirred at room temp overnight. The solvent
was removed in vacuo and the residue was suspended in water,
adjusted to pH to 3 with 2N HCl. The resulting solid was rinsed
with ether and dried in vacuo to afford 0.27 g (89%) of
[[(4-{[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)su-
lfonyl](methyl)amino]acetic acid. Electrospray Mass Spec 392.1
(M+H)+
[0624] A solution of
[[(4-[3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfon-
yl]-(methyl)amino]acetic acid (0.231 g, 0.586 mmol) was converted
to the desired hydroxamic acid as described in Example 131, to give
2-[[(4-{[{3-(4-chlorophenyl)-2-propynyl]oxy}phenyl)sulfonyl](methyl)amino-
]-N-hydroxyacetamide after reverse phase HPLC (0.097 g, 42%) as a
white solid. Electrospray Mass Spec 407.3 (M+H)+
EXAMPLE 133
N-Hydroxy-2-(methyl{[4-(prop-2-ynylamino)
phenyl]sulfonyl}amino)acetamide
[0625] To a solution of 5.0 g (0.028 mol) of t-butyl sarcosine
hydrochloride in 40 mL of chloroform and 7.0 mL of pyridine was
added 5.35 g (0.028 mol) of 4-fluorobenzenesulfonyl chloride. The
reaction was stirred at room temperature for 48 h and then
concentrated in vacuo. The residue was diluted with ether, washed
with water and dried over magnesium sulfate, filtered and
concentrated in vacuo. The resulting pale yellow solid was washed
with ether/hexanes (1:1) to give 5.7 g of
[(4-fluoro-benzenesulfonyl)-methyl-amino]-acetic acid
tert-butylester as a white solid. Electrospray Mass Spec 304.3
(M+H)+
[0626] To a solution of 1.820 g (6.00 mmol) of of
[(4-fluoro-benzenesulfon- yl)-methyl-amino]-acetic acid
tert-butylester in 25 mL of dimethylformamide was added 5.0 mL (4.0
g, 72.89 mmol) of propargylamine. The mixture was heated to
80.degree. C. and stirred for 48 h. The mixture was partitioned
between 400 mL of dichloromethane and 200 mL of 20% aqueous
NH.sub.4Cl solution. The organic layer was separated, washed with
200 mL of water, dried over anhydrous MgSO.sub.4, filtered, and
concentrated in vacuo. Silica gel column chromatography of the
residue, eluting with 1% MeOH/CH.sub.2Cl.sub.2, provides 1.067 g
(53%) of
2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid,
tert-butyl ester as a light brown oil. Electrospray Mass Spec 339.3
(M+H)+
[0627] To a solution of 0.160 g (0.047 mmol) of
2-(methyl{[4-(prop-2-ynyla- mino)phenyl]sulfonyl}amino)acetic acid,
tert-butyl ester in 1 mL of dichloromethane was added 1 mL of
trifluoroacetic acid and the reaction was stirred at room
temperature for 19 h. Concentration of the mixture in vacuo
provides 0.115 g (86%) of
2-(methyl{[4-(prop-2-ynylamino)phenyl]sul- fonyl}amino)acetic acid
as a brown glass. Electrospray Mass Spec 281.1 (M-H)-
[0628] According to the procedure of Example 25, 0.115 g (0.29
mmol) of
2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl}amino)acetic acid
provides 0.070 g (58%) of
N-hydroxy-2-(methyl{[4-(prop-2-ynylamino)phenyl]sulfonyl-
}amino)acetamide as an orange foam. Electrospray Mass Spec 298.2
(M+H)+
EXAMPLE 134
2-[(4-But-2-ynylthiophenylsulfonyl)methylamino]-N-hydroxyacetamide
[0629] To a solution of 1.820 g (6.00 mmol) of the product of
[(4-fluoro-benzenesulfonyl)-methyl-amino]-acetic acid
tert-butylester in, 25 mL of dimethylsulfoxide was added 4.809 g
(30.00 mmol) of potassium ethyl xanthate. The mixture was heated to
100.degree. C. and stirred for 24 h. It was then partitioned
between 400 mL of dichloromethane and 400 mL of dilute HCl
solution. The organic layer was separated, dried over anhydrous
MgSO.sub.4, filtered, and concentrated in vacuo. Silica gel column
chromatography of the residue, eluting with 1%
MeOH/CH.sub.2Cl.sub.2 provided 1.242 g (65%) of
bis-(4-[{N-(2-acetic acid)-N-methyl}sulfonamido]phenyl)disulfide,
bis-tert-butyl ester as a colorless powder. Electrospray Mass Spec
633.2 (M+H)+
[0630] To a solution of 0.633 g (1.00 mmol) of bis-(4-[{N-(2-acetic
acid)-N-methyl}sulfonamido]phenyl)disulfide, bis-tert-butyl ester
in a mixture of 3 mL of dioxane and 0.75 mL of water was added a
drop of 2N HCl solution and 0.289 g (1.10 mmol) of
triphenylphosphine. The mixture was stirred 3 h at room temperature
and the solvents were then removed in vacuo, heating the flask to
ensure thorough drying of the residue. It was then dissolved in 4
mL of dimethylformamide and 0.088 g (2.20 mmol) of a 60% dispersion
of NaH in mineral oil was added. The mixture was stirred 30 min at
room temperature and 0.25 mL (0.380 g, 2.86 mmol) of
1-bromo-2-butyne was added. The mixture was stirred an additional
30 min at room temperature then partitioned between 200 mL of
diethyl ether and 200 mL of dilute HCl solution. The organic layer
was separated, dried over anhydrous MgSO.sub.4, filtered, and
concentrated in vacuo. Silica gel column chromatography of the
residue provides 0.588 g (80%) of the thioether,
2-[(4-but-2-ynylthiophenylsulfonyl)methylamino]acetic acid
tert-butyl ester, as a colorless oil. Electrospray Mass Spec 370.3
(M+H)+
[0631] To a solution of 0.313 g (1.00 mmol) of
2-[(4-but-2-ynylthiophenyls- ulfonyl)methylamino]acetic acid
tert-butyl ester in 2 mL of dichloromethane was added 2 mL of
trifluoroacetic acid. The mixture was stirred at room temperature
for 2 h and then concentrated in vacuo. Trituration of the residue
with diethyl ether provides 0.262 g (90%) of the carboxylic acid,
2-[(4-but-2-ynylthiophenylsulfonyl)methylamino]aceti- c acid, as an
off-white solid. Electrospray Mass Spec 312.3 (M-H)-
[0632] According to the procedure of Example 25, 0.200 g (0.638
mmol) of 2-[(4-but-2-ynylthiophenylsulfonyl)methylamino]acetic acid
provides 0.147 g (70%) of the hydroxamic acid,
2-[(4-but-2-ynylthiophenylsulfonyl)methyl-
amino]-N-hydroxyacetamide, as a colorless solid. Electrospray Mass
Spec 329.2 (M+H)+
EXAMPLE 135
2-{{[4-(2-Butynyloxy)phenyl]sulfonyl}[4-(4-methyl-1-piperazinyl)-2-yl})-2--
butynyl]amino}-N-hydroxypropanamide
[0633] According to the procedure for Example 125, starting with
(2R)-2-(4-but-2-ynyloxy-benzenesulfonylamino)-propionic acid methyl
ester (from Example 107), the desired
2-{{[4-(2-butynyloxy)phenyl]sulfonyl}[4-(-
4-methyl-1-piperazinyl)-2-yl-2-butynyl]amino}-N-hydroxypropanamide
was obtained. Electrospray Mass Spec 463.4 (M+H)+
EXAMPLE 136
1-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxycyclohexaneca-
rboxamide
[0634] To a stirred suspension of methyl-1-amino-1-cyclohexane
carboxylate hydrochloride (10 g, 51.7 mmol) and
N,N-diisopropylethylamine in methylene chloride (200 mL) and
acetonitrile (50 mL), 4-but-2-ynyloxy-benzenesulfonyl chloride
(14.0 g, 56.8 mmol) was slowly added at room temperature. The
reaction mixture was stirred for 16 hrs and evaporated to dryness.
It was extracted with chloroform, washed well with water and dried
over anhydrous MgSO.sub.4. The chloroform layer was filtered and
concentrated. The product was crystallized from a mixture
acetone:hexane 1:10 to give methyl
1-({[4-(2-butynyloxy)phenyl]sulfonyl}a- mino)cyclohexanecarboxylate
as white crystals, 12.5 g.(66%), mp 118-2.degree. C. Electrospray
Mass Spec 366 (M+H).sup.+.
[0635] A mixture of methyl
1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cycl- ohexanecarboxylate
(4.5 g., 12.3 mmol), anhydrous potassium carbonate (20.0 g, excess)
and methyl iodide (2 g, 14.08 mmol) was refluxed in acetone for
sixteen hours. The reaction mixture was then cooled to room
temperature and filtered. The acetone layer was concentrated and
extracted with chloroform. The chloroform layer was washed well
with water, dried over anhydrous MgSO.sub.4, filtered and
concentrated to provide
methyl1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohex-
anecarboxylate as a yellow oil. Yield: 4.6 g.(quantitative)
Electrospray Mass Spec 380 (M+H).sup.+.
[0636] To a stirred solution of
methyl1-[{[4-(2-butynyloxy)phenyl]sulfonyl-
}(methyl)amino]cyclohexanecarboxylate (4.6 g, 12.1 mmol) in
methanol:THF (4:1, 100 ml), 10 N sodium hydroxide (15 ml) was added
at room temperature. The reaction was stirred for 16 h and
evaporated to dryness in vacuo and the residue was dissolved in 100
mL water. The pH was adjusted to 1 with 5N hydrochloric acid
solution and the mixture was extracted with chloroform, washed with
water, dried and concentrated to give
1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarbox-
ylic acid as a yellow solid. Yield: 4 g(88%); mp 124-6.degree. C.
Electrospray Mass Spec 364(M-H).sup.-.
[0637] To a stirred suspension of
1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(me-
thyl)amino]cyclohexanecarboxylic acid (4.0 gm, 10.9 mmol) in
methylene chloride (200 ml)/DMF (5 ml), oxalyl chloride (8.0 gm, 63
mmol) in methylene chloride (10 ml) was added slowly at 0.degree.
C. After the addition, the reaction mixture was stirred at room
temperature for 1 h. In a separate flask, hydroxylamine
hydrochloride (6.9 gm, 100 mmol) was dissolved in DMF/acetonitrile
(1:1, 100 ml) and triethylamine (20 gm, 200 mmol) was added. It was
stirred at room temperature for 1 h and diluted with methylene
chloride (50 ml). The acid chloride formed was concentrated to
dryness and redissolved in methylene chloride. Hydroxylamine was
cooled to 0.degree. C., and the acid chloride was added to the
hydroxylamine. The reaction mixture was stirred at room temperature
for 6 h and concentrated to dryness. It was extracted with
chloroform, washed well with water and dried over anhydrous
MgSO.sub.4. It was filtered and concentrated. Product was purified
by silica-gel column chromatography by eluting it with ethyl
acetate: hexane (3:1) to give as a white spongy solid; Yield 3.6 g
(88%); mp 89-92.degree. C.; Electrospray Mass Spec 381 (M+H).sup.+;
H.sup.1 NMR (CDCl.sub.3) .quadrature.: 1.35-1.41 (m, 2H), 1.55-1.72
(m, 6H), 1.80 (s, 3H), 2.23-2.26 (m, 2H), 3.41 (s, 3H), 4.81
(s,2H), 7.22 (dd, 2H), 7.89 (dd, 2H), 9.66 (bs, 1H).
EXAMPLE 137
1-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(3-pyridinylmethyl)amino]
N-hydroxycyclohexanecarboxamide
[0638] According to the procedure of Example 136, but using
3-picolyl chloride hydrochloride to alkylate the sulfonamide
instead of iodomethane, methyl
1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexan- ecarboxylate
was converted into 1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(3-py-
ridinylmethyl)amino]-N-hydroxycyclohexane-carboxamide, obtained as
a white solid. mp 179-81.degree. C.; Electrospray Mass Spec: 458
(M+H).sup.+; H.sup.1 NMR (DMSO) .quadrature.: 1.21-1.24 (m, 2H),
1.61-1.72 (m, 6H), 1.81 (s, 3H), 2.48 (m, 2H), 4.59 (s, 2H), 4.72
(s,2H), 6.91 (m,1H), 7.20 (dd,2H), 7.62 (m, 2H), 7.79 (dd, 2H),
7.84 (m, 1H), 12.42-12.58 (bs, 1H).
EXAMPLE 138
1-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxycyclohexanecarboxamid-
e
[0639] To a stirred solution of methyl
1-({[4-(2-butynyloxy)phenyl]sulfony- l}amino) cyclohexane
carboxylate (4.3 g, 11.8 mmol) in methanol:THF (4:1, 100 ml) 10 N
sodium hydroxide (15 ml) was added at room temperature. It was
stirred for 16 hrs and evaporated to dryness in vacuo. The residue
was dissolved in 100 mL water, pH adjusted to 7 with 5N
hydrochloric, acid solution. It was extracted with
chloroform/methanol (3:1), washed with water, dried and
concentrated to give 1-({[4-(2-butynyloxy)phenyl]su- lfonyl}amino)
cyclohexane carboxylic acid. Yield 4.0 g (98%); White solid, mp.
112-4.degree. C. Electrospray Mass Spec 349 (M-H).sup.-.
[0640] To a stirred suspension of
1-({[4-(2-butynyloxy)phenyl]sulfonyl}ami- no) cyclohexane
carboxylic acid (4.0 gm, 11.4 mmol) in methylene chloride (200
ml)/DMF (5 ml) oxalyl chloride (8.0 gm, 63 mmol) in methylene
chloride (10 ml) was added slowly at 0.degree. C. After addition,
reaction mixture was stirred at room temperature for 1 hr. In a
separate flask, hydroxylamine hydrochloride (6.9 gm, 100 mmol) was
dissolved in DMF/acetonitrile (1:1, 100 ml) and triethylamine (20
gm, 200 mmol) was added. It was stirred at room temperature for 1
hr and diluted with methylene chloride (50 ml). The acid chloride
formed was concentrated to dryness and redissolved in methylene
chloride. Hydroxylamine was cooled to 0.degree. C., and the acid
chloride was added to the hydroxylamine. Reaction mixture was
stirred at room temperature for 6 hrs and concentrated to dryness.
It was extracted with chloroform, washed well with water and dried
over anhydrous MgSO.sub.4. It was filtered and concentrated.
Product was purified by silica-gel column chromatography by eluting
it with ethyl acetate: hexane (3:1) to give
1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy
cyclohexanecarboxamide. White solid; Yield 3.2 g (78%); M.Pt.
82-84.degree. C.; Electrospray Mass Spec: 367 (M+H).sup.+; H.sup.1
NMR (CDCl.sub.3) .quadrature.: 1.35-1.41 (m, 2H), 1.55-1.72 (m,
6H), 1.80 (s, 3H), 2.23-2.26 (m, 2H), 4.81 (s,2H), 5.27 (s,1H) 7.22
(dd,2H), 7.89 (dd, 2H), 9.66 (bs, 1H).
EXAMPLE 139
1-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxycyclopentanecarboxami-
de
[0641] To a stirred suspension of methyl-1-amino-1-cyclopentane
carboxylate hydrochloride (15 g, 84.0 mmol) and
N,N-diisopropylethylamine in methylene chloride (200 mL) and
acetonitrile (50 mL), 4-butynyloxyphenylsulfonylchloride (24.7 g,
100 mmol) was slowly added at room temperature. Reaction mixture
was stirred for 16 hrs and evaporated to dryness. It was extracted
with chloroform, washed well with water and dried over anhydrous
MgSO.sub.4. Chloroform layer was filtered and concentrated. The
product was crystallized from a mixture acetone:hexane (1:1) to
give methyl 1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclopent-
ane carboxylate as white crystals, 26.8 g (91%), mp 81-3.degree. C.
Electrospray Mass Spec352 (M+H).sup.+.
[0642] To a stirred solution of methyl
1-({[4-(2-butynyloxy)phenyl]sulfony- l}amino) cyclopentane
carboxylate (5.5 g, 15.6 mmol) in methanol:THF (4:1, 100 ml) 10 N
sodium hydroxide (15 ml) was added at room temperature. It was
stirred for 16 h and evaporated to dryness in vacuo, the residue
was dissolved in 100 mL water, pH adjusted to 7 with 5N
hydrochloric acid solution. It was extracted with
chloroform;methanol (3:1) washed with water, dried and concentrated
to give 1-({[4-(2-butynyloxy)phenyl]sulfony- l}amino) cyclopentane
carboxylic acid. Yield 4.5 g (86%); White solid, mp.108-110
.degree. C. Electrospray Mass Spec 336 (M-H).sup.-.
[0643] To a stirred suspension of
1-({[4-(2-butynyloxy)phenyl]sulfonyl}ami- no) cyclopentane
carboxylic acid. (1.2 g, 3.56 mmol) in methylene chloride (200
ml)/DMF (5 ml) oxalyl chloride (8.0 g, 63 mmol) in methylene
chloride (10 ml) was added slowly at 0.degree. C. After addition,
reaction mixture was stirred at room temperature for 1 hr. In a
separate flask, hydroxylamine hydrochloride (6.9 g, 100 mmol) was
dissolved in DMF/acetonitrile (1:1, 100 ml) and triethylamine (20
g, 200 mmol) was added. It was stirred at room temperature for 1 hr
and diluted with methylene chloride (50 ml). The acid chloride
formed was concentrated to dryness and redissolved in methylene
chloride. Hydroxylamine was cooled to 0.degree. C., and the acid
chloride was added to the hydroxylamine. Reaction mixture was
stirred at room temperature for 6 hrs and concentrated to dryness.
It was extracted with chloroform, washed well with water and dried
over anhydrous MgSO.sub.4. It was filtered and concentrated.
Product was purified by silica-gel column chromatography by eluting
it with ethyl acetate: hexane (3:1) to give
1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy
cyclopentane-carboxamide. White solid; Yield 1.1 g (88%); mp
66-68.degree. C.; Electrospray Mass Spec: 353 (M+H).sup.+; H.sup.1
NMR (CDCl.sub.3) .quadrature.: 1.32-1.40 (m, 2H), 1.58-1.80 (m,
4H), 1.83 (s, 3H), 1.91-1.94 (m, 1H), 2.03-2.12 (m,1H), 4.70
(s,2H), 5.25 (s,1H), 7.20 (dd,2H), 7.85 (dd, 2H), 9.58 (bs,
1H).
EXAMPLE 140
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-[-
(2(4-morpholinylethyl)sulfanyl]-butanamide Hydrochloride
[0644] Step 1
[0645] A solution of D-penicillamine (0.5 g, 3.35 mmol) in methanol
(5 mL) was cooled to 0.degree. C. and crushed sodium hydroxide
(0.28 g, 6.87 mmol) was added to give a clear solution.
2-Bromoethanol (0.26 mL, 3.71 mmol) was added and stirred at
0.degree. C. for 1 h and at room temperature for an additional 1.5
h. The reaction was concentrated, and the oily residue was
dissolved in 3 mL water and 6 mL DMF and stirred with sodium
carbonate (0.82 g 7.2 mmol) and 4-butynyloxy-benzenesufonyl
chloride (0.78 g, 3.18 mmol) at room temperature overnight. The
reaction was concentrated and the residue was extracted with ethyl
acetate and water. The aqueous layer was acidified to pH .about.3
with concentrated HCl and extracted with ethyl acetate. The second
ethyl acetate extract was washed with water and brine, dried over
sodium sulfate, filtered and concentrated to obtain 1.2 g of
N-{[4-(2 butynyloxy)phenyl]sulfonyl}-3-[(-
2-hydroxyethyl)sulfanyl]valine as an oil. Yield 89.6%. Electrospray
Mass Spec 400.1 (M-H).sup.-.
[0646] Step 2
[0647] To a solution of
N-{[4-(2-butynyloxy)phenyl]sulfonyl}-3-[(2-hydroxy-
ethyl)sulfanyl]valine (1.2 g, 2.99 mmol), in dimethylacetamide (8
mL) was added potassium carbonate (3.3 g, 23.9 mmol),
benzyltriethylammonium chloride (0.20 g, 0.90 mmol) and
2-bromo-2-methyl-propane (5.5 mL, 47.9 mmol) and the mixture was
heated at 50.degree. C. overnight. The mixture was then diluted
with ethyl acetate and washed with water and brine, dried over
sodium sulfate, filtered and evaporated to obtain 1.10 g of
tert-butyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl)amino-3-[(2hydroxyethyl)s-
ulfanyl]-3-methylbutanoate as an oil. Yield .about.80.9%.
Electrospray Mass Spec 458.2 (M+H).sup.+.
[0648] Step 3
[0649] To a solution of tert-butyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl)am-
ino-3-[(2-sulfonyl}amino)-3-[(2-hydroxyethyl)sulfanyl]-3-methylbutanoate
(1.1 g, 2.41 mmol) in DMF (8 mL) was added iodomethane (0.18 mL,
2.89 mmol) and potassium carbonate (0.99 g, 7.22 mmol) and the
resulting mixture was stirred at room temperature overnight. After
evaporating the solvent, the residue was extracted with ethyl
acetate and water. The organic layer was washed with water and
brine, dried over sodium sulfate, filtered, and evaporated to
obtain 0.96 g of tert-butyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl](methyl)}amino)-3-[(2-hydroxyethyl)s-
ulfanyl]-3-methylbutanoate. Yield .about.85%. Electrospray Mass
Spec 472.2 (M+H).sup.+.
[0650] Step 4
[0651] To a 0.degree. dichloromethane solution (4 mL) of tert-butyl
2-({[4-(2-butynyloxy)
phenyl]sulfonyl)(methyl)]-amino)-3-[(2-hydroxyethyl-
)sulfanyl]-3-methylbutanoate (0.96 g, 2.04 mmol), carbon
tetrabromide (0.68 g, 2.04 mmol), was added a dichloromethane
solution (2 mL) of triphenylphosphine and the reaction mixture was
stirred at 0.degree. C. for 10 minutes and at room temperature
overnight. After evaporating the solvent, the oily mixture was
purified by column chromatography, eluting with hexane:ethyl
acetate (4:1) to give 0.71 g of tert-butyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)]amino)-3-[(2-bromoethyl)sul-
fanyl]-3-methylbutanoate. Yield: 66.4%. FAB Mass Spec 556
(M+Na).sup.+.
[0652] Step 5
[0653] To a solution of tert-butyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(m-
ethyl)]amino)-3-[(2-bromoethyl)sulfanyl]-3-methylbutanoate (0.65 g,
1.24 mmol) and morpholine (0.27 mL, 3.1 mmol) in DMF (6 mL) was
added potassium carbonate (0.4 g, 2.93 mmol). The mixture was
stirred at room temperature overnight. After evaporating the
solvent, the mixture was extracted with dichloromethane and water.
The organic layer was washed with water and brine, dried over
sodium sulfate, filtered and concentrated to obtain 0.65 g of
tert-butyl 2-({[4-(2-butynyloxy)phenyl]s-
ulfonyl)-(methyl)amino)]-3-methyl-3-[(2(4-morpholinylethyl)sulfanyl]-butan-
oate as an oil. Yield:96%. Electrospray Mass Spec 541.2
(M+H).sup.+.
[0654] Step 6
[0655] A solution of tert-butyl
2-{[4-(2-butynyloxy)phenyl]sulfonyl)(methy-
l)]amino)-3-methyl-3-[(2(4-morpholinylethyl)sulfanyl]-butanoate
(0.59 g, 1.1 mmol) and trifluoroacetic acid (5 mL) in
dichloromethane (10 mL) was stirred at room temperature overnight.
Evaporating the solvent provide 0.71 g of the trifluoroacetic acid
salt of N-{[4-2-butynyloxy)phenyl]sulf-
onyl}-3-{[2-4-morpholinyl)ethyl]sulfanyl}valine. Electrospray Mass
Spec 485.2 (M+H ).sup.+.
[0656] Step 7
[0657] A solution of
N-{[4-2-butynyloxy)phenyl]sulfonyl}-3-{[2-4-morpholin-
yl)ethyl]sulfanyl}valine (0.69 g, 1.42 mmol) in dichloromethane (6
mL) and DMF (0.22 mL, 2.85 mmol) was cooled in an ice bath and
oxalyl chloride (0.71 mL of 2M in CH.sub.2Cl.sub.2, 2.85 mmol) was
dropped in. The reaction mixture was stirred at 0.degree. C. for 10
minutes and at room temperature for 2 h. The reaction was recooled
to 0.degree., and a THF (4.5 mL) solution of triethylamine (0.8 mL,
5.70 mmol) and hydroxylamine (0.52 mL of 50% hydroxyamine in water,
8.55 mmol) was added in one portion. The reaction was warmed to
room temperature and stirred overnight. After evaporating the
solvent, the oily residue was extracted with ethyl acetate and
water. The organic layer was washed with water and brine, dried
over sodium sulfate, filtered, and evaporated to obtain 0.5 g of
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-meth-
yl-3 [(2(4-morpholinylethyl)sulfanyl]-butanamide as a light yellow
solid. Yield .about.86.2%. mp 45-50.degree. C. Electrospray Mass
Spec 500.2 (M+H).sup.+.
[0658] The above compound (0.39 g, 0.78 mmol) was dissolved in
dichloromethane (3 mL) and cooled in an ice bath. Then a 1M
hydrogen chloride solution in ethyl ether (0.86 mL, 0.86 mmol) was
dropped in. The mixture was stirred at 0.degree. C. for 10 minutes
and at room temperature for 1.5 h. The residue was diluted with
ethyl ether and filtered to give 0.37 g of
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)a- mino]-N-hydroxy-3
methyl-3-[(2(4-morpholinylethyl)sulfanyl]-butanamide hydrochloride
as a white solid. Mp 50.degree. C. (d). Electrospray Mass Spec
500.2 (M+H).sup.+.
EXAMPLE 141
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-{-
[2(4-methyl-1-ethyl-1-piperazinyl)ethyl]sulfanyl}butanamide
[0659] According to the procedure of Example 140, using
1-methylpiperazine in Step 5,
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-- 3
methyl-3-{[2(4-methyl-1-ethyl-1-piperazinyl)ethyl]sulfanyl}butanamnide
was obtained. mp 110-115.degree. C. Electrospray Mass Spec 513.3
(M+H).sup.+. Hydrochloride salt mp 90-95.degree. C. Electrospray
Mass Spec 513.3 (M+H).sup.+.
EXAMPLE 142
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-3-{-
[2-(diethylamino)ethyl]sulfanyl}butanamide
[0660] According to the procedure of Example 140, using
diethylamine in Step 5,
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3
methyl-3-{[2-(diethylamino)ethyl]sulfanyl}butanamide was obtained.
mp 55-57.degree. C. Electrospray Mass Spec 486.4 (M+H).sup.+.
Hydrochloride salt mp 87-90.degree. C. Electrospray Mass Spec 486.5
(M+H).sup.+.
EXAMPLE 143
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3
methyl-3-{[2(1-pyrrolidinyl)ethyl]sulfanyl}butanamide
[0661] According to the procedure of Example 140, using pyrrolidine
in Step 5,
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3
methyl-3-{[2(1-pyrrolidinyl)ethyl]sulfanyl}butanamide was obtained.
mp 55-57.degree. C. Electrospray Mass Spec 484.4(M+H).sup.+.
Hydrochloride salt mp 58-60.degree. C. Electrospray Mass Spec 484.4
(M+H).sup.+.
EXAMPLE 144
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3
methyl-3-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}butanamide
[0662] According to the procedure of Example 140, using imidazole
in Step 5,
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3-methyl-
-3-{[2-(1H imidazol-1-yl)ethyl]sulfanyl}butanamide was obtained. mp
97-100.degree. C. Electrospray Mass Spec 481.4 (M+H).sup.+.
Hydrochloride salt mp 67-70.degree. C. Electrospray Mass Spec 481.4
(M+H).sup.+.
EXAMPLE 145
Methyl
1-[2-({2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)]amino]-3-(hydr-
oxyamino)-1,1-dimethyl-3-oxopropyl}sulfanyl)ethyl]-2-pyrrolidinecarboxylat-
e
[0663] According to the procedure of Example 140, using proline
ethyl ester in Step 5, methyl
1-[2-({2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(meth-
yl)]amino]-3-(hydroxyamino
)-1,1-dimethyl-3-oxopropyl}sulfanyl)ethyl]-2-py-
rrolidine-carboxylate was obtained. mp 57-60.degree. C.
Electrospray Mass Spec 542.4 (M+H).sup.+. Hydrochloride salt mp
85-90.degree. C. Electrospray Mass Spec 542.5 (M+H).sup.+.
EXAMPLE 146
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3
methyl-3-[(2(4-morpholinylpropyl)sulfanyl]-butanamide
[0664] According to the procedure of Example 140, using
1-bromo-3-propanol in Step 1,
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy--
3-methyl-3-[(2(4-morpholinylpropyl)sulfanyl]-butanamide was
obtained. mp 48-52.degree. C. Electrospray Mass Spec 514.4
(M+H).sup.+. Hydrochloride salt mp 94-96.degree. C. Electrospray
Mass Spec 514.4(M+H).sup.+.
EXAMPLE 147
2-({[4-(2-Butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3
methyl-3-{[2(4-methyl-1-ethyl-1-piperazinyl)propyl]sulfanyl}butanamide
[0665] According to the procedure of Example 140, using
1-bromo-3-propanol in Step 1 and 1-methylpiperazine in Step 5,
2-({[4-(2-butynyloxy)phenyl]s- ulfonyl) (methyl)amino]-N-hydroxy-3
methyl-3-{[2(4-methyl-1-ethyl-1-pipera-
zinyl)propyl]sulfanyl}butanamide was obtained. mp 58-62.degree. C.
Electrospray Mass Spec 527.6 (M+H).sup.+. Hydrochloride salt mp
74-80.degree. C. Electrospray Mass Spec 527.4 (M+H).sup.+.
EXAMPLE 148
2-({[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-3
methyl-3-{[2-(diethylamino)propyl]sulfanyl}butanamide
[0666] According to the procedure of Example 140, using
1-bromo-3-propanol in Step 1 and diethylamine in Step 5,
2-({[4-(2-butynyloxy)phenyl]sulfony- l)(methyl)amino]-N-hydroxy-3
methyl-3-{[2-(diethylamino)propyl]sulfanyl}bu- tanamide was
obtained. mp 65-68.degree. C. Electrospray Mass Spec 500.4
(M+H).sup.+. Hydrochloride salt mp 58-60.degree. C. Electrospray
Mass Spec 500.4 (M+H).sup.+.
EXAMPLE 149
2-[(4-But-2-ynloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3-meth-
ylsulfanyl-butyramide
[0667] Step 1
[0668] A solution of D-penicillamine (0.5 g, 3.35 mmol) in methanol
was cooled to 0.degree. C. and crushed sodium hydroxide (0.28 g,
7.04 mmol) was added to give a clear solution. Iodomethane (0.23
mL, 3.69 mmol) was added and the reaction was stirred at 0.degree.
C. for 10 minutes and at room temperature for an additional 1.5 h.
After evaporating the solvent, the residue was dissolved in 2 mL of
water and acidified with 6N HCl to pH .about.3. After evaporating
the solvent again, the oily residue was dissolved in 3 mL of water
and 6 mL of DMF and stirred with sodium carbonate (1.17 g, 11.0
mmol) and 4-but-2-ynyloxy-benzenesufonyl chloride (0.9 g, 3.69
mmol) at room temperature overnight. The solvent was evaporated and
the residue was diluted with ethyl acetate and water. The aqueous
layer was acidified to pH .about.3 with concentrated HCl and
extracted with ethyl acetate. The second ethyl acetate extract was
washed with water and brine, dried over sodium sulfate, filtered
and concentrated to provide 0.94 g of
2-(4-but-2-ynyloxy-benenesulfonylamino)-
-3-methyl-3-methylsulfanyl-butyric acid as a white solid. Yield
75.8%. mp 108-110.degree. C. Electrospray Mass Spec 369.9
(M-H).sup.-.
[0669] Step 2
[0670] To a solution of
2-(4-but-2-ynyloxy-benenesulfonylamino)-3-methyl-3-
-methylsulfanyl-butyric acid (0.37 g, 1 mmol) dissolved in
dimethylacetamide (3 mL) was added potassium carbonate (1.12 g, 8.1
mmol), benzyltriethylammonium chloride (0.073 g, 0.32 mmol) and
2-bromo-2-methyl-propane (1.9 mL, 16.4 mmol). The mixture was
heated to 50.degree. C. overnight and then diluted with ethyl
acetate and washed, with water and brine, dried over sodium
sulfate, filtered and evaporated to provide 0.43 g of
2-(4-but-2-ynyloxy-benenesulfonylamino)-3-methyl-3-m-
ethylsulfanyl-butyric acid tert-butyl ester as an oil. Yield
.about.100%. Electrospray Mass Spec 427.9 (M+H).sup.+.
[0671] Step 3
[0672] A solution of
2-(4-but-2-ynyloxy-benenesulfonylamino)-3-methyl-3-me-
thylsulfanyl-butyric acid tert-butyl ester (0.4 g, 0.94 mmol) in
DMF (5 mL) was treated with iodomethane (0.07 mL, 1.13 mmol) and
0.39 g of potassium carbonate at room temperature overnight. After
evaporating the solvent, the residue was extracted with ethyl
acetate and water. The organic layer was washed with water and
brine, dried over sodium sulfate, filtered and evaporated to
provide 0.33 g of 2-[(4-but-2-ynyloxy-benenesu-
lfonyl)-3-methyl-amino]-3-methyl-3-methylsulfanyl-butyric acid
tert-butyl ester. Yield .about.80.4%. Electrospray Mass Spec 442
(M+H).sup.+.
[0673] Step 4
[0674] To a solution of
2-[(4-but-2-ynyloxy-benenesulfonyl)-3-methyl-amino-
]-3-methyl-3-methylsulfanyl-butyric acid tert-butyl ester (0.31 g,
0.7 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid
(3 mL) and the reaction was stirred at room temperature for 1 h.
The dichloromethane and TFA were evaporated to give the 0.29 g of
2-[(4-but-2-ynyloxy-benenes-
ulfonyl)-3-methyl-amino]-3-methyl-3-methylsulfanyl-butyric acid,
which was used for next step without further purification. Yield
.about.100%. Electrospray Mass Spec 383.9(M-H).sup.-.
[0675] Step 5
[0676] A solution of
2-[(4-but-2-ynyloxy-benenesulfonyl)-3-methyl-amino]-3-
-methyl-3-methylsulfanyl-butyric acid (0.24 g, 0.62 mmol) in
dichloromethane (2mL) was cooled in an ice bath and DMF (0.96 mL,
1.25 mmol) was added and followed by oxalyl chloride (0.62 mL of a
2M solution in CH.sub.2Cl.sub.2, 1.25 mmol). The reaction mixture
was stirred at 0.degree. C. for 10 minutes and at room temperature
for 2 h. The reaction was recooled to 0.degree. and a THF (1.5 mL)
solution of triethylamine (0.35 mL 2.49 mmol) and hydroxylamine
(0.23 mL of 50% hydroxylamine in water, 3.74 mmol) was added in one
portion. The reaction was warmed to room temperature and stirred
overnight. After removing solvent, the oily residue was diluted
with ethyl acetate and water. The organic layer was washed with
water and brine, dried over sodium sulfate, filtered and evaporated
to provide 2-[(4-but-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-
-hydroxy-3-methyl-3-methylsulfanyl-butyramide as a white solid
which was triturated with ethyl ether to give 0.23 g. Yield
.about.92%. mp 132-135.degree. C. Electrospray Mass Spec 401
(M+H).sup.+.
EXAMPLE 150
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3-eth-
ylsulfanyl-butyramide
[0677] According to the procedure of Example 149, using iodoethane
in Step 1 instead of iodomethane,
2-[(4-but-2-ynyloxy-benenesulfonyl)-methyl-amin-
o]-N-hydroxy-3-methyl-3-ethylsulfanyl-butyramide was obtained. mp
130-131.degree. C. Electrospray Mass Spec 425.2 (M+H).sup.+.
EXAMPLE 151
2-[(4-But-2-ynyloxy-benenesulfonyl-methyl-amino]-N-hydroxy-3-methyl-3-prop-
ylsulfanyl-butyramide
[0678] According to the procedure of Example 149, using iodopropane
in Step 1 instead of iodomethane,
2-[(4-but-2-ynyloxy-benenesulfonyl)-methyl-
-amino]-N-hydroxy-3-methyl-3-propylsulfanyl-butyramide was
obtained. mp 132-135.degree. C. Electrospray Mass Spec 429.2
(M+H).sup.+.
EXAMPLE 152
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3-(py-
ridin-3-ylmethylsulfanyl)-butyramide
[0679] According to the procedure of Example 149, using 3-picolyl
chloride hydrochloride in Step 1 instead of iodomethane,
2-[(4-but-2-ynyloxy-benen-
esulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3-(pyridin-3-ylmethylsulfanyl)-
-butyramide was obtained. mp 85-88.degree. C. Electrospray Mass
Spec 478.1 (M+H).sup.+.
EXAMPLE 153
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-methyl-3-ben-
zylsulfanyl-butyramide
[0680] According to the procedure of Example 149, using benzyl
bromide in Step 1 instead of iodomethane,
2-[(4-but-2-ynyloxy-benenesulfonyl)-methyl-
-amino]-N-hydroxy-3-methyl-3-benzylsulfanyl-butyramide was
obtained. mp 156-158.degree. C. Electrospray Mass Spec 477.2
(M+H).sup.+.
EXAMPLE 154
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-(methylsulfa-
nyl)-butyramide
[0681] According to the procedure of Example 149, using D-cysteine
in Step 1 instead of D-penicillamine,
2-[(4-but-2-ynyloxy-benenesulfonyl)-methyl--
amino]-N-hydroxy-3-(methylsulfanyl)-butyramide was obtained.
Electrospray Mass Spec 373.2 (M+H).sup.+.
EXAMPLE 155
2-[(4-But-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-(pyridin-3-y-
lmethylsulfanyl)-butyramide
[0682] According to the procedure of Example 149, using D-cysteine
in Step 1 instead of D-penicillamine and 3-picolyl chloride
hydrochloride instead of iodomethane,
2-[(4-but-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydro-
xy-3-(pyridin-3-ylmethylsulfanyl)-butyramide was obtained. mp
90-95.degree. C. Electrospray Mass Spec 450.2 (M+H).sup.+.
EXAMPLE 156
3-(Benzylthio)-2-[[[4-(2-butynyloxy)phenyl]sulfonyl]methylamino]-N-hydroxy-
propanamide
[0683] According to the procedure of Example 149, using D-cysteine
in Step 1 instead of D-penicillamine and benzyl bromide instead of
iodomethane,
2-[(4-but-2-ynyloxy-benenesulfonyl)-methyl-amino]-N-hydroxy-3-(pyridin-3--
ylmethylsulfanyl)-butyramide was obtained. Electrospray Mass Spec
449.2 (M+H).sup.+.
EXAMPLE 157
3-(Benzylthio)-2-[[[4-(2-butynyloxy)phenyl]sulfonyl]pyridin-3-ylmethylamin-
o]-N-hydroxypropanamide
[0684] According to the procedure of Example 149, using D-cysteine
in Step 1 instead of D-penicillamine and benzyl bromide instead of
iodomethane, and using 3-picolyl chloride hydrochloride instead of
iodomethane in Step 3,
3-(benzylthio)-2-[[[4-(2-butynyloxy)phenyl]sulfonyl]pyridin-3-ylmethyl-
amino]-N-hydroxy-propanamide was obtained. mp 74-78.degree. C.
Electrospray Mass Spec 526.2 (M+H).sup.+.
EXAMPLE 158
2-[[[4-(2-Butynyloxy-phenyl]sulfonyl]amino]-N-hydroxy-3-methyl-(3-methylth-
io)-butyramide
[0685] Step 1
[0686] A solution of D-penicillamine (0.5 g, 3.35 mmol) in methanol
was cooled to 0.degree. C. and crushed sodium hydroxide (0.28 g,
7.04 mmol) was added to give a clear solution. Iodomethane (0.23
mL, 3.69 mmol) was added and the reaction was stirred at 0.degree.
C. for 10 minutes and at room temperature for an additional 1.5 h.
After evaporating the solvent, the residue was dissolved in 2 mL of
water and acidified with 6N HCl to pH .about.3. After evaporating
the solvent again, the oily residue was dissolved in 3 mL of water
and 6 mL of DMF and stirred with sodium carbonate (1.17 g, 11.0
mmol) and 4-but-2-ynyloxy-benzenesufonyl chloride (0.9 g, 3.69
mmol) at room temperature overnight. The solvent was evaporated and
the residue was diluted with ethyl acetate and water. The aqueous
layer was acidified to pH .about.3 with concentrated HCl and
extracted with ethyl acetate. The second ethyl acetate extract was
washed with water and brine, dried over sodium sulfate, filtered
and concentrated to provide 0.94 g of
2-(4-but-2-ynyloxy-benenesulfonylamino)-
-3-methyl-3-methylsulfanyl-butyric acid as a white solid. Yield
75.8%. mp 108-110.degree. C. Electrospray Mass Spec 369.9
(M-H).sup.-.
[0687] Step 2
[0688] According to the procedure of Step 5, Example 149,
2-(4-but-2-ynyloxy-benenesulfonylamino)-3-methyl-3-methylsulfanyl-butyric
acid was converted into the corresponding hydroxamic acid,
2-[[[4-(2-butynyloxy-phenyl]sulfonyl]amino]-N-hydroxy-3-methyl-(3-methylt-
hio)-butyramide. mp 128-132.degree. C. Electrospray Mass Spec 386.9
(M+H).sup.+.
EXAMPLE 159
2-[(4But-2-ynyloxy-benenesulfonyl)-amino]-N-hydroxy-3-methyl-3-ethylsulfan-
yl-butyramide
[0689] According to the procedure of Example 158, using iodoethane
instead of iodomethane in Step 1,
2-[(4-but-2-ynyloxy-benenesulfonyl)amino]-N-hyd-
roxy-3-methyl-3-ethylsulfanyl-butyramide was obtained. mp
46-50.degree. C. Electrospray Mass Spec 401.3 (M+H).sup.+.
EXAMPLE 160
2-[(4-But-2-ynyloxy-benenesulfonyl)-amino]-N-hydroxy-3-methyl-3-propylsulf-
anyl-butyramide
[0690] According to the procedure of Example 158, using iodopropane
instead of iodomethane in Step 1,
2-[(4-but-2-ynyloxy-benenesulfonyl)-ami-
no]-N-hydroxy-3-methyl-3-propylsulfanyl-butyramide was obtained. mp
152-155.degree. C. Electrospray Mass Spec 415.2 (M+H).sup.+.
EXAMPLE 161
2-[(4-Butynyloxy-phenylsulfonyl)-amino]-N-hydroxy-3-methyl-[(3-pyridinylme-
thyl)thio]butyramide
[0691] According to the procedure of Example 158, using 3-picolyl
chloride hydrochloride instead of iodomethane in Step 1,
2-[(4-butynyloxy-phenylsu-
lfonyl)-amino]-N-hydroxy-3-methyl-[(3-pyridinylmethyl)thio]butyramide
was obtained. mp 95-100.degree. C. Electrospray Mass Spec 464.0
(M+H).sup.+.
EXAMPLE 162
2-[(4-Butynyloxy-phenyl)sulfonyl)-amino]-N-hydroxy-3-methyl-(3-benzylsulfa-
nyl)butyramide
[0692] According to the procedure of Example 158, using benzyl
bromide instead of iodomethane in Step 1,
2-[(4-butynyloxy-phenyl)sulfonyl)-amino-
]-N-hydroxy-3-methyl-(3-benzylsulfanyl)butyramide was obtained. mp
92-95.degree. C. Electrospray Mass Spec 463.1 (M+H).sup.+.
EXAMPLE 163
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-3-{[(1-methyl-1H-imid-
azol-2-yl]methylsulfanyl}butanamide
[0693] According to the procedure of Example 158, using
1-methyl-chloromethylimidazole instead of iodomethane in Step 1,
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-3-{[(1-methyl-1H-imi-
dazol-2-yl]methylsulfanyl}butanamide was obtained. mp
112-115.degree. C. Electrospray Mass Spec 467.1(M+H).sup.+.
EXAMPLE 164
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-3-methyl-3-{[2-(4-mor-
pholinyl)ethyl]sulfanyl}butanamide
[0694] According to the procedure of Example 158, using
4-(2-chloroethyl)morpholine hydrochloride instead of iodomethane in
Step 1,
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino-N-hydroxy-3-methyl-3-{[2-(4-
-morpholinyl)ethyl]sulfanyl}butanamide was obtained. mp 72.degree.
C. Electrospray Mass Spec 486.2 (M+H).sup.+.
EXAMPLE 165
tert-butyl{[2-({[4-2-butynyloxy)phenyl]sulfonyl}amino)-3-(hydroxyamino)-1,-
1-dimethyl-3-oxopropyl]sulfanyl}acetate
[0695] According to the procedure of Example 158, using tert-butyl
bromoacetate instead of iodomethane in Step 1,
tert-butyl{[2-({[4-2-butyn-
yloxy)phenyl]sulfonyl}amino)-3-(hydroxyamino)-1,1-dimethyl-3-oxopropyl]sul-
fanyl}acetate was obtained. mp 47-52.degree. C. Electrospray Mass
Spec 487 (M+H).sup.+.
EXAMPLE 166
tert-Butyl{[2-({[4-2-butynyloxy)phenyl]sulfonyl}amino)-3-(hydroxyamino)-1,-
1-dimethyl-3-oxopropyl]sulfanyl Acetic Acid, Sodium Salt
[0696] The product of Example 165 (0.6 g, 1.23 mM) was dissolved in
trifluoroacetic acid (5 mL) and dichloromethane (10 mL) and stirred
at room temperature overnight. After evaporating the solvent, the
residue was purified by preparative TLC, eluting with
dichloromethane:methanol (92:8) to obtain 0.23 g of
tert-butyl{[2-({[4-2-butynyloxy)phenyl]sulfony-
l}amino)-3-(hydroxyamino)-1,1-dimethyl-3-oxopropyl]sulfanyl acetic
acid. mp162-164.degree. C. (d). Electrospray Mass Spec 429.3
(M-H).sup.-. To this acid (0.22 g, 0.51 mmol) in methanol (12 mL),
was added 1N NaOH (0.52 mL, 0.52 mM) and the reaction was stirred
at room temperature for 1 h, and then concentrated to provide 0.24
g of tert-butyl{[2-({[4-2-butyny-
loxy)phenyl]sulfonyl}amino)-3-(hydroxyamino)-1,1-dimethyl-3-oxopropyl]sulf-
anyl acetic acid, sodium salt as a yellow-orange solid. m.p.
75.degree. C.(d). Electrospray Mass Spec 429 (M-H).sup.-.
EXAMPLE 167
2-[(4-Butynyloxy-phenylsulfonyl)-amino]-N-hydroxy-3-(methylthio)propanamid-
e
[0697] According to the procedure of Example 158, using D-cysteine
instead of D-penecillamine in Step 1,
2-[(4-butynyloxy-phenylsulfonyl)-amino]-N-h-
ydroxy-3-(methylthio)propanamide was obtained. mp 128-130.degree.
C. Electrospray Mass Spec 359.2 (M+H).sup.+.
EXAMPLE 168
2-[[4-Butynyloxy-phenylsulfonyl]-amino]-N-hydroxy-3-(benzylthio)propanamid-
e
[0698] According to the procedure of Example 158, using D-cysteine
instead of D-penicillamine and benzyl bromide instead of
iodomethane in Step 1,
2-[[4-butynyloxy-phenylsulfonyl]-amino]-N-hydroxy-3-(benzylthio)propanami-
de was obtained. mp 137-138.degree. C. Electrospray Mass Spec 435.1
(M+H).sup.+.
EXAMPLE 169
2-[[4-Butynyloxy-phenylsulfonyl]-amino]-N-hydroxy-3-(pyridinylthio)propana-
mide
[0699] According to the procedure of Example 158, using D-cysteine
instead of D-penicillamine and 3-picolyl chloride hydrochloride
instead of iodomethane in Step 1,
2-[[4-butynyloxy-phenylsulfonyl]-amino]-N-hydroxy-3-(pyridinylthio)propana-
mide was obtained. mp 115-120.degree. C. Electrospray Mass Spec
436.1 (M+H).sup.+.
EXAMPLE 170
2-({[4-(2-butynyloxy)phenyl]sulfonyl}-amino)-N-hydroxy-3-[(Z)-11-tetradece-
nylsulfanyl]propanamide
[0700] Cis-11-tetradecen-1-ol (1 g, 4.72 mmol )and carbon
tetrabromide (1.56 g 4.72 mmol) were dissolved in dichloromethane
(3 ml) and the solution was cooled in ice bath. A solution of
triphenylphosphine (1.24 g, 4.72 mmol) in 2 mL of dichloromethane
was added dropwise. After stirring at 0.degree. C. for 15 minutes
and at room temperature for 3 h, the solvent was evaporated and the
residue was diluted with ether. The ether solution was filtered and
concentrated and purified using column chromatography on silica gel
eluting with hexane:ethyl acetate (3:1) to give 0.23 g of
(Z)-14-bromo-3-tetradecene.
[0701] According to the procedure of Example 158, using D-cysteine
instead of D-penecillamine and (Z)-14-bromo-3-tetradecene instead
of iodomethane in Step 1,
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(Z)-1-
1-tetradecenylsulfanyl]propanamide was obtained. Electrospray Mass
Spec 539.5 (M+H).sup.+.
EXAMPLE 171
(2S)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hydroxypr-
opyl)sulfanyl]-3-methylbutanamide
[0702] Step 1
[0703] A solution of 2N sodium hydroxide (11.3 mL, 22.7 mmol) was
added to D-(-)-penicillamine (2.5 g, 16.8 mmol) at 0.degree. C.
Once all the solid was dissolved, a solution of 3-bromopropanol
(3.03 g, 21.8 mmol) in ethanol (17 mL) was slowly added at
0.degree. C. and the resulting mixture was stirred for 15 h at room
temperature. The mixture was treated with 1N hydrochloric acid
until pH is .about.6 and the solvents were removed to obtain
(2S)-2-amino-3-[(3-hydroxypropyl)sulfanyl]-3-methylbuta- noic acid
as a white solid. This solid was used for the next step without
further purification; Electrospray Mass Spec 208.1 (M+H)+
[0704] Step 2
[0705] The
(2S)-2-amino-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid
was dissolved in, dioxane:water (1:1) (40 mL). Triethylamine (5.1
mL, 50.4 mmol) was added to the solution followed by
2-butynyloxybenzenesulfonyl chloride (4.1 g, 16.8 mmol). The
resulting mixture was stirred for 15 h at room temperature. The
mixture was acidified to pH .about.2 with 1N hydrochloric acid and
partitioned between ethyl acetate and water. The organic layer was
dried over anhydrous sodium sulfate. Removal of the solvent gave
5.78 g (83%) of
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulf-
anyl]-3-methylbutanoic acid as a solid; .sup.1H NMR (300 MHz,
acetone-d.sub.6) .delta. 1.34 (s, 3H), 1.39 (s, 3H), 1.66 (m, 2H),
2.06 (m, 3H), 2.54-2.68 (m, 2H), 3.89 (m, 1H), 4.82 (m, 2H), 6.56
(d, 1H, J=9.0 Hz), 7.12(d, 2H, J=8.7 Hz), 7.81(d, 2H, J=8.7 Hz).
HRMS (C.sub.18H.sub.25NOS.sub.2)(M+H); calcd. 416.1196, found
416.1199.
[0706] Step 3
[0707] To a solution of
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl{amino)-3-
-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid (500 mg, 1.2
mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole
(194 mg, 1.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide
(322 mg, 1.68 mmol) followed by N-methylmorpholine (0.198 mL, 1.8
mmol) and the-resulting mixture was stirred for 1 h at room
temperature. A 50% aqueous solution of hydroxylamine (0.367 mL, 6
mmol) was added and the mixture was stirred for 15 h at room
temperature. The solvent was removed and the product was
partitioned between ethyl acetate and water. The organic layer was
washed with 1N hydrochloric acid, saturated aqueous sodium
bicarbonate solution, brine, and dried over anhydrous sodium
sulfate. Removal of the solvent gave
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hyd-
roxypropyl)sulfanyl]-3-methylbutanamide, which was triturated with
hexanes to obtain 130 mg (25%) of the pure product; HRMS
(C.sub.18H.sub.26N.sub.2- O.sub.6S.sub.2)(M+H); calcd. 431.1305,
found 431.1313.
EXAMPLE 172
(2S)-2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hydroxypr-
opyl)sulfanyl]-3-propanamide
[0708] According to the procedure of Example 171, starting with
D-cysteine instead of D-penicillamine,
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}ami-
no)-N-hydroxy-3-[(3-hydroxypropyl)sulfanyl]-3-propanamide was
obtained. HRMS (C.sub.16H.sub.22N.sub.2O.sub.6S.sub.2)(M+H); calcd.
403.0992, found 403.0991.
EXAMPLE 173
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-1,4-thia-
zepane-3-carboxamide
[0709] Step 1
[0710] To a solution of
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-
-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid from Example
171, (1 g, 2.41 mmol) in dimethylacetamide (6 mL) was added t-butyl
bromide (4.16 mL, 36.2 mmol), potassium carbonate (2.66 g, 19.28
mmol), and benzyltriethylammonium chloride (82 mg, 0.36 mmol) and
the resulting mixture was heated at 55 .degree. C. for 15 h. The
solvent was removed and the residue was partitioned with
ethylacetate and water. The organic layer was separated, washed
with brine and dried over anhydrous sodium sulfate. The solvent was
removed to obtain 600 mg (56%) of tert-butyl
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulf-
anyl]-3-methylbutanoate; .sup.1H NMR (300 MHz, CDCl.sub.3)
.quadrature. 1.22 (s, 9H), 1.35 (s, 3H), 1.39 (s, 3H), 1.76 (m,
2H), 1.80 (m, 3H), 2.41 (m, 1H), 2.68 (m, 2H), 3.71 (m, 3H), 4.69
(m, 2H), 5.74 (d, 1H, J=9.9 Hz), 7.03 (d,2H, J=7.2 Hz), 7.79 (d,
2H, J=7.2 Hz); HRMS(C.sub.22H.sub.33NO.sub.6S.sub.2)(M+Na); cald.
494.1641, found 494.1644.
[0711] Step 2
[0712] To a solution of tert-butyl
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfon-
yl}amino)-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoate (380 mg,
0.81 mmol) in tetrahydrofuran (5 mL) was added triphenylphospine
(255 mg, 0.97 mmol) followed by diethylazodicarboxylate (0.14 mL,
0.89 mmol) and the resulting mixture was stirred for 2 h at room
temperature. The solvent was removed and the crude product was
flash chromatographed to obtain 280 mg (62%) of tert-butyl
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dim-
ethyl-1,4-thiazepane-3-carboxylate; .sup.1H NMR (300 MHz,
CDCl.sub.3) 1.29 (S, 9H), 1.37 (s, 3H), 1.61 (s, 3H), 1.85 (m, 3H),
1.91 (m, 1H), 2.26 (m, 1H), 2.72 (m, 1H), 2.86 (m, 1H), 3.52 (m,
1H), 4.12 (m, 1H), 4.44 (s, 1H), 4.68 (m, 2H), 7.02 (d, 2H, J=9.0
Hz), 7.76 (d, 2H, J=9.0 Hz); HRMS
(C.sub.22H.sub.31NO.sub.5S.sub.2)(M+); cald. 453.1644, found
452.9784.
[0713] Step 3
[0714] A solution of tert-butyl
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-
-2,2-dimethyl-1,4-thiazepane-3-carboxylate (220 mg, 0.49 mmol) in
methylene chloride (4 mL) was added trifluoroacetic acid (1.5 mL)
and the mixture was stirred for 2 h at room temperature. The
solvent was removed in vacuo. Traces of trifluoroacetic acid was
removed by adding toluene (1 mL) and removing the solvent to obtain
170 mg (88%) of
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-1,4-thiazepane-3--
carboxylic acid; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.42 (s,
3H), 1.60 (s, 3H), 1.85 (m, 3H), 1.91 (m, 1H), 2.17 (m, 1H), 2.67
(m, 1H), 2.82 (m, 1H), 3.54 (m, 1H), 3.82 (m, 1H), 4.59 (s, 1H),
4.68 (m, 2H), 7.0 (d, 2H, J=8.7 Hz), 7.75 (d, 2H, J=8.7 Hz); HRMS
(C.sub.18H.sub.23NO.sub.5- S.sub.2)(M+); cald. 397.1018, found
397.0998.
[0715] Step 4
[0716] Following the procedure of Step 3, Example 171,
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-1,4-thiazepane-3--
carboxylic acid (140 mg, 0.35 mmol), N-hydroxybenzotriazole (57 mg,
0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (94 mg,
0.49 mmol), N-methylmorpholine (0.058 mL, 0.53 mmol), and aqueous
hydroxylamine (0.107 mL, 1.75 mmol) in dimethylformamide (3 mL)
provided 80 mg (56%) of
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-1,4-thi-
azepane-3-carboxamide; .sup.1H NMR(300 MHz, DMSO-d.sub.6)
.delta.1.26 (s, 3H), 1.56 (s, 3H), 1.87 (m, 1H), 1.91 (m, 3H), 2.06
(m, 1H), 2.73 (m, 2H), 3.20 (m, 1H), 4.21 (s, 1H), 4.80 (m, 1H),
4.90 (m, 2H), 7.16 (d, 2H, J=9.0 Hz), 7.79 (d, 2H, J=9.0 Hz); HRMS
(C.sub.18H.sub.24N.sub.2O.sub.5S.- sub.2)(M+Na); cald. 413.1199,
found 413.1205.
EXAMPLE 174
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepane-3-carb-
oxamide
[0717] Starting with D-cysteine, following the procedure of Steps 1
and 2 of Example 171,
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hy-
droxypropyl)-sulfanyl]-3-propanoic acid was obtained.
[0718] According to the procedure of Step 1 of Example 173, the
acid (2 g, 5.17 mmol) was converted into the corresponding t-butyl
ester using t-butylbromide (8.9 mL, 77.5 mmol), potassium carbonate
(5.7 g, 41.4 mmol), and benzyltriethylammonium chloride (177 mg,
0.77 mmol) in dimethylacetamide (12 mL) to obtain 1.5 g (66%) of
tert-butyl
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulf-
anyl]-3-propanoate; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.32
(s, 9H), 1.82 (m, 1H), 1.85 (m, 3H), 1.93 (br s, 1H), 2.71 (t, 2H,
J=6.9 Hz), 2.85 9m, 2H), 3.74 (m, 2H), 4.02 (m, 1H), 4.72 (m, 2H),
5.58 (d, 1H, J=8.4 Hz), 7.04 (d, 2H, J=8.7 Hz), 7.81 (d, 2H, J=8.7
Hz); Electrospray Mass Spec 444.1 (M+H)+;
[0719] Following the procedure for Step 2 of Example 173,
tert-butyl
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulf-
anyl]-3-propanoate (1.4 g, 3.16 mmol), triphenylphospine (993 mg,
3.79 mmol), and diethylazodicarboxylate (0.547 mL, 3.48 mmol) in
tetrahydrofuran (20 mL) provided 1.1 g (82%) of tert-butyl (3
S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylate;
.sup.1H NMR(300 MHz, CDCl.sub.3) 1.31 (s, 9H), 1.85 (m, 3H), 1.93
(m, 1H), 2.04 (m, 1H), 2.65 (m, 1H), 2.76 (m, 1H), 2.88 (m, 1H),
3.15 (m, 1H), 3.31 (m, 1H) 3.80 (m, 1H), 4.70 (m, 3H), 7.03 (d, 2H,
J=8.7 Hz), 7.77 (d, 2H, J=8.7 Hz); HRMS
(C.sub.20H.sub.27NO.sub.5S.sub.2)(M+H); calcd. 426.1403, found
426.1404.
[0720] Following the procedure of Step 3 of Example 173, tert-butyl
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylate
(800 mg, 1.88 mmol), trifluoroacetic acid (6 mL) in methylene
chloride (15 mL) provide 650 mg (94%) of
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl-
}-1,4-thiazepane-3-carboxylic acid; .sup.1H NMR (300 MHz,
acetone-d.sub.6): .delta.1.74 (m, 3H), 1.90 (m, 2H), 2.59 (m, 2H),
2.90 (m, 1H), 3.18 (m, 1H), 3.26 (m, 1H), 3.70 (m, 1H), 4.70 (m,
3H), 7.03 (d, 2H, J=8.7 Hz), 7.77 (d, 2H, J=8.7 Hz); HRMS
(C.sub.16H.sub.19NO.sub.5S.su- b.2)(M+H); calcd. 370.0777, found
370.0765.
[0721] Following the procedure Step 3 of Example 171,
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylic
acid (400 mg, 1.08 mmol), N-hydroxybenzotriazole (175 mg, 1.29
mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride
(290 mg, 1.51 mmol), N-methylmorpholine (200 .quadrature.L, 1.62
mmol), and 50% aqueous hydroxylamine (331 mL, 5.4 mmol) provided
200 mg (48%) of (3
S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepane-3-carbo-
xamide; HRMS (C.sub.16H.sub.20N.sub.2O.sub.5S.sub.2)(M+H); calcd.
385.0886, found 385.0886.
EXAMPLE 175
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepane-3-carb-
oxamide 1,1-dioxide
[0722] To a cooled (0.degree. C.) solution of
(3S)-4-({[4-(2-butynyloxy)ph-
enyl]sulfonyl}-N-hydroxy-1,4-thiazepane-3-carboxamide (80 mg, 0.21
mmol) in chloroform (2 mL) was added 32% peracetic acid (0.132 mL,
0.63 mmol) and the reaction mixture was stirred overnight at room
temperature. The solvent was removed and the residue was dissolved
in ethyl acetate and dried over anhydrous sodium sulfate. Removal
of the solvent gave 60 mg (69%) of
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazep-
ane-3-carboxamide 1,1-dioxide; .sup.1H NMR(300 MHz, DMSO-d.sub.6)
.delta.1.80 (br s, 2H), 1.84 (m, 3H), 3.07-3.80 (m, 5H), 4.00 (m,
1H), 4.53 (m, 1H), 4.84 (m, 2H), 7.03 (d, 2H, J=8.7 Hz), 7.77 (d,
2H, J=8.7 Hz), 9.05 (s, 1H), 10.32 (s, 1H); MS (ES)(M+H));
416.9.
EXAMPLE 176
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-hydroxyphenyl)a-
cetamide
[0723] To a solution of 167.2 mg (1.00 mmol) of D-4-hydroxyphenyl
glycine in 3.7 ml of CH.sub.3CN was added 0.56 ml (2.09 mmol) of
bis(trimethylsilyl)trifluoroacetamide, and the reaction mixture was
gently refluxed for 2 h. The resulting clear solution was cooled to
40 .degree. C., and 0.096 ml (1.2 mmol) pyridine and 269.2 mg
(1.099 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride were
added. The reaction mixture was heated at 70 .degree. C. for 3 h
and stirred at room temperature for 14 h. The solvent was
evaporated and the resulting oily residue was treated with 15%
NaHSO.sub.4 and stirred for 1 h. The mixture was extracted with
ethyl acetate. The combined organics were then dried, over
MgSO.sub.4, filtered and concentrated in vacuo. The crude material
was triturated in hexane to get 319 mg (85%) of
({[4-(2-butynyloxy)phenyl- ]sulfonyl}amino)(4-hydroxyphenyl)acetic
acid as a pale yellow solid. Electrospray Mass Spec 374.3
(M-H).sup.-.
[0724] To a solution of 12.18 g (32.48 mmol) of product of
({[4-(2-butynyloxy)phenyl]sulfonyl}amino)(4-hydroxyphenyl)acetic
acid in 5 ml of DMF at room temperature was added 165.65 g (1.95
mol) of NaHCO.sub.3, 17.4 g (90.9 mmol) of EDC, 10.53 g (77.95
mmol) of HOBT and 61.2 g (487.2 mmol) of O-t-butylhydroxylamine
hydrochloride. The reaction was stirred at 50.degree. C. for 6 h,
then at room temperature overnight. DMF was removed. The resulting
light brown solid was. diluted with ethyl acetate/water, extracted
with ethyl acetate, washed with brine, dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The crude material was washed
with 3-5 ml dichloromethane, The product,
'N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(4-hydroxy-
phenyl)acetamide, (12 g, 83%) was obtained as a light yellow solid.
Electrospray Mass Spec 447.4 (M+H).sup.+
[0725] A 450 mg (1.007 mmol) portion of
'N-(tert-butoxy)-2-({[4-(2-butynyl-
oxy)phenyl]sulfonyl}amino)-2-(4-hydroxyphenyl)acetamide was stirred
in neat TFA at room temperature for 72 h. TFA was removed in vacuo.
The residue was chromatographed on preparative TLC, eluting with 1%
HOAc and 10% MeOH in dichloromethane to provide 33.8 mg (9%) of
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-hydroxyphenyl)-
acetamide as a white solid. Electrospray Mass Spec 391.4
(M+H).sup.+
EXAMPLE 177
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-[4-(2-propynyloxy)-
phenyl]acetamide
[0726] To a solution of 321.6 mg (0.72 mmol) of
'N-(tert-butoxy)-2-({[4-(2-
-butynyloxy)phenyl]sulfonyl}amino)-2-(4-hydroxyphenyl)acetamide
from Example 176 in 3 ml DMF at 0.degree. C. was added 199 mg (1.44
mmol) of K.sub.2CO.sub.3. The reaction mixture was stirred for 15
min, 94.4 mg (0.79 mmol) of propargyl bromide was added, and
reaction mixture was stirred at room temperature overnight. DMF was
removed in vacuo. The residue was diluted with ethyl acetate,
washed with 1N HCl solution, water and brine. The organic layer was
dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
crude material was chromatographed on silica gel, eluting with
hexane/ethyl acetate (5:1, 4:1 then 3:1) to provide 75 mg (17%) of
'N-(tert-butoxy)-2-({[4-(2-butynyloxy)phenyl]sulfo-
nyl}amino)-2-[4-(2-propynyloxy)phenyl]acetamide as a white solid.
Electrospray Mass Spec 485.4 (M+H).sup.+
[0727] The 75 mg (0.154 mmol) sample of
'N-(tert-butoxy)-2-({[4-(2-butynyl-
oxy)phenyl]sulfonyl}amino)-2-[4-(2-propynyloxy)phenyl]acetamide was
stirred in neat TFA at room temperature for 72 h. TFA was removed
in vacuo. The residue was chromatographed on prep. TLC eluting with
1% HOAc in 10% MeOH/CH.sub.2Cl.sub.2 to provide 11.1 mg (17%) of
2-({[4-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-[4-(2-propynyloxy)ph-
enyl]acetamide as a white solid was obtained. High Resolution Mass
Spec 429.11155 (M+H).sup.+; Calc'd for
C.sub.21H.sub.21N.sub.2O.sub.6S 429.11149.
EXAMPLE 178
2-[{[(4-(2-Butynyloxy)phenyl]sulfonyl{(methyl)amino]-N-hydroxy-2-(4-methox-
yphenyl)acetamide
[0728] To 50 mL of methanol cooled to 0.degree. C. was dropwise
added 3.75 mL of thionyl chloride followed by 5.0 g (0.030 mmol) of
D-4-hydroxyphenylglycine. The reaction was heated to reflux for 5 h
then stirred overnight at room temperature. The resulting mixture
was concentrated in vacuo and the residue was diluted with ether.
The resulting solid was collected by filtration and dried in vacuo
to provide 5.9 g of amino-(4-hydroxy-phenyl)-acetic acid methyl
ester as a white solid. Electrospray Mass Spec 182.2
(M+H).sup.+
[0729] To a solution of 5.0 g (0.023 mmol) of
amino-(4-hydroxy-phenyl)-ace- tic acid methyl ester dissolved in 30
mL of chloroform was added 30 mL of pyridine followed by 5.85 g
(0.023 mmol) of 4-but-2-ynyloxy-benzenesulfon- yl chloride. The
reaction was stirred overnight at room temperature and then diluted
with ethyl acetate. The organics were washed with 5% HCl solution
and water, dried over magnesium sulfate, fitered and concentrated
in vacuo. The residue was chromatographed on silica gel eluting
with ethyl acetate/hexanes (1:3) to provide
[{[4-(2-butynyloxy)phenyl]sulfonyl}amino](4-hydroxyphenyl)acetate
as pale yellow crystals.
[0730] To a solution of 0.350 g (0.900 mmol) of
[{[4-(2-butynyloxy)phenyl]- sulfonyl}amino](4-hydroxyphenyl)acetate
dissolved in 3 mL of DMF was added 0.079 g (1.979 mmol) of a 60%
oil dispersion of sodium hydride. The reaction was stirred for 30
min at room temperature and then 0.224 mL of iodomethane was added.
After 5 h the reaction was diluted with water and extracted with
ether. The combined organics were washed with water, dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue
was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:3) top provide
[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-met-
hoxyphenyl)acetate as a white waxy solid. Electrospray Mass Spec
418.1 (M+H).sup.+
[0731] According to the procedures of Examples 11 and 9
[{[4-(2-butynyloxy)-phenyl]sulfonyl}(methyl)amino](4-methoxyphenyl)acetat-
e was hydrolyzed to the carboxylic acid and then converted into the
hydroxamic acid,
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hy-
droxy-2-(4-methoxyphenyl)-acetamide. Electrospray Mass Spec 419.3
(M+H).sup.+
EXAMPLE 179
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(4-m-
orpholinyl)ethoxy]phenyl}acetamide
[0732] To a solution of 6.62 g (0.017 mmol) of
[{[4-(2-butynyloxy)phenyl]s- ulfonyl}amino](4-hydroxyphenyl)acetate
from Example 178 in 50 mL of DMF was added 3.08 g (0.020 mmol) of
tert-butyldimethylsilyl chloride followed by 2.89 g (0.043 mmol) of
imidazole. The reaction was stirred at room temperature for 5 h and
then diluted with ether. The resulting mixture was washed with
water, dried over magnesium sulfate, filtered and concentrated in
vacuo to give 7.06 g of [4-(tert-butyl-dimethyl-silanylox-
y)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamino)-acetic acid
methyl ester as a white solid. Electrospray Mass Spec 504.4
(M+H).sup.+
[0733] To a solution of 7.06 g (0.014 mmol) of
[4-tert-butyl-dimethyl-sila-
nyloxy)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamiio)-acetic acid
methyl ester dissolved in 50 mL of DMF was added 0.618 g (0.015
mmol) of a 60% oil dispersion of sodium hydride. The reaction was
stirred for 30 min at room temperature and then 2.62 mL of
iodomethane was added. After 5 h the reaction was diluted with
water and extracted with ether. The combined organics were washed
with water, dried over magnesium sulfate, filtered and concentrated
in vacuo. The residue was chromatographed on silica gel eluting
with ethyl acetate/hexanes (1:3) to provide
[4-(tert-butyl-dimethyl-silanyloxy)-phenyl][(4-but-2-ynloxy-benzenesulfon-
yl)-methyl-amino]-acetic acid methyl ester as a white waxy solid.
Electrospray Mass Spec 518:4 (M+H).sup.+
[0734] To a solution of 6.0 g (0.012 mmol) of
[4-(tert-butyl-dimethyl-sila-
nyloxy)-phenyl]-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic
acid methyl ester in 100 mL of THF was added 11.6 mL of a 1.0M
solution of tetrabutylammonium fluoride in THF. The reaction was
stirred for 1 h at room temperature and then acidified with 5% HCl
solution and extracted with ethyl acetate. The organics were dried
over magnesium sulfate, filtered and concentrated in vacuo. The
residue was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:1) to give 2.7 g of methyl
[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-hydroxyphenyl)-
acetate as a white solid. Electrospray Mass Spec 404.2
(M+H).sup.+
[0735] To a solution of 0.25 g (0.620 mmol) of methyl
[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-hydroxyphenyl)acetate-
in 10 mL of acetone was added 0.342 g of potassium carbonate, 0.231
g (1.241 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 1
equivalent of sodium iodide. The reaction was heated to reflux for
5 h, diluted with water and extracted with chloroform. The organics
were dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with
chloroform/methanol (9:1) to provide 0.156 g of methyl
2-[{[4-(2-butynyloxy phenyl]sulfonyl}(methyl)am-
ino]-2-{4-[2-(4-morpholinyl)ethoxy]phenyl}acetate.
[0736] According to the procedures of Examples 11 and 9 methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-{4-[2-(4-morpholiny-
l)ethoxy]phenyl}acetate was hydrolyzed to the carboxylic acid and
then converted into the hydroxamic acid,
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}-
(methyl)amino]-N-hydroxy-2-{4-[2-(4-morpholinyl)ethoxy]phenyl}-acetamide.
Electrospray Mass Spec 518.3 (M+H).sup.+
EXAMPLE 180
tert-Butyl
2-(4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hy-
droxyamino)-2-oxoethyl]phenoxy}ethylcarbamate
[0737] To a solution 0.488 g (1.861 mmol) of triphenylphosphine in
10 mL of THF was added 0.287 g (1.861 mmol) of tert-butyl
N-(2-hydroxyethyl)-carbamate followed by 0.500 g (1.241 mmol) of
methyl
[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-hydroxyphenyl)acetate
(from Example 179) and 0.293 mL (1.861 mmol) of diethyl
azodicarboxylate. The reaction was stirred overnight at room
temperature and then concentrated in vacuo. The residue was
chromatographed on silica gel eluting with ethyl acetate/hexanes
(1:3) to give 0.677 g of methyl
(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)[{[4-(2-butynyloxy)phenyl-
]sulfonyl(methyl) amino]acetate as a white solid. Electrospray Mass
Spec 547.4 (M+H).sup.+
[0738] According to the procedures of Examples 11 and 25 methyl
(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)[{[4-(2-butynyloxy)phenyl-
]sulfonyl}(methyl)amino]acetate was hydrolyzed to the carboxylic
acid and then converted into the hydroxamic acid, tert-butyl
2-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino-
)-2-oxoethyl]phenoxy}ethylcarbamate. Electrospray Mass Spec. 548.5
(M+H).sup.+
EXAMPLE 181
2-[4-(2-Aminoethoxy)phenyl]-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)a-
mino]-N-hydroxyacetamide
[0739] To a solution of 0.156 g(0.285 mmol) of tert-butyl
2-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino-
)-2-oxoethyl]phenoxy-ethylcarbamate from Example 180 dissolved in 2
mL of dichloromethane was added 3.0 mL of a 1.0M solution of HCl in
ether. The reaction was stirred at room temperature for 3 h and
then diluted with ether. The resulting solid was collected by
filtration and dried in vacuo to give 0.099 g of the hydrochloride
salt of 2-[4-(2-aminoethoxy)phenyl]--
2-[{[-4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxyacetamide
as a tan solid. Electrospray Mass Spec 448.3 (M+H).sup.+
EXAMPLE 182
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-{4-[2-(dimethylamino-
)ethoxy]phenyl}-N-hydroxyacetamide
[0740] To a solution of 0.390 g (1.489 mmol) of triphenylphosphine
in 8 mL of THF was added 0.150 mL (1.489 mmol) of
N,N-dimethylethanolamine followed by 0.400 g (0.993 mmol) of methyl
[{[4-(2-butynyloxy)phenyl]sulf-
onyl}(methyl)amino](4-hydroxyphenyl)acetate (from Example 179) and
0.234 mL (1.489 mmol) of diethyl azodicarboxylate. The reaction was
stirred overnight at room temperature and then concentrated in
vacuo. The residue was chromatographed on silica gel eluting with
ethyl acetate/hexanes (1:3) to give 0.246 g of
methyl[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl-
)amino]{4-[2-(dimethylamino)ethoxy]phenyl}acetate as a white solid.
Electrospray Mass Spec 475.2 (M+H).sup.+
[0741] According to the procedures of Examples 11 and 9
methyl[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]{4-[2-(dimethylami-
no)ethoxy]phenyl}acetate was hydrolyzed to the carboxylic acid and
then converted into the hydroxamic acid,
2-[{[4-(2butynyloxy)phenyl]sulfonyl}(-
methyl)amino]-2-{4-[2-(dimethylamino)ethoxy]phenyl}-N-hydroxyacetamide.
Electrospray Mass Spec 476.4 (M+H).sup.+
EXAMPLE 183
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(1-p-
yrrolidinyl)ethoxy]phenyl}acetamide
[0742] According to the procedure of Example 182, using
1-(2-hydroxyethyl)pyrrolidine instead of N,N-dimethylethanolamine,
2-[{[4-(2-butynyloxy)phenyl]sulfonyl)(methyl)amino]-N-hydroxy-2-{4-[2-(1--
pyrrolidinyl)-ethoxy]phenyl}acetamide was obtained as a tan solid.
Electrospray Mass Spec 502.2 (M+H).sup.+
EXAMPLE 184
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(2-o-
xo-1-pyrrolidinyl)ethoxy]phenyl}acetamide
[0743] According to the procedure of Example 180, using
1-(2-hydroxyethyl)-2-pyrrolidinone instead of tert-butyl
N-(2-hydroxyethyl)-carbamate,
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methy-
l)amino]-N-hydroxy-2-{4-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}acetamide
was obtained as a white foam. Electrospray Mass Spec 516.2
(M+H).sup.+
EXAMPLE 185
tert-butyl
4-(2-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2--
(hydroxyamino)-2-oxoethyl]phenoxy}ethyl)-1-piperazinecarboxylate
[0744] According to the procedure of Example 180, using tert-butyl
N-(2-hydroxyethyl)piperazine carbamate instead of tert-butyl
N-(2-hydroxyethyl)-carbamate, tert-butyl
4-(2-{4-[1-[{[4-(2-butynyloxy)ph-
enyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}ethyl)-1--
piperazinecarboxylate was obtained as a white solid. Electrospray
Mass Spec 617.4 (M+H).sup.+
EXAMPLE 186
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(1-p-
iperazinyl)ethoxy]phenyl}acetamide
[0745] To a solution of 0.300 g (0.487 mmol) of tert-butyl
4-(2-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyam-
ino)-2-oxoethyl]phenoxy}ethyl)-1-piperazinecarboxylate (from
Example 185) in 1 mL of dichloromethane was added 1 mL of
trifluoroacetic acid. The reaction was stirred at room temperature
for 3 h and then concentrated in vacuo. The residue was diluted
with chloroform/methanol(9:1) and washed with saturated sodium
bicarbonate solution. The organics were dried over sodium sulfate,
filtered and concentrated in vacuo. The residue was diluted with 2
mL of dichloromethane and 0.25 mL of methanol and 1 mL of a 1.0M
solution of HCl in ether was added. After 30 minutes the mixture
was concentrated in vacuo to provide 0.189 g of the hydrochloride
salt of
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-{4-[2-(1--
piperazinyl)ethoxy]phenyl}acetamide as a tan solid. Electrospray
Mass Spec 517.3 (M+H).sup.+
EXAMPLE 187
tert-Butyl
3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hy-
droxyamino)-2-oxoethyl]phenoxy}propylcarbamate
[0746] According to the procedure of Example 180, Mitsunobu
reaction of tert-butyl N-(3-hydroxypropyl)carbamate and methyl
[{[4-(2-butynyloxy)-phenyl]sulfonyl-(methyl)amino](4-hydroxyphenyl)acetat-
e provides methyl
(4-{3-[(tert-butoxycarbonyl)amino]propoxy}phenyl)[{[4-(2-
-butynyloxy)phenyl]sulfonyl}(methyl)amino]acetate.
[0747] According to the procedures of Examples 11 and 25 this
methyl ester was converted into the hydroxamic acid tert-butyl
3-{4-[1-[{[4-(2-butynyl-
oxy)-phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}-p-
ropyl-carbamate, obtained as a white foam. Electrospray Mass Spec
560.2 (M-H).sup.-
EXAMPLE 188
2-[4(3-Aminopropoxy)phenyl]-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)a-
mino]-N-hydroxyacetamide
[0748] Hydrogen chloride gas was bubbled through a solution of
0.371 g (0.661 mmol) of tert-butyl
3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(me-
thyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate
(from Example 187) dissolved in 5 mL of dichloromethane for 5
minutes. The reaction was stopped at let sit at room temperature
for 1 h and then the solvent was evaporated. The residue was
triturated with ether, filtered and dried in vacuo to give 0.314 g
of 2-[4-(3-aminopropoxy)phenyl]-2-[{[4-
-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxyacetamide as
a white solid. Electrospray Mass Spec 462.2 (M+H).sup.+
EXAMPLE 189
tert-Butyl
(3S)-3-{4-[(1R)-1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)am-
ino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}-1-pyrrolidinecarboxylate
[0749] According to the procedure of Example 180, using tert-butyl
N-(3-pyrrolidinol)carbamate instead of tert-butyl
N-(2-hydroxyethyl)-carb- amate, tert-butyl
(3S)-3-{4-[(1R)-1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(me-
thyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}-1-pyrrolidinecarboxylate
was obtained as a white solid. Electrospray Mass Spec 574.1
(M+H).sup.+
EXAMPLE 190
(2R)-2-[{[4-(2-Butynyloxy)phenyl]sulfonyl{(methyl)amino]-N-hydroxy-2-{4-[(-
3S)-pyrrolidinyloxy]phenyl}ethanamide
[0750] According to the procedure of Example 188, 0.20 g (0.349
mmol) of tert-butyl
(3S)-3-{4-[(1R)-1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)a-
mino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}-1-pyrrolidinecarboxylate
(the product of Example 189) was converted into 0.157 g of
(2R)-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}-(methyl)amino]-N-hydroxy-2-}4--
[(3S)-pyrrolidinyloxy]phenyl}ethanamide hydrochloride, obtained as
a tan glass. Electrospray Mass Spec 474.1 (M+H).sup.+
EXAMPLE 191
tert-Butyl (2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)
amino)-2-(hydroxyamino)-2-oxoethyl)phenoxy]ethyl)-(methyl)carbamate
[0751] According to the procedure of Example 182, starting with the
t-butyl carbamate of 2-(methylamino)ethanol, tert-butyl
(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino)-2-(hydroxyamin-
o)-2-oxoethyl)phenoxy]ethyl)-(methyl) carbamate was obtained. mp
62.degree. C. (d). Electrospray Mass Spec 562.3.(M+H).sup.+
EXAMPLE 192
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino)-N-hydroxy-2-{4-[2-(met-
hylamino)ethoxy]phenyl}acetamide
[0752] According to the procedure of Example 181, tert-butyl
(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino)-2-(hydroxyamin-
o)-2-oxoethyl)phenoxy]ethyl)-(methyl) carbamate from Example 191
was converted into the hydrochloride salt of
2-({[4-(2-butynyloxy)phenyl]sulf-
onyl}(methyl)amino)-N-hydroxy-2-{4-[2-(methylamino)ethoxy]phenyl}acetmide.
mp 165.degree. C.(d). Electrospray Mass Spec 462.4 (M+H).sup.+.
EXAMPLE 193
Ethyl
3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxy-
amino)-2-oxoethy]phenoxy}propylcarbamate
[0753] Step 1
[0754] Through a solution of 7.0 g (12.8 mmol) of methyl
(4-{3-[(tert-butoxycarbonyl)amino]propoxy}phenyl)[{[4-(2-butynyloxy)pheny-
l]sulfonyl}(methyl)amino]acetate (from Example 187) dissolved in
dichloromethane was bubbled hydrogen chloride gas for 1.5 h. The
reaction was stopped and let sit at room temperature for 30
minutes. The reaction was then poured into water, neutralized with
1N sodium hydroxide solution to pH .about.8 and extracted with
dichloromethane. The organics were washed with water and brine,
dried over sodium sulfate, filtered and concentrated to give 5.41 g
of methyl [4-3(3-aminopropoxy)phenyl][{[4-(2--
butynyloxy)phenyl]sulfonyl}methyl)amino]acetate. Electrospray Mass
Spec 461.1 (M+H).sup.+
[0755] Step 2
[0756] To a solution of methyl
[4-3-(3-aminopropoxy)phenyl][{[4-(2-butynyl-
oxy)phenyl]sulfonyl}methyl)amino]acetate (0.5 g, 1.1 mmol) and
N,N-diisopropylethyl amine (0.95 mL, 5.4 mmol) in dichloromethane,
cooled in an ice bath was dropwise added a dichloromethane (1 ml)
solution of ethyl chlorofornate (0.178 ml, 1.1 mmol). The reaction
was stirred at 0.degree. C. for 10 minutes and at room temperature
for 2 h. The reaction was diluted with dichloromethane, washed with
water and brine, dried over sodium sulfate, filtered, and
concentrated. The residue was separated using column chromatogaphy
on silica gel eluting with dichloromethane:methanol (100:2) to give
0.5 g of methyl
[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl)a-
mino]propoxy]phenyl) acetate. Yield 76.3%. Electrospray Mass Spec
533.1 (M+H).sup.+.
[0757] Step 3
[0758] A mixture of methyl
[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amin-
o}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetate (0.45 g, 0.85
mmol) and 1N NaOH (4.2 ml, 4.23 mmol) in THF (5 ml ) and methanol
(5 ml) was stirred at room temperature for 2 h. After removing the
solvent, the residue was dissolved in water, neutralized with HCl
to pH .about.5-6 and extracted with dichloromethane. The organic
layer was washed with water and brine, dried over sodium sulfate,
filtered and concentrated to provide 0.36 g of
[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-(3--
[(ethoxycarbonyl)amino]propoxy]phenyl)acetic acid as a solid. Yield
81.8%. Electrospray Mass Spec 519.1 (M+H).sup.+.
[0759] Step 4
[0760] To
[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxyc-
arbonyl)amino]propoxy]phenyl)acetic acid (0.35 g, 0.67 mmol) and
1-(3-dimethyl aminopropyl) 3-ethyl carbodiimide (0.2 g, 1.01 mmol )
in DMF (8 ml), 1-hydroxybenzotriazole (0.13 g, 0.95 mmol) was added
and the reaction was stirred at room temperature for 2 h.
Hydroxylamine (0.23 ml of 50% in water, 3.71 mmol) was added and
the reaction was stirred overnight. After evaporating the solvent,
the residue was extracted with ethyl acetate and water, the organic
layer was washed with saturated NaHCO.sub.3, water and brine, dried
over Na.sub.2SO.sub.4, and concentrated. The residue was purified
with preparative TLC plates (eluting with ethyl acetate:methanol
(85:15) to provide 0.1 g of ethyl
3-{4-[1-[{[M-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino-
)-2-oxoethyl]phenoxy}propylcarbamate as a yellow solid. mp
60-62.degree. C. Electrospray Mass Spec 532 (4+H).sup.+.
EXAMPLE 194
2-{4-[3-(Acetylamino)propoxy]phenyl}-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}-
(methyl)amino]-N-hydroxyacetamide
[0761] According to the procedure of Example 193, using acetyl
chloride instead of ethyl chloroformate in Step 2,
2-{4-[3-(acetylamino)propoxy]ph-
enyl}-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxyacetami-
de was obtained. mp 88.degree. C. (d). Electrospray Mass Spec 504
(M+H).sup.+.
EXAMPLE 195
Butyl
3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxy-
amino)-2-oxoethyl]phenoxy}propylcarbamate
[0762] According to the procedure of Example 193, using n-butyl
chloroformate instead of ethyl chloroformate in Step 2, butyl
3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino-
)-2-oxoethyl]phenoxy}-propylcarbamate was obtained. mp
50-55.degree. C. Electrospray Mass Spec 562 (M+H).sup.+.
EXAMPLE 196
Benzyl3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxy-
amino)-2-oxoethyl]phenoxy}propylcarbamate
[0763] According to the procedure of Example 193, using benzyl
chloroformate instead of ethyl chloroformate in Step 2, benzyl
3-=55
4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(hydroxyamino)-2-
-oxoethyl]phenoxy}propylcarbamate was obtained. mp 48-50.degree. C.
Electrospray Mass Spec 596.4 (M+H).sup.+.
EXAMPLE 197
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-(4-({3-[(m-
ethylsulfonyl)amino]propoxy}phenyl)acetamide
[0764] According to the procedure of Example 193, using
methanesulfonyl chloride instead of ethyl chloroformate in Step 2,
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-(4-{3-[(m-
ethylsulfonyl)amino]propoxy}phenyl)acetamide was obtained. mp
65-70.degree. C. Electrospray Mass Spec 540.4 (M+H).sup.+.
EXAMPLE 198
2-(4-{3[(Anilinocarbonyl)amino]propoxy}phenyl)-2-[{[4-(2-butynyloxy)phenyl-
]sulfonyl}(methyl)amino]-N-hydroxyacetamide
[0765] According to the procedure of Example 193, using phenyl
isocyanate instead of ethyl chloroformate in Step 2,
2-(4-{3-[(anilinocarbonyl)amino-
]propoxy}phenyl)-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hyd-
roxyacetamide was obtained. mp 135.degree. C. (d). Electrospray
Mass Spec 581 (M+H).sup.+.
EXAMPLE 199
tert-Butyl
2-{4-[(1R)-1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydro-
xyamino)-2-oxoethyl]phenoxy}ethylcarbamate
[0766] Step 1
[0767] To a 0.degree. solution of 2.50 g (11.48 mmol) of
amino-(4-hydroxy-phenyl)-acetic acid methyl ester (from Example
178) in 125 mL of dichloromethane was added 10 mL of
N,N-diisopropylethylaxnine followed by 2.97 g (11.48 mmol) of
9-fluorenylmethyl chlorformate and the resulting mixture was
stirred at 0.degree. for 2 h and room temperature for 2 h. The
reaction mixture was then concentrated and the residue was diluted
with ethyl acetate and water. The organics were washed, with water,
dried over magnesium sulfate, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:3) to provide
methyl(2R)-{[(9H-fluoren-9-ylmethoxy)car-
bonyl]amino}(4-hydroxyphenyl)ethanoate as a white solid.
Electrospray Mass Spec 404.1 (M+H).sup.+.
[0768] Step 2
[0769] To a solution of 0.465 g (1.77 mmol) of triphenylphosphine
in 10 mL of THF was added 0.286 g (1.77 mmol) of tert-butyl
N-(2-hydroxyethyl)-carbamate followed by 0.476 g (1.18 mmol) of
methyl
(2R)-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino)(4-hydroxyphenyl)ethanoate
and 0.279 mL (1.77 mmol) of diethyl azodicarboxylate. The reaction
was stirred overnight at room temperature and then concentrated in
vacuo. The residue was chromatographed on silica gel eluting with
ethyl acetate/hexanes (1:3) to give 0.383 g of methyl
(2R)-(4-{2[(tert-butoxyca-
rbonyl)amino]ethoxy}phenyl){[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethano-
ate as a white solid. Electrospray Mass Spec 547.2 (M+H).sup.+
[0770] Step 3
[0771] A solution of 1.695 g (3.10 mmol) of methyl
(2R)-(4-{2-[(tert-butox-
ycarbonyl)amino]ethoxy}phenyl){[(9H-fluoren-9-ylmethoxy)carbonyl]amino}eth-
anoate in 10 mL of diethylamine was stirred at room temperature for
2 h and then concentrated in vacuo. The residue was chromatographed
on silica gel eluting with a gradient starting with ethyl
acetate/hexanes (1:2) and ending with chloroform/methanol (9:1) to
provide 0.717 g of methyl
(2R)-amino(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)ethanoate
as a colorless oil. Electrospray Mass Spec 325.2 (M+H).sup.+
[0772] Step 4
[0773] To a solution of 0.682 g (2.10 mmol) of methyl
(2R)-amino(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)ethanoate
dissolved in 10 mL of chloroform and 2.2 mL of pyridine was added
0.566 g (2.315 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride.
The reaction was stirred at room temperature for 15 h and then
diluted with ether. The organics were washed with water, 5% HCl
solution and brine, dried over magnesium sulfate, filtered and
concentrated in vacuo to provide 0.691 g of methyl
(2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-bu-
tynyloxy)phenyl]sulfonyl}amino)ethanoate as a white foam.
Electrospray Mass Spec 533.1 (M+H).sup.+
[0774] Step 5
[0775] According to the procedure of Example 11, 0.388 g (0.729
mmol) of
methyl(2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butyny-
loxy)phenyl]sulfonyl}amino)ethanoate provided 0.378 g of
(2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy{phenyl)({[4-(2-butynyloxy)p-
henyl]sulfonyl}amino)ethanoic acid as a white foam. Electrospray
Mass Spec 519.4 (M+H).sup.+
[0776] Step 6
[0777] According to the procedure of Example 25, 0.159 g of
(2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)p-
henyl]sulfonyl}amino)ethanoic acid provided 0.127 g of tert-butyl
2-{4-[(1R)-1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxyamino)-2-
-oxoethyl]phenoxy}ethylcarbamate as a pale yellow glass.
Electrospray Mass Spec 534.3 (M+H).sup.+
EXAMPLE 200
(2R)-2-[4-(2-Aminoethoxy)phenyl]-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amin-
o)-N-hydroxyethanamide
[0778] Through a solution of 0.35 g (0.664 mmol) of the product of
Example 199, tert-butyl
2-{4-[(1R)-1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2--
(hydroxyamino)-2-oxoethyl]phenoxy}ethylcarbamate, in 10 mL of
dichloromethane was bubbled hydrogen chloride gas for 10 minutes.
The reaction was stoppered and let sit at room temperature for 30
minutes. The reaction was then diluted with 15 mL of ether and the
resulting white precipitate was collected by filtration and dried
in vacuo to give 0.283 g of
(2R)-2-[4-(2-Aminoethoxy)phenyl]-2-({[4-(2-butynyloxy)phenyl]sulfony-
l}amino)-N-hydroxyethanamide as a white solid. Electrospray Mass
Spec 434.3 (M+H).sup.+
EXAMPLE 201
(2R)-2-{4-[2-(Acetylamino)ethoxy]phenyl}-2-({[4-(2-butynyloxy)phenyl]sulfo-
nyl}amino)-N-hydroxyethanamide
[0779] Step 1
[0780] To a solution of 0.300 g (0.564 mmol) of methyl
(2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)p-
henyl]sulfonyl}amino)ethanoate (from Example 199) in 1.5 mL of
dichloromethane was added 1.5 mL of trifluoroacetic acid and the
resulting mixture was stirred for 2 h at room temperature and then
concentrated in vacuo. The residue was diluted with ethyl acetate
and the organics were washed with saturated sodium bicarbonate
solution, dried over sodium sulfate, filtered and concentrated to
provide 0.244 g of
methyl(2R)-[4-(2-aminoethoxy)phenyl]({[4-(2-butynyloxy)phenyl]sulfonyl}am-
ino)ethanoate pure enough for use in the next step. Electrospray
Mass Spec 433.3 (M+H).sup.+
[0781] Step 2
[0782] A solution of 0.219 g (0.507 mmol) of
methyl(2R)-[4-(2-aminoethoxy)-
phenyl]({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate in 2.5 mL
of acetic anhydride and 0.25 mL of pyridine was stirred at room
temperature for 15 h and then concentrated in vacuo. The residue
was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:1) to provide 0.213 g of methyl
(2R)-{4-[2-acetylamino)ethoxy]phenyl}({[4-(2-butynyloxy)phenyl]-
sulfonyl}amino)-ethanoate as a white foam. Electrospray Mass Spec
475.3 (M+H).sup.+
[0783] Step 3
[0784] According to the procedure of Example 11, 0.192 g (0.405
mmol) of methyl (2R)-{4-[2-C
acetylamino)ethoxy]phenyl}({[4-(2-butynyloxy)phenyl]s-
ulfonyl}amino)ethanoate provided 0.165 g of
(2R)-{4-[2-(acetylamino)ethoxy-
]phenyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoic acid as a
white solid. Electrospray Mass Spec 461.3 (M+H).sup.+
[0785] Step 4
[0786] According to the procedure of Example 25, 0.142 g of
(2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)p-
henyl]sulfonyl}amino)ethanoic acid provided 0.099 g of
(2R)-2-{4-[2-(Acetylamino)ethoxy]phenyl}-2-({[4-(2-butynyloxy)phenyl]sulf-
onyl}amino)-N-hydroxyethanamide as a white solid. Electrospray
Mass-Spec 498.4 (M+Na).sup.+
EXAMPLE 202
tert-Butyl
4-(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxy-
amino)-2-oxoethyl)phenoxy]ethyl)-1-piperazinecarboxylate
[0787] According to the procedure of Example 199, using tert-butyl
N-(2-hydroxyethyl)piperazine carbamate as the alcohol in Step 2,
tert-butyl
4-(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydrox-
yamino)-2-oxoethyl)phenoxy]ethyl)-1-piperazinecarboxylate was
obtained as a yellow solid. mp 92-95.degree. C. Electrospray Mass
Spec 603.1 (M+H).sup.+.
EXAMPLE 203
tert-Butyl
4-(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxy-
amino)-2-oxoethyl)phenoxy]ethyl)-(methyl)carbamate
[0788] According to the procedure of Example 199, using the t-butyl
carbamate of 2-(methylamino)ethanol as the alcohol in Step 2,
tert-butyl
4-(2-{4-[1-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-2-(hydroxyamino)-2-o-
xoethyl)phenoxy]ethyl)-(methyl)carbamate was obtained. mp
90-92.degree. C. Electrospray Mass Spec 548.5 (M+H).sup.+.
EXAMPLE 204
2-{[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(methylamino)-
ethoxy]phenyl})acetamide
[0789] According to the procedure of Example 181, the product of
Example 203 provided
2-{[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-
-(methyl-amino)ethoxy]phenyl})acetamide. mp 105-108.degree. C.
Electrospray Mass Spec 448.3 (M+H).sup.+.
EXAMPLE 205
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(1-pyrrolidi-
nyl)ethoxy]phenyl}acetamide
[0790] Step 1
[0791] To a 0.degree. solution of 16.58 g (0.076 mol) dissolved in
100 mL of dichloromethane was added 22.11 g (0.101 mol) of
di-tert-butyl dicarbonate followed by 25 mL (0.179 mol) of
triethylamine. The reaction was stirred at 0.degree. for 1.5 h and
then at room temperature for 2 h. The reaction was then washed with
water and brine, dried over sodium sulfate, filtered and
concentrated. The residue was chromatographed on silica gel eluting
with hexanes/ethyl acetate (1:1) to provide methyl
[(tert-butoxycarbonyl)amino]4-hydroxyphenyl}acetate as a white
solid.
[0792] Step 2
[0793] According to the procedure of Step 2 in Example 199,
Mitsunobu reaction of 2.25 g (8.0 mmol) of methyl
[(tert-butoxycarbonyl)amino]4-hyd- roxyphenyl}acetate and 1.41 mL
(12.0 mmol) of 1-(2-hydroxyethyl)pyrrolidin- e provided methyl
[(tert-butoxycarbonyl)amino]{4-[2-(1-pyrrolidinyl)ethoxy-
]phenyl}acetate after column chromatography on silica gel. Yield
65.2 Electrospray Mass Spec 379.2 (M+H).sup.+.
[0794] Step 3
[0795] To a solution of methyl
[(tert-butoxycarbonyl)amino]{4-[2-(1-pyrrol-
idinyl)-ethoxy]phenyl}acetate was dissolved in dichloromethane,
hydrogen chloride gas was bubbled in for 5 minutes. The reaction
was then stirred at room temperature for 0.5 h. The solvent was
removed to provide 1.80 g of methyl
amino{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetate dihydrochloride as
a light pink solid Yield .about.100%. mp 80.degree. C. (d).
Electrospray Mass Spec 279.2 (M+H).sup.+.
[0796] Step 4
[0797] To a 0.degree. solution of methyl
amino{4-[2-(1-pyrrolidinyl)ethoxy- ]phenyl}acetate dihydrochloride
(1.67 g; 4.55 mmol) in dichloromethane (10 mL) was added
4-but-2-ynyloxy-benzenesufonyl chloride followed by triethyl amine
was dropped in. The mixture was stirred at room temperature
overnight and then diluted with dichloromethane. The organic layer
was washed with water and brine, dried over sodium sulfate,
filtered and concentrated. The residue was purified using column
chromatography on silica gel eluting with ethyl acetate to obtain
2.52 g of methyl
({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(1-pyrrolidinyl)-
ethoxy]phenyl}acetate as an oil. Yield 92.6%. Electrospray Mass
Spec 487.1 (M+H).sup.+.
[0798] Step 5
[0799] A mixture of methyl
({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2--
(1-pyrrolidinyl)ethoxy]phenyl}acetate (2.52 g, 5.19 mmol) and 5N
NaOH (5.18 mL) in THF (32 mL) and methanol (32 mL) was stirred at
room temperature for 2h. After removing the solvent, the residue
was dissolved in water and neutralized with HCl to pH .about.6. The
precipitated solid was filtered to provide 1.61 g of
({[4-(2-butynyloxy)phenyl]sulfonyl}amin-
o){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetic acid as a white solid
. Yield 66%. mp 245-247.degree. C. Electrospray Mass Spec 473.2
(M+H).sup.+.
[0800] Step 6
[0801] To a 0.degree. solution of
({[4-(2-butynyloxy)phenyl]sulfonyl}amino-
){4-[2-(1-pyrrolidinyl)ethoxy]phenyl}acetic acid (1.58 g, 3.35
mmol) and DMF (0.52 ml, 6.69 mmol) in dichloromethane (29 ml) was
added oxalyl chloride (3.35 ml of 2M in CH.sub.2Cl.sub.2; 6.69
mmol). The reaction mixture was stirred at 0.degree. C. for 10
minutes and at room temperature for 2 h, then cooled again. A THF
(2 ml) solution of triethylamine (1.87 ml 13.38 mmol) and
hydroxylamine (2.05 mL of 50% hydroxylamine in water, 33.5 mmol)
was added in one portion. The reaction was stirred at room
temperature overnight. After removing the solvent, the oily residue
was extracted with ethyl acetate and water. The organic layer was
washed with water and brine, dried over sodium sulfate, filtered
and evaporated. Preparative TLC chromatography eluting with
dichloromethane:methanol (8:2) provided 0.33 g of
2-({[4-(2-butynyloxy)ph-
enyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}aceta-
mide. mp 70.degree. C. This compound (0.28 g, 0.57 mmol) was
dissolved in dichloromethane (3 ml) and methanol (2 ml) cooled in
ice bath. Then 1M hydrogen chloride in ethyl ether (0.86 ml, 0.86
mmol) was dropped in. The mixture was stirred at 0.degree. C. for
10 minutes and at room temperature for 1.5 h, and then concentrated
to obtain 0.27 g of the hydrochloride salt. mp 68-70.degree. C.
Electrospray Mass Spec 488.1 (M+H).sup.+.
EXAMPLE 206
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(4-morpholin-
yl)ethoxy]phenyl}acetamide
[0802] According to the procedure of Example 205, using
4-(2-hydroxyethyl)morpholine as the alcohol in Step 2, provided
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(4-morpholi-
nyl)ethoxy]phenyl}acetamide. mp 80-86.degree. C. Electrospray Mass
Spec 504.1 (M+H).sup.+. Hydrochloride salt mp 72.degree. C. (d).
Electrospray Mass Spec 504.1 (M+H).sup.+.
EXAMPLE 207
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino){4-[2-(dimethylamino)ethoxy]phe-
nyl}-N-hydroxyacetamide
[0803] According to the procedure of Example 205, using
N,N-dimethylethanloamine as the alcohol in Step 2, provided
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino){4-[2-(dimethylamino)ethoxy]ph-
enyl}-N-hydroxyacetamide hydrochloride. Electrospray Mass Spec
462.4 (M+H).sup.+.
EXAMPLE 208
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(4-methyl-1,-
3-thiazol-5-yl)ethoxy]phenyl}acetamide
[0804] According to the procedure of Example 205, using
4-methyl-5-thiazoleethanol as the alcohol in Step 2, provided
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(4-methyl-1-
,3-thiazol-5-yl)ethoxy]phenyl}acetamide as a white solid. High
Resolution Mass Spec: m/z 516.12504 (M+H).sup.+, calcd for
C.sub.24H.sub.26N.sub.3O.- sub.6S.sub.2 516.12576.
EXAMPLE 209
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-{2-[2-(2-methox-
yethoxy)ethoxy]ethoxy}phenyl)acetamide
[0805] According to the procedure of Example 205, using
tri(ethylene glycol)monomethylether as the alcohol in Step 2,
provided
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-(4-{2-[2-(2-thoxy-
ethoxy)methoxy]ethoxy}-phenyl)acetamide as a yellow oil. High
Resolution Mass Spec: m/z 537.1903 (M+H).sup.+, calcd for
C.sub.25H.sub.33N.sub.2O.s- ub.9S 537.19013.
EXAMPLE 210
2-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(2-methoxyet-
hoxy)ethoxy]phenyl}acetamide
[0806] According to the procedure of Example 205, using di(ethylene
glycol)monomethylether as the alcohol in Step 2, provided
2-({[4-(2-butynyloxy)-phenyl]sulfonyl}amino)-N-hydroxy-2-{4-[2-(2-methoxy-
ethoxy)ethoxy]phenyl}acetamide as a yellow oil. High Resolution
Mass Spec: m/z 491.15081 (M-H).sup.-, calcd for
C.sub.23H.sub.27N.sub.2O.sub.8S 491.14936.
EXAMPLE 211
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-phenylacet-
amide
[0807] Step 1
[0808] Solid 4-(2-butynyloxy)phenyl]sulfonyl chloride was added to
excess 40% aqueous methylamine, and the resultant solution was
stirred at room temperature for two hours. Evaporation under
reduced pressure, followed by recrystallization from methanol gave
N-methyl-[4-(2-butynyloxy)phenyl]- sulfonamide]as colorless
crystals, mp 78-80.degree. C.
[0809] Step 2
[0810] A mixture of 2.39 g. (10 mmol) of the above sulfonamide,
2.29 g (10 mmol) of methyl alpha-bromophenylacetate, and 2.0 g of
powdered potassium carbonate in 10 ml of DMF was stirred at room
temperature for 18 hours. The mixture was combined with 100 ml of
water, and the resultant crystals were collected by filtration to
give methyl 2-[{[4-(2-butynyloxy)phenyl]s-
ulfonyl}(methyl)amino]-2-phenylacetate as colorless crystals: NMR
(CDCl.sub.3) .delta. 1.869 (t, 3H), 2.744 (s,3H), 3.605 (s, 3H),
4.696-4.736 (m,2H), 5.862 (s, 1H), 7.062 (d,2H), 7.199-7.378 (m,
5H), 7.781 (d,2H).
[0811] Step 3
[0812] A solution of 1.50 g of methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl-
}(methyl)amino]-2-phenylacetate and 1.50 g of KOH in a
methanol/water/THF mixture was stirred at room temperature for 18
hours. The solution was then evaporated, the residue was dissolved
in water and then acidified with 2N hydrochloric acid, and the
precipitate was collected and dried to give 1.07 g of
2-[{[4-(2-butynyloxy)-phenyl]sulfonyl}(methyl)amino]-2-phe-
nylacetic acid as colorless crystals, Calc'd for
C.sub.19H.sub.19NO.sub.5S- : C, 61.11; H, 5.13, N, 3.75. Found: C,
60.66; H, 5.16, N, 3.53.
[0813] Step 4
[0814] The above acid (500 mg, 1.3 mmol) was dissolved in 5 ml
dichloromethane and 1 ml DMF, and this was cooled to 0.degree. C.
and a solution of 3 ml of oxalyl chloride in 5 ml dichloromethane
was added slowly, and this was stirred for 45 min. at 0.degree.
C.-room temperature. This mixture was evaporated under reduced
pressure and the residue was dissolved in 5 ml of dichloromethane,
and this solution was added at room temperature to a solution
prepared at 0.degree. C. from 3.0 g of hydroxylamine hydrochloride
in 10 ml of DMF, 15 ml of triethylamine, and 10 ml of acetonitrile.
This mixture was stirred at room temperature for 18 hours, solvent
was evaporated, and the residue was combined with water. Extraction
of this mixture with dichloromethane, drying over sodium sulfate,
and evaporation of the solvent gave
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-2-phenylace-
tamide as colorless crystals, Electrospray Mass Spec 389.3
(M+H)+
EXAMPLE 212
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophenyl)-N-h-
ydroxyacetamide
[0815] In a similar manner as described in Example 211, a mixture
of 2.39 g N-methyl-[4-(2-butynyloxy)phenyl]sulfonamide], methyl
alpha-bromo(4-chlorophenyl)acetate, and powdered potassium
carbonate in DMF was stirred at room temperature for 18 hours. The
mixture was combined with water and the precipitate was collected
and purified by chromatography on silica gel using hexane-ethyl
acetate, 4:1 to give methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophe-
nyl)acetate as a yellow oil which was then used in the subsequent
step without further purification.
[0816] This ester was reacted with excess methanolic lithium
hydroxide at room temperature, followed by evaporation of the
methanol. The residue was dissolved in water and acidified with 2N
hydrochloric acid to give
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-(4-chlorophenyl)ace-
tic acid as colorless crystals, mp 170-172.degree. C., Electrospray
Mass Spec 406.4 (M-H)-
[0817] Reaction of this acid in a procedure similar to that of
Example 211, gave
2-[{[4-(2-butynyloxy)-phenyl]sulfonyl}(methyl)amino]-2-(4-chlor-
ophenyl)-N-hydroxyacetamide as colorless crystals, Electrospray
Mass Spec 423.1 (M+H)+
EXAMPLE 213
2-[{[4-(2-Butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-[(4-chlorophenyl)sul-
fanyl]-N-hydroxypentanamide
[0818] Step 1
[0819] A solution of 7.17 g (30 mmol)
N-methyl-[4-(2-butynyloxy)-phenyl]su- lfonamide] in 25 ml of DMF
was cooled to 0.degree. C. and 30 ml of 1M sodium
hexamethyldisilazide (30 mmol) was slowly added and this mixture
was stirred for 15 min and then added to a solution of 6.89 g (30
mmol) of methyl 2-bromo-5-chloropentanoate in 25 ml of DMF and was
stirred at room temperature for 18 hours. The mixture was combined
with water and the precipitate was collected and purified by
chromatography on silica gel using hexane-ethyl acetate, 4:1 to
give methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)-amino]-5-chloropentanoate
Electrospray Mass Spec 410.2 (M+Na)+
[0820] Step 2
[0821] A solution of 4.80 g of methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl-
}(methyl)amino]-5-chloropentanoate of Step 1 and 15 g of sodium
iodide in 25 ml of acetone was stirred at room temperature for 3
days. Solvent was removed under reduced pressure, and the residue
was washed with water. The product was dried to give methyl
2-[{[4-(2-butynyloxy)phenyl]sulfonyl-
}(methyl)amino]-5-iodopentanoate as a pale yellow solid,
Electrospray Mass Spec 480.2 (M+H)+
[0822] Step 3
[0823] A solution of 0.958 g (2.0 mmol) of methyl
2-[{[4-(2-butynyloxy)phe-
nyl]sulfonyl}(methyl)amino]-5-iodopentanoate, 0.35 g (2.4 mmol) of
4-chlorobenzenethiol, and 0.323 g of diisopropylethylamine in 50 ml
of isopropyl alcohol was stirred at room temperature for 18 hours.
Evaporation of solvent gave 0.8 g of methyl
2-[{[4-(2-butynyloxy)-phenyl]-
sulfonyl}-(methyl)amino]-5-[(4-chlorophenyl)sulfanyl]-pentanoate as
colorless crystals, mp 88-89.degree. C., Electrospray Mass Spec
496.1 (M+H)+
[0824] Step 4
[0825] This ester (0.496 g) was hydrolyzed with methanolic LiOH,
followed by acidification to give
2-[{[4-(2-butynyloxy)-phenyl]sulfonyl}-(methyl)a-
mino]-5-[(4-chlorophenyl)sulfanyl]-N-methylnorvaline (0.421 g) as a
colorless powder, mp 143-145.degree. C., ESI MS m/z 480.0 (M-H)
calcd. for C.sub.22H.sub.24ClNO.sub.5S.sub.2 482.02. From 0.362 g
of this acid, and using the procedure of Example 211 there was
obtained 0.30 g of
2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-[(4-chlorophenyl)su-
lfanyl]-N-hydroxypentanamide as colorless crystals, mp
144-145.5.degree. C., Electrospray Mass Spec 497.1 (M+H)+
EXAMPLE 214
1-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic Acid
Hydroxyamide
[0826] To a solution of 0.147 g (0.325 mmol) of the product of
Example 58,
4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1-carbo-
xylic acid tert-butyl ester, in 3.0 mL of dichloromethane was added
0.3 mL of trifluoroacetic acid and the reaction was stirred at room
temperature for 1 h. The reaction was then concentrated in vacuo
and the residue was diluted with dichloromethane. The organics were
washed with saturated sodium bicarbonate solution, dried over
sodium sulfate, filtered and concentrated in vacuo to provide 0.053
g of 1-(4-but-2-ynyloxy-benzenesul- fonyl)-piperazine-2-carboxylic
acid hydroxyamide as a tan solid. Electrospray Mass Spec 354.2
(M+H)+
EXAMPLE 215
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piperazine-2-
-carboxylic Acid Hydroxyamide
[0827] Step 1
[0828] To a solution of ethyl 2-piperazinecarboxylate (0.71 g, 4.5
mmol) in toluene (8.4 mL) was added triethylamine (0.67 mL, 4.82
mmol). To this was added dropwise a solution of 4-morpholine
carbonyl chloride (0.67 g, 4.51 mmol) in toluene (8.4 mL). The
reaction was heated at reflux overnight and then cooled to
0.degree. C. and filtered. The filtrate was concentrated in vacuo
and purified via column chromatography on silica gel eluting with
chloroform/methanol (15/1) to provide 478 mg (39%) of the acylated
product, ethyl 4-(4-morpholinylcarbonyl)-2-piperazinecarboxy- late,
as a gold oil. Electrospray Mass Spec: 272.3 (M+H).sup.+.
[0829] Step 2
[0830] The ethyl 4-(4-morpholinylcarbonyl)-2-piperazinecarboxylate
(0.41 g, 1.55 mmol) was dissolved in pyridine (1.44 mL). To this
solution was added a solution of 4-but-2-ynyloxy-benzenesulfonyl
chloride (0.38 g, 1.55 mmol) in pyridine (1 mL). The reaction was
stirred overnight and then poured into water. The mixture was
extracted three times with chloroform. The organics were combined,
washed with 10% HCl, twice with water, then brine and dried over
Na.sub.2SO.sub.4. The solution was filtered and concentrated in
vacuo to provide 0.6 g (81%) of
1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piperazine--
2-carboxylic acid ethyl ester as a gold oil. Electrospray Mass Spec
480.2 (M+H).sup.+.
[0831] Step 3
[0832] The
1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-p-
iperazine-2-carboxylic acid ethyl ester. (0.56 g, 1.18 mmol) was
dissolved in THF/MeOH/H2O (3 mL each) and treated with lithium
hydroxide monohydrate (0.099 g, 2.3 mmol). The reaction was heated
at reflux overnight and then concentrated and acidified to pH 4
with acetic acid. The solution was extracted with methylene
chloride and then washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to provide
0.298 g (53%) of 1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(-
morpholine-4-carbonyl)-piperazine-2-carboxylic acid as a yellow
powder. Electrospray Mass Spec 452.2 (M+H).sup.+.
[0833] Step 4
[0834] To a solution of 2M oxalyl chloride in CH.sub.2Cl.sub.2
(0.55 mL, 1.1 mmol) at 0.degree. C. was added DMF (0.085 mL, 1.1
mmol) and the mixture was stirred at 0.degree. C. for 15 min, then
let warm to room temperature and stirred for an additional 1 h. A
solution of the
1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(morpholine-4-carbonyl)-piperazine--
2-carboxylic acid, (0.25 g, 0.554 mmol) in 2.54 mL of DMF, was then
added to the reaction mixture and the reaction was stirred for 2 h
at room temperature.
[0835] In a separate flask, triethylamine (1.16 mL, 8.31 mmol) was
added to a 0 .degree. C. mixture of hydroxylamine hydrochloride
(0.38 g, 5.54 mmol) 5.23 mL of THF and 1.5 mL of water. After this
mixture had stirred for 15 min at 0.degree. C., the acid chloride
solution was added to it in one portion and the resulting solution
was allowed to warm to room temperature with stirring overnight.
The reaction mixture next was diluted with CH.sub.2Cl.sub.2 and
washed with water and saturated sodium bicarbonate solution. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude residue was triturated with ether
to provide 0.161 g (62%) of the
1-(4-but-2-ynyloxy-benezenesulfonyl-
)-4-(morpholine-4-carbonyl)-piperazine-2-carboxylic acid
hydroxyamide as a beige powder. Electrospray Mass Spec 466.9
(M+H).sup.+.
EXAMPLE 216
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 1-diethylamide 3-hydroxyamide
[0836] In the same manner as described in Example 215, using
diethylcarbamoyl chloride in Step 1, the desired hydroxamic acid,
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 1-diethylamide 3-hydroxyamide, was obtained as a gold oil.
Electrospray Mass Spec 453.3 (M+H).sup.+.
EXAMPLE 217
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(pyrrolidine-1-carbonyl)-piperazine--
2-carboxylic Acid Hydroxyamide
[0837] In the same manner as described in Example 215, using
1-pyrrolidinecarbonyl chloride in Step 1, the desired hydroxamic
acid,
1-(4-but-2-ynyloxy-benzenesulfonyl)-4-(pyrrolidine-1-carbonyl)-piperazine-
-2-carboxylic acid hydroxyamide, was obtained as a white powder.
Electrospray Mass Spec 451.4 (M+H).sup.+.
EXAMPLE 218
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 1-diisopropylamide 3-hydroxyamide
[0838] In the same manner as described in Example 215, using
diisopropylcarbamoyl chloride in Step 1, the desired hydroxamic
acid,
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 1-diisopropylamide 3-hydroxyamide, was obtained as a white
powder. Electrospray Mass Spec 481.5 (M+H).sup.+.
EXAMPLE 219
Benzyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-3-[(hydroxyamino)carbonyl]-1-p-
iperazinecarboxylate
[0839] In the same manner as described in Example 215, using benzyl
chloroformate in Step 1, the desired hydroxamic acid, benzyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-3-[(hydroxyamino)carbonyl]-1-nyloxy)-
phenyl]sulfonyl}-3-[hydroxyamino)carbonyl]-1-piperazinecarboxylate,
was obtained as a white powder. Electrospray Mass Spec 488.2
(M+H).sup.+.
EXAMPLE 220
4-(4-But-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 3-hydroxyamide 1-(methyl-phenyl-amide)
[0840] Step 1
[0841] The product of Example 57,
4-(4-but-2-ynyloxy-benzenesulfonyl)-pipe- razine-1,3-dicarboxylic
acid 1-tert-butyl ester 3-ethyl ester (3.8 g, 8.1 mmol), was,
dissolved in dichloromethane (3 mL). To this solution was added
trifluoroacetic acid (3 mL) and the reaction was allowed to stir
overnight. The reaction was then concentrated in vacuo and the
residue triturated with dichloromethane to provide 2.64 g (88%) of
1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid
ethyl ester. Electrospray Mass Spec 367.3(M+H).sup.+.
[0842] Step 2
[0843] In the same manner as described in Step 1 of Example 215,
the 1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic
acid ethyl ester (1.0 g, 2.7. mmol) was treated with
N-methyl-N-phenylcarbamoyl chloride to provide 1.33 g (98%) of
ethyl 1-{[4-(2-butynyloxy)phenyl]sulf-
onyl}-4-[(methylanilino)carbonyl]-2-piperazine-carboxylate as a
brown oil. Electrospray Mass Spec 500.2 (M+H).sup.+.
[0844] Step 3
[0845] In the same manner as described in Step 3 of Example 215,
the ethyl
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(methylanilino)carbonyl]-2-pipera-
zinecarboxylate (1.28 g, 2.57 mmol) provided 0.84 g (69%) of the
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(methylanilino)carbonyl]-2-yl]-2--
piperazinecarboxylic acid as a beige powder. Electrospray Mass Spec
472.2 (M+H).sup.+.
[0846] Step 4
[0847] In the same manner as described in Step 4 of Example 215,
the
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(methylanilino)carbonyl]-2-yl]-2--
piperazinecarboxylic acid (0.74 g, 1.57 mmol) provided 0.45 g (59%)
of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-1,3-dicarboxylic
acid 3-hydroxyamide 1-(methyl-phenyl-amide)as a beige powder.
Electrospray Mass. Spec 487.1 (M+H).sup.+.
EXAMPLE 221
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-3-hydroxy-N-1-(4-methoxyphenyl)-1,3-
-piperazinedicarboxamide
[0848] Step 1
[0849] To a solution of p-anisidine (0.5 g, 4.06 mmol) in
dichloromethane (21 mL) was added pyridine (0.36 mL, 4.46 mmol)
followed by 4-nitrophenylchloroformate (0.9 g, 4.46 mmol). The
reaction was stirred for 72 hours and then diluted with
dichloromethane, washed with water, brine, dried over MgSO4 to
provide 1.2 g (100%) of the desired carbamate as a solid.
[0850] To a solution of the carbamate (0.5 g, 1.75 mmol) in
chloroform (41 mL) was added triethylamine (0.32 mL, 2.2 mmol)
followed by trimethylsilyl chloride (0.24 mL, 1.9 mmol). The
reaction was stirred for five hours at which time
1-(4-but-2-ynyloxy-benzensulfonyl)-piperazine-2-- carboxylic acid
ethyl ester from Step 1, Example 220, (0.6 g, 1.6 mmol) was added.
The reaction was stirred overnight and then diluted with
chloroform, washed with water, brine, dried over Na.sub.2SO.sub.4,
filtered, concentrated in vacuo and purified via column
chromatography on silica gel eluting with dichloromethane:methanol
(90:10) to provide 0.44 g (48%) of ethyl
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-methoxyanilin-
o)carbonyl]-2-piperazinecarboxylate as a gold sap. Electrospray
Mass Spec516.2 (M+H).sup.+.
[0851] Step 2
[0852] In the same manner as described in Step 3 of Example 215,
the ethyl
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-methoxyanilino)carbonyl]-2-pip-
erazine-carboxylate (0.40 g, 0.78 mmol) provided 0.066 g (17%) of
the
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-methoxyanilino)carbonyl]-2-pip-
erazinecarboxylic acid. Electrospray Mass Spec 488.1
(M+H).sup.+.
[0853] Step 3
[0854] In the same manner as described in Step 4 of Example 215,
the
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-methoxyanilino)carbonyl]-2-pip-
erazinecarboxylic acid (0.067 g, 0.14 mmol) provided 0.033 g (50%)
of the
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-3-hydroxy-N-1-(4-methoxyphenyl)-1,-
3-piperazine-dicarboxamide as a brown powder. Electrospray Mass
Spec 503.6 (M+H).sup.+.
EXAMPLE 222
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-1-(4-fluorophenyl)-N-3-hydroxy-1,3--
piperazinedicarboxamide
[0855] Step 1
[0856] In the same manner as described in Step 1 of Example 221,
4-fluoroaniline (0.60 g, 5.4 mmol) and 4-nitrophenylchloroformate
provided 1.29 g (87%) of the desired carbamate as a yellow powder.
Electrospray Mass Spec 276.1 (M-H).sup.-.
[0857] The carbamate (1.15 g, 4.16 mmol) was reacted with ethyl
2-piperazinecarboxylate, also as in Step 1 of Example 221, to
provide 0.451 g (37%) of the desired urea, ethyl
4-[(4-fluroanilino)carbonyl]-2-p- iperazinecarboxylate, as a gold
oil. Electrospray Mass Spec 296.3 (M+H).sup.+.
[0858] Step 2
[0859] In the same manner as described in Step 2 of Example 215,
ethyl 4-[(4-fluoroanilino)carbonyl]-2-piperazinecarboxylate (0.41
g, 1.4 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride provided
0.49 g (70%) of ethyl
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-fluoroanilino)carbonyl]--
2-piperazinecarboxylate as a white powder. Electrospray Mass Spec
504.4 (M+H).sup.+.
[0860] Step 3
[0861] In the same manner as described in Step 3 of Example 215,
ethyl
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4fluoroanilino)carbonyl]-2-piper-
azinecarboxylate (0.45 g, 0.91 mmol) provided 0.026 g (61%) of
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-fluoroanilino)carbonyl]-2-pipe-
razinecarboxylic acid. Electrospray Mass Spec 476.4
(M+H).sup.+.
[0862] Step 4
[0863] In the same manner as described in Step 4 of Example 215,
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(4-fluoroanilino)carbonyl]-2-pipe-
razinecarboxylic acid (0.24 g, 0.50 mmol) provided 0.080 g (32%) of
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-1-(4fluorophenyl)-N-3-hydroxy-1,3--
piperazinedicarboxamide as a yellow powder. Electrospray Mass Spec
491.4 (M+H).sup.+.
EXAMPLE 223
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-1-(3,5-dichlorophenyl)-N-3-hydroxy--
1,3-piperazinedicarboxamide
[0864] Step 1
[0865] To a solution of ethyl 2-piperazinecarboxylate (0.9 g, 5.7
mmol) in chloroform (11 mL) was added 3,5-dichlorophenyl isocyanate
(1.05 g, 5.7 mmol). The reaction was stirred overnight after which
time a precipitate had formed. The reaction was concentrated and
the solid was chromatographed on silica gel using ethyl acetate as
eluant to provide 0.53 g (27%) of ethyl
4-[(3,5-dichloroanilino)carbonyl]-2-piperazinecarbo- xylate as an
off white powder. Electrospray Mass Spec 346.1 (M+H).sup.+.
[0866] Step 2
[0867] In the same manner as described in Step 2 of Example 215,
ethyl 4-[(3,5-dichloroanilino)carbonyl]-2-piperazinecarboxylate
(0.49 g, 1.42 mmol) and 4-but-2-ynyloxy-benzenesulfonyl chloride
provided 0.73 g (92%) of the desired sulfonamide. Electrospray Mass
Spec 554.1 (M+H).sup.+.
[0868] Step 3
[0869] In the same manner as described in Step 3 of Example 215,
the sulfonamide (0.64 g, 1.14 mmol) provided 0.54 g (90%) of
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(3,5-dichloroanilino)carbonyl]-2--
piperazinecarboxylic acid. Electrospray Mass Spec 527.9
(M+H).sup.+.
[0870] Step 4
[0871] In the same manner as described in Step 4 of Example 215,
the
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(3,5-dichloroanilino)carbonyl]-2--
piperazinecarboxylic acid (0.46 g, 0.88 mmol) provided 0.150 g
(31%) of
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-1-(3,5-dichlorophenyl)-N-3-hydroxy-
-1,3-piperazinedicarboxamide as a white powder. Electrospray Mass
Spec 540.8 (M+H).sup.+.
EXAMPLE 224
4-Acetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic
Acid Hydroxyamide
[0872] Step 1
[0873] To a solution of 0.170 g (0.466 mmol) of
1-(4-but-2-ynyloxy-benzene- sulfonyl)-piperazine-2-carboxylic acid
ethyl ester in 10 mL of dichloromethane cooled at 0.degree. was
added 0.2 mL of triethylamine, 0.05 g of DMAP and 0.3 mL (0.93
mmol) of acetyl chloride. After stirring for 13 h the mixture was
diluted with ethyl acetate and washed with saturated aqueous sodium
bicarbonate. The organic layer was dried over sodium sulfate,
filtered and concentrated in vacuo. The resulting residue was
chromatographed on silica gel eluting with ethyl acetate hexanes
(2:1) to provide 0.13 g (68%) of
4-acetyl-1-(4-but-2-ynyloxy-benzenesulfo-
nyl)-piperazine-2-carboxylic acid ethyl ester as a brown oil.
Electrospray Mass Spec: 409.3 (M+H)+
[0874] Step 2
[0875] According to the procedure of Example 54, 0.151 g (0.369
mmol) of of
4-acetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic
acid ethyl ester provided 0.107 g (76%) of the carboxylic acid,
4-acetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic
acid, as a brown oil. Electrospray Mass Spec: 381.3 (M+H)+
[0876] Step 3
[0877] According to the procedure of Example 25, 0.1157 g (0.304
mmol) of
4-acetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic
acid followed by flash chromatography with methylene
chloride/methanol (10:1) provided 0.082 g (68%) of the hydroxamic
acid, 4-acetyl-1-(4-but-2-ynylox-
y-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide, as a
brown solid. Electrospray Mass Spec: 396.3 (M+H)+
EXAMPLE 225
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-propionyl-piperazine-2-carboxylic
Acid Hydroxyamide
[0878] According to the procedure of Example 224, using propionyl
chloride in Step 1,
1-(4-but-2-ynyloxy-benzenesulfonyl)-4-propionyl-piperazine-2-c-
arboxylic acid hydroxyamide was obtained as a grey solid.
Electrospray Mass Spec: 410.3 (M+H)+
EXAMPLE 226
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-(thiophene-2-carbonyl)-piperazine-2--
carboxylic Acid Hydroxyamide
[0879] According to the procedure of Example 224, using
thiophene-2-carbonyl chloride in Step 1,
1-(4-but-2-ynyloxy-benzenesulfon-
yl)-4-(thiophene-2-carbonyl)-piperazine-2-carboxylic acid
hydroxyamide was obtained as a grey solid. Electrospray Mass Spec:
464.3 (M+H)+
EXAMPLE 227
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-methanesulfonyl-piperazine-2-carboxy-
lic Acid Hydroxyamide
[0880] According to the procedure of Example 224, using
methanesulfonyl chloride chloride in Step 1,
1-(4-but-2-ynyloxy-benzenesulfonyl)-4-methan-
esulfonyl-piperazine-2-carboxylic acid hydroxyamide was obtained as
a white powder. Electrospray Mass Spec: 432.1 (M+H)+
EXAMPLE 228
4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazine-1-carbox-
ylic Acid Methyl Ester
[0881] According to the procedure of Example 224, using methyl
chloroformate in Step 1,
4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycar-
bamoyl-piperazine-1-carboxylic acid methyl ester was obtained as a
grey powder. Electrospray Mass Spec: 412.2 (M+H)+
EXAMPLE 229
{2-[4-(4-But-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazin-1-yl]-
-2-oxo-ethyl}-carbamic Acid tert-butyl Ester
[0882] To a solution of 0.14 g (0.8 mmol) of
N-(tert-butoxycarbonyl)glycin- e dissolved in 3 mL of DMF was added
0.13 g (0.963 mmol) of 1-hydroxybenzotriazole hydrate (HOBT)
followed by 0.203 g (1.06 mmol) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).
The resulting mixture was stirred at room temperature for 1 h and
0.191 g (0.522 mmol) of
1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxyl- ic acid
ethyl ester in 3 mL of DMF was added dropwise. After stirring the
reaction for 14 h the solution was diluted with ethyl acetate and
washed with water. The organic layer was dried over sodium sulfate,
filtered and concentrated in vacuo. The resulting residue was
chromatographed on silica gel eluting with ethyl acetate/hexanes
(1:1) to provide 0.26 g (95%) of the sulfonamide, ethyl
4-{2-[(tert-butoxycarbonyl)amino]acetyl}--
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-piperazine-carboxylate, as a
clear oil. Electrospray Mass Spec: 524.2 (M+H)+
[0883] Hydrolysis of the carboxylic acid and subsequent conversion
into the corresponding hydroxamic acid, as in Example 224, provided
{2-[4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazin-1-yl-
]-2-oxo-ethyl}-carbamic acid tert-butyl ester as a grey powder.
Electrospray Mass Spec: 511.1 (M+H)+
EXAMPLE 230
4-Aminoacetyl-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic
Acid Hydroxyamide
[0884] To a solution of 0.157 g (0.31 mmol) of the product of
Example 229,
{2-[4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazin-1-yl-
]-2-oxo-ethyl}-carbamic acid tert-butyl ester, in 4.0 mL of
methylene chloride was added 1.0 mL of trifluoroacetic acid. The
resulting solution was stirred at room temperature for 1 h and then
reduced to dryness. The resulting residue was dissolved in ethyl
acetate and washed with saturated aqueous sodium bicarbonate and
then brine. The organic layer was dried over sodium sulfate,
filtered and concentrated in vacuo to furnish 0.121 g (95%) of
4-aminoacetyl-1-(4-but-2-ynyloxy-benzenesulfonyl-
)-piperazine-2-carboxylic acid hydroxyamide as a yellow solid.
Electrospray Mass Spec: 411.1 (M+H)+
EXAMPLE 231
1-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-[(2,2,5-trimethyl-1,3-dio-
xan-5-yl)carbonyl]-2-piperazinecarboxamide
[0885] According to the procedure of Example 229, using
2,2,5-trimethyl-[1,3]dioxane-5-carboxylic acid, the hydroxamic acid
1-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-[(2,2,5-trimethyl-1,3-di-
oxan-5-yl)carbonyl]-2-piperazinecarboxamide was obtained as a white
solid. Electrospray Mass Spec: 510.2 (M+H)+
EXAMPLE 232
1-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-[3-hydroxy-2-(hydroxymeth-
yl)-2-methylpropanoyl]-2-piperazinecarboxamide
[0886] To a solution of the product of Example 231 in 5 mL of THF
was added 0.5 mL of 1.0M hydrogen chloride in ether. The resulting
solution was stirred at room temperature for 20 h and then
concentrated in vacuo furnishing 0.054 g (99%) of the diol,
1-{[4-(2-butynyloxy)phenyl]sulfonyl-
}-N-hydroxy-4-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoyl]-2-piperazine-
carboxamide, as a white solid. Electrospray Mass Spec: 470.2
(M+H)+
EXAMPLE 233
4-(4-Bromo-benzyl)-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carbox-
ylic Acid Hydroxyamide
[0887] To a solution of 0.30 g (0.820 mmol) of
1-(4-but-2-ynyloxy-benzenes- ulfonyl)-piperazine-2-carboxylic acid
ethyl ester (Step 1, Example 220) in 10 mL of DMF was added 0.339 g
(2.459 mmol) of potassium carbonate followed by 0.205 g (0.820
mmol) of p-bromobenzyl bromide. The reaction was stirred at room
temperature for 15 h, then diluted with ether and water. The
organics were washed with water, dried over sodium sulfate,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel eluting with ethyl acetate/hexanes (1:1) to provide
0.438 g of
4-(4-bromo-benzyl)-1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carbo-
xylic acid ethyl ester as a colorless oil. Electrospray Mass Spec
534.9, 536.8 (M+H)+
[0888] Hydrolysis of the carboxylic acid following the procedure of
Example 11 and subsequent conversion into the corresponding
hydroxamic acid, as in Example 9, provided
4-(4-bromo-benzyl)-1-(4-but-2-ynyloxy-ben-
zenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide as a tan
foam. Electrospray Mass Spec: 521.98, 523.91 (M+H)+
EXAMPLE 234
1-(4-But-2-ynyloxy-benzenesulfonyl)-4-pyridin-3-ylmethyl-piperazine-2-carb-
oxylic Acid Hydroxyamide
[0889] Following the procedure of Example 233, using 3-picolyl
chloride hydrochloride to alkylate
1-(4-but-2-ynyloxy-benzenesulfonyl)-piperazine-- 2-carboxylic acid
ethyl ester, 1-(4-but-2-ynyloxy-benzenesulfonyl)-4-pyrid-
in-3-ylmethyl-piperazine-2-carboxylic acid hydroxyamide was
obtained as a white solid. Electrospray Mass Spec: 445.1 (M+H)+
EXAMPLE 235
(3S)-4-({[4-(2-Butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-c-
arboxylic Acid Hydroxyamide
[0890] Step 1
[0891] A solution of D-penicillamine (0.5 g, 3.35 mmol) in methanol
(5 ml) was cooled to 0.degree. C. and crushed sodium hydroxide
(0.28 g, 6.87 mmol) was added to give a clear solution.
2-Bromoethanol (0.26 ml. 3.71 mmol) was added and the reaction was
stirred at 0.degree. C. for 1 hour and then at room temperature for
an additional 1.5 hours. The solvent was evaporated and the oily
residue was dissolved in 3 mL water and 6 mL DMF and stirred with
sodium carbonate (0.82 g 7.2 mmol) and 4-butynyloxy-benezenesufonyl
chloride (0.78 g, 3.18 mmol) at room temperature overnight. After
evaporating the solvent, the residue was diluted with ethyl acetate
and water. The aqueous layer was acidified to pH .about.3 with
concentrated HCl and extracted with dichloromethane. The organic
layer was washed with water and brine, dried over sodium sulfate,
filtered and concentrated to obtain 1.2 g of
(2S)-2-{[4-(2butynyloxy)phen-
yl]sulfonyl}amino)-3-[(2-hydroxyethyl)sulfanyl]-3-methylbutanoic
acid as an oil. Yield 89.6%. Electrospray Mass Spec 400.1
(M-H).sup.-.
[0892] Step 2
[0893] To a solution of
(2S)-2-{[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3--
[(2-hydroxyethyl)sulfanyl]-3-methylbutanoic acid (1.2 g, 2.99 mmol)
in dimethylacetamide (8 mL) was added potassium carbonate (3.3 g,
23.9 mmol), benzyltriethylammonium chloride (0.20 g, 0.90 mmol) and
2-bromo-2-methyl-propane (5.5 mL, 47.9 mmol). The mixture was
heated at 50.degree. C. overnight, cooled to room temperature and
diluted with ethyl acetate. The organics were washed with water and
brine, dried over sodium sulfate, filtered and evaporated to
provide 1.10 g of tert-butyl
(2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl})-3-[(2-hydroxyethyl)sulfanyl]--
3-methylbutanoate as an oil. Yield .about.80.9%. Electrospray Mass
Spec 458.2 (M+H).sup.+.
[0894] Step 3
[0895] To a THF solution (15 mL) of tert-butyl
(2S)-2-({[4-(2-butynyloxy)p-
henyl]sulfonyl})-3-[(2-hydroxyethyl)sulfanyl]-3-methylbutanoate
(0.59 g, 1.29 mmol) and triphenylphosphine (0.51 g, 1.94 mmol),
diethylazodicarboxylate (0.31 mL, 1.94 mmol) was slowly added. The
mixture was stirred at room temperature overnight. After removing
the solvent, the residue was diluted with ethyl acetate. The
organic layer was washed with water and brine, dried over sodium
sulfate, filtered and concentrated. The residue was purified by
column chromatography on silica gel eluting with hexanes:ethyl
acetate (4:1) to give 0.36 g of tert-butyl
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3--
carboxylate. Yield 64.3%. Electrospray Mass Spec 440.1
(M+H).sup.+.
[0896] Step 4
[0897] To a solution of tert-butyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2-
,2-dimethyl-thiomorpholine-3-carboxylate (0.31 g, 0.71 mmol) in
dichloromethane (7 mL) was added trifluoroacetic acid (3 mL) and
the resulting mixture was stirred at room temperature for 1 hour,
after which the solvents were evaporated and toluene was added. The
toluene and excess trifloroacetic acid were removed to give 0.25 g
of
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3--
carboxylic acid, which was used for the next step without further
purification. Yield:92.6%. mp 129-131.degree. C. %. Electrospray
Mass Spec 381.8(M-H).sup.-.
[0898] Step 5
[0899] To a 0.degree. C. solution of
4-({[4-(2-butynyloxy)phenyl]sulfonyl)-
-2,2-dimethyl-thiomorpholine-3-carboxylic acid (6a) (0.25 g, 0.65
mmol) in dichloromethane (5 mL) and DMF (0.1 mL, 1.3 mmol), oxalyl
chloride (0.65 mL of 2M in CH.sub.2Cl.sub.2; 1.31 mmol) was added
dropwise. The reaction mixture was stirred at 0.degree. C. for 10
minutes and at room temperature for 2 hours, then recooled to
0.degree. C. A THF (1 mL) solution of triethylamine (0.34 mL, 2.61
mmol) and hydroxylamine (0.24 mL of 50% hydroxylamine in water,
3.92 mmol) was added in one portion. The reactions was stirred at
room temperature overnight. After removing the solvent, the oily
residue was diluted with ethyl acetate and water. The organic layer
was washed with water and brine, dried over sodium sulfate,
filtered and evaporated to give 0.18 g of a solid which was
triturated with ether to give 0.14 g of
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)
-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide as a
white solid. Yield 55%. mp 185-186.degree. C. Electrospray Mass
Spec 399.1(M+H).sup.+
EXAMPLE 236
9-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-6-thia-9-azaspiro[4,5]deca-
ne-10-carboxamide
[0900] According to the procedure of Example 235, using
alpha-amino-1-mercapto-cyclopentaneacetic acid (Reich, et al.
Bioorg. Med. Chem. Lett. 4(9) 1167 (1994)), the desired
9-({[4-(2-butynyloxy)phen-
yl]sulfonyl}-N-hydroxy-6-thia-9-azaspiro[4,5]-decane-10-carboxamide
was obtained. mp 206-208.degree. C. Electrospray Mass Spec
425(M+H).sup.+.
EXAMPLE 237
9-({[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4-azaspiro[5,5]unde-
cane-5-carboxamide
[0901] According to the procedure of Example 235, using
alpha-amino-1-mercapto-cyclohexaneacetic acid (Reich, et al.
Bioorg. Med. Chem. Lett. 4(9) 1167 (1994)), the desired
9-({[4-(2-butynyloxy)phenyl]su-
lfonyl}-N-hydroxy-1-thia-4-azaspiro[5,5]undecane-5-carboxamide was
obtained. mp 117-119.degree. C. Electrospray Mass Spec
480(M+H).sup.+.
EXAMPLE 238
4-({[4-(2-Butynyloxy)phenyl]sulfonyl)-2,2-diethyl-thiomorpholine-3-carboyl-
ic Acid Hydroxyamide
[0902] According to the procedure of Example 235, using
3-ethyl-3-sulfanylnorvaline (Reich, et al. Bioorg. Med. Chem. Lett.
4(9) 1167 (1994)), the desired
4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dieth-
yl-thiomorpholine-3-carboxylic acid hydroxyamide was obtained. mp
212-214 .degree. C. Electrospray Mass Spec 427.1(M+H).sup.+.
EXAMPLE 239
4-({[4-(2-Butynyloxy)phenyl]sulfonyl)-N-hydroxy-thiomorpholine-3-carboxami-
de
[0903] According to the procedure of Steps 1 and 2 of Example 235,
using D-cysteine, the desired tert-butyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl)a-
mino)-{3-[(2-hydroxyethyl)thio]propanoate was obtained.
Electrospray Mass Spec 430.2 (M+H).sup.+.
[0904] To a solution of tert-butyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl)am-
ino)-{3-[(2-hydroxyethyl)thio]propanoate (0.5 g, 1.16 mmol) and
carbon tetrabromide (0.38 g, 1.16 mmol) in dichloromethane (3 mL),
a dichloromethane solution (1 mL) of triphenylphosphine was added
dropwise. The reaction mixture was stirred at 0.degree. C. for 10
minutes and at room temperature overnight. After removing the
solvent, the oily residue was separated by column chromatography on
silica gel eluting with hexane:ethyl acetate (3:2) to give 0.33 g
of tert-butyl
S-(2-bromoethyl)-N-({[4-(2-butynyloxy)phenyl]sulfonyl)-cysteine.
Yield .about.57.8%. Electrospray Mass Spec 492.1; 494.1
(M+H).sup.+.
[0905] To a solution of tert-butyl
S-(2-bromoethyl)-N-({[4-(2-butynyloxy)-- phenyl]sulfonyl)-cysteine
(0.31 g, 0.63 mmol) dissolved in DMF and cooled in an ice bath was
added 3 equivalents of potassium carbonate and the reaction was
stirred at room temperature for 1 hour. After removing the solvent,
the residue was extracted with ethyl acetate and water. The organic
layer was washed with water and brine, dried over sodium sulfate,
filtered and concentrated to give 0.25 g of tert-butyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl)-thiomorpholine-3-carboxylate
as an oil. Yield .about.100%. Electrospray Mass Spec 412.3
(M+H).sup.+.
[0906] According to the procedures of Steps 4 and 5 of Example 235,
tert-butyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl)-thiomorpholine-3-carboxy-
late was converted into
4-({[4-(2-butynyloxy)phenyl]sulfonyl)-N-hydroxy-th-
iomorpholine-3-carboxamide. mp 150-154.degree. C. Electrospray Mass
Spec 371.2 (M+H).sup.+.
EXAMPLE 240
4-([4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-3-morpholinecarboxamide
[0907] Step 1
[0908] To a 0.degree. solution of D-serine methyl ester
hydrochloride (0.62 g, 4 mmol) in 5 mL of dichloromethane was added
triethylamine (1.67 mL, 12 mmol) followed by a dichloromethane (6
mL) solution of 4-(2-butynyloxy)-benzenesufonyl chloride (0.98 g, 4
mmol). The reaction was stirred at room temperature overnight and
then the mixture was poured into water. The organic layer was
washed with 2N citric acid, water and brine, dried over sodium
sulfate, filtered and concentrated to give 1.16 g of methyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-hydroxypropanoa- te.
Yield .about.89.2%. mp 72-74.degree. C. Electrospray Mass Spec
328.2 (M+H).sup.+.
[0909] Step 2
[0910] To a THF solution (10 mL) of methyl
2-({[4-(2-butynyloxy)phenyl]-su- lfonyl}amino)-3-hydroxypropanoate
(0.33 g, 1 mmol) and triphenylphosphine (0.32 g, 1.2 mmol),
diethylazodicarboxylate (0.19 mL, 1.2 mmol) was added dropwise. The
mixture was stirred at room temperature overnight. After removing
the solvent, the residue was extracted with ether. The organic
layer was washed with 1N NaHCO.sub.3, water and brine, dried over
sodium sulfate, filtered and concentrated. The residue was purified
by column chromatography on silica gel eluting with hexane:ethyl
acetate (1:1) to provide 0.18 g of
1-({[4-(2-butynyloxy)phenyl]sulfonyl}-2-aziridinecarbox- ylic acid,
methyl ester. Yield 58.0%. Electrospray Mass Spec
310.2(M+H).sup.+.
[0911] Step 3
[0912] To a 0.degree. solution of
1-({[4-(2-butynyloxy)phenyl]sulfonyl}-2-- aziridine-carboxylic
acid, methyl ester (0.55 g, 1.78 mmol) in 2-bromoethanol (1.26 mL,
17.8 mmol) was dropwise added boron trifluoride etherate (0.18 mL).
The mixture was stirred at 0.degree. C. for 30 minutes and stirred
at room temperature for 6 hours. The reaction was diluted with
ethyl acetate. The organic layer was washed with 1N NaHCO.sub.3,
water and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by column chromatography on
silica gel eluting with hexane:ethyl acetate, (7:3) to obtain 0.2 g
of
3-(2-bromo-ethoxy)-2-(4-[2-butynyloxy]-benzenesulfonyl-amino)-propionic
acid methyl ester. Yield: 26%. mp 45-46.degree. C. Electrospray
Mass Spec 434.1.436.1 (M+H).sup.+.
[0913] Step 4
[0914] To a solution of
3-(2-bromo-ethoxy)-2-(4-[2-butynyloxy]-benzenesulf-
onylamino)-propionic acid methyl ester (0.15 g, 0.35 mmol)
dissolved in DMF (2 mL) and cooled in an ice bath was added
potassium carbonate (0.16 g, 1.15 mmol) and the reaction was
stirred at room temperature for 1 hour. After removing the solvent,
the residue was extracted with ethyl acetate and water. The organic
layer was washed with water and brine, dried over sodium sulfate,
filtered, and concentrated to give 0.09 g of
4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid,
methyl ester as an oil. Yield .about.73.8%. Electrospray Mass Spec
354.2 (M+H).sup.+.
[0915] Step 5
[0916] A solution of
4-([4-(2-4butynyloxy)phenyl]sulfonyl}-morpholine-3-ca- rboxylic
acid, methyl ester (0.1 g, 0.28 mmol) in 2.4 mL of
THF:methanol:water [4:1:1]was cooled in an ice bath and 2N LiOH
(0.3 mL, 0.59 mmol) was added. The reaction was stirred at
0.degree. C. for 30 minutes and at room temperature for 2 hours.
After evaporating the solvent, the residue was diluted with ether
and filtered. The solid was dissolved in water, neutralized with 1N
HCl to pH .about.3 and extracted with dichloroethane. The organic
layer was washed with water and brine, dried over sodium sulfate,
filtered and concentrated to give 0.06 g of
4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid.
Yield .about.69.8%. mp 40-42.degree. C. Electrospray Mass Spec
338.1 (M-H).sup.-.
[0917] Step 6
[0918] A solution of
4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-car- boxylic acid
(0.52 g, 1.53 mmol) and DMF (0.24 mL, 3.1 mmol) in dichloromethane
(6 mL) was cooled in an ice bath and oxalyl chloride (1.54 mL of 2M
in CH.sub.2Cl.sub.2; 3.1 mmol) was added dropwise. The reaction
mixture was stirred at 0.degree. C. for 10 minutes and at room
temperature for 2 hours and then recooled to 0.degree.. A THF (4.5
mL) solution of triethyl amine (0.86 mL, 6.13 mmol) and
hydroxylamine (0.56 mL of 50% hydroxyamine in water, 9 mmol) was
added in one portion. The reaction was stirred at room temperature
overnight. After removing the solvent, the oily residue was diluted
with ethyl acetate and water. The organic layer was washed with
water and brine, dried over sodium sulfate, filtered and evaporated
to obtain 0.42 g of 4-([4-(2-butynyloxy)phenyl]su-
lfonyl}-N-hydroxy-3-morpholinecarboxamide. Yield .about.77.8%. mp
68-72.degree. C. Electrospray Mass Spec 355.2(M+H).sup.+.
EXAMPLE 241
9-Benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4,9-diazasp-
iro[5.5]undecane-5-carboxamide
[0919] Step 1
[0920] To a stirred suspension of sodium hydride (4.6 g of 60% oil
dispersion, 100 mmol) in dry TMF (200 ml) at 0.degree. C. were
added simultaneously, in a dropwise manner, ethyl isocyanatoacetate
(10.3 g, 100 mmol) and 1-benzyl-4-piperidone (17.5 g, 100 mmol).
After the addition reaction mixture was warmed up to room
temperature and stirred for 4 h. The reaction mixture was then
carefully quenched with saturated ammonium chloride solution. The
reaction mixture was extracted with chloroform and washed with
saturated brine solution. The organic layer was dried over
anhydrous MgSO.sub.4, filtered and concentrated. The crude brown
oil, ethyl(1-benzyl-4-piperidinylidene)(formylamino)acetate, was
pure enough for use in the next step. Yield, 28.9 g (96%);
Electrospray Mass Spec: 303 (M+H).sup.+.
[0921] Step 2
[0922] A mixture of
ethyl(1-benzyl-4-piperidinylidene)(formylamino)acetate (3.0 g, 10.0
mmol), 2-mercaptoethanol (2.7 g, 35 mmol) and sodium methoxide (1
g) was heated at 80.degree. C. for 8 h under nitrogen. The reaction
mixture was then cooled to room temperature and quenched with
saturated ammonium chloride solution. It was extracted with
chloroform, washed twice with brine and dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The oily, residue was
purified by silica gel column chromatography eluting with 5%
methanol:chloroform to provide
ethyl{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}(formylamino)ac-
etate as a yellow oil; Yield: 2.8 g (73%); Electrospray Mass Spec:
381 (M+H).sup.+.
[0923] Step 3
[0924]
Ethyl{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}(formylam-
ino)acetate (2.8 g, 7.3 mmol) was dissolved in 50 ml of ethanol and
5N hydrochloric acid (4 ml) and refluxed for 2 h. The reaction
mixture was then concentrated to dryness to provide ethyl
amino{1-benzyl-4-[(2-hydrox- yethyl)sulfanyl]-4-piperidinyl}acetate
as a brown oil which was used for the next step with out
purification. Yield: 3.0 g (quantitative); Electrospray Mass Spec:
353 (M+H).sup.+.
[0925] Step 4
[0926] To a stirred solution of ethyl
amino{1-benzyl-4-[(2-hydroxyethyl)su- lfanyl]-4-piperidinyl}acetate
(2.1 g, 5 mmol) and 4-but-2-ynyloxy benzenesulfonyl chloride (1.24
g, 5.1 mmol) in dichloromethane (200 ml) at 0.degree. C.,
N,N-diisopropylethylamine (3.0 g, 23.6 mmol) was added slowly.
After the addition, the reaction mixture was stirred at room
temperature for 4 h and quenched with water. The reaction mixture
was washed with water, dried over anhydrous MgSO.sub.4, filtered
and concentrated. It was purified by silica gel column
chromatography eluting with 80% ethyl acetate:hexane to give ethyl
{1-benzyl-4-[(2-hydroxyethyl)-
sulfanyl]-4-piperidinyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)acetate
as a brown oil; Yield: 1.0 g (85%); Electrospray Mass Spec: 561
(M+H).sup.+.
[0927] Step 5
[0928] A mixture of ethyl
{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperid-
inyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)acetate (5.0 g, 8.9
mmol), tributylphosphine (4.04 g, 20 mmol) and
1,1-(azodicarbonyl)-dipiperidine (5.04 g, 20 mmol) was stirred in
dry THF at room temperature for 6 h. The reaction mixture was
quenched with water, extracted with chloroform and washed well with
water. The organic layer was dried over anhydrous MgSO.sub.4,
filtered and concentrated. The product was purified by silica gel
column chromatography eluting with 60% ethyl acetate/hexane to give
ethyl-9-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-thia-4,9-diazaspiro-
[5.5]undecane-5-carboxylate as a pale yellow oil; Yield: 4.2 g
(87.5%); Electrospray Mass. Spec: 543 (M+H).sup.+.
[0929] Step 6
[0930] A mixture of
ethyl-9-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1--
thia4,9-diazapiro[5.5]undecane-5-carboxylate (4.0 g, 7.38 mmol) and
5N sodium hydroxide (20 ml) was refluxed in THF:methanol (1:1, 100
ml) for 8 h. The reaction mixture was concentrated and the residue
was carefully neutralized with concentrated hydrochloric acid. The
separated sticky mass was extracted with chloroform, washed once
with water, dried over anhydrous MgSO.sub.4, filtered and
concentrated. The brown spongy solid,
9-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1-thia-4,9-diazaspiro[5.5]--
undecane-5-carboxylic acid, was used for the next step with out
purification. Yield: 3.5 g (93%); mp 123-128.degree. C.;
Electrospray Mass Spec: 515 (M+H).sup.+.
[0931] Step 7
[0932] To a stirred suspension of
9-benzyl-4-{[4-(2-butynyloxy)phenyl]sulf-
onyl}-1-thia-4,9-diazaspiro[5.5]undecane-5-carboxylic acid (3.0 g,
5.8 mmol) in dichloromethane (200 ml)/DMF (5 ml), oxalyl chloride
(5.0 g, 39.6 mmol) in dichloromethane (10 ml) was added slowly at
0.degree. C. After the addition, the reaction mixture was stirred
at room temperature for 1 h. In a separate flask, hydroxylamine
hydrochloride (6.9 g, 100 mmol) was dissolved in DMF/acetonitrile
(1:1, 100 ml) and triethylamine (20 g, 200 mmol) was added. It was
stirred at room temperature for 1 h and diluted with
dichloromethane (50 ml). The acid chloride formed was concentrated
to dryness and redissolved in dichloromethane. The hydroxylamine
solution was cooled to 0.degree. C., and the acid chloride was
added to the hydroxylamine. The reaction mixture was stirred at
room temperature for 6 h and concentrated to dryness. It was
extracted with chloroform, washed well with water, dried over
anhydrous MgSO.sub.4, filtered and concentrated. The product was
purified by silica gel column chromatography eluting with 5%
methanol:chloroform. The hydrochloride salt was prepared by
dissolving the free base in methanolic hydrochloric acid to give
9-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-th-
ia-4,9-diazaspiro[5.5]undecane-5-carboxamide hydrochloride as a
yellow spongy solid; Yield 1.8 g (58%); mp 151-153.degree. C.;
Electrospray Mass Spec: 530 (M+H).sup.+; H.sup.1 NMR (DMSO)
.quadrature.: 1.8 (s, 3H), 1.9 (m, 2H), 2.3-2.6 (m,4H), 2.7-2.85
(m, 3H), 3.0-3.1 (m,1H), 3.5 (s,2H), 3.8-4.2 (m, 2H), 4.7 (s,1H),
4.8 (s,2H) 7.0 (d, 2H), 7.3-7.5(m,5H), 7.8 (d,2H), 10.6 (s,1H),
11.1 (s,1H).
EXAMPLE 242
9-methyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia-4,9-diazasp-
iro[5.5]undecane-5-carboxamide
[0933]
9-Methyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-thia4,9-d-
iazaspiro[5.5]undecane-5-carboxamide was prepared according to the
procedure of Example 241. Starting from ethyl isocyanatoacetate and
1-methyl-4-piperidone,
9-methyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hy-
droxy-1-thia-4,9-diazaspiro[5.5]-undecane-5-carboxamide was
isolated as white solid mp 195-198; Electrospray Mass Spec: 454
(M+H).sup.+. H.sup.1 NMR (DMSO) .quadrature.: 1.8 (s, 3H), 1.9 (m,
2H), 2.3-2.6 (m,4H), 2.7-2.85 (m, 3H), 3.0-3.1 (m,1H), 3.5 (s,2H),
3.8-4.2 (m, 2H), 4.7 (s,1H), 4.8 (s,2H), 7.0 (d, 2H), 7.3-7.5
(m,5H), 7.8 (d,2H), 10.6 (s,1H), 11.1 (s,1H).
EXAMPLE 243
N-Hydroxy-2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]-
oxy}phenyl)sulfonyl]-3-thiomorpholine Carboxamide
[0934] Step 1
[0935] To a solution of 8.0 mL (51 mmol) of
2-(3-butynyloxy)tetrahydro-2H-- pyran in 50 mL of THF under
nitrogen atmosphere at -23.degree. C. was added dropwise a solution
of 33 mL (53 mmol) of 1.6M butyllithium in hexanes, maintaining the
temperature at -23.degree. C. The resulting solution was stirred at
0.degree. C. for 2 h, recooled to -23.degree. C. and 2.4 g (76.5
mmol) of paraformaldehyde was added in several portions. The mixre
was stirred at -23.degree. C. for 1 h and let warm to room
temperature and stirred for 18 h. The reaction mixture was poured
into a large excess of ice water and extracted with ether. The
organics were washed with brine until neutral, dried over MgSO4,
filtered and concentrated in vacuo. The residue was kugelrohr
distilled to provide 7.26 g (77%) of
5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol as a colorless
liquid. EI Mass Spec: 185.1 (M+H).sup.+
[0936] Step 2
[0937] To a stirred solution of 5.15 mL (59.8 mmol) of
1,2-dibromoethane in 50 mL of DMF at room temperature was added
over 45 min a solution of 10 g (50 mmol) of D-penicillamine methyl
ester hydrochloride and 22.5 mL (150.45 mmol) of
1,8-diazabicyclo[5.4.0]undec-7-ene in 100 mL of DMF. The reaction
was stirred for 2.5 h, poured into a solution of saturated NaHCO3
and extracted with ethyl acetate. The organics were washed with
brine, dried over MgSO4, filtered and concentrated in vacuo to
provide 8.24 g (87%) of methyl (3S)-2,2-dimethyl-3-thiomorpholine
carboxylate as a pale yellow oil. Electrospray Mass Spec: 190.1
(M+H).sup.+
[0938] Step 3
[0939] To a solution of 0.5 g (2.6 mmol) of
4-hydroxybenzenesulfonyl chloride (J. Org. Chem. 1973, 38, 1047) in
5 mL of chloroform at room temperature was added 0.706 mL (2.86
mmol) of N,O-bis(trimethylsilyl)acet- amide. The reaction mixture
was stirred for 1 h and added a solution of 0.41 g (2.16 mmol) of
methyl (3S)-2,2-dimethyl-3-thiomorpholinecarboxylat- e in 1 mL of
chloroform in one portion, followed by 0.48 mL (4.37 mmol) of
N-methylmorpholine. The resulting mixture was stirred for 18 h and
10 mL of methanol was added and the resulting mixture was heated to
reflux for 1 h. The reaction was diluted with ethyl acetate, washed
with water, 5% HCl and brine, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was triturated with
ether:hexanes (1:2) to provide 0.62 g (83%) of
4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carb-
oxylic acid methyl ester as a pale yellow solid. Electrospray Mass
Spec: 344.4 (M-H).sup.-
[0940] Step 4
[0941] To a solution of 3.31 g (9.6 mmol) of of
4-(4-hydroxy-benzenesulfon-
yl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and
2.12 g (11.5 mmol) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol
in 15 mL of THF was added 3.0 g (11.5 mmol) of triphenylphosphine,
followed by dropwise addition of 1.8 mL (11.5 mmol) of diethyl
azodicarboxylate. The resulting solution was stirred at room
temperature for 18 h. The reaction was diluted with ethyl acetate,
washed with water and 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 3.03 g
(62%) of methyl 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyra-
n-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine
carboxylate as a colorless oil. Electrospray Mass Spec: 534.4
(M+Na).sup.+
[0942] Step 5
[0943] A solution of 0.418 g (0.817 mmol) of methyl
2,2-dimethyl-4[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl-
)sulfonyl]-3-thiomorpholine carboxylate, 4.0 mL (4.08 mmol) of 1N
NaOH, 4.0 mL of methanol and 4.0 mL of THF was heated to reflux for
5 h. The reaction was concentrated and the residue was diluted with
water, acidified to pH5 and extracted with ethyl acetate. The
organics were washed with water and brine, dried over MgSO4,
filtered and concentrated in vacuo to provide 0.342 g (84%) of
2,2-dimethyl-4-[(4-{[5-(tetrahydro-2-
H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine
carboxylic acid as a colorless oil. Electrospray Mass Spec: 496.5
(M-H).sup.-
[0944] Step 6
[0945] To a solution of 0.28 g (0.56 mmol) of
2,2-dimethyl-4-[(4-{[5-(tetr-
ahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine
carboxylic acid and 0.091 g (0.675 mmol) of 1-hydroxybenzotriazole
in 2.5 mL of DMF was added 0.151 g (0.788 mmol) of
1-(3-dimethylaminopropyl)-3-e- thylcarbodiimide hydrochloride and
stirred at room temperature for 1 h. Then 0.173 mL (2.8 mmol) of
50% aqueous hydroxylamine was added and the reaction was stirred
for 18 h. The resulting mixture was diluted with ethyl acetate,
washed with water, brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with 5% methanol/dichloromethane. The product was
triturated with ether to provide 0.024 g (8%) of
N-hydroxy-2,2-dimethyl-4-[(4-{[5-(tetrah-
ydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine
carboxamide as a white solid. Electrospray Mass Spec: 513.4
(M+H).sup.+
EXAMPLE 244
N-Hydroxy-4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-
-thiomorpholine Carboxamide
[0946] To a solution of 0.33 g (0.663 mmol) of
2,2-dimethyl-4-[(4-{[5-(tet-
rahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine
carboxylic acid (Step 5, Example 243) and 0.108 g (0.796 mmol) of
1-hydroxybenzotriazole in 3 mL of dichloromethane and 1 mL of DMF
was added 0.169 g (0.88 mmol) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimid- e hydrochloride and
the reaction was stirred at room temperature for 1 h. Then 0.203 mL
(3.31 mmol) of 50% aqueous hydroxylamine was added and the reaction
was stirred for 18 h. The reaction was diluted with ethyl acetate,
washed with water and brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was dissolved in 10 mL of
methanol and 0.028 g (0.11 mmol) of pyridinium p-toluenesulfonate
was added and the reaction was heated to reflux for 18 h. The
reaction was concentrated in vacuo and the residue was
chromatographed on silica gel eluting with 2.5%
MeOH/CH.sub.2Cl.sub.2 to provide 0.59 g (21%) of
N-hydroxy-4-({4-[(5-hydr-
oxy-2-phentynyl)oxy]phenyl}sulfonyl)-2,2-dimenthyl-3-thiomorpholine
carboxamide as a white solid. Electrospray Mass Spec: 429.1
(M+H).sup.+
EXAMPLE 245
tert-Butyl
5-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholiny-
l}sulfonyl)phenoxy]-3-pentynylcarbamate
[0947] Step 1
[0948] A mixture of 2.61 g (5.1 mmol) of methyl
2,2-dimethyl-4-[(4-{[5-(te-
trahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholin-
e carboxylate and 0.32 g (1.275 mmol) of pyridinium p-toluene
sulfonate in 50 mL of methanol was heated to reflux for 18 h. The
reaction was concentrated in vacuo and the residue was
chromatographed on silica gel eluting with ethyl acetate:hexanes
(1:4) to provide 2.2 g (100%) of methyl
4-({4-[(5-hydroxy-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-t-
hiomorpholine carboxamide as a colorless oil. Electrospray Mass
Spec: 428.1 (M+H).sup.+
[0949] Step 2
[0950] To a solution of 2.123 g (8.093 mmol) of triphenylphosphine
and 0.373 mL (4.61 mmol) of pyridine in 40 mL of dry THF under
nitrogen was added 1.73 g (4.046 mmol) of methyl
4-({4-[(5-hydroxy-2-pentynyl)oxy]phen-
yl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide. The
solution was cooled in a water bath and 1.34 g (4.046 mmol) of
carbon tetrabromide was added and the resulting mixture was stirred
for 3 h. The resulting suspension was filtered and the filtrate was
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with ethyl acetate:hexanes (1:8) to provide 1.726 g
(87%) of methyl
4-({4-[(5-bromo-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpho-
line carboxamide as a pale yellow oil. Electrospray Mass Spec:
492.0 (M+H).sup.+
[0951] Step 3
[0952] A solution of 1.74 g (3.55 mmol) of
methyl-4-({4-[(5-bromo-2-pentyn-
yl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide
and 0.277 g (4.26 mmol) of sodium azide in 15 mL of DMF was stirred
at room temperature for 18 h. The reaction was diluted with ether,
washed with water and brine, dried over MgSO.sub.4, filtered and
concentrated in vacuo to provide 1.6 g (100%) of methyl
4-({4-[(5-azido-2-pentynyl)oxy]ph-
enyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as a pale
brown oil. Electrospray Mass Spec: 453.2 (M+H).sup.+
[0953] Step 4
[0954] To a solution of 0.453 g (1.0 mmol) of methyl
4-({4-[(5-azido-2-pentynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpho-
line carboxylate in 7 mL of ether and 1 mL of THF was dropwise
added 0.275 mL (1.1 mmol) of tributylphosphine at room temperature.
The reaction was stirred for 1 h and then cooled to -50.degree. C.
(acetonitrile/dry ice bath). A solution of 0.24 g (1.1 mmol) of
di-tert-butyldicarbonate in 3.5 mL of ether was added and stirred
at -50.degree. C. for 2 h. Then 3.5 mL of saturated solution of
NaHCO.sub.3 was added and the reaction was let warm to room
temperature. The resulting mixture was diluted with ethyl acetate,
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuo. The residue was chromatographed on silica gel eluting
with ethyl acetate:hexanes (1:6) to provide 0.21 g (40%) of
methyl-4-{[4-({5-[(tert-butoxycarbonyl)amino]-2-pentynyl}oxy)phenyl]sulfo-
nyl}-2,2-dimethyl-3-thiomorpholine carboxylate as a colorless oil.
Electrospray Mass Spec: 527.2 (M+H).sup.+
[0955] Step 5
[0956] According to the procedure of Step 5 of Example 243, 0.2 g
(0.38 mmol) of
methyl-4-{[4-({5-[(tert-butoxycarbonyl)amino]-2-pentynyl}oxy)phe-
nyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylate provided
0.159 g (82%) of
4-{[4-({5-[(tert-butoxycarbonyl)amino]-2-pentynyl}oxy)phenyl]sul-
fonyl}-2,2-dimethyl-3-thiomorpholine carboxylic acid as a colorless
oil. Electrospray Mass Spec: 513.2 (M+H).sup.+
[0957] Step 6
[0958] According to the procedure of Step 6 of Example 243, 0.155 g
(0.3 mmol) of
4-{[4-({5-[(tert-butoxycarbonyl)amino]-2-pentynyl}oxy)phenyl]sul-
fonyl}-2,2-dimethyl-3-thiomorpholinecarboxylic acid provided 0.058
g (37%) of tert-butyl
5-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpho-
linyl}sulfonyl)phenoxy]-3-pentynylcarbamate as a cream solid.
Electrospray Mass Spec: 528.1. (M+H).sup.+
EXAMPLE 246
4-({(4-[(5-Amino-2-pentynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3--
thiomorpholine carboxamide
[0959] A solution of 0.071 g (0.135 mmol) of tert-butyl
5-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholinyl}sulfonyl-
)phenoxy]-3-pentynylcarbamate from Example 245, 1 mL of
trifluoroacetic acid and 3 mL of dichloromethane was stirred for
1.5 h. The solution was concentrated in vacuo and the residue was
triturated with ether to provide 0.058 g (79%) of
4-({4-[(5-amino-2-pentynyl)oxy]phenyl}sulfonyl)--
N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide as a pale
orange solid. Electrospray Mass Spec: 428.3 (M+H).sup.+
EXAMPLE 247
4-[(4-{[4-(Benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-N-hydroxy-2,2-dimethy-
l-3-thiomorpholine Carboxamide
[0960] Step 1
[0961] To a suspension of 1.4 g (34.0 mmol) of 60% sodium hydride
in mineral oil in 40 mL of DMF was added 3.44 g (40 mmol) of
2-butyne-1,4-diol and the reaction was stirred at room temperature
for 3 h. Then 4.04 mL (34.0 mmol) of benzyl bromide was added and
the reaction was stirred for 18 h. The reaction was quenched with
water and extracted with ether. The organics were washed with
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with ethyl
acetate:hexanes (1:9) to provide 2.013 g (34%) of the desired
product, 4-(benzyloxy)-2-butyn-1-ol, as a colorless oil. CI Mass
Spec: 159.1 (M-water+H).sup.+ and 2.47 g (27%) of
1-({[4-(benzyloxy)-2-butynyl]oxy}methyl)benzene as a colorless oil.
EI Mass spec: 266.1 (M).sup.+
[0962] Step 2
[0963] According to the procedure of Step 4 of Example 243,
Mitsunobu coupling of 0.345 g (1.0 mmol) of
4-(4-hydroxy-benzenesulfonyl)-2,2-dimet-
hyl-thiomorpholine-3-carboxylic acid methyl ester and 0.211 g (1.2
mmol) of 4-(benzyloxy)-2-butyn-1-ol provided 0.211 g (42%) of
methyl
4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiom-
orpholine carboxylate as a pale yellow oil. Electrospray Mass Spec:
504.2 (M+H).sup.+
[0964] Step 3
[0965] According to the procedure of Step 5 of Example 243, 0.2 g
(0.397 mmol) of methyl
4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2--
dimethyl-3-thiomorpholine carboxylate provided 0.135 g (65%)
4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiom-
orpholine carboxylate as white solid. Electrospray Mass Spec: 490.1
(M+H).sup.+
[0966] Step 4
[0967] According to the procedure of Step 6 of Example 243, 0.12 g
(0.245 mmol) of
4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethy-
l-3-thiomorpholine carboxylate provided 0.03 g (25%) of
4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-N-hydroxy-2,2-dimeth-
yl-3-thiomorpholine carboxamide as a beige solid. Electrospray Mass
Spec: 505.2 (M+H).sup.+
EXAMPLE 248
N-Hydroxy-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]o-
xy}phenyl)sulfonyl]-3-thiomorpholine Carboxamide
[0968] Step 1
[0969] To a solution of 1.86 mL (0.02 mol) of 4-pentyn-1-ol and
4.56 mL (0.05 mol) of 3,4-dihydro-2H-pyran in 60 mL of
dichloromethane at 0.degree. C. was added 0.038 g (0.2 mmol) of
p-toluenesulfonic acid monohydrate. The reaction was stirred at
room temperature for 2.5 h, then washed with water, saturated
solution of NaHCO.sub.3, brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was kugelrohr distilled to
provide 3.4 g (100%) of the THP-ether of 4-pentyn-1-ol as a
colorless liquid. According to the procedure of Step 1 of Example
243, 3.24 g (19.26 mmol) of this ether provided 3.51 g (92%) of
6-(tetrahydro-2H-pyran-2-yloxy)-2-hexyn-1-ol as a pale yellow oil.
CI Mass Spec: 199.2 (M+H).sup.+
[0970] Step 2
[0971] According to the procedure of Step 4 of Example 243,
Mitsunobu coupling of 3.4 g (9.842 mmol) of
4-(4-hydroxy-benzenesulfonyl)-2,2-dimet-
hyl-thiomorpholine-3-carboxylic acid methyl ester and 2.34 g (11.81
mmol) of 6-(tetrahydro-2H-pyran-2-yloxy)-2-hexyn-1-ol provided 3.33
g (64%) of
methyl-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]oxy-
}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil.
Electrospray Mass Spec: 526.3 (M+H).sup.+
[0972] Step 3
[0973] According to the procedure of Step 5 of Example 243, 0.21 g
(0.4 mmol) of
methyl-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-he-
xynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate provided
0.163 g (80%) of
2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]o-
xy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid as a pale
yellow oil. Electrospray Mass Spec: 510.2 (M+H).sup.+
[0974] Step 4
[0975] According to the procedure of Step 6 of Example 243, 0.231 g
(0.45 mmol) of
2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]o-
xy}phenyl)sulfonyl]-3-thiomorpholine carboxylic acid provided 0.082
g (35%) of
N-hydroxy-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-
-hexynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide as a
beige solid. Electrospray Mass Spec: 527.3 (M+H).sup.+
EXAMPLE 249
N-Hydroxy-4-({4-[(6-hydroxy-2-hexynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3--
thiomorpholine Carboxamide
[0976] According to the procedure of Step 1 of Example 245, 0.078 g
(0.15 mmol) of
N-hydroxy-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-
-hexynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxamide provided
0.048 g (74%) of
N-hydroxy-4-({4-[(6-hydroxy-2-hexynyl)oxy]phenyl}sulfonyl)-2,2-
-dimethyl-3-thiomorpholine carboxamide as a beige solid.
Electrospray Mass Spec: 443.2 (M+H).sup.+
EXAMPLE 250
tert-Butyl
6-[4-({(3S)-3-[(hydroxyamino)carbonyl-2,2-dimethylthiomorpholin-
yl}sulfonyl)phenoxy]-4-hexynylcarbamate
[0977] According to the procedures of Steps 1-4 of Example 245,
methyl-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]oxy-
}phenyl)sulfonyl]-3-thiomorpholinecarboxylate (from Example 248)
provided
methyl-4-{[4-({6-[(tert-butoxycarbonyl)amino]-2-hexynyl}oxy)phenyl]sulfon-
yl}-2,2-dimethyl-3-thiomorpholin carboxylate as a colorless oil.
Electrospray Mass Spec: 541.3 (M+H).sup.+
[0978] A solution of 0.764 g (1.41 mmol) of
methyl-4-4-{[4-({6-[(tert-buto-
xycarbonyl)amino]-2-hexynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpho-
linecarboxylate and 3.77 g (28.2 mmol) of lithium iodide in 30 mL
of ethyl acetate was heated to reflux for 18 h. The resulting
reaction was acidified, washed with water, an aqueous solution of
Na.sub.2S.sub.2O.sub.3, brine, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with 0.5% methanol/dichloromethane to provide 0.417 g
(56%) of
4-{[4-({6-[(tert-butoxycarbonyl)amino]-2-hexynyl}oxy)phenyl]sulfonyl}-2,2-
-dimethyl-3-thiomorpholine carboxylic acid as a white solid.
Electrospray Mass Spec: 527.2(M+H).sup.+
[0979] According to the procedure of Step 6 of Example 243, 0.4 g
(0.76 mmol) of
4-{[4-({6-[(tert-butoxycarbonyl)amino]-2-hexynyl}oxy)phenyl]sulf-
onyl}-2,2-dimethyl-3-thiomorpholine carboxylic acid provided 0.162
g (39%) of tert-butyl
6-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorp-
holinyl}sulfonyl)phenoxy]-4-hexynylcarbamate as a cream solid.
Electrospray Mass Spec: 541.9 (M+H).sup.+
EXAMPLE 251
(3S)-4-({4-[(6-Amino-2-hexynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-
-3-thiomorpholine Carboxamide
[0980] Hydrogen chloride gas was bubbled into a solution of 0.104 g
(0.192 mmol) of tert-butyl
6-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylth-
iomorpholinyl}sulfonyl)-phenoxy]-4-hexynylcarbamate in 6 mL of
dichloromethane and 2 mL of methanol for 5 min, and the reaction
was stoppered and let stand for 1 h and then concentrated in vacuo.
The residue was triturated with ether to provide 0.092 g (100%) of
(3S)-4-({4-[(6-amino-2-hexynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethy-
l-3-thiomorpholine carboxamide as a cream solid. Electrospray Mass
Spec: 442.1 (M+M).sup.+
EXAMPLE 252
tert-Butyl
7-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorpholi-
nyl}sulfonyl)phenoxy]-5-heptynylcarbamate
[0981] According to the procedures of Steps 1 and 2 of Example 248,
starting with 5-hexyn-1-ol, methyl
2,2-dimethyl-4-[(4-{[7-(tetrahydro-2H-- pyran-2-yloxy)-2-heptyn
-oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate was obtained as
a pale yellow oil: Electrospray Mass Spec: 562.1 (M+Na).sup.+
[0982] The tetrahydropyranyl ether of methyl
2,2-dimethyl-4-[(4-{[7-(tetra-
hydro-2H-pyran-2-yloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-3-thiomorpholineca-
rboxylate was removed according to the procedure of Step 1 of
Example 245 to give methyl
4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dime-
thyl-3-thiomorpholine carboxylate as a colorless oil. Electrospray
Mass Spec: 456.1 (M+H).sup.+
[0983] According to the procedures of Steps 2-4 of Example 245,
methyl
4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorp-
holinecarboxylate was converted into the corresponding
BOC-protected carbamate, methyl
(3S)-4-{[4-({7-[(tert-butoxycarbonyl)amino]-2-heptynyl}-
oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylate
obtained as a colorless oil. Electrospray Mass Spec: 555.1
(M+H).sup.+
[0984] The methyl ester of methyl
(3S)-4-{[4-({7-[(tert-butoxycarbonyl)ami-
no]-2-heptynyl}oxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholine
carboxylate was converted into the analogous carboxylic acid using
lithium iodide according to the procedure of Example 250 to provide
(3S)-4-{[4-({7-[(tert-butoxycarbonyl)amino]-2-heptynyl}oxy)phenyl]sulfony-
l}-2,2-dimethyl-3-thiomorpholine carboxylic acid as a white solid.
Electrospray Mass Spec: 541.2 (M+H).sup.+
[0985] According to the procedure of Step 6 of Example 243, 0.315 g
(0.582 mmol) of
(3S)-4-{[4-({7-[(tert-butoxycarbonyl)amino]-2-heptynyl}oxy)pheny-
l]sulfonyl}-2,2-dimethyl-3-thiomorpholine carboxylic acid was
converted into 0.113 g (36%) of the corresponding hydroxamic acid,
tert-butyl
7-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfon-
yl)phenoxy]-5-heptynylcarbamate obtained as a white solid.
Electrospray Mass Spec: 556.1 (M+H).sup.+
EXAMPLE 253
(3S)-4-({4-[(7-Amino-2-heptynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethy-
l-3-thiomorpholine Carboxamide
[0986] According to the procedure of Example 251, 0.106 g (0.19
mmol) of tert-butyl
7-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorphol-
inyl}sulfonyl)phenoxyl]-5-heptynylcarbamate provided 0.091 g (98%)
of
(3S)-4-({4-[(7-amino-2-heptynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimeth-
yl-3-thiomorpholine carboxamide as a cream solid. Electrospray Mass
Spec: 456.2 (M+H).sup.+
EXAMPLE 254
(3S)-N-Hydroxy-2,2-dimethyl-4-(4-[(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl-
)-3-thiomorpholine Carboxamide
[0987] Step 1
[0988] According to the procedure of Step 2 of Example 248,
Mitsunobu coupling of 0.345 g (1.0 mmol) of
4-(4-hydroxy-benzenesulfonyl)-2,2-dimet-
hyl-thiomorpholine-3-carboxylic acid methyl ester and 0.159 g (1.2
mmol) of 3-phenyl-2-propyn1-ol provided 0.254 g (55%) of methyl
(3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)-oxy]phenyl}sulfonyl)-3-thi-
omorpholine carboxylate as a pale yellow solid. Electrospray Mass
Spec: 460.1 (M+H).sup.+
[0989] Step 2
[0990] According to the procedure of Example 250, lithium iodide
mediated ester cleavage of 0.282 g (0.61 mmol) of methyl
(3S)-2,2-dimethyl-4-({4-[-
(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl)-3-thiomorpholinecarboxylate
provided 0.215 g (79%) of
(3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)o-
xy]phenyl}sulfonyl)-3-thiomorpholine carboxylic acid as a white
solid. Electrospray Mass Spec: 446.0 (M+H).sup.+
[0991] Step 3
[0992] According to the procedure of Example 9, 0.195 g (0.438
mmol) of
(3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl}sulfonyl)-3-thio-
morpholine-carboxylic acid provided 0.159 g (79%) of
(3S)-N-hydroxy-2,2-dimethyl-4-({4[(3-phenyl-2-propynyl)oxy]phenyl}sulfony-
l)-3-thiomorpholine carboxamide as an off white solid. Electrospray
Mass Spec: 460.9 (M+H).sup.+
EXAMPLE 255
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomor-
pholine Carboxamide 1(S)-oxide
EXAMPLE 266
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomor-
pholine Carboxamide 1(R)-oxide
[0993] To a 0.degree. C. solution of 2.40 g (6.03 mmol) of the
product of Example 235,
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thio-
morpholine-3-carboxylic acid hydroxyamide, in 180 mL of
dichloromethane and 36 mL of methanol was added 0.885 g (5.126
mmol) of m-chloroperbenzoic acid in four equal portions, as a
solid. Thirty minutes after all, of the m-chloroperbenzoic acid had
been added, the reaction was diluted with dichloromethane and
washed with saturated sodium bicarbonate solution. The organics
were dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with a
gradient of chloroform/methanol (100:1) to (10:1) to provide 1.48 g
of a high R.sub.f sulfoxide diastereomer and 0.22 g of a low
R.sub.f sulfoxide diastereomer, both white solids, arbitrarily
assigned as (3S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydro-
xy-2,2-dimethyl-3-thiomorpholine carboxamide 1(S)-oxide and
(3S)-4-{[4-(2-butynyloxy)-phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiom-
orpholine carboxamide 1(R)-oxide respectively. Electrospray Mass
Spec 415.3 (M+H).sup.+
EXAMPLE 257
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomor-
pholine Carboxamide 1,1-dioxide
[0994] To a 0.degree. suspension of 0.200 g (0.503 mmol) of the
product of Example 235,
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thio-
morpholine-3-carboxylic acid hydroxyamide, in 5 mL of chloroform
was added 0.32 mL (1.508 mmol) of a 32% solution of peracetic acid.
The reaction became homogeneous and was allowed to warm to room
temperature and stirred for an additional 3 h. An additional 0.3 mL
of 32% peracetic acid was added and the reaction was stirred
overnight at room temperature and then concentrated in vacuo. The
residue was diluted with ethyl acetate and the organics were washed
with water and saturated sodium bicarbonate solution, dried over
sodium sulfate, filtered and concentrated. The residue was
chromatographed on silica gel eluting with chloroform/methanol
(100:1) to provide 0.138 g of (3S)-4-{[4-(2-butynylox-
y)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomorpholine
carboxamide 1,1-dioxide as a bown solid. Electrospray Mass Spec
431.3 (M+H).sup.+
EXAMPLE 258
(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2propynyloxy)phenyl]sulfonyl}-3-thiomor-
pholine Carboxamide
[0995] Step 1
[0996] To a 0.degree. suspension of 14.92 g (0.10 mmol) of
D-penicillamine in 300 mL of dichloroethane and 2.0 mL of DMF was
added 22.4 mL of DBU followed by 19.0 mL of trimethylsilyl
chloride. The ice bath was removed and the reaction was stirred for
3 h, after which an additional 29.9 mL of DBU was added. The
reaction was stirred overnight at room temperature and then 10 mL
of methanol was added and the reaction was stirred for 1h. The
resulting white precipitate was filtered off, washed with 10 mL of
methanol and dried in vacuo to provide 16 g of
(3S)-2,2-dimethyl-3-thiomo- rpholine carboxylic acid as a white
solid.
[0997] Step 2
[0998] To a 0.degree. suspension of 32 g (0.18 mol) of the above
carboxylic acid in 365 mL of dioxane was added 36.6 mL of
concentrated sulfuric acid over 10 minutes followed by 225 mL of
isobutylene. The reaction was warmed to room temperature and
stirred for 15 h with a dry ice/acetone condensor. The reaction was
then poured into a mixture of 1 L of 2M sodium bicarbonate solution
and 400 mL of ethyl acetate. The organics were dried over sodium
sulfate, filtered and concentrated to give 22 g of tert-butyl
(3S)-2,2-dimethyl-3-thiomorpholine carboxylate as a white solid.
Electrospray Mass Spec 232.3 (M+H).sup.+
[0999] Step 3
[1000] To a suspension of 20.0 g (0.104 mol) of
4-hydroxybenzenesulfonyl chloride in 200 mL of chloroform was added
28.25 mL (0.114 mol) of bis(trimethylsilyl)acetamide and the
reaction was stirred at room temperature for 1 h, after which all
of the solids have dissolved. To this mixture was added 20.0 g
(0.087 mol) of tert-butyl (3S)-2,2-dimethyl-3-thiomorpholine
carboxylate followed by 19.2 mL of 4-methylmorpholine and the
reaction was stirred overnight at room temperature. After the
addition of 400 mL of methanol to the reaction; the resulting
mixture was stirred overnight at room temperature and then
concentrated in vacuo. The residue was diluted with ethyl acetate
and the organics were washed with water and 5% HCl solution, dried
over magnesium sulfate, filtered and concentrated in vacuo. The
resulting white solid was washed with ether/hexanes (1:2) and dried
in vacuo to give 28.4 g (85%) of tert-butyl
(3S)-4-[(4-hydroxyphenyl)sulfonyl]-2,2-dimethyl-3-thi- omorpholine
carboxylate as a white solid. Electrospray Mass Spec 386.5
(M-H).sup.-
[1001] Step 4
[1002] According to the procedure of Step 2 of Example 248,
Mitsunobu coupling of 0.30 g (0.775 mmoL) of tert-butyl
(3S)-4-[(4-hydroxyphenyl)su-
lfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.054 mL (0.93
mmol) of propargyl alcohol gave 0.313 g of tert-butyl
(3S)-2,2-dimethyl-4-{[4-(-
2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxylate as a
white solid. Electrospray Mass Spec 426.4 (M+H)+
[1003] Step 5
[1004] Through a solution of 0.271 g (0.638 mmol) of tert-butyl
(3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholinec-
arboxylate in 10 mL of dichloromethane was bubbled hydrogen
chloride gas for 10 minutes. The reaction was then stoppered and
let sit overnight at room temperature. The solvent was evaporated
to give 0.221 g of
(3S)-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine
carboxylic acid as a white solid. Electrospray Mass Spec 368.2
(M-H)-
[1005] Step 6
[1006] According to the procedure of Example 9, 0.196 g (0.531
mmol) of
(3S)-2,2-dimenthyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiomorpholine-
carboxylic acid gave 0.192 g of the hydroxamic acid,
(3S)-N-hydroxy-2,2-dimethyl-4-{[4-(2-propynyloxy)phenyl]sulfonyl}-3-thiom-
orpholine carboxamide as a white solid. Electrospray Mass Spec
385.1 (M+H)+
EXAMPLE 259
(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2-pentynyloxy)phenyl]sulfonyl}-3-thiomo-
rpholine Carboxamide
[1007] According to the procedure of Example 258, using
2-pentyn-1-ol in Step 4,
(3S)-N-hydroxy-2,2-dimethyl-4-{[4-(2-pentynyloxy)phenyl]sulfonyl}-
-3-thiomorpholine carboxamide was obtained as a white solid.
Electrospray Mass Spec 413.2 (M+H).sup.+
EXAMPLE 260
(3S)-N-Hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimeth-
yl-3-thiomorpholine Carboxamide
[1008] Step 1
[1009] According to the procedure of Step 2 of Example 248,
Mitsunobu coupling of 2.5 g (6.46 mmoL) of tert-butyl
(3S)-4-[(4-hydroxyphenyl
sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.667 g
(7.752 mmol) of 2-butyne-1,4-diol gave 1.42 g of tert-butyl
(3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thio-
morpholine carboxylate as a colorless oil.
[1010] Step 2
[1011] The alcohol (0.300 g, 0.662 mmol) was dissolved in 3 mL of
acetic anhydride and 0.3 mL of pyridine. The reaction was stirred
overnight at room temperature and then concentrated in vacuo. The
residue was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:3) to provide 0.279 g (85%) of
tert-butyl(3S)-4-[(4-{[4-(acetyloxy)-2-butynyl]o-
xy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate as a
colorless oil. Electrospray Mass Spec 498.1 (M+H)+
[1012] Step 3
[1013] Through a solution of 0.250 g (0.503 mmol) of
tert-butyl(3S)-4-[(4-{[4-(acetyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-d-
imethyl-3-thiomorpholine carboxylate in 10 mL of dichloromethane
was bubbled hydrogen chloride gas for 10 minutes. The reaction was
then stoppered and let sit overnight at room temperature. The
solvent was evaporated to give 0.192 g of
(3S)-4-[(4-{[4-(acetyloxy)-2-butynyl]oxy}ph-
enyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylic acid as a
colorless oil. Electrospray Mass Spec 440.1 (M-H)-
[1014] Step 4
[1015] According to the procedure of Example 9, 0.150 g (0.340
mmol) of
(3S)-4-[(4-{[4-(acetyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3--
thiomorpholine carboxylic acid gave 0.127 g of the hydroxamic acid,
(3S)-N-hydroxy-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimet-
hyl-3-thiomorpholine carboxamide as a white solid. Electrospray
Mass Spec 415.2 (M+H)+
EXAMPLE 261
4-[4-({(3S)-3-[(Hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfony-
l)phenoxy]-2-butynyl Acetate
[1016] According to the procedure of Example 25, 0.196 g (0.444
mmol) of
(3S)-4-[(4-{[4-(acetyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3--
thiomorpholine carboxylic acid from Step 3 of Example 260 gave
0.086 g of
4-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfon-
yl)phenoxy]-2-butynyl acetate as a tan amorphous solid.
Electrospray Mass Spec 457.1 (M+H)+
EXAMPLE 262
(3S)-N-Hydroxy-4-({4-[(6-hydroxy-2,4-hexadiynyl)oxy]phenyl}sulfonyl)-2,2-d-
imethyl-3-thiomorpholine Carboxamide
[1017] According to the procedures for Example 260, using
2,4-hexadiyn-1, 6-diol in Step 1,
(3S)-N-hydroxy-4-({4-[(6-hydroxy-2,4-hexadiynyl)oxy]phe-
nyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxamide was
obtained as a tan solid. Electrospray Mass Spec 439.1 (M+H)+
EXAMPLE 263
(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2,4-pentadiynyloxy)phenyl]sulfonyl}-3-t-
hiomorpholine Carboxamide
[1018] According to the procedures of Steps 4-6 of Example 258,
using 2,4 pentadiyn-1-ol (EP 478,195) in Step 4,
(3S)-N-hydroxy-2,2-dimethyl-4-{[4
2,4-pentadiynyloxy)phenyl]sulfonyl}-3-thiomorpholine carboxamide
was obtained as a white solid. Electrospray Mass Spec 408.9
(M+H)+
EXAMPLE 264
(3S)-4-({4-[(4-Fluoro-2-butynyl)oxy]phenyl}sulfonyl)N-hydroxy
-2,2-dimethyl-3-thiomorpholine Carboxamide
[1019] To a 0.degree. solution of 0.300 g (0.659 mmol) of
tert-butyl
(3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thio-
morpholine carboxylate from Step 1 of Example 260 in 75 mL of
dichloromethane was added 0.17 mL of (diethylamino)sulfur
trifluoride and the reaction was stirred overnight at room
temperature. The reaction was quenched with brine and the organic
layer was separated and dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with ethyl acetate/hexanes (1:10) to give the
propargylic fluoride as a brown oil. Electrospray Mass Spec 457.8
(M+H)+
[1020] According to the procedures of Steps 3 and 4 of Example 260
the tert-butyl ester was hydrolyzed to the carboxylic acid and then
converted into the hydroxamic acid,
(3S)-4-({4-[(4fluoro-2-butynyl)oxy]phenyl}sulfo-
nyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholine carboxamide obtained
as a light brown solid. Electrospray Mass Spec 417.3 (M+H)+
EXAMPLE 265
4-({4-([4-Amino-2-butynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3-th-
iomorpholine Carboxamide
[1021] Step 1
[1022] According to the procedure of Step 2 of Example 248,
Mitsunobu coupling of 0.10 g (0.288 mmoL) of methyl
(3S)-4-[(4-hydroxyphenyl)sulfon-
yl]-2,2-dimethyl-3-thiomorpholinecarboxylate and 0.031 g (0.363
mmol) of 2-butyne-1,4-diol gave 0.078 g of methyl
(3S)-4-({4-[(4-hydroxy-2-butynyl-
)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholine carboxylate as
a colorless oil.
[1023] Step 2
[1024] To a solution of 1.59 g (3.85 mmol) of methyl
(3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thio-
morpholine carboxylate in 50 mL of dichloromethane was added 1.34
mL (9.63 mmol) of triethylamine followed by 0.36 mL (4.62 mmol) of
methanesulfonyl chloride. The reaction was stirred at room
temperature for 3 h and then diluted with ether. The organics were
washed with 5% HCl solution and water, dried over magnesium
sulfate, filtered and concentrated. The residue was used in the
next step without purification.
[1025] Step 3
[1026] To a solution of the above mesylate (1.06 g, 2.16 mmol) in
12 mL of DMF was added 0.168 g (2.59 mmol) of sodium azide. The
reaction was stirred at room temperature for 12 h and then diluted
with ethyl acetate. The organics were washed with water, dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue
was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:3) to give 0.823 g of the azide, methyl
(3S)-4-({4-[(4-azido-2-butynyl)oxy]phenyl}sulfonyl)-2,2-
-dimethyl-3-thiomorpholine carboxylate.
[1027] Step 4
[1028] To a solution of 0.811 g (1.852 mmol) of the azide in 13 mL
of ether and 3.5 mL of THF was added 0.692 mL (2.777 mmol) of
tributylphosphine and the reaction was stirred for 4 h. The
reaction was then cooled to -40.degree. C. and a solution of 0.647
g (2.962 mmol) of di-tert-butyl dicarbonate in 9 mL of ether was
added dropwise. The reaction was stirred at -40.degree. C. for 1 h
and then saturated sodium bicarbonate solution was added (10 mL)
and the reaction was warmed to room temperature and stirred
overnight. The organics were washed with water, dried over
magnesium sulfate, filtered and concentrated. The residue was
chromatographed on silica gel eluting with ethyl acetate/hexanes
(1:3) to give 0.301 g of the NH-carbamate methyl, ester, methyl
4-{[4-({4-[(tert-butoxycarbonyl)amino]-2-butynyl}oxy)phenyl]sulfon-
yl}-2,2-dimethyl-3-thiomorpholine carboxylate.
[1029] Step 5
[1030] According to the procedure of Example 11 0.300 g (0.586
mmol) of the NH-carbamate methyl ester gave 0.149 g of the
NH-carbamate carboxylic acid,
4-{[4-({4-[(tert-butoxycarbonyl)amino]-2-butynyl}oxy)phenyl]sulfony-
l}-2,2-dimethyl-3-thiomorpholine carboxylic acid which was
subsequently converted into 0.057 g of the hydroxamic acid
following the procedure of Example 25. Bubbling hydrogen chloride
gas through a dichloromethane solution of the NH-carbamate
hydroxamic acid then provided 0.057 g of
4-({4-[(4-amino-2-butynyl)oxy]phenyl}sulfonyl)-N-hydroxy-2,2-dimethyl-3-t-
hiomorpholine carboxamide hydrochloride. Electrospray Mass Spec
414.4 (M+H)+
EXAMPLE 266
tert-Butyl
4-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholiny-
l}sulfonyl)phenoxy]-2-butynylcarbamate
[1031] According to the procedure of Example 25, 0.106 g (0.213
mmol) of
4-{[4-({4-[(tert-butoxycarbonyl)amino]-2-butynyl}oxy)phenyl]sulfonyl}-2,2-
-dimethyl-3-thiomorpholine carboxylic acid provided 0.052 g of
tert-butyl
4-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholinyl}sulfonyl-
)phenoxy]-2-butynylcarbamate as a white solid. Electrospray Mass
Spec 514.1 (M+H)+
EXAMPLE 267
tert-butyl
4-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholiny-
l}sulfonyl)phenoxy]-2-butynyl(methyl)carbamate
[1032] Step 1
[1033] To a solution of 2.714 g (0.01 mol) of triphenylphosphine in
21 mL of THF and 0.41 mL of pyridine was added 2.137 g (5.174 mmol)
of methyl
(3S)-4-({4-[(4-hydroxy-2-butynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thio-
morpholine carboxylate (from Step 1 of Example 265) followed by
1.716 g (5.174 mmol) of carbon tetrabromide. The reaction was
stirred at room temperature for 4 h and then concentrated in vacuo.
The residue was chromatographed on silica gel eluting with ethyl
acetate/hexanes (1:3) to give 1.523 g (62%) of the propargylic
bromide.
[1034] Step 2
[1035] To a solution of 0.50 g (1.050 mmol) of the propargylic
bromide in 5 mL of THF was added 5.25 mL (0.010 mmol) of a 2.0M
solution of methylamine in THF followed by 0.020 g of
tetrabutylammonium iodide. The reaction was stirred at room
temperature for 4 h and then diluted with ether. The organics were
washed with water, dried over sodium sulfate, filtered and
concentrated. The residue chromatographed on silica gel eluting
first with ethyl acetate then with chloroform/methanol (9:1) to
give 0.365 g (82%) of the methylamine, methyl
2,2-dimethyl-4-[(4-{[4-(met-
hylamino)-2-butynyl]oxy}phenyl)sulfonyl]-3-thiomorpholinecarboxylate
as a colorless oil. Electrospray Mass Spec 427.3 (M+H)+
[1036] Step 3
[1037] To a solution of 0.331 g (0.777 mol) of methyl
2,2-dimethyl-4-[(4-{[4-methylamino)-2-butynyl]oxy}phenyl)sulfonyl]-3-thio-
morpholinecarboxylate in 5 mL of THF was added 9 mg of
4-dimethylaminopyridine followed by 0.186 g (0.855 mmol) of
di-tert-butyl dicarbonate. The reaction was stirred for 4 h and
then concentrated in vacuo. The residue chromatographed on silica
gel eluting first with ethyl acetate/hexanes (1:10) to (1:3) to
give 0.344 g of methyl
4-{[4-({4-[(tert-butoxycarbonyl)(methyl)amino]-2-butynyl}oxy)phenyl]sulfo-
nyl}-2,2-dimethyl-3-thiomorpholinecarboxylate as a pale yellow oil.
Electrospray Mass Spec 527.6 (M+H)+
[1038] Step 4
[1039] According to the procedures of Example 11 and Example 25,
0.312 g (0.593 mmol) of methyl
4-{[4-({4-[(tert-butoxycarbonyl)(methyl)amino]-2-b-
utynyl}oxy)-phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate
was converted into 0.049 g of the hydroxamic acid, tert-butyl
4-[4-({3-[(hydroxyamino)carbonyl]-2,2-dimethyl-4-thiomorpholinyl}sulfonyl-
)phenoxy]-2-butynyl(methyl)carbamate obtained as a white solid.
Electrospray Mass Spec 528.1 (M+H)+
EXAMPLE 268
7-[4-({(3S)-3-[(Hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfony-
l)phenoxy]-5-heptynyl Acetate
[1040] Step 1
[1041] According to the procedures of Step 1 of Example 248,
starting with 5-hexyn-1-ol provided
6-(tetrahydro-2H-pyran-2-yloxy)-2-heptyn-1-ol.
[1042] According to the procedure of Step 4 of Example 243,
Mitsunobu coupling of 0.775 g (2.0 mmol) of tert-butyl
(3S)-4-[(4-hydroxyphenyl)sul- fonyl]-2,2-dimethyl-3-thiomorpholine
carboxylate (Step 3, Example 258) and 0.510 g (2.4 mmol) of
6-(tetrahydro-2H-pyran-2-yloxy)-2-heptyn-1-ol provided 0.975 g
(84%) of tert-butyl (3S)-2,2-dimethyl-4-[(4-{[7-(tetrahy-
dro-2H-pyran-2-yloxy)-2-heptynYL]oxy}phenyl)-sulfonyl]-3-thiomorpholinecar-
boxylate as a colorless oil. Electrospray Mass Spec: 604.2
(M+Na).sup.+
[1043] Step 2
[1044] According to the procedure of Step 1 of Example 245 the
tetrahydropyranyl ether of 0.659 g (1.13 mmol) of tert-butyl
(3S)-2,2-dimethyl-4-[(4-{[7-(tetrahydro-6-2H-pyran-2-yloxy)-2-heptynyl]ox-
y}phenyl)sulfonyl]-3-thiomorpholinecarboxylate was cleaved to
provide 0.472 g (84%) of tert-butyl
(3S)-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}-
sulfonyl)-2,2-dimethyl-3-thiomorpholinecarboxylate as a colorless
oil. Electrospray Mass Spec: 498.3 (M+H).sup.+
[1045] Step 3
[1046] A mixture of 0.452 g (0.908 mmol) of tert-butyl
(3S)-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thi-
omorpholinecarboxylate, 2.6 mL (27 mmol) of acetic anhydride and
0.22 mL (2.7 mmol) of pyridine was stirred at room temperature for
6 h and concentrated in vacuo. The residue was chromatographed on
silica gel eluting with ethyl acetate:hexanes (1:5) to provide
0.476 g (97%) of tert-butyl
(3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-2,2-
-dimethyl-3-thiomorpholinecarboxylate as a colorless oil.
Electrospray Mass Spec: 540.0 (M+H).sup.+
[1047] Step 4
[1048] According to the procedure of Example 251, lithium iodide
mediated ester cleavage of 0.456 g (0.845 mmol) of tert-butyl
(3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-
-thiomorpholinecarboxylate provided 0.409 g (100%) of
(3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-
-thiomorpholinecarboxylic acid as a colorless oil. Electrospray
Mass Spec: 446.0 (M+H).sup.+
[1049] Step 5
[1050] According to the procedure of Example 9, 0.192 g (0.398
mmol) of
(3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-
-thiomorpholine-carboxylic acid provided 0.125 g (63%) of
7-[4-({(3S)-3-[(hydroxyamino)carbonyl]-2,2-dimethylthiomorpholinyl}sulfon-
yl)phenoxy]-5-heptynyl acetate as a white solid. Electrospray. Mass
Spec: 499.0 (M+H).sup.+
EXAMPLE 269
(3S)-N-Hydroxy-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimet-
hyl-3-thiomorpholinecarboxamide
[1051] A mixture of 0.152 g (0.305 mmol) of
7-[4-({(3S)-3-[(hydroxyamino)--
carbonyl]-2,2-dimethylthiomorpholinyl}sulfonyl)phenoxy]-5-heptynyl
acetate, 3 mL of aqueous ammonium hydroxide and 3 mL of methanol
was stirred at room temperature for 18 h and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with 1.5%
methanol/dichloromethane to provide 0.09 g (65%) of
(3S)-N-hydroxy-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dime-
thyl-3-thiomorpholinecarboxamide as a white solid. Electrospray
Mass Spec: 457.0 (M+H).sup.+
EXAMPLE 270
(3S,5S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,5-trimethyl-3-t-
hiomorpholinecarboxamide
[1052] Step 1
[1053] To a stirred solution of 0.445 g (2.4 mmol) of 75%
1-bromo-2-propanol in 2 mL of DMF was added a solution of 0.4 g
(2.0 mmol) of D-penicillamine hydrochloride and 0.6 mL (4.0 mmol)
of 1,8 diazabicyclo[5.4.0]undec-7-ene in 4.0 mL of DMF over 15
minutes. The reaction was stirred for 3 h and 0.489 g (2.0 mmol) of
4-but-2-ynyloxybenzenesulfonyl chloride and 0.3 mL (2.0 mmol) of
1,8 diazabicyclo[5.4.0]undec-7-ene were added. The reaction was
stirred for 18 h and diluted with ethyl acetate. The organics were
washed with water and brine, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with ethyl acetate:hexanes (1:5) to provide 0.248 g
(29%) of the hydroxy-acid sulfonamide as a colorless oil.
Electrospray Mass Spec: 430.0 (M+H).sup.+
[1054] Step 2
[1055] To a solution of 0.07 g (0.163 mmol) of the above
hydroxy-acid sulfonamide in 1.6 mL of THF was added 0.051 g (0.195
mmol) of triphenyphosphine, followed by 0.031 mL (0.195 mmol) of
diethylazodicaboXylate. The reaction was stirred at room
temperature for 18 h and diluted with ethyl acetate. The organics
were washed with water and brine, dried over MgSO.sub.4, filtered
and concentrated in vacuo. The residue was chromatographed by
preparative TLC eluting three times with ethyl acetate/hexanes:
(1:5) to provide 0.027 g (39%) of methyl
(3S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2,5-trimethyl-3-thiomorpho-
linecarboxylate as a colorless oil [Electrospray Mass Spec: 412.2
(M+H).sup.+] and 0.021 g (31%) of methyl
(3S,5R)-4-{[4-(2-butynyloxy)phen-
yl]sulfonyl}-2,2,5-trimethyl-3-thiomorpholine-carboxylate as a
colorless oil [Electrospray Mass Spec: 412.2 (M+H).sup.+]
[1056] Step 3
[1057] Lithium iodide mediated ester cleavage of 0.384 g (0.933
mmol) of methyl
(3S,5S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2,5-trimethyl-3-th-
iomorpholine-carboxylate according to the procedure of Example 250,
provided 0.356 g (96%) of
(3S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,-
2,5-trimethyl-3-thiomorpholine-carboxylic acid as a white solid.
Electrospray Mass Spec: 397.9 (M+H).sup.+
[1058] Step 4
[1059] According to the procedure of Example 9, 0.330 g (0.829
mmol) of
(3S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2,5-trimethyl-3-thiomorpho-
linecarboxylic acid provided 0.23 g (67%) of
(3S,5S)-4-{[4-(2-butynyloxy)p-
henyl]sulfonyl}-N-hydroxy-2,2,5-trimethyl-3-thiomorpholinecarboxamide
as a white solid. Electrospray Mass Spec: 413.0 (M+H).sup.+
EXAMPLE 271
(3S,5R)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,5-trimethyl-3-t-
hiomorpholinecarboxamide
[1060] Step 1
[1061] Lithium iodide mediated ester cleavage of 0.335 g (0.814
mmol) of methyl
(3S,5R)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2,5-trimethyl-3-thi-
omorpholine-carboxylate according to tne procedure of Example 250,
provided 0.305 g (94%) of (3
S,5R)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-
,2,5-trimethyl-3-thiomorpholine-carboxylic acid as a white solid.
Electrospray Mass Spec: 398.0 (M+H).sup.+
[1062] Step 2
[1063] According to the procedure of Example 9, 0.28 g (0.707 mmol)
of
(3S,5R)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2,5-trimethyl-3-thiomorpho-
linecarboxylic acid provided 0.16 g (55%) of
(3S,5R)-4-{[4-(2-butynyloxy)p-
henyl]sulfonyl}-N-hydroxy-2,2,5-trimethyl-3-thiomorpholinecarboxamide
as a white solid. Electrospray Mass Spec: 413.2 (M+H).sup.+
EXAMPLE 272
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,6-trimethyl-3-t-
hiomorpholinecarboxamide
[1064] Step 1
[1065] To a solution of 1.47 g (4.53 mmol) of
3,3'-dithiobis[D-valine], dimethyl ester bis hydrochloride in 25 mL
of methylene chloride at 0.degree. was added 2.5 mL (18.1 mmol) of
triethylamine followed by 2.77 g (11.3 mmol) of
4-but-2-ynyloxy-benzenesulfonyl chloride, portionwise. The reaction
was stirred at room temperature for 22 h and then reduced to
dryness. To the resulting residue was added ethyl acetate which was
washed with 1M HCl water and brine. The organic layer was dried
over sodium sulfate, filtered, reduced to dryness and
chromatographed on silica gel eluting with ethyl acetate (2:1) to
provide 1.97 g (59%) of the disulfonamide,
3,3-dithiobis[N-[[4'-(2-butynyloxy)phenyl]sulfonyl]-D-- valine]
dimethyl ester as a white powder. Electrospray Mass Spec: 741.0
(M+H)+
[1066] Step 2
[1067] To a mixture of 3.474 g (4.70 mmol) of
3,3'-dithiobis[N-[[4-(2-buty- nyloxy)phenyl]sulfonyl]-D-valine]
dimethyl ester, 6.5 g (46.95 mmol) of potassium carbonate and 30 mL
of DMF cooled to 0.degree. was added dropwise 4.06 mL (46.95 mmol)
of allyl bromide. After stirring overnight at room temperature the
mixture was diluted with ethyl acetate and subsequently was washed
with water and brine. The organic layer was dried over sodium
sulfate, filtered and reduced to dryness. The residue was
chromatographed on silica gel eluting with ethyl acetate (3:1) to
provide 2.97 g (77%) of
3,3'-dithiobis[N-allyl-N-[[4-(2-butynyloxy)phenyl]sulfony-
l]-D-valine] dimethyl ester as white foam. Electrospray Mass Spec:
821.0 (M+H)+
[1068] Step 3
[1069] To a solution of 0.7124 g (0.869 mmol) of
3,3'-dithiobis[N-allyl-N--
[[4-(2-butynyloxy)phenyl]sulfonyl]-D-valine] dimethyl ester in 10
mL of THF was added 0.2 mL of water and 3.26 mL (13.04 mmol) of
tributylphosphine. This mixture was heated at reflux for 20 h,
concentrated in vacuo, dissolved in ethyl acetate, washed with 1M
citric acid and brine. The organic layer was dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was
chromatographed on silica gel eluting with ethyl acetate (4:1) to
provide 0.36 g (50%) of the thiol, methyl
(2S)-2-(allyl{[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-methyl-3-s-
ulfanylbutanoate as yellow oil. Electrospray Mass Spec: 412.2
(M+H)+
[1070] Step 4
[1071] To a solution of 0.4262 g (1.037 mmol) of methyl
(2S)-2-(allyl{[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-methyl-3-sulfanyl-
butanoate in 20 mL of cyclohexane was added 50 mg of benzoyl
peroxide. The resulting solution was heated at reflux for 3 h.
After cooling to room temperature and concentrating in vacuo the
residue was chromatographed on silica gel eluting with ethyl
acetate (4:1) to provide 0.222 g (52%) of a 60:40 mixture of C-6
thiomorpholine diastereomers, methyl
(3S)-4-{[4(2-butynyloxy)phenyl]sulfonyl}-2,2,6-trimethyl-3-thiomorpholine-
carboxylate, as clear oil. Electrospray Mass Spec: 412.2 (M+H)+
[1072] Step 5
[1073] To a solution of 0.1079 g (0.2625 mmol) of methyl
(3S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2,6-trimethyl-3-thiomorpholin-
ecarboxylate in 2 mL of THF and 2 mL of methanol was added 1.31 mL
(1.31. mmol) of 1M sodium hydroxide. The resulting solution was
heated at reflux for 6 h. After cooling to room temperature the pH
was adjusted to 3-4 by addition of 1N HCl. The mixture was
extracted 3 times with a total of 150 ml of chloroform. The
combined organic layers were dried over sodium sulfate, filtered
and concentrated in vacuo to provide 0.096 g (92%) of the
carboxylic acid,
(3S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2,6-trim-
ethyl-3-thiomorpholinecarboxylic acid, as a white powder.
Electrospray Mass Spec: 396.2 (M-H)-
[1074] Step. 6
[1075] According to the procedure of Example 25, 0.25 g (0.63 mmol)
of
(3S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2,6-trimethyl-3-thiomorpholin-
ecarboxylic acid furnished 0.114 g (44%) of the hydroxamic acid,
(3S,6S)-4-f{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2,6-trimethyl-3-
-thiomorpholinecarboxamide, as a white powder. Electrospray Mass
Spec: 413.1 (M+H)+
EXAMPLE 273
tert-Butyl{(2R,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)c-
arbonyl]-6,6-dimethylthiomorpholinyl}methylcarbamate
[1076] Step 1
[1077] To a solution of 8.164 g (9.96 mmol) of
3,3'-dithiobis[N-allyl-N-[[-
4-(2-butynyloxy)-phenyl]sulfonyl]-D-valine] dimethyl ester (from
Example 272) in 300 mL of methylene chloride at 0.degree. was added
a solution of 0.52 mL (9.9 mmol) of bromine in 25 mL of
dichloromethane dropwise with the exclusion of light. The resulting
solution was stirred overnight and was then washed with saturated
aqueous sodium thiosulfate and brine. The organic layer was dried
over sodium sulfate, filtered and concentrated in vacuo. Flash
chromatography of the resulting residue on silica gel eluting with
ethyl acetate (4:1) provided 7.03 g (72%) of a 2:1 mixture of
bromide diastereomers, methyl
(3S)-6-(bromomethyl)-4-{[4-(2-butynyloxy-
)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate, as a
white foam. Electrospray Mass Spec: 490.0 & 492.0 (M+H)+
[1078] Step 2
[1079] To a solution of 16.45 g (0.0336 mmol) of methyl
(3S)-6-(bromomethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3--
thiomorpholinecarboxylate in 200 mL of DMSO was added 21.87 g
(0.336 mol) of sodium azide. The resulting mixture was heated at
60.degree., for 4.5 h, cooled to room temperature, diluted with 1 L
of water and twice extracted with 1 L of ether. The organic layer
was dried over sodium sulfate, filtered, reduced to dryness and
chromatographed on silica gel eluting with ethyl acetate (4:1) to
provide 13.35 g (88%) of a 2:1 diastereomeric mixture of azides,
methyl (3S)-6-(azidomethyl)-4-{[4-(2-bu-
tynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate
as a white foam. Electrospray Mass Spec: 453.1 (M+H)+
[1080] Step 3
[1081] To a solution of 13.168 g (0.0291 mol) of methyl
(3S{6-(azidomethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3-t-
hiomorpholinecarboxylate in 200 mL of ether was added 8.0 mL
(0.03201 mol) of tributylphosphine dropwise over 0.5 h. The
solution was stirred overnight, cooled to -50.degree. and then
treated with a solution of 6.99 g (0.032 mol) of
di-t-butyldicarbonate in 30 mL of ether dropwise over 0.5 h. After
1.5 h 50 mL of saturated aqueous sodium bicarbonate was added and
the cooling bath was removed. The resulting mixture was twice
extracted with 300 mL of ethyl acetate. Combined organic layers
were dried over sodium sulfate, filtered, concentrated in vacuo and
chromatographed on silica gel eluting with hexanes/ethyl acetate
(4:1) to provide 9.91 g (65%) of a 2:1 mixture of carbamates. These
diastereomers could be separated by careful iterative gradient
flash chromatography eluting with hexanes/ethyl acetate (20:1)-(3:
1). The less polar diastereomer (methyl
(3S,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-{[4-
-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate,
Electrospray Mass Spec: 527.2 (M+H)+) was eluted first closely
followed by (methyl
(3S,6S)-6-([(tert-butoxycarbonyl)amino]methyl}4-{[4-(2butynylo-
xy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate,
Electrospray Mass Spec: 527.1 (M+H)+).
[1082] Step 4
[1083] To a solution of 3.24 g (6.16 mmol) of methyl
(3S,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-{[4-(2-butynyloxy)phenyl-
]sulfonyl}-2,2-7-dimethyl-3-thiomorpholinecarboxylate in 50 mL of
ethyl acetate was added 11 g (82.2 mmol) of lithium iodide. The
resulting mixture was heated at reflux for 14 h, cooled to room
temperature and 10 mL of water was added. The aqueous layer was
acidified to pH 3-4 with 1M HCl and back extracted with ethyl
acetate. Combined organic layers were washed with water, brine,
dried over sodium sulfate, filtered and concentrated in vacuo. The
residue was chromatographed on silica gel eluting with
dichloromethane/methanol 10:1 furnishing 2.45 g (78%) of the
desired carboxylic acid,
(3S,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-
-{[4-(2-butynyloxy)phenyl]sulfonyl)
-2,2-dimethyl-3-thiomorpholinecarboxyl- ic acid, as a white foam.
Electrospray Mass Spec: 513.3 (M+H)+
[1084] Step 5
[1085] According to the procedure of Example 25, 2.42 g (4.73 mmol)
of
(3S,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-{[4-(2-butynyloxy)phenyl-
]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylic acid furnished
0.796 g (32%) of the hydroxamic acid,
tert-butyl{(2R,5S)-4-{[4-(2-bultynyloxy)phe-
nyl]sulfonyl}-5-[(hydroxyamino)-carbonyl]-6,6-dimethylthiomorpholinyl}meth-
ylcarbamate, as a white foam following chromatography on silica gel
eluting with dichloromethane/methanol (10:1). Electrospray Mass
Spec: 528.3 (M+H)+
EXAMPLE 274
tert-Butyl{(2S,5S)-4-{4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)ca-
rbonyl]-6,6-dimethylthiomorpholinyl}methylcarbamate
[1086] Step 1
[1087] According to the procedure of Step 4 of Example 273 lithium
iodide mediated ester cleavage of 0.83 g (1.58 mmol) of methyl
(3S,6S)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-{[4-(2-butynyloxy)phenyl-
]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate (Step 3 of
Example 273) furnished 0.641 g (79%) of the carboxylic acid,
(3S,6S)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-{[4-(2-butynyloxy)phenyl-
]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylic acid, as a white
foam. Electrospray Mass Spec 513.2: (M+H)+
[1088] Step 2
[1089] According to the procedure of Example 25, 0.639 g (1.25
mmol) of
(3S,6S)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-{[4-(2-butynyloxy)phenyl-
]sulfonyl}-2,2-dimenthyl-3-thiomorpholinecarboxylic acid furnished
0.359 g (54%) of the hydroxamic acid, tert-butyl
{(2S,5S)-4-{[4-(2-butynyloxy)phe-
nyl]sulfonyl}-5-[(hydroxyamino-carbonyl]-6,6-dimethylthiomorpholinyl}methy-
lcarbamate, as a white foam following chromatography on silica gel
eluting with dichloromethane/methanol (10:1). Electrospray Mass
Spec 528.3 (M+H)+
EXAMPLE 275
(3S,6R)-Trans-6-(aminomethyl)-4-{[4(2butynyloxy)phenyl]sulfonyl}-N-hydroxy-
-2,2-dimethyl-3-thiomorpholinecarboxamide Hydrochloride
[1090] Through a solution of 0.796 g (1.51 mmol) of
tert-butyl{(2R,5S)-4-{[4(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)c-
arbonyl]-6,6-dimethyl-thiomorpholinyl}methylcarbamate (Example 273)
in 30 mL of dichloromethane cooled to 0.degree. was bubbled
hydrogen chloride gas for 3 minutes. The flask was sealed and
stirred at room temperature for 1 h. The resulting mixture was
concentrated in vacuo to, provide 0.674 g (96%) of
(3S,6R)-trans-6-(aminomethyl)-4-{[4-(2-butynyloxy)phenyl-
]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide
hydrochloride as a brown solid. Electrospray Mass Spec 428.3:
(M+H)+
EXAMPLE 276
(3S,6)-Cis-6-(aminomethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy--
2,2-dimethyl-3-thiomorpholinecarboxamide Hydrochloride
[1091] According to the procedure of Example 275, 0.41 g (0.778
mmol) of the product of Example 214 furnished 0.34 g (94%) of
(3S,6S)-cis-6-(aminomethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydrox-
y-2,2-dimethyl-3-thiomorpholine-carboxamide hydrochloride as a
brown solid. Electrospray Mass Spec: 428.1 (M+H)+
EXAMPLE 277
tert-Butyl{(2S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)c-
arbonyl]-6,6-dimethylthiomorpholinyl}acetate
[1092] Step 1
[1093] To a solution of 21.1 g (0.0285 mol) of
3,3'-dithiobis[N-[[4-(2-but- ynyloxy)phenyl]sulfonyl]-D-valine]
dimethyl ester (Step 1, Example 272) in 200 mL of DMF was added
11.8 g (0.0855 mol) potassium carbonate followed by a solution of
118.9 g (0.0855 mol) tert-butyl (E)-4-bromo-2-butenoate in 30 mL of
DMF dropwise. The resulting mixture was stirred overnight, diluted
with 1 L of water and twice extracted with a total of 1 L of ether.
Combined organic extracts were washed with brine, dried over sodium
sulfate, filtered and concentrated in vacuo. The residue was
chromatographed on silica gel eluting with ethyl acetate (4:1) to
provide 22.87 (79%) of
18-(tert-butyl)-9,14-dimethyl(5E,9S,14S,17E)-8,15-bis{[4-(-
2-butynyloxy)phenyl]-sulfonyl}-2,2,10,10,13,13-hexamethyl-4-oxo-3-oxa-11,1-
2-dithia-8,15-diazaoctadeca-5,17-diene-9,14,18-tricarboxylate as a
brown oil. Electrospray Mass Spec: 1021.0 (M+H)+
[1094] Step 2
[1095] To a solution of 22.87 g (0.02241 mol) of
18-(tert-butyl)-9,14-dime-
thyl(5E,9S,14S,17E)-8,15-bis{[4(2-butynyloxy)phenyl]sulfonyl}-2,2,10,10,13-
,13-hexamethyl-4-oxo-3-oxa-11,12-dithia-8,15-diazaoctadeca-5,17-diene-9,14-
,18-tricarboxylate in 300 mL of TBF was added 30 mL of water and 90
mL (0.2241 mol) of tributylphosphine. The resulting mixture was
heated at reflux overnight, cooled to room temperature and
concentrated in vacuo. The residue was dissolved in ethyl acetate,
washed with 1M citric acid, brine, dried over sodium sulfate,
filtered and concentrated in vacuo. The residue was chromatographed
on silica gel eluting with ethyl acetate (4:1) to provide 17.63 g
(77%) of the thiomorpholine, methyl
(3S,6S)-6-[2-(tert-butoxy)-2-oxoethyl]-4-{[4-(2-butynyloxy)phenyl]sulfony-
l}-2,2-dimethyl-3-thiomorpholinecarboxylate, as a brown oil.
Electrospray Mass Spec: 512.2 (M+H)+
[1096] Step 3
[1097] To a solution of 2.273 g (4.45 mmol) of methyl
(3S,6S)-6-[2-(tert-butoxy)-2-oxoethyl]4-{[4-(2-butynyloxy)phenyl]sulfonyl-
}-2,2-dimethyl-3-thiomorpholine-carboxylate in 30 mL of ethyl
acetate was added 2.98 g (22.2 mmol) of lithium iodide. This
mixture was heated at reflux for 20 h and then was cooled to room
temperature. Water (100 mL) was added and the aqueous layer was
acidified to pH 3-4 with 1M HCl. The mixture was back extracted
twice with 200 mL of ethyl acetate. The combined organic layers
were washed with water, saturated aqueous sodium thiosulfate and
then brine. Sodium sulfate was added to dry the organic layer which
was subsequently filtered, concentrated in vacuo and
chromatographed on silica gel eluting with dichloromethane/methanol
(10:1) to furnish 1.535 g (69%) of the mono acid,
(3S,6S)-6-[2-(tert-buto-
xy)-2-oxoethyl]-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomo-
rpholinecarboxylic acid, as a yellow powder. Electrospray Mass
Spec: 496.1 (M-H)- and 0.2 g (11%) of the diacid,
(3S,6S)-4-{[4-(2-butynyloxy)phenyl]-
sulfonyl}-6-(carboxymethyl)-2,2-dimethyl-3-thiomorpholinecarboxylic
acid, as a yellow powder. Electrospray Mass Spec: 440 (M-H)-
[1098] Step 4
[1099] According to the procedure of Example 25, 0.201 g (0.404
mmol) of
(3S,6S)-6-[2-(tert-butoxy)-2-oxoethyl]-4-}[4-(2-butynyloxy)phenyl]sulfony-
{-2,2-dimethyl-3-thiomorpholinecarboxylic acid furnished 0.074 g
(36%) of the hydroxamic acid,
tert-butyl{(2S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfon-
yl}-5-[(hydroxyamino)carbonyl]-6,6-dimethylthiomorpholinyl}acetate,
as a white powder following chromatography on silica gel eluting
with dichloromethane/methanol (10:1). Electrospray Mass Spec: 513.1
(M+H)+
EXAMPLE 278
{(2S,5S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)carbonyl]-6-
,6-dimethylthiomorpholinyl}acetic Acid
[1100] To a solution of 0.056 g (0.1092 mmol) of
tert-butyl{(2S,5S)-4-{([4-
-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)carbonyl]-6,6-dimethylthi-
omorpholinyl}acetate (Example 277) in 2 mL of dichloromethane was
added 2 mL of trifluoroacetic acid. After 2 h the solution was
concentrated in vacuo providing 0.052 g (96%) of the carboxylic
acid,
{(2S,5S)-4-{[4-(2-butynyloxy)-phenyl]sulfonyl}-5-[(hydroxyamino)carbonyl]-
-6,6-dimethylthiomorpholinyl}acetic acid, as a light powder.
Electrospray Mass Spec: 457.1 (M+H)+
EXAMPLE 279
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-6-[2-(hydroxyamino)-
-2-oxoethyl]-2,2-dimethyl-3-thiomorpholinecarboxamide
[1101] According to the procedure of Example 25, 0.6967 g (1.58
mmol) of the dicarboxylic acid from Example 277,
(3S,6S)-4-{[4-(2-butynyloxy)pheny-
l]sulfonyl}-6-(carboxymethyl)-2,2-dimethyl-3-thiomorpholinecarboxylic
acid, furnished 0.093 g (12%) of the dihydroxamic acid,
(3S,6S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-6-[2-(hydroxyamino-
)-2-oxoethyl]-2,2-dimethyl-3-thiomorpholine-carboxamide, as a light
powder following chromatography on silica gel eluting with
dichloromethane/methanol (10:1). Electrospray Mass Spec: 471.9
(M+H)+
EXAMPLE 280
(3S,6S)-6-(2-Amino-2-oxoethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydr-
oxy-2,2-dimethyl-3-thiomorpholinecarboxamide
[1102] Step 1
[1103] According to the procedure of Example 278, 2.33 g (4.55
mmol) of methyl
(3S,6S)-6-[2-(tert-butoxy)-2-oxoethyl]-4-{[4-(2-butynyloxy)phenyl]-
sulfonyl)-2,2-dimenthyl-3-thiomorpholinecarboxylate (Step 2,
Example 277) furnished 1.92 g (93%) of the carboxylic acid,
[(2S,5S)-4-{[4-(2-butynylo-
xy)phenyl]sulfonyl}-5-(methoxycarbonyl)-6,6-dimethylthiomorpholinyl]acetic
acid, as a white solid. Electrospray Mass Spec: 454.1 (M-H)-
[1104] Step 2
[1105] To a solution of 1.21 g (2.66 mmol) of
[(2S,5S)-4-{[4-(2-butynyloxy-
)-phenyl]sulfonyl}-5-(methoxycarbonyl)-6,6-dimethylthiomorpholinyl]acetic
acid dissolved in 15 mL of DMF was added 0.884 g (6.64 mmol) of
1-hydroxybenzotriazole hydrate (HOBT) followed by 1.53 g (7.98
mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC). The resulting mixture was stirred at room
temperature for 1 h and then 3 mL of a 28% ammonium hydroxide
solution was added. The reaction was stirred overnight and then
diluted with ethyl acetate. The organics were washed with 5% HCl
solution, water and saturated sodium bicarbonate solution and then
dried over sodium sulfate, filtered and concentrated in vacuo to
provide 0.83 g (69%) of the amide,
methyl(3S,6S)-6-(2-amino-2-6oxoethyl)--
4-{[4-(2-butynyloxy)-phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxy-
late, as a yellow oil. Electrospray Mass Spec 455.1 (M+H)+
[1106] Step 3
[1107] Lithium iodide mediated ester cleavage, according to the
procedure of Step 4. of Example 273, of 0.825 g (1.82 mmol) of
methyl(3S,6S)-6-(2-amino-2oxoethyl)-4-{[4(2butynyloxy)phenyl]sulfonyl}-2,-
2-dimethyl-3-thiomorpholinecarboxylate furnished 0.65 g (81%) of
the carboxylic acid,
(3S,6S)-6-(2-amino-2-oxoethyl)-4-{[4-(2-butynyloxy)pheny-
l]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylic acid, as a
viscous oil. Electrospray Mass Spec 441.1: (M+H)+
[1108] Step 4
[1109] According to the procedure of Example 25 0.077 g (0.175
mmol) of
(3S,6S)-6-(2-amino-2-oxoethyl)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-d-
imethyl-3-thiomorpholinecarboxylic acid furnished 0.043 g (54%) of
the hydroxamic acid,
3S,6S)-6-(2-amino-2-oxoethyl)-4-{[4-(2-butynyloxy)phenyl-
]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide, as a
light powder following chromatography on silica gel eluting with
dichloromethane/methanol (10:1). Electrospray Mass Spec: 455.1
(M+H)+
EXAMPLE 281
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-6-[2-dimethylamino)-2-oxoethy-
l]-N-hydroxy-2,2-(dimethyl-3-thiomorpholinecarboxamide
[1110] Step 1
[1111] To a solution of 1.535 g (3.09 mmol) of
(3S,6S)-6-[2(tert-butoxy)-2-
-oxoethyl]-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorphol-
ine-carboxylic acid (Example 277) in 15 mL of dichloromethane was
added sequentially 0.43 mL (3.09 mmol) of triethylamine, 0.905 g
(3.55 mmol) of bis(2oxo-3-oxazolidinyl)phosphinic chloride, 0.493 g
(3.09 mmol) of O-benzyl hydroxylamine and an additional 1.29 mL
(9.27 mmol) of triethylamine. After stirring overnight the mixture
was concentrated in vacuo and partitioned between ethyl acetate and
saturated aqueous sodium bicarbonate. The organic layer was washed
consecutively with water and brine. Sodium sulfate was added to dry
the organic layer which was subsequently filtered, concentrated in
vacuo and chromatographed on silica gel eluting with hexanes/ethyl
acetate (4:1) to furnish 1.5 g (81%) of
tert-butyl((2S,5S)-5-{[(benzyloxy)amino]carbonyl}-4-{[4-(2-butyn-
yloxy)phenyl]sulfonyl}-6,6-dimethyl-thiomorpholinyl)acetate as a
white solid. Electrospray Mass Spec: 603.1 (M+H)+
[1112] Step 2
[1113] According to the procedure of Example 278 0.3237 g (0.538
mmol) of
tert-butyl((2S,5S)-5-{[(benzyloxy)amino]carbonyl}4-{[4-(2-butynyloxy)phen-
ylsulfonyl}-6,6-dimethylthiomorpholinyl)acetate furnished 0.294 g
(100%) of the carboxylic acid,
((2S,5S)-5-{[(benzyloxy)amino]carbonyl}-4-{[4-(2--
butynyloxy)phenyl]sulfonyl}-6,6-dimethylthiomorpholinyl)acetic
acid, as a white solid. Electrospray Mass Spec: 547.0 (M+H)+
[1114] Step 3
[1115] To a solution of 0.283 g (0.518 mmol) of
((2S,5S)-5-{[(benzyloxy)am-
ino]carbonyl}-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-6,6-dimethylthiomorphol-
inyl)acetic acid dissolved in 15 mL of DMF was added 0.083 g (0.662
mmol) of 1-hydroxybenzotriazole hydrate (HOBT) followed by 0.132 g
(0.689 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC). The resulting mixture was stirred at room
temperature for 1 h and then 3 mL of a 3M solution of dimethylamine
in THF was added. The reaction was then stirred overnight and then
diluted with ethyl acetate. The organics were washed with 5% HCl
solution, water and saturated sodium bicarbonate solution and then
dried over sodium sulfate, filtered and concentrated in vacuo to
provide 0.14 g (47%) of the amide, (3S,6S)-N-(benzyloxy)-4-{[4-(-
2-butynyloxy)phenyl]sulfonyl}-6-[2-(dimethylamino)-2-oxoethyl]-2,2-dimenth-
yl-3-thiomorpholinecarboxamide, as a clear oil. Electrospray Mass
Spec 574.1 (M+H)+
[1116] Step 4
[1117] To a solution of 0.064 g (0.116 mmol) of
(3S,6S)-N-(benzyloxy)-4-{[-
4-(2-butynyloxy)phenyl]sulfonyl}-6-[2-(dimethylamino)-2-oxoethyl]-2,2-dime-
thyl-3-thiomorpholinecarboxamide in 0.8 mL of triflouroacetic acid
cooled at 0.degree. was added 0.335 mL (0.335 mmol) of a 1.0M
solution of boron tris(trifluoroacetate). The resulting solution
was stirred for 2 h, concentrated in vacuo and purified by
chromatography on silica gel eluting with dichloromethane/methanol
(10:1) to provide 0.051 g (94%) of the hydroxamic acid,
(3S,6S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-6-[2-(d-
imethylamino)-2-oxoethyl]-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxami-
de, as a brown powder. Electrospray Mass Spec 484.1 (M+H)+
EXAMPLE 282
(3S,6S)-4-{[4-(2Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-6-[2-(4-
-morpholinyl)-2-oxoethyl]-3-thiomorpholinecarboxamide
[1118] Step 1
[1119] To a solution of 0.179 g (0.327 mmol) of the product of Step
2 of Example 281,
((2S,5S)-5-{[(benzyloxy)amino]carbonyl}-4-{[4-(2-butynyloxy)-
phenyl]sulfonyl}-6,6-dimethylthiomorpholinyl)acetic acid, dissolved
in 5 mL of DMF was added 0.096 mL (0.69 mmol) of triethylamine, 50
mg of DMAP, 0.031 mL (0.36 mmol) of morpholine and 0.078 mL (0.36
mmol) of diphenylphosphoryl azide. After stirring for 12 h the
solution was partitioned between ethyl acetate and water. The
organic phase was washed with brine, dried over sodium sulfate,
filtered and concentrated in vacuo. The residue was purified by
chromatography on silica gel eluting with hexanes/ethyl acetate
(1:1) to furnish 0.1586 g (79%) of
(3S,6S)-N-(benzyloxy)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-6-
-[2-(4-morpholinyl)-2-oxoethyl]-3-thiomorpholinecarboxamide as a
light solid. Electrospray Mass Spec 616.4 (M+H)+
[1120] Step 2
[1121] According to the procedure of Step 4 of Example 281 0.1431 g
(0.233 mmol) of
(3S,6S)-N-(benzyloxy)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-d-
imethyl-6-[2-(4-morpholinyl)-2-oxoethyl]-3-thiomorpholinecarboxamide
furnished 0.1014 g (83%) of the hydroxamic acid,
(3S,6S)-4-{[4-(2-butynyl-
oxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimenthyl-6-[2-(2-(4-morpholinyl)-2-oxo-
ethyl]-3-thiomorpholinecarboxamide, as a brown solid. Electrospray
Mass Spec 523.8 (M-H)-
EXAMPLE 283
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-6-[2-(-
4-methyl-1-piperazinyl)-2-oxoethyl]-3-thiomorpholinecarboxamide
Hydrochloride
[1122] Step 1
[1123] According to the procedure of Step 1 of Example 282, 0.234 g
(0.428 mmol) of the product of Step 2 of Example 281,
((2S,5S)-5-{[(benzyloxy)am-
ino]carbonyl}-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-6,6-dimethylthiomorphol-
inyl)acetic acid and 0.052 mL (0.47 mmol) of 1-methylpiperazine
furnished 0.23 g (86.1%) of
(3S,6S)-N-(benzyloxy)-4-{[4-(2-butynyloxy)phenyl]sulfon-
yl}-2,2-dimethyl-6-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-3-thiomorpholin-
ecarboxamide as a white solid after chromatography on silica gel
eluting with dichloromethane/methanol (20:1). Electrospray Mass
Spec 629.1 (M+H)+
[1124] Step 2
[1125] To a solution of 0.2 g (0.3185 mmol) of
(3S,6S)-N-(benzyloxy)-4-{[4-
-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-6-[2-(4-methyl-1-piperazinyl)-
-2-oxoethyl]-3-thiomorpholinecarboxamide in 3 mL of triflouroacetic
acid cooled at 0.degree. was added 0.96 mL (0.96 mmol) of a 1.0M
solution of boron tris(trifluoroacetate). The resulting solution
was stirred for 2 h, concentrated in vacuo and then purified by
chromatography on silica gel eluting with dichloromethane/methanol
(10:1) to provide the free base which was then dissolved in 3 mL of
methanol. Through this solution cooled to 0.degree. was bubbled HCl
gas for 2 minutes. The solution was concentrated in vacuo yielding
0.12 g (66%) of (3S,6S)-4-{[4-(2-butynylox-
y)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-6-[2-(4-methyl-1-piperazinyl)-2--
oxoethyl]-3-thiomorpholinecarboxamide hydrochloride as a brown
powder. Electrospray Mass Spec 539.0 (M+H)+
EXAMPLE 284
(3S,6S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-6-(2-{[2-(dimethylamino)ethyl-
]amino}-2-oxoethyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide
[1126] Step 1
[1127] According to the procedure of Step 1 of Example 282, 0.234 g
(0.428 mmol) of
((2S,5S)-5-{[(benzyloxy)amino]carbonyl}-4-{[4-(2-butynyloxy)phen-
yl]sulfonyl}-6,6-dimethylthiomorpholinyl)acetic acid and 0.052 mL
(0.47 mmol) of N, N-dimethylethylenediamine furnished 0.129 g (49%)
of
(3S,6S)-N-(benzyloxy)-4-{[-(2-butynyloxy)phenyl]sulfonyl}-6-(2-{[2-(dimet-
hylamino)ethyl]amino}-2-oxoethyl)-2
2-dimenthyl-3-thiomorpholinecarboxamid- e after chromatography on
silica gel eluting with dichloromethane/methanol (20:1) as a white
solid. Electrospray Mass Spec 617.0 (M+H)+
[1128] Step 2
[1129] According to the procedure of Step 2 of Example 283 0.111 g
(0.18 mmol) of
(3S,6S)-N-(benzyloxy)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-6-(2--
([2-(dimethyl-amino)ethyl]amino}-2-oxoethyl)-2,2-dimethyl-3-thiomorpholine-
carboxamide and furnished 0.051 g (50%) of desired hydrochloride
salt,
(3S,6S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-6-(2-{[2-(dimethylamino)ethy-
l]amino}-2-oxoethyl)-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide
hydrochloride, as a brown powder. Electrospray Mass Spec 527.0
(M+H)+
EXAMPLE 285
Methyl
(3S,6S)-6-{[(tert-butoxycarbonyl)amino]methyl}-4-{[(2-butynyloxy)ph-
enyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecarboxylate
[1130] To a solution of 0.6138 g (1.35 mmol) of the product of Step
1 of Example 280,
[(2S,5S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-(methoxycarb-
onyl)-6,6-dimethylthiomorpholinyl]acetic acid, in 10 mL of
t-butanol was added 0.188 mL (1.35 mmol) of triethylamine and 0.291
mL (1.35 mmol) of diphenylphosphoryl azide. The solution was heated
at reflux for 12 h, cooled to room temperature, concentrated in
vacuo and chromatographed on silica gel eluting with hexanes/ethyl
acetate (4:1) to provide 0.414 g (58%) of the carbamate, methyl
(3S,6S)-6-{[(tert-butoxycarbonyl)amino]met-
hyl}-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3-thiomorpholinecar-
boxylate. Electrospray Mass Spec: 527.1 (M+H)+.
EXAMPLE 286
(4S)-3-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-5,5-dimethyl-1,3-thiaz-
olidine-4-carboxamide
[1131] Step 1
[1132] To a room temperature solution of 4.3 g (32.3 mmol) of
5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid (J. Med Chem. 1989,
32(2), 466-472.) in 30 ml of dioxane:water (2:1) containing 4.9 mL
(35.5 mmol) of triethylamine was added 7.9 g (32.3 mmol) of
4-butynyloxybenzenesulfonyl chloride. The mixture was stirred at
25.degree. C. for 18 h. The resulting mixture was diluted with
ethyl acetate and washed with 1 N aqueous hydrochloric acid
(3.times.). The organic phase was dried over anhydrous magnesium
sulfate and concentrated in vacuo to afford a foam which was
chromatographed on silica gel eluting with methanol/dichloromethane
to give (4S)-3-{[4-(2-butynyloxy)phenyl]sul-
fonyl}-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid as a white
solid. Electrospray Mass Spec 368.1 (M-H)-
[1133] Step 2
[1134] To oxalyl chloride (4.5 mL of a 2 M solution in
dichloromethane) in dichloromethane at 0.degree. C. was added DMF
(0.69 mL). After 15 min a solution of
(4S)-3-{[4-(2-butynyloxy)phenyl]sulfonyl}-5,5-dimethyl-1,3-th-
iazolidine-4-carboxylic acid (1.58 g, 4.5 mmol) in DMF was added
and the resulting reaction mixture was stirred at room temperature
for 1 h.
[1135] In a separate flask, 9.4 mL of triethylamine was added to a
0.degree. C. mixture of 3.13 g of hydroxylamine hydrochloride in 97
mL of tetrahydrofuran and 24 mL of water. After this mixture had
been stirred for 15 min. at 0.degree. C., the acid chloride
solution was added to it in one portion and the resulting solution
was allowed to warm to room temperature and stirred for another 18
h. Ethyl acetate and aqueous sodium bicarbonate were then added to
the reaction flask. The organic phase was washed with aqueous
sodium bicarbonate and dried over anhydrous potassium carbonate.
Concentration in vacuo and trituration with ether/dichloromethane
gave (4S)-3-([4-(2-butynyloxy)phenyl]sulfonyl}-N-hy-
droxy-5,5-dimethyl-1,3-thiazolidine-4-carboxamide as a white powder
(1.2 g). Electrospray Mass Spec 385.3 (M+H)+
EXAMPLE 287
tert-Butyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(hydroxyamino)ca-
rbonyl]-1-piperidinecarboxylate
[1136] Step 1
[1137] 4-Amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid
(1.0 g, 4.09 mmol) in dioxane (5 mL) and water (2.5 mL) was treated
with triethylamine (0.63 mL, 4.5 mmol) and 0.8 mL of 5N aqueous
sodium hydroxide and 4-(2-butynyloxy)phenyl sulfonyl chloride (1.0
g, 4.09 mmol) was then added. After 40 h, ethyl acetate and 1N
aqueous hydrochloric acid was added. The organic phase was washed
an additional 2.times. with 1N aqueous hydrochloric acid and once
with brine, then dried over anhydrous magnesium sulfate to give an
oil (0.98 g) which was chromatographed on silica gel eluting with
dichloromethane/methanol to give
1-(tert-butoxycarbonyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)--
4-piperidinecarboxylic acid as a white powder (0.36 g).
Electrospray Mass Spec 453.1 (M+H)+.
[1138] Step 2
[1139] To oxalyl chloride (0.70 mL of a 2 M solution in
dichloromethane) in dichloromethane (1 mL) at 0.degree. C. was
added dimethylformamide (0.11 mL). After 15 min a solution of
1-(tert-butoxycarbonyl)-4-({[4-(2-b-
utynyloxy)phenyl]sulfonyl}amino)-4-piperidinecarboxylic acid (0.315
g, 0.70 mmol) in dimethylformamide was added and the resulting
reaction mixture was stirred at room temperature for 1 h.
[1140] In a separate flask, 1.46 mL of triethylamine was added to a
0.degree. C. mixture of 0.486 g of hydroxylamine hydrochloride in
15 mL of tetrahydrofuran and 3.7 mL of water. After this mixture
stirred for 15 min at 0.degree. C., the acid chloride solution was
added to it in one portion and the resulting solution was allowed
to warm to room temperature and stirred for another 18 h. Ethyl
acetate and aqueous sodium bicarbonate were then added to the
reaction flask. The organic phase was washed with aqueous sodium
bicarbonate (3.times.) and dried over anhydrous potassium
carbonate. Concentration in vacuo gave tert-butyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(hydroxyamino)c-
arbonyl]-1-piperidinecarboxylate as a hard foam (0.142 g).
Electrospray mass spec 468.2 (M+H)+.
EXAMPLE 288
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-4-piperidinecarboxam-
ide
[1141] To a solution of tert-butyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl}am-
ino)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.114 g)
from Example 287, in dioxane (1 mL) was added 4N hydrochloric acid
in dioxane (2 mL). After 4 hours the reaction mixture was
concentrated in vacuo. Trituration with dichloromethane and diethyl
ether gave
4-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-4-piperidinecarboxa-
mide as an off-white powder. Electrospray Mass Spec 368.2
(M+H)+
EXAMPLE 289
1-Benzoyl-4-{[4-(2-butynyloxy)phenyl]sulfony}-N-hydroxy-1,4-diazepane-5-ca-
rboxamide
[1142] Step 1
[1143] To a solution of tert-butyl 1,4-diazepane-5-carboxylate (WO
98/08823)(4.5 g, 22.5 mmol) in dioxane (225 mL) was added water
(200 mL) and 1N aqueous sodium hydroxide (22.5 mL). Di-tert-butyl
dicarbonate (4.91 g, 22.5 mmol) was then added. After 18 hours
triethylamine (9.4 mL, 67 mmol), 4-dimethylaminopyridine (0.274 g,
2.25 mmol) and 4-(2-butynyloxy)phenyl]sulfonyl chloride (6.61 g, 27
mmol) were added. After stirring overnight 1 N aqueous hydrochloric
acid (100 mL) was added and the mixture was extracted with
dichloromethane. The combined organic extracts were dried over
anhydrous potassium carbonate and concentrated in vacuo.
Chromatography on silica gel eluting with dichloromethane/methanol
gave a yellow glass (4.52 g). Chromatography of this material on
silica gel with hexane/ethyl acetate gave di(tert-butyl)
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-1,5-dicarboxylate
as a glass (0.83 g). Electrospray Mass Spec 509.3 (M+H)+
[1144] Step 2
[1145] Treatment of di(tert-butyl)
4-{[4-(2-butynyloxy)phenyl]sulfonyl}1,4-
-diazepane-1,5-dicarboxylate (0.83 g, 1.63 mmol) with 2N
hydrochloric acid in dioxane (30 mL) at 25.degree. C. for 2 hours
gave, after concentration in vacuo, a quantitative yield of
tert-butyl 4-{[4-(2-butynyloxy)phenyl]s-
ulfonyl}-1,4-diazepane-5-carboxylate. Electrospray Mass Spec 409.3
(M+H)
[1146] Step 3
[1147] tert-Butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-car- boxylate
(0.425 g, 0.96 mmol) in dichloromethane at 25.degree. C. (10 mL)
was treated with triethylamine (0.28 mL, 2.02 mmol) followed by
benzoyl chloride (0.12 mL, 1.06 mmol) and dimethylaminopyridine (10
mg). After 18 hours aqueous workup gave tert-butyl
1-benzoyl-4-{[4-(2-butynyloxy)phenyl-
]sulfonyl}-1,4-diazepane-5-carboxylate. .sup.1H NMR(dmso-d6, 300
MHz):1.24 (s, 9H, t-bu), 1.82 (s, 3H, CH3), 2.0-4.0 (m, 8H, CH2),
4.65 (s, 1H, CH), 4.85 (s, 2H, CH2), 7.0-7.9 (m, 9H, ArH).
Treatment with trifluoroacetic acid (4 mL) in dichloromethane (10
mL) for 6 hours gave, after concentration in vacuo followed by
chromatography on silica gel eluting with dichloromethant/methanol,
1-benzolyl-4-{[4-(2-butynyloxy)phenyl]sulf-
onyl}-1,4-diazepane-5-carboxylic acid as a foam (0.328 g).
[1148] Step 4
[1149] To oxalyl chloride (0.72 mL of a 2 M solution in
dichloromethane) in dichloromethane (1 mL) at 0.degree. C. was
added dimethylformamide (0.11 mL). After 15 min a solution of
1-benzoyl-4-{[4-2-butynyloxy)phenyl-
]sulfonyl}-1,4-diazepane-5-carboxylic acid (0.328 g, 0.718 mmol) in
dimethylformamide was added and the resulting reaction mixture was
stirred at room temperature for 1 h.
[1150] In a separate flask, 1.5 mL of triethylamine was added to a
0.degree. C. mixture of 0.50 g of hydroxylamine hydrochloride in
15.4 mL of tetrahydrofuran and 3.8 mL of water. After this mixture
stirred for 15 min at 0.degree. C., the acid chloride solution was
added to it in one portion and the resulting solution was allowed
to warm to room temperature and stirred for another 18 h. Ethyl
acetate and aqueous sodium bicarbonate were then added to the
reaction flask. The organic phase was washed with aqueous sodium
bicarbonate (3.times.) and dried over anhydrous potassium
carbonate. Concentration in vacuo gave a thick gum (0.35 g) which
was chromatographed on silica gel eluting with
dichloromethane/methanol to give an off-white foam (0.22 g) which
was triturated with diethyl ether to give
1-benzoyl-4-([4-(2-butynyloxy)pheny-
l]sulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide as an off white
powder (0.173 g). Electrospray Mass Spec 472.3 (M+H)+
EXAMPLE 290
1-Benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1
4-diazepane-5-carboxamide
[1151] Step 1
[1152] To 10 mL of a methanolic solution of the product of Step 2
of Example 289, tert-butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepan- e-5-carboxylate,
(0.37 g, 0.84 mmol) was added triethylamine (0.25 mL, 1.8 mmol),
benzyl bromide (011 mL, 0.92 mmol) and a catalytic amount of
tetrabutylammonium iodide. After 18 hours 5% aqueous sodium
bicarbonate was added and the mixture extracted with dichlormethane
(4.times.). The combined organic extracts were dried over anhydrous
magnesium sulfate and concentrated in vacuo to give an oil (0.51
g). Chromatography on silica gel gave tert-butyl
1-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-dia-
zepane-5-carboxylate as a clear colorless oil (0.34 g).
[1153] Step 2
[1154] To a solution of tert-butyl
1-benzyl-4-{[4-(2-butynyloxy)phenyl]sul-
fonyl}-1,4-diazepane-5-carboxylate (034 g, 0.68 mmol) in
dicloromethane (2 mL) at 0.degree. C. was added trifluoroacetic
acid (1.23 mL). After 2.5 h the reaction mixture was allowed to
warm to 25.degree. C. whereupon an additional 1 mL of
trifluoroacetic acid was added. After 18 h the reaction mixture was
concentrated in vacuo to provide
1-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic
acid as a white powder. Electrospray Mass Spec 443.4 (M+H)+
[1155] Step 3
[1156] In a manner analogous to that described in Step 4 of Example
289,
1-benzyl-4-{[4-(2-butynyloxy)phenyl]sulfony}-1,4-diazepane-5-carboxylic
acid (0.68 mmol) was converted into
1-benzyl-4-{[4-(2-butynyloxy)phenyl]s-
ulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide (0.169 g), obtained
as a white solid. Electrospray Mass Spec 458.2 (M+H)+
EXAMPLE 291
tert-Butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)carbonyl]-
-1,4-diazepane-1-carboxylate
[1157] Step 1
[1158] In a manner analogous to that described in Step 2 of Example
290, 2.86 g (5.78 mmol) of di(tert-butyl)
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-
-1,4-diazepane-1,5-dicarboxylate (from Step 1 of Example 289) was
converted into
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carbo- xylic
acid which was purified by chromatography on silica gel to give a
yellow solid. Electrospray Mass Spec 353.1 (M+H)+
[1159] Step 2
[1160] To a solution of
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane- -5-carboxylic
acid (2.9 mmol) in dioxane (30 mL) and water (30 mL) was added 1N
aqueous sodium hydroxide (9 mL). Di-tert-butyl dicarbonate (0.63 g,
2.9 mmol) was then added. After 18 h 1 N aqueous hydrochloric acid
(15 mL) was added and the mixture was extracted with
dichloromethane (3.times.). The combined organic extracts were
dried over anhydrous sodium sulfate and concentrated in vacuo to
give tert-butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-diazepane-5-carboxylic
acid -1-carboxylate as a brown foam (1.24 g).
[1161] Step 3
[1162] To a solution of tert-butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,- 4-diazepane-5-carboxylic
acid-1-carboxylate (0.74 g, 1.6 mmol) in dimethylformamide (8 mL)
at 0.degree. C. was added 1-hydroxybenzotriazole (0.39 g, 2.9 mmol)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.56 g, 2.9
mmol). After 45 min 50% aqueous hydroxyl amine (0.26 mL) was added.
After 2 hours the reaction mixture was diluted with ethyl acetate
and water. The aqueous phase was extracted with ethyl acetate
3.times.. The combined organic phases were washed with aqueous
sodium bicarbonate 3.times. and with water 4.times.. The organic
phase was dried over anhydrous sodium sulfate and concentrated in
vacuo to give tert-butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-5-[(hydroxyamino)carbonyl]-1,4-diaze-
pane-1-carboxylate (0.62 g). Electrospray Mass Spec 468.1
(M+H)+
EXAMPLE 292
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-5-carboxamide
[1163] To the product of Example 291, tert-butyl
4-{[4-(2-butynyloxy)pheny-
l]sulfonyl}-5-[(hydroxyamino)carbonyl]-1,4-diazepane-1-carboxylate
(0.32 g, 0.68 mmol), was added 4N hydrochloric acid in dioxane (9
mL). After 10 min the reaction mixture was concentrated in vacuo.
Trituration of the residue with diethyl ether gave
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hy-
droxy-1,4-diazepane-5-carboxamide as an off-white powder (0.27 g).
Electrospray Mass Spec 368.2 (M+H)+
EXAMPLE 293
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-methyl-1,4-diazepane-5-ca-
rboxamide
[1164] Triethylamine (0.08 mL) was added to a suspension of the
product of Example 292,
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-diazepane-
-5-carboxamide (0.10 g), in methanol (6 mL) to give a solution
which was cooled to 0.degree. C. Iodomethane (0.025 mL) was then
added. After 30 min the reaction mixture was allowed to warm to
25.degree. C. After 20 min additional iodomethane (0.02 mL) was
added followed by additional triethylamine (0.015 mL). After 18
hours the reaction mixture was diluted with dichloromethane and
water. The aqueous phase was washed with dichloromethane
(3.times.). The combined organic extracts were dried over anhydrous
sodium sulfate and concentrated in vacuo. The material obtained was
combined with material from a previous reaction run on the same
scale and chromatographed on silica gel to give
4-{[4-(2-butynyloxy)phenyl]sulf-
onyl}-N-hydroxy-1-methyl-1,4-diazepane-5-carboxamide (0.067 g).
Electrospray Mass Spec 382.2 (M+H)+
EXAMPLE 294
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepine-5-carboxamid-
e
[1165] Step 1
[1166] To D,L-homocysteine (6.69 g, 49.4 mmol) was added 2N aqueous
potassium hydroxide (32 mL) and the resulting solution was cooled
to 0.degree. C. 2-Bromoethanol (4.2 mL, 59.3 mmol) in ethanol (56
mL) was then added dropwise and the reaction mixture was allowed to
warm to 25.degree. C. After 18 h the reaction mixture was acidified
to pH 5 and concentrated to give
2-(amino)-4-[(2-hydroxyethyl)sulfanyl]butanoic acid (WO 9808823) as
a white paste. To this material was added water (110 mL) and
dioxane (110 mL). and triethylamine (20.7 mL, 148 mmol) and to the
resulting solution was added 4-(2-butynyloxy)phenylsulfonyl
chloride (14.2 g, 54.3 mmol). After 20 h the reaction mixture was
acidified to pH 1 with 1N aqueous hydrochloric acid and extracted
with dichloromethane (3.times.). The combined organic extracts were
dried over anhydrous sodium sulfate and concentrated in vacuo to
give 2-({[4-(2-butynyloxy)phe-
nyl]sulfonyl}amino)-4-[(2-hydroxyethyl)sulfanyl]butanoic acid as an
oil (20.8 g). Electrospray Mass Spec 385.8 (M-H)-.
[1167] Step 2
[1168] To a solution of
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4[(2-h-
ydroxyethyl)sulfanyl]butanoic acid (20.8 g) in ether and methanol
was dropwise added trimethylsilyldiazomethane (25 mL. 2.0 M in
hexanes). The reaction mixture was concentrated in vacuo and the
resulting oil was chromatographed on silica gel eluting with
hexane/ethyl acetate to give methyl
2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(2-hydroxyethyl)sul-
fanyl] butanoate as a light yellow oil (6.68 g). Electrospray Mass
Spec 401.9 (M+H)+.
[1169] Step 3
[1170] To methyl 2
({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-4-[(2-hydroxy-
ethyl)-sulfanyl] butanoate (5.5 g, 13.7 mmol) in tetrahydrofuran
(100 mL) was added triphenylphosphine (4.3 g, 16.4 mmol). Diethyl
azodicarboxylate (2.4 mL, 15.1 mmol) was then added dropwise. After
2 h the reaction mixture was concentrated in vacuo to give an oil
which was chromatographed on silica gel eluting with hexanedethyl
acetate to give methyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepine-5-carboxylate
as a white solid (4.04 g). mp 95-98.degree. C. Electrospray Mass
Spec 384.0 (M+H)+.
[1171] Step 4
[1172] To methyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepine-5-car- boxylate
(0.27 g, 0.7 mmol) was added 5 N aqueous sodium hydroxide (7 mL)
and methanol (7 mL). The reaction mixture was heated at reflux for
5 minutes. Upon cooling to 25.degree. C. the reaction mixture was
acidified to pH 1 with 1N aqueous hydrochloric acid. The mixture
was extracted with dichloromethane (3.times.) and the combined
organic extracts were dried over anhydrous sodium sulfate.
Concentration in vacuo gave
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepine-5-carboxylic
acid as a white powder (0.26 g). Electrospray Mass Spec 370.0
(M+H)+.
[1173] Step 5
[1174] A solution of
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepine-5- -carboxylic
acid (0.23 g, 0.62 mL) in dimethylformamide (3.5 mL) at 0.degree.
C. was treated with 1-hydroxybenzotriazole (0.15 g, 1.1 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.21 g, 1.1 mmol).
After 45 min 50% aqueous hydroxylamine (0.2 mL) was added dropwise
and the reaction mixture was allowed to warm to 25.degree. C. After
72 h ethyl acetate and water were added and the organic phase
washed with ethyl acetate (3.times.). The combined organic extracts
were dried over anhydrous sodium sulfate and concentrated in vacuo
to give
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1,4-thiazepine-5-carboxami-
de as a hard white foam (0.20 g). Electrospray Mass Spec 385
(M+H)+.
EXAMPLE 328
(2R)-5-(acetylamino)-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydrox-
ypentanamide
[1175] Step A.
(2R)-5-(tert-butyloxycarbonylamino)-2-({[4-(but-2-ynyloxy)p-
henyl]sulfonyl}amino)-N-hydroxypentanoic Acid
[1176] D-Orn(Boc) (4.0 g, 17.2 mmol) was dissolved in dioxane (20
mL) and water (20 mL) and 4-but-2-ynyloxy-benzenesulfonyl chloride
(4.0 g, 16.4 mmol) and triethylamine (4.4 mL, 31.6 mmol) were
added. The mixture was stirred at room temperature for 18 hours.
The solvent was evaporated and the residue dissolved in ethyl
acetate and washed with brine and dried over MgSO.sub.4 and
concentrated. The crude product was used directly in Step B.
[1177] Step B. Coupling of Sulfonylated Amino Acid to Hydroxylamine
Resin
[1178]
4-O-Methylhydroxylamine-phenoxymethyl-copoly(styrene-1%-divinylbenz-
ene)-resin.sup.1 (20.0 g, 1.1 meq/g) was placed in a 250 mL solid
phase synthesis vessel (Chem Glass) and suspended in DMF (100 mL).
D-2-(4-but-2-ynyloxy-benzenesulfonylamino)-5-tert-butoxycarbonylaminopent-
anoic acid (9 g, 1.0 eq.) HOBt (16.2 g, 6.0 eq.) and DIC (12.5 mL,
4.0 eq.) were added. The reaction was shaken on an orbital shaker
at room temperature for 16 hours. The reaction was filtered and
washed with DMF (3.times.50 mL), DCM (3.times.50 mL), MeOH
(2.times.50 mL), and DCM (2.times.50 mL) The resin was dried in
vacuo at room temperature.
[1179] Step C. Removal of the Boc Group
[1180] The dried resin from Step B was placed in a 250 mL solid
phase synthesis vessel and 2,6-lutidine (1.5 M solution in DCM, 50
mL) followed by trimethylsilyltriflate (1.0 M solution in DCM, 50
mL) were added. The reaction was shaken for 30 minutes, then
filtered and the resin washed with DCM (2.times.50 mL).
2,6-Lutidine (1.5 M solution in DCM, 50 mL) followed by
trimethylsilyltriflate (1.0 M solution in DCM, 50 mL) were again
added and the reaction was shaken for a further 30 minutes, then
filtered and the resin washed with DCM (2.times.50 mL), DMF
(3.times.50 mL), DCM (3.times.50 mL), MeOH (2.times.50 mL), and DCM
(2.times.50 mL) The resin was dried in vacuo at room
temperature.
[1181] Step D: Acylation of Ornitine Side Chain
[1182] The resin from Step C was split into 24 empty 25 mL SPE
column (Jones Chromatography USA, Inc. Part # 120-1024-H) and
suspended in DMF (4 mL). To the first tube was added acetic acid
(76 uL, 2.0 eq.) HOBt (541 mg, 6.0 eq.) and DIC (417 uL, 4.0 eq.)
were added. The reaction was shaken on an orbital shaker at room
temperature for 16 hours. The reaction was filtered and washed with
DMF (3.times.20 mL), DCM (3.times.20 mL), MeOH (2.times.20 mL), and
DCM (2.times.20 mL).
[1183] Step E: Cleavage of the Product From Resin
[1184] The resin prepared in Step D was suspended in DCM (1.0 mL)
and TFA (1.0 mL) was added. The reaction was shaken for 1 hour at
room temperature. The reaction was filtered and the resin washed
with DCM (2.times.1 mL). The filtrate and the washing were combined
and concentrated to dryness on a Savant SpeedVac. MeOH (1 mL) was
added and the mixture concentrated.
[1185] The crude product was purified by reverse phase HPLC under
the under the conditions described for Example 62B.
[1186] The hydroxamic acid compounds described in Table 2 below are
synthesized according to the procedures of Example 328 using either
D-Orn(Boc) or D-Lys(Boc) and the following acids in Step D: acetic
acid, 5-benzimidazole carboxylic acid, benzoic acid, 4-bromobenzoic
acid, butyric acid, 3-chlorothiophene-2-carboxylic acid,
4-chlorobenzoic acid, cyclohexane carboxylic acid,
3,4-dichlorophenyl acetic acid, 2,5-dimethyl-3-furoic acid,
3,5-dimethylisoxazole-4-carboxylic acid, hydrocinnamic acid,
isonicotinic acid, nicotinic acid, o-anisic acid,: p-anisic acid,
p-nitrophenyl acetic acid, phenylacetic acid, 3-quinoline
carboxylic acid, 3-thiophenecarboxylic acid, trans-cinnamic acid,
and oleic acid.
2TABLE 2 HPLC retention Exam- time.sup.5 ple R (min.) MS.sup.3 (M +
H) 328 D-Orn(Ac) 1.91 398 329 D-Orn(5-benzimidazolyl) 1.98 500 330
D-Orn(benzoyl) 2.33 460 331 D-Orn(4-bromobenzoyl) 2.59 539 332
D-Orn(butyryl) 2.12 426 333 D-Orn(3-chlorothiophene-2- 2.43 501
carbonyl) 334 D-Orn(4-chlorobenzoyl) 2.55 494 335
D-Orn(cyclohexylcarbonyl) 2.44 466 336 D-Orn(2,5-dimethyl-3-fu-
royl) 2.74 543 337 D-Orn(3,4-dichlorophenyl acetyl) 2.45 478 338
D-Orn(3,5-dimethylisoxazole-4- 2.18 479 carbonyl) 339
D-Orn(hydrocinnamoyl) 2.48 488 340 D-Orn(isonicotinyl) 1.78 461 341
D-Orn(nicotinyl) 1.81 461 342 D-Orn(o-methoxybenzoyl) 2.41 490 343
D-Orn(p-methoxybenzoyl) 2.36 490 344 D-Orn(p-nitrobenzoyl) 2.45 519
345 D-Orn(phenylacetyl) 2.38 474 346 D-Orn(3-quinoline carbonyl)
2.06 511 347 D-Orn(3-thiophene carbonyl) 2.28 466 348
D-Orn(cinnamoyl) 2.52 486 349 D-Lys(5-benzimidazolyl) 2.01 514 350
D-Lys(benzoyl) 2.39 474 351 D-Lys(4-bromobenzoyl) 2.65 553 352
D-Lys(3-chlorothiophene-2- 2.5 515 carbonyl) 353
D-Lys(4-chlorobenzoyl) 2.61 509 354 D-Lys(cyclohexylcarbonyl) 2.49
480 355 D-Lys(3,4-dichlorophenyl acetyl) 2.63 557 356
D-Lys(2,5-dimethyl-3-furoyl) 2.51 492 357 D-Lys(3,5-dimethylisoxaz-
ole-4- 2.22 493 carbonyl) 358 D-Lys(hydrocinnamoyl) 2.51 502 359
D-Lys(isonicotinyl) 2.01 475 360 D-Lys(o-methoxybenzoyl) 2.47 504
361 D-Lys(p-methoxybenzoyl) 2.41 504 362 D-Lys(p-nitrobenzoyl) 2.5
533 363 D-Lys(phenylacetyl) 2.42 488 364 D-Lys(3-quinoline
carbonyl) 2.1 525 365 D-Lys(3-thiophene carbonyl) 2.33 480 366
D-Lys(cinnamoyl) 2.57 500 367 D-Orn(Z-octadec-9-enoyl) 4.35 620
.sup.5LC conditions: Hewlett Packard 1100; YMC ODS-A 4.6 mm .times.
50 mm 5 u column at 23.degree. C.; 10 uL injection; Solvent A:
0.05% TFA/water; Solvent B: 0.05% TFA/acetonitrile; Gradient: Time
0: 98% A; 0.5 min: 98% A; 4.5 min: 5% A, 5.0 min: 5% A. Flow rate
2.5 mL/min; Detection: 220 and 254 nm DAD.
EXAMPLE 368
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5(hydroxyamino)-5-oxo-
pentyl]thiophene-2-carboxamide
[1187] Step A:
(2R)-2-(4-But-2-ynyloxy-benzenesulfonylamino)-5-tert-butoxy-
carbonylaminopentanoic acid O-tert-butylhydroxyamide
[1188]
(2R)-2-(4but-2-ynyloxy-benzenesulfonylamino)-5-tert-butoxycarbonyla-
minopentanoic acid (10 g, 22.7 mmol) prepared as described in
Example 328 Step A was dissolved in DCM (100 mL) and HOBt (3.7 g,
27.4 mmol), O-tert-Butyl hydroxylamine hydrochloride (4.2 g, 33.4
mmol) triethylamine (9.4 mL, 67 mmol) and EDC (5 g, 32.2 mmol) were
added in that order. The reaction was stirred at room temperature
for 16 hours, then diluted with ethyl acetate and washed with
water, dried over MgSO.sub.4 and concentrated.
[1189] Step B:
(2R)-2-(4-But-2-ynyloxy-benzenesulfonylamino)-5-aminopentan- oic
acid O-tert-butylhydroxyamide
[1190] The residue from Step A was dissolved in 2,6-lutidine (1.5 M
in DCM, 33 mL, 50 mmol) and trimethylsilyltriflate (1.0 M in DCM,
33 mL, 33 mmol) was added. The reaction was stirred for 2 hours
then diluted with ethyl acetate and washed with water and saturated
aqueous sodium bicarbonate. The organic phase was dried over
MgSO.sub.4 and concentrated.
[1191] Step C:
N-[(4R)-4-({[4(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(O-te-
rt-butylhydroxyamino)-5-oxopentyl]thiophene-2-carboxamide
[1192] The residue from Step B (102 mg, 0.25 mmol) was dissolved in
DCM (2 mL). Triethylamine (104 uL, 0.75 mmol), DMAP (0.3 mg, 0.025
mmol) and thiophene-2-carbonyl chloride (55 mg, 0.37 mmol) were
added. The reaction was shaken on an orbital shaker for 16 hours
then concentrated to dryness.
[1193] Step D:
N-[(4R)-4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hyd-
roxyamino)-5-oxopentyl]-thiophene-2-carboxamide
[1194] The residue from Step C was dissolved in DCM (1 mL) and TFA
(1 mL) was added. The solution was shaken at 40.degree. C. for 5
hours, then concentrated. The residue was dissolved in MeOH and
purified by reverse phase HPLC under the conditions described below
to give Example 368 (8.5 mg) Electrospray Mass Spec 466 (M+H)+;
HPLC retention time.sup.5 3.06 minutes. Flow Rate: 22.5
mL/minute.
EXAMPLE 369
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[(ethylamino)carbonyl-
]amino}-N-hydroxypentanamide
[1195] Step A
[1196] The residue from Example 368 Step B (102 mg, 0.25 mmol) was
dissolved in DCM (2 mL) and triethylamine (69 uL, 0.5 mmol) and
ethyl isocyanate (22 uL, 0.27 mmol) were added. The reaction was
shaken on an orbital shaker for 16 hours then concentrated to
dryness.
[1197] Step B
[1198] The procedure used in Example 368, Step D was used to give
Example 369 (7.2 mg) Electrospray Mass Spec 427 (M+H)+; HPLC
retention time.sup.5 2.26 minutes.
EXAMPLE 370
(2R)-5-[(Anilinocarbonyl)amino]-2-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amin-
o)-N-hydroxypentanamide
[1199] Step A
[1200] The residue from Example 368 Step B (102 mg, 0.25 mmol) was
dissolved in DCM (2 mL) and triethylamine (69 uL, 0.5 mmol) and
phenyl isocyanate (2230 uL, 0.27 mmol) were added. The reaction was
shaken on an orbital shaker for 16 hours then concentrated to
dryness.
[1201] Step B
[1202] The procedure used in Example 368 Step D was used to give
Example 370 (21.3 mg) Electrospray Mass Spec 475 (M+H)+; HPLC
retention time.sup.5 2.7 minutes.
EXAMPLE 371
Octyl
(4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino)-5-(hydroxyamino)-5-
-oxopentylcarbamate
[1203] Step A
[1204] The residue from Example 368 Step B (102 mg, 0.25 mmol) was
dissolved in DCM (2 mL) and diisopropylethylamine (87 uL, 0.5 mmol)
and octyl chloroformate (54 uL, 0.27 mmol) were added. The reaction
was shaken on an orbital shaker for 16 hours then concentrated to
dryness.
[1205] Step B
[1206] The procedure used in Example 368 Step D was used to give
Example 371 (5.2 mg) Electrospray Mass Spec 512 (M+H)+; HPLC
retention time.sup.5 2.52 minutes.
EXAMPLE 372
4-Methoxyphenyl
(4R)-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}amino-5-(hydrox-
yamino)-5-oxopentylcarbamate
[1207] Step A
[1208] The residue from Example 368 Step B (102 mg, 0.25 mmol) was
dissolved in DCM (2 mL) and diisopropylethylamine (87 uL, 0.5 mmol)
and 4-methoxyphenyl chloroformate (41 uL, 0.27 mmol) were added.
The reaction was shaken on an orbital shaker for 16 hours then
concentrated to dryness.
[1209] Step B
[1210] The procedure used in Example 368 Step D was used to give
Example 372 (14.7 mg) Electrospray Mass Spec 506 (M+H)+; HPLC
retention time.sup.5 2.82 minutes.
EXAMPLE 373
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-5-{[(diethylamino)carbon-
yl]amino}-N-hydroxypentanamide
[1211] Step A
[1212] The residue from Example 368 Step B (102 mg, 0.25 mmol) was
dissolved in DCM (2 mL) and triethylamime amine (69 uL, 0.5 mmol)
and diethyl carbamoyl chloride (35 uL, 0.27 mmol) were added. The
reaction was shaken on an orbital shaker for 16 hours then
concentrated to dryness.
[1213] Step B
[1214] The procedure used in Example 368 Step D was used to give
Example 373 (19.7 mg) Electrospray Mass Spec 455 (M+H)+; HPLC
retention time.sup.5 2.52 minutes.
EXAMPLE 374
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[(methylani-
lino)carbonyl]amino}pentanamide
[1215] Step A
[1216] The residue from Example 368 Step B (102 mg, 0.25 mmol) was
dissolved in DCM (2 mL) and triethylamime amine (69 uL, 0.5 mmol)
and methylphenyl carbamoyl chloride (46 mg, 0.27 mmol) were added.
The reaction was shaken on an orbital shaker for 16 hours then
concentrated to dryness.
[1217] Step B
[1218] The procedure used in Example 368 Step D was used to give
Example 374 (28 mg) Electrospray Mass Spec 489 (M+H)+; HPLC
retention time.sup.5 2.73 minutes.
EXAMPLE 375
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[(1-methyl--
1H-imidazol-4-yl)sulfonyl]amino}pentanamide
[1219] Step A
[1220] The residue from Example 368 Step B (102 mg, 0.25 mmol) was
dissolved in DCM (2 mL) and diisopropylethylamine (87 uL, 0.5 mmol)
and 1-methylimidazole-4-sulfonyl chloride (50 mg, 0.27 mmol) were
added. The reaction was shaken on an orbital shaker for 16 hours
then concentrated to dryness.
[1221] Step B
[1222] The procedure used in Example 368 Step D was used to give
Example 375 (9.5 mg) Electrospray Mass Spec 500 (M+H)+; HPLC
retention time.sup.5 2.28 minutes.
EXAMPLE 376
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-[(2-morpholi-
n-4-ylacetyl)amino]pentanamide
[1223] Step A
[1224] The residue from Example 368 Step B (102 mg, 0.25 mmol) was
dissolved in DCM (2 mL) and triethylamime amine (87 uL, 0.5 mmol),
DMAP (0.3 mg, 0.025 mmol) and chloroacetyl chloride (30 uL, 0.27
mmol) were added. The reaction was shaken on an orbital shaker for
16 hours then concentrated to dryness.
[1225] Step B
[1226] The residue from Step A was dissolved in DCM (2 mL) and
morpholine (87 uL, 1.0 mmol) was added. The reaction was shaken at
room temperature for 16 hours, then concentrated to dryness.
[1227] Step C
[1228] The procedure used in Example 368 Step D was used to give
Example 376 (23.1 mg) Electrospray Mass Spec 483 (M+H)+; HPLC
retention time.sup.5 1.92 minutes.
EXAMPLE 377
(2R)-2-({[4-(But-2-ynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-5-{[2-(4-methy-
lpiperazin-1-yl)acetyl]amino}pentanamide
[1229] Step A
[1230] The residue from Example 376 Step A was dissolved in DCM (2
mL) and N-methyl piperazine (110 uL, 1.0 mmol) was added. The
reaction was shaken at room temperature for 16 hours, then
concentrated to dryness.
[1231] Step B
[1232] The procedure used in Example 368 Step D was used to give
Example 377 (16.8 mg) Electrospray Mass Spec 496 (M+H)+; HPLC
retention time.sup.5 1.89 minutes.
EXAMPLE 378
(2R)-5-{[2-(Benzylamino)acetyl]amino}-2-({[4-(but-2-ynyloxy)phenyl]sulfony-
l}amino)-N-hydroxypentanamide
[1233] Step A
[1234] The residue from Example 376 Step A was dissolved in DCM (2
mL) and benzylamine (110 uL, 1.0 mmol) was added. The reaction was
shaken at room temperature for 16 hours, then concentrated to
dryness.
[1235] Step B
[1236] The procedure used in Example 368, Step D was used to give
Example 378 (20.2 mg) Electrospray Mass Spec 503 (M+H)+; HPLC
retention time.sup.5 3.64 minutes.
EXAMPLE 379
(3S)-4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3,4-dihyd-
ro-2H-1,4-thiazine-3-carboxamide
[1237] Step 1
[1238] The product of Step 3 of Example 243,
4-(4-hydroxy-benzenesulfonyl)-
-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester (2.00
g, 5.746 mmol), and 2-butyn-1-ol (0.52 mL, 6.916 mmol) underwent
Mitsunobu coupling according to the procedure of Step 4 of Example
243 to provide 1.68 g of methyl
(3S)-4-({[4-(2-butynyloxy)-phenyl]sulfonyl)-2,2-dimethyl-
-thiomorpholine-3-carboxylate as a white solid.
[1239] Step 2
[1240] To a 0.degree. C. solution of 1.68 g (4.23 mmol) of methyl
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3--
carboxylate in 100 mL of dichloromethane and 16 mL of methanol was
added 0.730 g of m-chloroperbenzoic acid in four equal portions, as
a solid. Thirty minutes after all of the m-chloroperbenzoic acid
had been added, the reaction was diluted with dichloromethane and
washed with saturated sodium bicarbonate solution. The organics
were dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with a
gradient of ethyl acetate/hexanes (1:1) to ethyl acetate to provide
1.50 g of a 3:1 mixture of sulfoxide diastereomers, methyl
(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dime-
thyl-thiomorpholine-3-carboxylate-1oxide, which was used for the
next step.
[1241] Step 3
[1242] A solution of 1.50 g (3.632 mmol) of methyl
(3S)-4-({[4-(2butynylox-
y)-phenyl]sulfonyl}-2,2-dimethyl-thiomorpholine-3-carboxylate-1-oxide
in 20 mL of acetic anhydride was heated to reflux for 4 h and then
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with ethyl acetate/hexanes (1:10) to provide 0.985 g of
methyl(3S)-4-{[4-2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3,4-dihydro-2-
H-1,4-thiazine-3-carboxylate as a colorless oil. Electrospray Mass
Spec 396.1 (M+H)+.
[1243] Step 4
[1244] Lithium iodide (0.770 g, 5.75 mmol) mediated ester cleavage
of 0.227 g (0.575 mmol) of
methyl(3S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2-
,2-dimethyl-3,4-dihydro-2H-1,4-thiazine-3-carboxylate according to
the procedure of Example 250 provided 0.205 g of
(3S)-4-{[4-(2-butynyloxy)phe-
nyl]sulfonyl}-2,2-dimethyl-3,4-dihydro-2H-1,4-thiazine-3-carboxylic
acid as a white solid. Electrospray Mass Spec 382.0 (M+H)+
[1245] Step 5
[1246] According to the procedure of Example 9, 0.200 g (0.525
mmol) of (3
S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-3,4-dihydro-2H-1,4-t-
hiazine-3-carboxylic acid was converted into 0.173 g of the
corresponding hydroxamic acid, (3
S)-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-
-dimethyl-3,4-dihydro-2H-1,4-thiazine-3-carboxamide, obtained as a
white solid. Electrospray Mass Spec 396.9 (M+H)+.
Pharmacology
[1247] Representative compounds of this invention were evaluated as
inhibitors of the enzymes MMP-1, MMP-9, MMP-13 and TNF-a converting
enzyme (TACE). The standard pharmacological test procedures used,
and results obtained which establish this biological profile are
shown below.
Test Procedures for Measuring MMP-1, MMP-9, and MMP-13
Inhibition
[1248] These standard pharmacological test procedures are based on
the cleavage of a thiopeptide substrates such as
Ac-Pro-Leu-Gly(2-mercapto-4-- methyl-pentanoyl)-Leu-Gly-OEt by the
matrix metalloproteinases MMP-1, MMP-13 (collagenases) or MMP-9
(gelatinase), which results in the release of a substrate product
that reacts colorimetrically with DTNB
(5,5'-dithiobis(2-nitro-benzoic acid)). The enzyme activity is
measured by the rate of the color increase. The thiopeptide
substrate is made up fresh as a 20 mM stock in 100% DMSO and the
DTNB is dissolved in 100% DMSO as a 100 mM stock and stored in the
dark at room temperature. Both the substrate and DTNB are diluted
together to 1 mM with substrate buffer (50 mM HEPES pH 7.5, 5 mM
CaCl.sub.2) before use. The stock of enzyme is diluted with buffer
(50 mM HEPES, pH 7.5, 5 mM CaCl.sub.2, 0.02% Brij) to the desired
final concentration. The buffer, enzyme, vehicle or inhibitor, and
DTNB/substrate are added in this order to a 96 well plate (total
reaction volume of 200 .mu.l) and the increase in color is
monitored spectrophotometrically for 5 minutes at 405 nm on a plate
reader and the increase in color over time is plotted as a linear
line.
[1249] Alternatively, a fluorescent peptide substrate is used. In
this test procedure, the peptide substrate contains a fluorescent
group and a quenching group. Upon cleavage of the substrate by an
MMP, the fluorescence that is generated is quantitated on the
fluorescence plate reader. The assay is run in HCBC assay buffer
(50 mM HEPES, pH 7.0, 5 mM Ca.sup.+2, 0.02% Brij, 0.5% Cysteine),
with human recombinant MMP-1, MMP-9, or MMP-13. The substrate is
dissolved in methanol and stored frozen in 1 mM aliquots. For the:
assay, substrate and enzymes are diluted in HCBC buffer to the
desired concentrations. Compounds are added to the 96 well plate
containing enzyme and the reaction is started by the addition of
substrate. The reaction is read (excitation 340 nm, emission 444
nm) for 10 min. and the increase in fluorescence over time is
plotted as a linear line.
[1250] For either the thiopeptide or fluorescent peptide test
procedures, the slope of the line is calculated and represents the
reaction rate. The linearity of the reaction rate is confirmed
(r.sup.2>0.85). The mean (x.+-.sem) of the control rate is
calculated and compared for statistical significance (p<0.05)
with drug-treated rates using. Dunnett's multiple comparison test.
Dose-response relationships can be generated using multiple doses
of drug and IC.sub.50 values with 95% CI are estimated using linear
regression.
Test Procedure for Measuring TACE Inhibition
[1251] Using 96-well black microtiter plates, each well receives a
solution composed of 10 .mu.L TACE (final concentration 1
.mu.g/mL), 70 .mu.L Tris buffer, pH 7.4 containing 10% glycerol
(final concentration 10 mM), and 10 .mu.L of test compound solution
in DMSO (final concentration 1 .mu.M, DMSO concentration <1%)
and incubated for 10 minutes at room temperature. The reaction is
initiated by addition of a fluorescent peptidyl substrate (final
concentration 100 .mu.M) to each well and then shaking on a shaker
for 5 sec.
[1252] The reaction is read (excitation 340 nm, emission 420 nm)
for 10 min. and the increase in fluorescence over time is plotted
as a linear line. The slope of the line is calculated and
represents the reaction rate.
[1253] The linearity of the reaction rate is confirmed
(r.sup.2>0.85). The mean (x.+-.sem) of the control rate is
calculated and compared for statistical significance (p<0.05)
with drug-treated rates using Dunnett's multiple comparison test
Dose-response relationships can be generate using multiple doses of
drug and IC.sub.50 values with 95% CI are estimated using linear
regression.
Human Monocytic THP-1 Cell Differentiation Assay For Soluble
Proteins (THP-1 Soluble Protein Assay)
[1254] Mitogenic stimulation of THP-1 cells cause differentiation
into macrophage like cells with concomitant secretion of tumor
necrosis factor (TNF-a) and TNF receptor (TNF-R p75/80 and TNF-R
p55/60) and Interleukin-8 (IL-8), among other proteins. In
addition, non-stimulated THP-1 cells shed both the p75/80 and the
p55/60 receptors over time. The release of membrane bound TNF-a and
possibly TNF-R p75/80 and TNF-R p55/60, but not IL-8, is mediated
by an enzyme called TNF-a converting enzyme or TACE. This assay can
be used to demonstrate either an inhibitory or a stimulatory
compound effect on this TACE enzyme and any cytotoxic. consequence
of such a compound.
[1255] THP-1 cells (from ATCC) are a human monocytic cell line
which were obtained from the peripheral blood of a one year old
male with acute monocytic leukemia. They can be grown in culture
and differentiated into macrophage like cells by stimulation with
mitogens.
[1256] For the assay, THP-1 cells are seeded from an ATCC stock
which was previously grown and frozen back at 5.times.106/ml/vial.
One vial is seeded into a T25-flask with 16 mls of RPMI-1640 within
glutamax (Gibco) media containing 10% fetal bovine serum, 100
units/ml penicillin, 100 .mu.g/ml streptomycin, and 5.times.10
.sup.-5 M 2-mercapto-ethanol (THP-1 media). Each vial of cells are
cultured for about two weeks prior to being used for an assay and
then are used for only 4 to 6 weeks to screen compounds. Cells are
subcultured on Mondays and Thursdays to a concentration of
1.times.105/ ml.
[1257] To perform an assay, the THP-1 cells are co-incubated in a
24 well plate with 50 ml/well of a 24 mg/ml stock of
Lipopolysacharide (LPS) (Calbiochem Lot# B13189) at 37.sub.iC in 5%
CO.sub.2 at a concentration of 1.091.times.10.sup.6 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 media is plated in appropriate wells to give
a final volume of 1.2 ml/well. Standard and test compounds are
dissolved in DMSO at a concentration of 36 mM and diluted from here
to the appropriate concentrations in THP-1 media 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% final concentration.
Positive control wells were included in the experiment which had
mitogen added but no drug. Vehicle control wells were included as
well, 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 which had
vehicle but no mitogen or drug added to the cells. Compounds can be
evaluated for their effect on basal (non-stimulated) shedding of
the receptors by replacing the LPS with 50 ml/well of THP-1 media
Plates are placed into an incubator set at 5% CO2 and at 37o C.
After 4 hours of incubation, 300 ml/well of tissue culture
supernatant (TCS) is removed for use in an TNF-a ELISA. Following
24 hours of incubation, 700 ml/well of TCS is removed and used for
analysis in TNF-R p75/80, TNF-R p55/60 and IL-8 ELISAs.
[1258] In addition, at the 24 hours timepoint, and the cells for
each treatment group are collected by resuspension in 500
.mu.l/well of THP-1 media and transferred into a FACS tube. Two
ml/tube of a 0.5 mg/ml stock of propidium iodide (PI) (Boerhinger
Mannheim cat. # 1348639) is added. The samples are run on a Becton
Dickinson FaxCaliber FLOW cytometry machine and the amount of dye
taken up by each cell is measured in the high red wavelength (FL3).
Only cells with compromised membranes (dead or dying) can take up
PI. The percent of live cells is calculated by the number of cells
not stained with PI, divided by the total number of cells in the
sample. The viability values calculated for the drug treated groups
were compared to the viability value calculated for the vehicle
treated mitogen stimulated group ("vehicle positive control") to
determine the "percent change from control". This "percent change
from control" value is an indicator of drug toxicity.
[1259] The quantity of soluble TNF-a, TNF-R p75/80 and TNF-R p55/60
and IL-8 in the TCS of the THP-1 cell cultures are obtained with
commercially available ELISAs from R&D Systems, by
extrapolation from a standard curve generated with kit standards.
The number of cells that either take up or exclude PI are measured
by the FLOW cytometry machine and visualized by histograms using
commercially available Cytologic software for each treatment group
including all controls.
[1260] Biological variability in the magnitude of the response of
THP-1 cell cultures requires that experiments be compared on the
basis of percent change from "vehicle positive control" for each
drug concentration. Percent change in each soluble protein
evaluated from the "vehicle positive control" was calculated for
each compound concentration with the following formula:
% Change=pg/ml(compound)-pg/ml(veh pos control).times.100 pg/ml(veh
pos control)-pg/ml(veh neg control)
[1261] For the soluble protein (TMF-a, p75/80, p55/60, IL-8)
studies under stimulated conditions, the mean pg/ml of duplicate
wells were determined and the results expressed as percent change
from "vehicle positive control". For the soluble protein (p75/80
and p55/60 receptors) studies under non-stimulated conditions, the
mean pg/ml of duplicate wells were determined and the results
expressed as percent change from "vehicle positive control"
utilizing the following formula: 1 % Change = pg / ml ( compound
neg control ) - pg / ml ( veh neg control pg / ml ( veh neg control
) .times. 100
[1262] IC50 values for each compound are calculated by non-linear
regression analysis using customized software utilizing the JUMP
statistical package.
[1263] For the cell viability studies, the viabilities (PI
exclusion) of pooled duplicate wells were determined and the
results expressed as % change from "vehicle positive control". The
viability values calculated for the compound treated groups were
compared to the viability value calculated for the "vehicle
positive control" to determine "percent change from control" as
below. This value "percent change from control" is an indicator of
drug toxicity. 2 % Change = % live cells ( compound ) % live cells
( veh pos control ) - 1 .times. 100
[1264] References
[1265] Bjornberg, F., Lantz, M. Olsson, I., and Gullberg, U.
Mechanisms involved in the processing of the p55 and the p75 tumor
necrosis factor (TNF) receptors to soluble receptor forms.
Lymphokine Cytoline Res. 13:203-211, 1994.
[1266] Gatanaga, T., Hwang, C., Gatanaga,. M., Cappuccini, F.,
Yamamoto, R., and Granger, G. The regulation of TNF mRNA synthesis,
membrane expression, and release by PMA- and LPS-stimulated human
monocytic TMP-1 cells in vitro. Cellular Immun. 138:1-10, 1991.
[1267] 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.
[1268] Results of the above in vitro matrix metalloproteinase
inhibition, TACE inhibition and THP standard pharmacological test
procedures are given in Tables 1-15 below.
3TABLE 1 50 Example # R MMP-1.sup.a MMP-9.sup.a MMP-13.sup.a
TACE.sup.a THP.sup.b 25 H 47%(10) 753 185 4.8 39 30 Me 4385 282 40
6.0 60 27 iPr 2965 42 18 32 75 105 iBu 1743 213 52 6.8 87 106 tBu
880 224 41 17 91 129 C.sub.6H.sub.10-4-OH 1037 192 28 7.4 92 35
Me.sub.2 10,000 1377 396 12.9 9 139 --(CH.sub.2).sub.4-- >10,000
3685 1272 37 26 138 --(CH.sub.2).sub.5-- 5167 2174 619 27 19 267
--(CH.sub.2).sub.2N(BOC)-(CH.sub.2).sub.2-- >10,000 -- 530 37 60
288 --(CH.sub.2).sub.2NH--(CH.sub.2).sub.2- -- >10,000 --
>10,000 50 25 167 CH.sub.2SCH.sub.3 1739 228 40 3.5 77 158
C(Me).sub.2SCH.sub.3 1024 164 30 25 78 159 C(Me).sub.2SEt 852 424
42 12 76 160 C(Me).sub.2SPr 1401 1007 65 15 67 169
CH.sub.2SCH.sub.2-3-Pyridyl 1908 160 28 2.9 77 161
C(Me).sub.2SCH.sub.2-3-Pyridyl 476 130 7.9 6.4 81 168
CH.sub.2SCH.sub.2Ph 1970 141 16 4.5 62 162 C(Me).sub.2SCH.sub.2Ph
310 138 8.3 19 49 163 C(Me).sub.2SCH.sub.2-3-Me-2-imidazole 1719
306 47 18 77 164 C(Me).sub.2S(CH.sub.2).sub.2N[(CH.sub.2).sub.2].s-
ub.2O 1570 204 20 64 70 170 CH.sub.2S(CH.sub.2).sub.10CH.dbd.CHEt
>10,000 1574 322 272 7 165 C(Me).sub.2SCH.sub.2CO.sub.2tBu 2431
587 177 69 84 166 C(Me).sub.2SCH.sub.2CO.sub.2H 1897 2942 241 -- 55
171 C(Me).sub.2S(CH.sub.2).sub.3--OH 2140 -- 36 25 67 172
CH.sub.2S(CH.sub.2).sub.3--OH >1,000 -- 169 11 70
.sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3 .mu.M
[1269]
4TABLE 2 51 Example # R.sub.1 R.sub.2 MMP-1.sup.a MMP-9.sup.a
MMP-13.sup.a TACE.sup.a THP.sup.b 17 H Me 1895 309 99 6.8 33 23 H
CH.sub.2-3-Pyridyl 1156 40 20 7.2 63 124 H
(CH.sub.2).sub.2N[(CH.sub.2).sub.2].sub.2O 1768 211 54 13 24 107 Me
Me 330 68 28 4.5 83 33 Me CH.sub.2-3-Pyridyl 239 65 26 5.0 80 135
Me CH.sub.2CCCH.sub.2N[(CH- .sub.2).sub.2].sub.2NMe 921 142 66 21
76 9 iPr Me 40 11 4.5 7.4 94 108 iPr Et 92 119 67 33 76 109 iPr
CH.sub.2CCH 210 233 53 55 85 110 iPr Pr 196 477 153 66 47 111 iPr
(CH.sub.2).sub.3Ph 308 1423 303 481 35 112 iPr CH.sub.2-o-Pr 189
397 142 57 50 113 iPr CH.sub.2CH(CH.sub.3).sub.2 299 918 309 107 0
123 iPr (CH.sub.2).sub.2N[(CH.sub.2).sub.2].sub.2O 244 628 89 102
35 118 iPr (CH.sub.2).sub.3NEt.sub.2 121 86 45 154 77 119 iPr
(CH.sub.2).sub.3N[(CH.sub.2).sub.2].sub.2O 129 94 46 124 61 120 iPr
(CH.sub.2).sub.3N[(CH.sub.2).sub.2].sub.2NMe 111 211 161 149 61 121
iPr (CH.sub.2).sub.4NEt.sub.2 120 256 114 177 65 122 iPr
(CH.sub.2).sub.4N[(CH.sub.2).sub.2].sub.2NMe 86 135 50 126 69 114
iPr CH.sub.2-3-Pyridyl 236 193 94 93 75 125 iPr
CH.sub.2CCCH.sub.2N[(CH.sub.2).sub.2].sub.2NMe 505 846 151 108 72
126 iPr CH.sub.2CCCH.sub.2NEt.sub.2 212 149 36 73 93 127 iPr
CH.sub.2CCCH.sub.2NHMe 187 53 37 104 83 137 --(CH.sub.2).sub.5--
CH.sub.2-4-Pyridyl 482 79 48 191 0 115 C.sub.8H.sub.11 Me 94 14 6.6
31 89 116 C.sub.8H.sub.11 CH.sub.2-3-Pyridyl 218 336 53 204 75 117
C.sub.8H.sub.11 CH.sub.2PhO(CH.sub.2).sub.2N[(CH.sub.2).sub.2]-
.sub.2NH 74 76 33 274 88 130 C.sub.6H.sub.10-4-OH Me 169 30 15 23
92 136 --(CH.sub.2).sub.5-- Me 682 3753 1629 574 0 128
C.sub.6H.sub.10-4-NEt.sub.2 Me 2368 184 212 376 51 213
(CH.sub.2).sub.3SPh-p-Cl Me 453 -- 9.0 210 87 .sup.aIC.sub.50 (nM)
.sup.bInhibition @ 3 .mu.M
[1270]
5TABLE 3 52 Example # R.sub.2 R.sub.3 MMP-1.sup.a MMP-9.sup.a
MMP-13.sup.a TACE.sup.a THP.sup.b 154 CH.sub.2SCH.sub.3 Me 47 19
5.4 3.3 90 149 C(Me).sub.2SCH.sub.3 Me 17 13 4.6 29 88 150
C(Me).sub.2SEt Me 25 20 9.3 51 86 151 C(Me).sub.2SPr Me 24 31 14 31
82 156 CH.sub.2SCH.sub.2Ph Me 70 11 4.5 4.8 75 157
CH.sub.2SCH.sub.2Ph CH.sub.2-3-Pyridyl 111 32 3.8 98 79 153
C(Me).sub.2SCH.sub.2Ph Me 13 5.5 2.0 160 46 155
CH.sub.2SCH.sub.2-3-Pyridyl Me 61 14 4.8 5.9 93 152
C(Me).sub.2SCH.sub.2-3-Pyridyl Me 8.7 3.7 1.7 74 85 140
C(Me).sub.2S(CH.sub.2).sub.2--N[(CH.sub.2).sub.2].sub.2O Me 45 103
9.2 86 80 141 C(Me).sub.2S(CH.sub.2).sub.2--N[(CH.sub.2).sub.2].su-
b.2NMe Me 17 8.3 7.6 101 86 142
C(Me).sub.2S(CH.sub.2).sub.2--NEt.s- ub.2 Me 72 10 14 131 89 144
C(Me).sub.2S(CH.sub.2).sub.2-1-Imidazol- yl Me 16 26 5.9 60 89 145
C(Me).sub.2S(CH.sub.2).sub.2-NProlineEt Me 18 7.1 2.5 109 83 143
C(Me).sub.2S(CH.sub.2).sub.3--NC.sub.4H.s- ub.8 Me 72 9.5 16 219 88
146 C(Me).sub.2S(CH.sub.2).sub.3--N[(CH.su- b.2).sub.2].sub.2O Me
13 5.3 3.6 132 84 147 C(Me).sub.2S(CH.sub.2).-
sub.3--N[(CH.sub.2).sub.2].sub.2NMe Me 21 5.3 5.3 157 89 148
C(Me).sub.2S(CH.sub.2).sub.3-NEt.sub.2 Me 25 4.8 5.2 88 87
.sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3 .mu.M
[1271]
6TABLE 4 53 Example # X Y R.sub.1 R.sub.2 R.sub.3 MMP-1.sup.a
MMP-9.sup.a MMP-13.sup.a TACE.sup.a THP.sup.b 17 O CH
CH.sub.2CCCH.sub.3 H Me 1895 309 99 8.8 33 133 NH CH CH.sub.2CCH H
Me .about.10,000 1511 751 120 8 134 S CH CH.sub.2CCCH.sub.3 H Me
4948 111 84 38 14 131 O N CH.sub.2CCCH.sub.3 H Me .about.10,000 402
428 29 18 132 O -- CH.sub.2CCPh-4-Cl H Me >10,000 2373 1121 1100
27 .sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3 .mu.M
[1272]
7TABLE 5 54 Example # MMP-1.sup.a MMP-9.sup.a MMP-13.sup.a
TACE.sup.a THP.sup.b 41 121 24 10 7.0 93 .sup.aIC.sub.50 (nM)
.sup.b% Inhibition @ 3 .mu.M
[1273]
8TABLE 6 55 Example # R.sub.1 R.sub.2 MMP-1.sup.a MMP-9.sup.a
MMP-13.sup.a TACE.sup.a THP.sup.b 211 H Me 496 43 20 8.0 -- 176 OH
H .about.10,000 898 103 4.0 89 178 OMe Me 482 43 14 23 91 177
OCH.sub.2CCH H <10,000 310 57 4.8 64 180 O(CH.sub.2).sub.2NHBOC
Me 599 34 9.3 265 89 198 O(CH.sub.2).sub.2NHBOC H .about.10,000 862
139 42 84 201 O(CH.sub.2).sub.2NHAc H .about.10,000 569 73 9.4 77
181 O(CH.sub.2).sub.2NH.sub.2 Me 645 26 24 16 92 200
O(CH.sub.2).sub.2NH.sub.2 H .about.10,000 518 176 15 78 191
O(CH.sub.2).sub.2N(Me)BOC Me 1154 37 60 64 90 192
O(CH.sub.2).sub.2NHMe Me 927 11 27 26 95 203
O(CH.sub.2).sub.2N(Me)BOC H >10,000 859 126 49 73 204
O(CH.sub.2).sub.2NHMe H .about.10,000 349 146 18 73 182
O(CH.sub.2).sub.2NMe.sub.2 Me 487 22 15 16 92 207
O(CH.sub.2).sub.2NMe.sub.2 H >10,000 -- 112 53 51 208
O(CH.sub.2).sub.2-4-Thiazolyl-5-Me H >10,000 -- 230 69 74 212 Cl
Me 798 -- 36 62 86 .sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3
.mu.M
[1274]
9TABLE 7 56 Example # R.sub.1 R.sub.2 MMP-1.sup.a MMP-9.sup.a
MMP-13.sup.a TACE.sup.a THP.sup.b 179
O(CH.sub.2).sub.2N[(CH.sub.2).sub.2].sub.2O Me 546 29 11 52 97 206
O(CH.sub.2).sub.2N[(CH.sub.2).sub.2].sub.2O H >10,000 -- 147 33
70 185 O(CH.sub.2).sub.2N[(CH.sub.2).sub.2].s- ub.2NBOC Me 839 53
27 309 89 188 O(CH.sub.2).sub.2N[(CH.sub.2).sub.- 2].sub.2NH Me 568
32 21 31 93 183 O(CH.sub.2).sub.2NC.sub.4H.sub.8 Me 497 55 42 40 93
205 O(CH.sub.2).sub.2NC.sub.4H.sub.8 H .about.10,000 -- 146 24 66
188 O(CH.sub.2).sub.3NH.sub.2 Me 469 48 41 25 94 187
O(CH.sub.2).sub.3NHBOC Me 910 46 13 199 91 184
O(CH.sub.2).sub.2NC(.dbd.O)C.sub.3H.sub.6 Me 434 55 11 35 94 189
O-3-.beta.-PyrollidineBOC Me 2437 297 120 231 92 190
O-3-.beta.-PyrollidineNH Me 527 37 29 32 94 194
O(CH.sub.2).sub.3NHAc Me 592 -- 15 61 94 197
O(CH.sub.2).sub.3NHSO.sub.2CH.sub.3 Me 569 -- 24 25 94 196
O(CH.sub.2).sub.3NHCO.sub.2CH.sub.2Ph Me 25% @ 1 -- 31 109 87 193
O(CH.sub.2).sub.3NHCO.sub.2Et Me .about.1000 -- 29.3 81 91 198
O(CH.sub.2).sub.3NHCONHPh Me 834 -- 11 62 92 195
O(CH.sub.2).sub.3NHCO.sub.2nBu Me >1000 -- 28 122 90 202
O(CH.sub.2).sub.2N[(CH.sub.2).sub.2].sub.2NBOC H >10,000 345 113
45 209 O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OMe H
.about.10,000 -- 132 39 75 210 O(CH.sub.2).sub.2O(CH.sub.2).sub.2O-
Me H >10,000 -- 278 17 -- .sup.aIC.sub.50 (nM) .sup.b%
Inhibition @ 3 .mu.M
[1275]
10TABLE 8 57 Example # R MMP-1.sup.a MMP-9.sup.a MMP-13.sup.a
TACE.sup.a THP.sup.b 214 H 676 14 7.6 23 71 56 Me 3344 667 158 41
32 233 CH.sub.2Ph-4-Br 2833 69 55 184 33 234 CH.sub.2-3-Py 3197 108
49 28 25 224 Ac 357 88 22 13 81 225 COEt 1002 727 230 17 76 230
COCH.sub.2NH.sub.2 8497 1225 410 127 27 229 COCH.sub.2NHBOC 1009
322 85 64 85 226 CO-2-Thienyl 498 251 119 12 86 228 COOCH.sub.3 201
71 9.2 9.0 81 58 BOC 456 24 17 21 79 215
CON[(CH.sub.2).sub.2].sub.2O 695 60 39 35 51 216 CONEt.sub.2 1752
221 97 28 59 218 CON(iPr).sub.2 3291 822 213 49 56 217
CONC.sub.4H.sub.8 1248 209 83 28 73 227 SO.sub.2CH.sub.3 96 51 6.4
7.3 81 220 CON(Me)Ph 1640 561 62 20 60 231
COCH[(CH.sub.2O).sub.2CH(CH.sub.3).sub.2] 2448 1115 355 59 73 232
COCH(CH.sub.2OH).sub.2 1677 785 289 44 72 221 CONHPh-4-OMe 1511 576
182 69 58 222 CONHPh-4-F 941 173 75 30 61 219 CO.sub.2CH.sub.2Ph
176 45 10 -- 87 223 CONHPh-3,5-Cl 1717 642 153 83 42
.sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3 .mu.M
[1276]
11TABLE 9 58 Example # X R.sub.1 R.sub.2 MMP-1.sup.a MMP-9.sup.a
MMP-13.sup.a TACE.sup.a THP.sup.b 240 O CH.sub.2CCCH.sub.3 H 162
170 26 4.5 80 239 S CH.sub.2CCCH.sub.3 H 148 21 12 2.9 84 258 S
CH.sub.2CCH Me 0.6 -- 0.8 19 91 238, 38 S CH.sub.2CCCH.sub.3 Me 6.6
12 3.0 8.4 94 256 S.dbd.O CH.sub.2CCCH.sub.3 Me 43 145 48 25 92 255
S.dbd.O CH.sub.2CCCH.sub.3 Me 46 29 8.7 24 95 257 SO.sub.2
CH.sub.2CCCH.sub.3 Me 24 64 23 24 91 259 S
CH.sub.2CCCH.sub.2CH.sub.3 Me 5.9 -- 5.0 28 92 40 S
CH.sub.2CC(CH.sub.2).sub.3CH.sub.3 Me 29 7.8 6.6 23 82 236 S
CH.sub.2CCCH.sub.3 --(CH.sub.2).sub.4-- 24 -- 11 43 94 237 S
CH.sub.2CCCH.sub.3 --(CH.sub.2).sub.5-- 62 -- 12 212 90 241 S
CH.sub.2CCCH.sub.3 --(CH.sub.2).sub.2NBn(CH.sub.2).sub.2-- 3.1 --
0.5 786 94 238 S CH.sub.2CCCH.sub.3 Et 38 -- 6.8 228 73 242 S
CH.sub.2CCCH.sub.3 --(CH.sub.2).sub.2NMe(CH.sub.2).sub.2-- -- -- --
869 73 .sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3 .mu.M
[1277]
12TABLE 10 59 Example # R.sub.1 MMP-1.sup.a MMP-9.sup.a
MMP-13.sup.a TACE.sup.a THP.sup.b 254 CH.sub.2CCPh 13 -- 11 173 77
263 CH.sub.2CCCCH 5.7 -- 11 42 88 264 CH.sub.2CCCH.sub.2F 11 -- 2.5
35 94 61 CH.sub.2CCCH.sub.2OH 24 70 13 40 89 260
CH.sub.2CCCH.sub.2OH 33 -- 8.1 20 95 261 CH.sub.2CCCH.sub.2OAc 103
-- 1.1 45 92 247 CH.sub.2CCCH.sub.2OCH.sub.2Ph 53 108 2.5 160 57
265 CH.sub.2CCCH.sub.2NH.sub.2 97 8.7 7.5 87 40 266
CH.sub.2CCCH.sub.2NHBOC 26 31 4.0 74 79 267
CH.sub.2CCCH.sub.2N(Me)BOC 364 1265 37 112 15 244
CH.sub.2CC(CH.sub.2).sub.2OH 35 72 14 62 57 246
CH.sub.2CC(CH.sub.2).sub.2NH.sub.2 1052 41 27 138 4 245
CH.sub.2CC(CH.sub.2).sub.2NHBOC 300 2384 6.6 112 37 243
CH.sub.2CC(CH.sub.2).sub.2OTHP 194 178 4.1 87 52 248
CH.sub.2CC(CH.sub.2).sub.3OTHP 98 48 7.3 92 21 249
CH.sub.2CC(CH.sub.2).sub.3OH 159 377 86 40 51 251
CH.sub.2CC(CH.sub.2).sub.3NH.sub.2 226 28 8.7 28 22 250
CH.sub.2CC(CH.sub.2).sub.3NHBOC 42 160 1.7 153 27 262
CH.sub.2CCCCCH.sub.2OH 9.9 -- 14 39 81 252 CH.sub.2CC(CH.sub.2).su-
b.4NHBOC 87 -- 4.3 199 70 253 CH.sub.2CC(CH.sub.2).sub.4NH.sub.2 92
-- 7.3 40 37 268 CH.sub.2CC(CH.sub.2).sub.4OAc 29 -- 2.9 78 78 269
CH.sub.2CC(CH.sub.2).sub.4OH 101 -- 17 53 77 .sup.aIC.sub.50 (nM)
.sup.b% Inhibition @ 3 .mu.M
[1278]
13TABLE 11 60 Example # R.sub.1 R.sub.2 MMP-1.sup.a MMP-9.sup.a
MMP-13.sup.a TACE.sup.aa THP.sup.b 272 Me(cis) H 7.8 166 8.7 24 92
273 .beta.-CH.sub.2NHBOC H 16 61 9.2 87 90 274
.alpha.-CH.sub.2NHBOC H 24 107 16 59 84 275 .beta.-CH.sub.2NH.sub.2
H 30 22 16 128 82 276 .alpha.-CH.sub.2NH.sub.2 H 21 64 24 57 94 277
.alpha.-CH.sub.2CO.sub.2tBu H 7.8 -- 7.6 234 69 276
.alpha.-CH.sub.2CO.sub.2H H 17 -- 6.7 20 89 280
.alpha.-CH.sub.2CONH.sub.2 H 35 -- 29 42 91 281
.alpha.-CH.sub.2CON(CH.sub.3).sub.2 H 50 -- 23 130 76 282
.alpha.-CH.sub.2CON[(CH.sub.2).sub.2].sub.2O H 25 -- 20 95 91 279
.alpha.-CH.sub.2CONHOH H 21 -- 4.5 46 87 271 H .alpha.-Me 47 -- 88
45 82 270 H .beta.-Me 32 -- 81 86 62 379 C.dbd.C 316 -- 271 16 85
283 .alpha.-CH.sub.2CON[(CH.sub.2).sub.2].sub.2NMe H 28 -- 23 143
90 284 .alpha.-CH.sub.2CONH(CH.sub.2).sub.2NMe.sub.2 H 31 -- 76 125
88 .sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3 .mu.M
[1279]
14TABLE 12 61 Example # R.sub.1 MMP-1.sup.a MMP-9.sup.a
MMP-13.sup.a TACE.sup.a THP.sup.b 49 Ph 362 75 65 17 32
.sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3 .mu.M
[1280]
15TABLE 13 62 Exam- ple # X MMP-1.sup.az MMP-9.sup.a MMP-13.sup.a
TACE.sup.a THP.sup.b 290 NCH.sub.2Ph 287 25 7.5 83 45 292 NH 274 --
33 24 83 293 NMe 238 -- 21 23 82 291 NBOC 92 -- 5.4 74 75 289 NCOPh
113 12 4.0 10 93 294 S +113 +113 -- 13 87 .sup.aIC.sub.50 (nM)
.sup.b% Inhibition @ 3 .mu.M
[1281]
16TABLE 14 63 Example # X n R MMP-1.sup.a MMP-9.sup.a MMP-13.sup.a
TACE.sup.a THP.sup.b 286 S 0 Me 3036 1794 852 20 73 173 S 2 Me 20
-- 16 111 80 174 S 2 H 408 -- 36 20 80 175 SO.sub.2 2 H 1027 -- 50
28 83 .sup.aIC.sub.50 (nM) .sup.b% Inhibition @ 3 .mu.M
[1282]
17TABLE 15 In Vitro Inhibition of TACE 64 Example % Inhibition at 1
uM IC 50 nM 62B 46.2 63 47.6 64 67.4 420 .+-. 50 65 102 398 .+-.
136 66 45.6 67 46.2 68 70.4 885 69 48.5 70 21.1 71 86.7 402 .+-. 55
72 57.4 550 73 79 451 .+-. 31 74 73.8 297 .+-. 119 75 55.8 387 76
29.7 77 105 6.9 .+-. 3.3 78 101 11.8 .+-. 4.6 79 107 5.7 .+-. 2.5
80 105 10.8 .+-. 3.7 81 106 4.99 .+-. 1.1 82 98.4 7.1 83 105 45.1
.+-. 9.5 84 100.7 7.8 .+-. 0.4 85 102 8.3 .+-. 2.7 86 37.5 87 47.8
88 8.4 89 56.8 90 58.9 462 .+-. 58 91 95 328 .+-. 38 92 101.5 490
.+-. 139 93 61.7 546 94 38.2 95 98.6 120 96 22 97 67.5 283 .+-. 42
98 2.5 99 28.5 100 15.4 101 30.2 102 27.3 103 52.8 104 38.5 295
29.3 296 10.9 297 110.9 298 40 299 10.4 300 11 301 24.6 302 3 303
27.4 304 28.9 305 13.4 306 8.7 307 29.4 308 29.5 309 11.4 310 27.9
311 15.7 312 4.7 313 6.3 314 25 315 5.7 316 4 317 6.5 318 11.9 319
10.5 320 7.4 321 4.7 322 11.8 323 17.6 324 14.7 325 6.9 326 58.6
327 5.5 328 6.26 329 6.88 330 3.58 331 5.32 332 5.13 333 4.21 334
4.7 335 6.5 336 6.11 337 4.2 338 3.73 339 4.6 340 6.67 341 4.88 342
4.54 343 3.54 344 5.24 345 4.43 346 4.63 347 3.15 348 6.25 349 9.41
350 6.28 351 9.57 352 4.96 353 6.1 354 5.89 355 12.38 356 9.36 357
14.13 358 8.84 359 9.28 360 4.97 361 6.32 362 4.55 363 3.39 364
7.79 365 14.63 366 106 367 38 368 151 369 14.2 370 2.4 371 377 372
8.4 373 16.9 374 18.2 375 24.6 376 21.9 377 26.5 378 22.8
[1283] 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 TNF-a converting enzyme (TACE) and are therefore
useful in the treatment of disorders such as arthritis, tumor
metastasis, tissue ulceration, abnormal wound healing, periodontal
disease, graft rejection, insulin resistance, bone disease and HIV
infection.
[1284] The compounds of this invention are also useful in treating
or inhibiting pathological changes mediated by matrix
metalloproteinases such as atherosclerosis, atherosclerotic plaque
formation, reduction of coronary thrombosis from atherosclerotic
plaque rupture, restenosis, MMP-mediated osteopenias, inflammatory
diseases of the central nervous system, skin aging, angiogenesis,
tumor metastasis, tumor growth, osteoarthritis, rheumatoid
arthritis, septic arthritis, corneal ulceration, proteinuria,
aneurysmal aortic disease, degenerative cartilage loss following
traumatic joint injury, demyelinating diseases of the nervous
system, cirrhosis of the liver, glomerular disease of the kidney,
premature rupture of fetal membranes, inflammatory bowel disease,
age related macular degeneration, diabetic retinopathy,
proliferative vitreoretinopathy, retinopathy of prematurity, ocular
inflammation, keratoconus, Sjogren's syndrome, myopia, ocular
tumors, ocular angiogenesis/neovascularization and corneal graft
rejection.
[1285] Compounds of this invention may be administered neat or with
a pharmaceutical carrier to a patient in need thereof. The
pharmaceutical carrier may be solid or liquid.
[1286] Applicable solid carriers can include one or more substances
which may also act as flavoring agents, lubricants, solubilizers,
suspending agents, fillers, glidants, compression aids, binders or
tablet-disintegrating agents or an encapsulating material. In
powders, the carrier is a finely divided solid which is in
admixture with the finely divided active ingredient. In tablets,
the active ingredient is mixed with a carrier having the necessary
compression properties in suitable proportions aid compacted in the
shape and size desired. The powders and tablets preferably contain
up to 99% of the active ingredient. Suitable solid carriers
include, for example, calcium phosphate, magnesium stearate, talc,
sugars, lactose, dextrin, starch, gelatin, cellulose, methyl
cellulose, sodium carboxymethyl cellulose polyvinylpyrrolidine, low
melting waxes and ion exchange resins.
[1287] Liquid carriers may be used in preparing solutions,
suspensions, emulsions, syrups and elixirs. The active ingredient
of this invention can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fat. The liquid carrier can contain other suitable
pharmaceutical, additives such a solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers or osmo-regulators. Suitable examples of liquid
carriers for oral and parenteral administration include water
(particularly containing additives as above, e.g., cellulose
derivatives, preferable sodium carboxymethyl cellulose solution),
alcohols (including monohydric alcohols and polyhydric alcohols,
e.g., glycols) and their derivatives, and oils (e.g., fractionate
coconut oil and arachis oil). For parenteral administration the
carrier can also be an oily ester such as ethyl oleate and
isopropyl myristate. Sterile liquid carriers are used in sterile
liquid form compositions for parenteral administration.
[1288] Liquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by, for example,
intramuscular, intraperitoneal or subcutaneous injection. Sterile
solutions can also be administered intravenously. Oral
administration may be either liquid or solid composition form.
[1289] The compounds of this invention may be administered rectally
in the form of a conventional suppository. For administration by
intranasal or intrabronchial inhalation or insufflation, the
compounds of this invention may be formulated into an aqueous or
partially aqueous solution, which can then be utilized in the form
of an aerosol. The compounds of this invention may also be
administered transdermally through the use of a transdermal patch
containing the active compound and a carrier that is inert to the
active compound, is non-toxic to the skin, and allows delivery of
the agent for systemic absorption into the blood stream via the
skin. The carrier may take any number of forms such as creams and
ointments, pastes, gels, and occlusive devices. The creams and
ointments may be viscous liquid or semi-solid emulsions of either
the oil in water or water in oil type. Pastes comprised of
absorptive powders dispersed in petroleum or hydrophilic petroleum
containing the active ingredient may also be suitable. A variety of
occlusive devices may be used to release the active ingredient into
the blood stream such as a semipermeable membrane covering a
reservoir containing the active ingredient with or without a
carrier, or a matrix containing the active ingredient. Other
occlusive devices are known in the literature.
[1290] The dosage to be used in the treatment of a specific patient
suffering MMP or TACE dependent condition must be subjectively
determined by the attending physician. The variables involved
include the severity of the dysfunction, and the size, age, and
response pattern of the patient. Treatment will generally be
initiated with small dosages less than the optimum dose of the
compound. Thereafter the dosage is increased until the optimum
effect under the circumstances is reached for oral, parenteral,
nasal, or intrabronchial administration will be determined by the
administering physician based on experience with the individual
subject treated and standard medical principles.
[1291] Preferably the pharmaceutical composition is in unit dosage
form, e.g., as tablets or capsules. In such form, the composition
is sub-divided in unit dose containing appropriate quantities of
the active ingredient; the unit dosage form can be packaged
compositions, for example packed powders, vials, ampoules,
prefilled syringes or sachets containing 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.
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