U.S. patent application number 10/870839 was filed with the patent office on 2004-11-18 for alkynyl containing hydroxamic acid compounds as matrix metalloproteinase/tace inhibitors.
This patent application is currently assigned to WYETH. Invention is credited to Baker, Jannie L., Chen, James M., Du, Mila T., Levin, Jeremy I., Sandanayaka, Vincent P., Venkatesan, Aranapakam M., Zask, Arie.
Application Number | 20040229924 10/870839 |
Document ID | / |
Family ID | 26852070 |
Filed Date | 2004-11-18 |
United States Patent
Application |
20040229924 |
Kind Code |
A1 |
Levin, Jeremy I. ; et
al. |
November 18, 2004 |
Alkynyl containing hydroxamic acid compounds as matrix
metalloproteinase/TACE inhibitors
Abstract
Compounds of the formula: 1 useful in the treatment of
arthritis, tumor metastasis, tissue ulceration, abnormal wound
healing, periodontal disease, bone disease, diabetes (insulin
resistance) and HIV infection.
Inventors: |
Levin, Jeremy I.; (New City,
NY) ; Venkatesan, Aranapakam M.; (Rekgo Park, NY)
; Chen, James M.; (San Ramon, CA) ; Zask,
Arie; (New York, NY) ; Sandanayaka, Vincent P.;
(Northboro, MA) ; Du, Mila T.; (Suffern, NY)
; Baker, Jannie L.; (Hardeeville, SC) |
Correspondence
Address: |
WYETH
PATENT LAW GROUP
5 GIRALDA FARMS
MADISON
NJ
07940
US
|
Assignee: |
WYETH
|
Family ID: |
26852070 |
Appl. No.: |
10/870839 |
Filed: |
June 17, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10870839 |
Jun 17, 2004 |
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10029655 |
Dec 21, 2001 |
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6753337 |
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10029655 |
Dec 21, 2001 |
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09492686 |
Jan 27, 2000 |
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6358980 |
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60155184 |
Jan 27, 1999 |
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Current U.S.
Class: |
514/357 ;
514/408; 514/517; 514/575; 546/336; 548/577; 558/414; 562/623 |
Current CPC
Class: |
A61K 31/351 20130101;
A61K 31/445 20130101; A61K 31/496 20130101; C07D 309/08 20130101;
A61K 31/435 20130101; C07D 211/60 20130101; C07D 211/66 20130101;
C07D 211/62 20130101 |
Class at
Publication: |
514/357 ;
514/575; 562/623; 514/408; 514/517; 558/414; 546/336; 548/577 |
International
Class: |
A61K 031/445; C07D
213/56; A61K 031/44; A61K 031/255 |
Claims
1. A compound of formula 29wherein: R.sub.1 is hydrogen, aryl,
heteroaryl, alkyl of 1-8 carbon atoms, alkenyl of 2-6 carbon atoms,
alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, or
--C.sub.4-C.sub.8-cycloheteroalkyl; R.sub.2 and R.sub.3 are each,
independently, hydrogen, alkyl of 1-6 carbon atoms, --CN, or --CCH;
R.sub.7 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl,
alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of
1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, --C(O)--R.sub.1,
--SO.sub.2--R.sub.1, --C(O)--NHR.sub.1, --C(O)--NR.sub.5R.sub.6,
--C(O)R.sub.1NR.sub.5R.sub.6, --C(O)--OR.sub.1, or
--C(NH)--NH.sub.2; R.sub.5 and R.sub.6 are each independently,
hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon
atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or
--C.sub.4-C.sub.8-cycloheteroalkyl; R.sub.8 and R.sub.9, together
with the carbon atom or atoms to which they are attached, form a
--C.sub.4-C.sub.8-cycloheteroalkyl ring which is 30 wherein K is O,
S or NR.sub.7 and R.sub.7 is as defined hereinabove; R.sub.10 and
R.sub.11 are each, independently, hydrogen, aryl heteroaryl,
cycloalkyl of 3-6 carbon atoms, --C.sub.4-C.sub.8-cycloheteroalkyl,
alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, or
alkynyl of 2-18 carbon atoms; R.sub.12 is hydrogen, aryl,
heteroaryl, cycloalkyl of 3-6 carbon atoms,
--C.sub.4-C.sub.8-cycloheteroalkyl, or alkyl of 1-6 carbon atoms; A
is O, S, SO, SO.sub.2, NR.sub.7, or CH.sub.2; X is O, S, SO,
SO.sub.2, NR.sub.7, or CH.sub.2; Y is aryl or heteroaryl, with the
proviso that A and X are not bonded to adjacent atoms of Y; and n
is 0-2; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein Y is phenyl, pyridyl, thienyl,
furanyl, imidazolyl triazolyl, thiadiazolyl.
3. (Canceled).
4. A method of inhibiting pathological changes mediated by
TNF-.alpha. converting enzyme (TACE) in a mammal in need thereof
which comprises administering to said mammal a therapeutically
effective amount of a compound having the formula 31wherein:
R.sub.1 is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon atoms,
alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,
cycloalkyl of 3-6 carbon atoms, or
--C.sub.4-C.sub.8-cycloheteroalkyl; R.sub.2 and R.sub.3 are each,
independently, hydrogen, alkyl of 1-6 carbon atoms, --CN, or --CCH;
R.sub.7 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl,
alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of
1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, --C(O)--R.sub.1,
--SO.sub.2--R.sub.1, --C(O)--NHR.sub.1, --C(O)--NR.sub.5R.sub.6,
--C(O)R.sub.1NR.sub.5R.sub.6, --C(O)--OR.sub.1, or
--C(NH)--NH.sub.2; R.sub.5 and R.sub.6 are each, independently,
hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon
atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or
--C.sub.4-C.sub.8-cycloheteroalkyl; R.sub.8 and R.sub.9, together
with the carbon atom or atoms to which they are attached, form a
--C.sub.4-C.sub.8-cycloheteroalkyl ring which is 32 wherein K is O,
S or NR.sub.7 and R.sub.7 is as defined hereinabove; R.sub.10 and
R.sub.11 are each, independently, hydrogen, aryl heteroaryl,
cycloalkyl of 3-6 carbon atoms, --C.sub.4-C.sub.8-cycloheteroalkyl,
alkyl of 1-18 carbon atoms, alkenyl of 2-18 carbon atoms, or
alkynyl of 2-18 carbon atoms; R.sub.12 is hydrogen, aryl
heteroaryl, cycloalkyl of 3-6 carbon atoms,
--C.sub.4-C.sub.8-cycloheteroalkyl, or alkyl of 1-6 carbon atoms; A
is O, S, SO, SO.sub.2, NR.sub.7, or CH.sub.2; X is O, S, SO,
SO.sub.2, NR.sub.7, or CH.sub.2; Y is aryl or heteroaryl, with the
proviso that A and X are not bonded to adjacent atoms of Y; and n
is 0-2; or a pharmaceutically acceptable salt thereof.
5. The method of claim 4 wherein the condition treated is
rheumatoid arthritis, graft rejection, cachexia, inflammation,
fever, insulin resistance, septic shock, congestive heart failure,
inflammatory disease of the central nervous system, inflammatory
bowel disease or HIV infection.
6. A pharmaceutical composition comprising a compound having the
formula 33wherein: R.sub.1 is hydrogen, aryl, heteroaryl, alkyl of
1-8 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6
carbon atoms, cycloalkyl of 3-6 carbon atoms, or
--C.sub.4-C.sub.8-cycloheteroalkyl; R.sub.2 and R.sub.3 are each,
independently, hydrogen, alkyl of 1-6 carbon atoms, --CN, or --CCH;
R.sub.7 is hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl,
alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of
1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, --C(O)--R.sub.1,
--SO.sub.2--R.sub.1, --C(O)--NHR.sub.1, --C(O)--NR.sub.5R.sub.6,
--C(O)R.sub.1NR.sub.5R.sub.6, --C(O)--OR.sub.1, or
--C(NH)--NH.sub.2; R.sub.5 and R.sub.6 are each, independently,
hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon
atoms, aryl, aralkyl, heteroaryl, heteroaralkyl or
--C.sub.4-C.sub.8--cycloheter- oalkyl; R.sub.8 and R.sub.9,
together with the carbon atom or atoms, to which they are attached,
form a --C.sub.4-C.sub.8-cycloheteroalkyl ring which is 34 wherein
K is O, S or NR.sub.7 and R.sub.7 is as defined hereinabove;
R.sub.10 and R.sub.11 are each, independently, hydrogen, aryl
heteroaryl, cycloalkyl of 3-6 carbon atoms,
--C.sub.4-C.sub.8-cycloh- eteroalkyl, alkyl of 1-18 carbon atoms,
alkenyl of 2-18 carbon atoms, or alkynyl of 2-18 carbon atoms;
R.sub.12 is hydrogen, aryl heteroaryl, cycloalkyl of 3-6 carbon
atoms, --C.sub.4-C.sub.8-cycloheteroalkyl, or alkyl of 1-6 carbon
atoms; A is O, S, SO, SO.sub.2, NR.sub.7, or CH.sub.2; X is O, S,
SO, SO.sub.2, NR.sub.7, or CH.sub.2; Y is aryl or heteroaryl, with
the proviso that A and X are not bonded to adjacent atoms of Y; and
n is 0-2; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 2 wherein the cycloheteroalkyl ring formed
by R.sub.8 and R.sub.9 is selected from the group consisting of
piperidine, piperazine, morpholine, tetrahydropyran,
tetrahydrofuran and pyrrolidine.
8. The compound of claim 7 wherein K is NR.sub.7.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/155,184, filed Jan. 27, 1999.
FIELD OF INVENTION
[0002] This invention relates to acetylenic 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,
osteoarthritis, sepsis, AIDS, ulcerative colitis, multiple
sclerosis, Crohn's disease and degenerative cartilage loss.
BACKGROUND OF THE INVENTION
[0003] Matrix metalloproteinases (MMPs) are a group of enzymes that
have been implicated in the pathological destruction of connective
tissue and basement membranes. These zinc containing endopeptidases
consist of several subsets of enzymes including collagenases,
stromelysins and gelatinase. Of these classes, the gelatinases have
been shown to be the MMPs most intimately involved with the growth
and spread of tumors. It is known that the level of expression of
gelatinase is elevated in malignancies, and that gelatinase can
degrade the basement membrane which leads to tumor metastasis.
Angiogenesis, required for the growth of solid tumors, has also
recently been shown to have a gelatinase component to its
pathology. Furthermore, there is evidence to suggest that
gelatinase is involved in plaque rupture associated with
atherosclerosis. Other conditions mediated by MMPs are restenosis,
MMP-mediated osteopenias, inflammatory diseases of the central
nervous system, skin aging, tumor growth, osteoarthritis,
rheumatoid arthritis, septic arthritis, corneal ulceration,
abnormal wound healing, bone disease, proteinuria, abysmal aortic
disease, degenerative cartilage loss following traumatic joint
injury, demyelinating diseases of the nervous system, cirrhosis of
the liver, glomerular disease of the kidney, premature rupture of
fetal membranes, inflammatory bowel disease, periodontal disease,
age related macular degeneration, diabetic retinopathy,
proliferative vitreoretinopathy, retinopathy of prematurity, ocular
inflammation, keratoconus, Sjogren's syndrome, myopia, ocular
tumors, ocular angiogenesis/neovascularization and corneal graft
rejection. For recent reviews, see: (1) Recent Advances in Matrix
Metalloproteinase Inhibitor Research, R P. Beckett, A. F Davidson,
A H. Drummond, P. Huxley and M Whittaker, Research Focus, Vol. 1,
16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3)
Curr. Medicinal to Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther.
Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995)
5(12): 1287-1196: (6) Exp. Opin. Ther. Patents (1998) 8(3):
281-259.
[0004] 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, 3. M; Brahn, E. J.
Women's Health 17, 6(6), 627; Isomaki, P.; Punnonen, J. Ann. Met
1997, 29, 499; Camussi, G.; Lupia, E. Drugs, 1998, 55(5), 613.1
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. E; 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. antibodies 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.
[0005] 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.
[0006] Sulfone hydroxamic acid inhibitors of MMPs, of general
structure I have been disclosed [Burgess, L. E.; Rizzi, J. P.;
Rawson, D. J. Eur Patent Appl. 818442. Groneberg, R. D.;
Neuenschwander, K. W.; Djuric, S. W.; McGeehan, G. M.; Burns, C.
J.; Condon, S. M.; Morrossette, M. M.; Salvino, J. M.; Scotese, A.
C.; Ullrich, J. W. PCT Int. Appl. WO 97/24117. Bender, S. L.;
Broka, C. A.; Campbell, JA; Castelhano, A. L.; Fisher, L. E.;
Hendricks, R. T.; Sarma, K. Eur. Patent Appl. 780386. Venkatesan A.
M.; Grosu, G. T.; Davis, J. M.; Hu, B.; O'Dell, M. J. PCT Int.
Appl. WO 98/38163.]. An exemplification of this class of MMP
inhibitor is RS-130830, shown below. 2
[0007] Within the sulfone-hydroxamic acid class of MMP inhibitor,
the linker between the sulfone and hydroxamic acid moieties has
been extended to three carbons (I, n=2) without significant loss in
potency [Barta, T. E.; Becker, D. P.; Villamil, C. I.; Freskos, J.
N.; Mischke, B. V.; Mullins, P. B.; Heintz, R K; Getman, D. P.;
McDonald, J. L PCT Int. Appl. WO 98/39316. McDonald, J. J.; Barta,
T. E.; Becker, D. P.; Bedell L. L; Rao, S. N.; Freskos, J. N.;
Mischke, B. V. PCT Int. Appl. WO 98/38859.].
[0008] Piperidine sulfone hydroxamic acids, II (n=1) have been
reported [Becker, D. P.; Villamil, C. I.; Boehm, T. L.; Getman, D.
P.; McDonald, J. J.; DeCrescenzo, G. A. PCT Is Appl. WO 98/39315.].
Similar piperidine derivatives in which the methylene linking the
piperidine ring to the sulfone has been deleted (E, n=0) have been
reported [Venkatesan. A. M.; Grosu, G. T.; Davis, J. M.; Baker, J.
L. PCT Int. Appl. WO 98/37877.]. 3
[0009] Sulfone-hydroxamic acids III, in which a hydroxyl group has
been placed alpha to the hydroxamic acid, have been disclosed
[Freskos, J. N.; Boehm, T. L.; Mischke, B. V.; Heintz, R. M;
McDonald, J. J.; DeCrescenzo, G. A.; Howard, S. C. PCT Int. Appl.
WO 98/39326. Robinson, R. P. PCT Int. Appl. WO 98/34915.]. 4
[0010] Sulfone-based MMP inhibitors of general structure IV, which
utilize a thiol as the zinc chelator, have been reported [Freskos,
J. N.; Abbas, Z. S.; DeCrescenzo, G. A.; Getman, D. P.; Heintz, R.
M.; Mischke, B. V.; McDonald, J. J. PCT Int. Appl. WO 98/03164].
5
[0011] Inhibitors of stromelysin with general structure V have been
disclosed [Shuker S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S.
W. Science, 1996, 274, 1531-1534. Hajduk, P. J.; Sheppard, G.;
Nettesheim, D. G.; Olejniczak E. T.; Shuker, S. B.; Meadows, R. P.;
Steinman D. H.; Carrera, Jr., G. M.; Marcotte, P. A.; Severin, J.;
Walter, K; Smith, H.; Gubbins, E.; Simmer, R.; Holzman, T. F.;
Morgan, D. W.; Davidsen, S. K.; Summers, J. B.; Fesik, S. W. J. Am.
Chem. Soc. 1997, 119, 5818-5827. Olejniczak, E. T.; Hajduk, P. J.;
Marcotte, P. A.; Nettesheim, D. G.; Meadows, R. P.; Edalji R.;
Holzman, T. F.; Fesik, S. W. J. Am. Chem. Soc. 1997, 119,
5828-5832. Fesik, S. W.; Summers, J. B.; Davidsen, S. K.; Sheppard,
G. S.; Steinman, D. H; Carrera, G. M; Flodjancic, A.; Holms, J. H.
PCT Int. Appl. WO 97/18188.]. 6
[0012] Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some
aryl substituted thio and aryl substituted sulfonyl acetohydroxamic
acid derivatives of general formula 1. These compounds were
prepared to study the Mannich reaction. Subsequently, they were
tested for their fungicidal activity. 7
[0013] Some sulfone carboxylic acids are disclosed in U.S. Pat. No.
4,933,367. Those compounds were shown to exhibit hypoglycemic
activity.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The present invention relates to novel, low molecular
weight, non-peptide inhibitors of matrix metalloproteinases (MMPs)
and TNF-converting enzyme TACE) for the treatment of arthritis,
tumor metastasis, tissue ulceration, abnormal wound healing,
periodontal disease, bone disease, diabetes (insulin resistance)
and HIV infection.
[0015] In accordance with this invention there is provided a group
of compounds of general formula I: 8
[0016] wherein:
[0017] R.sub.1 is hydrogen, aryl, heteroaryl, alkyl of 1-8 carbon
atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,
cycloalkyl of 3-6 carbon atoms, or
--C.sub.4-C.sub.8-cycloheteroalkyl;
[0018] R.sub.2 and R.sub.3 are each, independently, hydrogen, alkyl
of 1-6 carbon atoms, --CN, or --CCH;
[0019] R.sub.7 is hydrogen, aryl, aralkyl, heteroaryl,
heteroaralkyl, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon
atoms, alkynyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms,
--C(O)--R.sub.1, --SO.sub.2--R.sub.1, --C(O)--NHR.sub.1,
--C(O)--NHR.sub.5R.sub.6, --C(O)R.sub.1NR.sub.5R.sub.6,
--C(O)--OR.sub.1, --C(NH)--NH.sub.2.
[0020] R.sub.8, R.sub.9, R.sub.10 and R.sub.11 are each,
independently, hydrogen, aryl or heteroaryl, cycloalkyl of 3-6
carbon atoms, --C.sub.4-C.sub.8-cycloheteroalkyl, alkyl of 1-18
carbon atoms, alkenyl of 2-18 carbon atoms, alkynyl of 2-18 carbon
atoms; with the proviso that one of the pairs R8 and R9, R9 and R10
or R10 and R11, together with the carbon atom or atoms to which
they are attached, form a cycloalkyl ring of 3-6 carbon atoms, or a
C.sub.4-C.sub.8-cycloheteroalkyl ring;
[0021] R.sub.12 is hydrogen, aryl or heteroaryl, cycloalkyl of 3-6
carbon atoms, --C.sub.4-C.sub.8-cycloheteroalkyl, or alkyl of 1-6
carbon atoms;
[0022] A is O, S, SO, SO.sub.2, NR.sub.7, or CH.sub.2;
[0023] X is O, S, SO, SO.sub.2, NR.sub.7, or CH.sub.2;
[0024] Y is aryl or heteroaryl, with the proviso that A and X are
not bonded to adjacent atoms of Y; and
[0025] n is 0-2; or a pharmaceutically acceptable salt thereof.
[0026] In some preferred aspects of the invention, y is phenyl,
pyridyl, thienyl, furanyl, imidazolyl, triazolyl or thiadiazolyl,
with the proviso that A and X are not bonded to adjacent atoms of
Y.
[0027] In still other preferred embodiments of the invention Y is
phenyl, thienyl or furanyl.
[0028] In accordance with certain preferred embodiments of the
invention R.sub.8 and R.sub.9, together with the carbon atom to
which they are attached form a C.sub.4-C.sub.8 cycloheteroalkyl
ring and K is NR.sub.7.
[0029] The most preferred matrix metalloproteinase and TACE
inhibiting compounds of this invention are:
[0030]
1-(4-Bromo-benzyl-4-(4-but-2-ynyxoy-benzenesulfonyl)-piperdine-4-ca-
rboxylic acid hydroxyamide;
[0031]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine--
4-carboxylic acid hydroxyamide;
[0032]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl-piperdine-4--
carboxylic acid hydroxyamide;
[0033]
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic
acid hydroxamide;
[0034]
1-(4-Bromo-benzyl)4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4
carboxylic acid hydroxyamide;
[0035] 1-(4-Bromo-benzyl)
4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-- carboxylic acid
hydroxyamide;
[0036]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperdine-4-
-carboxylic acid hydroxyamide;
[0037]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-
-carboxylic acid hydroxamide;
[0038]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine
carboxylic acid hydroxamide;
[0039]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperid-
ine-4 carboxylic acid hydroxamide;
[0040]
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine
carboxylic acid hydroxyamide;
[0041]
(4-Bromo-benzyl)-4-[4-(4-piperdine-but-2-ynyloxy)benzenesulfonyl]-p-
iperdine-4-carboxylic acid hydroxyamide;
[0042]
1-(4-Bromo-benzyl)[4-(4-morpholin-yl-but-2-ynyloxy)benzenesulfonyl]-
-piperdine-4-carboxylic acid hydroxyamide;
[0043]
4-(4-But-2-ynyloxy-phenylsulfanyl)-hydroxycarbamoyl-piperidine-1-ca-
rboxylic acid tert-butyl ester;
[0044] 4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic
acid hydroxyamide;
[0045]
1-(4-Bromo-benzyl-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4-car-
boxylic acid hydroxyamide;
[0046]
(4-But-2-ynyloxy-phenylsufanylmethyl)-tetrahydro-pyran-4-carboxylic
acid hydroxyamide;
[0047]
4-(But-2-ynyloxy-benzenesulfonylmethyl)-tetrahydro-pyran-4-carboxyl-
ic acid hydroxyamide;
[0048]
4-(4-But-2-ynyloxy-benzenesulfinylmethyl)-tetrahydro-pyran-4-carbox-
ylic acid hydroxyamide;
[0049]
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxytetrahydro-2H-pyran
carboxamide;
[0050]
1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperdine
carboxamide;
[0051]
4-{[4-(2-butynyloxy)phenyl]sulfonyl)-N-hydroxy-1-isopropyl-4-piperi-
dine carboxamide;
[0052]
1-([4-(2-butynyloxy)phenyl]sulfonyl)-N-hydroxy-1-(3-pyridinylmethyl-
)-4 piperidine carboxamide;
[0053]
3-{[4-(2-Butynyloxy)phenyl]sulfonyl)-1-ethyl-N-hydroxy-3-piperidine-
carboxamide,
[0054]
3-([4-2-butynyloxy)phenyl]sulfonyl)-1{4-chlorobenzyl-N-hydroxy-3-pi-
peridinecarboxamide;
[0055]
4-([4-(2-Butynyloxy)phenyl]sulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-
-benzyl]-piperidine-4-carboxylic acid hydroxyamide;
[0056]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-(3-pentanyl)-piperidine-4-ca-
rboxylic acid hydroxyamide;
[0057]
1-(4-Chloro-benzyl-4-(4-prop-2-ynyloxy-benzenesulfonyl)piperidine-4-
-carboxylic acid hydroxyamide;
[0058]
tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}methyl)-4-[(hydroxy-
amino) carbonyl]-1-piperidinecarboxylate;
[0059]
4-({[4-(But-2-ynyloxy)phenyl]thio}methyl-N-hydroxypiperidine-4-carb-
oxamide;
[0060]
tert-Butyl-4-({[4-(2-butynyloxy)phenyl]sulfinyl}methyl)-4-[(hydroxy-
amino)-carbonyl]-1-piperidinecarboxylate;
[0061]
4-[[[4-2-Butynyloxy)phenyl]sulfinyl]methyl]-N-hydroxy-4-piperidine--
carboxamide;
[0062]
tert-Butyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydrox-
yamino)-carbonyl]piperidine-1-carboxylate;
[0063]
tert-butyl-4-{[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4[(hydroxyam-
ino)-carbonyl]-1-piperidinecarboxylate;
[0064]
1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4-p-
iperidinecarboxamide;
[0065]
1-(2-Butynyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydrox-
y-4 piperidinecarboxamide hydrochloride;
[0066]
N-1-(tert-Butyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-h-
ydroxy-1,4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1,4-1]sulf-
onyl}methyl)-N-4-hydroxy-1,4-piperinedicarboxamide;
[0067] Methyl
4{([4-(2-butynyloxy)phenyl]sulfonyl)methyl)-4-[(hydroxyamino-
)carbonyl]-1-piperidinecarboxylate;
[0068] Benzyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamin-
o)carbonyl]-1-piperidinecarboxylate;
[0069]
1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-b-
utynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide;
[0070]
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl-N-hydroxy-1-[(2,2,5-tri-
methyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide;
[0071]
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[3-hydroxy-
-2-(hydroxymethyl)-2-methylpropanoyl]-4-piperidinecarboxamide;
[0072]
1-[Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-
-N-hydroxy)-4-1]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4--
oxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide;
[0073]
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-
-2-butynyl-phenyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)-4-pip-
eridinecarboxamide;
[0074]
4-({[4-But-2-ynyloxy)phenyl]sulfonyl}methyl)-1-N-hydroxypiperidine--
4-carboxamide triflouroacetic acid salt;
[0075] 2
chloro-5{chloromethyl)thiophene-4-({[4-(But-2-ynyloxy)phenyl]-sul-
fonyl}methyl)-1-[(5-chlorothien-2-yl)methyl]-N-hydroxypiperidine-4-carboxa-
mide triflouroacetic acid salt;
[0076]
4-({([4-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-pyridin-4-ylm-
ethyl)piperidin carboxamide triflouroacetic acid salt;
[0077]
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl}N-hydroxy-4-pyridin-3
ylcarbonyl)piperidine carboxamide triflouroacetic acid salt;
[0078]
1-Benzoyl-4-({[4{but-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxypip-
eridine-4-carboxamide;
[0079]
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(thien-2--
ylcarbonyl)piperidine carboxamide;
[0080] 4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-1-methyl-N
4-hydroxy piperidine-1,4-dicarboxamide;
[0081]
4-{[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1-phenyl-
piperidine-1,4-dicarboxamide;
[0082] 4
([{-(But-2-ynyloxy)phenyl]sulfonyl}methyl-N-1-N-1-diethyl-N-4-hyd-
roxypiperdine-1,4-dicarboxamide;
[0083]
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(morpholi-
n-4-ylcarbonyl)piperdine-4-carboxamide;
[0084]
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1-methy-
l-N-1-phenylpiperidine-1,4-dicarboxamide;
[0085]
Octyl-4-({[4-but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino-
)-carbonyl]piperidine-1-carboxylate;
[0086]
4-Methoxyphenyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(h-
ydroxyamino) carbonyl]piperidine-1-carboxylate;
[0087]
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(phenylsu-
lfonyl) piperidine-4-carboxamide;
[0088]
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(1-methy-
l-1H-imidazol-4-yl)sulfonyl]piperidine-4-carboxamide;
[0089]
1-[2-Benzylamino)acetyl]-4-({[4-but-2-ynyloxy)phenyl]sulfonyl}methy-
l)-N-hydroxypiperidine-4-carboxamide;
[0090]
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(2-morpho-
lin-4-ylacetyl)piperidine carboxamide;
[0091] 4-({[4
(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[2-(4-met-
hylpiperazin-1-yl)acetyl]piperidine-4-carboxamide;
[0092]
1-Acetyl-4-(but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic
acid hydroxamide;
[0093]
1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic
acid hydroxamide;
[0094] 1-(4-Methoxybenzoyl)-4-(but-2-ynyloxy
benzenesulfonyl)piperidine-4-- carboxylic acid hydroxamide;
[0095]
4-(4-But-2-ynloxybenzenesulfonyl)-N-hydroxy-1-(pyrrolidine-1-carbon-
yl)-4-piperidinecarboxamide;
[0096] Ethyl
4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-
-1-piperidinecarboxylate;
[0097]
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl)su-
lfonyl]-4-piperidinecarboxamide;
[0098]
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl-
)-4-piperidinecarboxamide;
[0099]
4-4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-2-thienylcarbonyl)-4--
piperidinecarboxamide;
[0100]
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl)-s-
ulfonyl]-4-piperidinecarboxamide;
[0101]
4-4-but-2-ynyloxybenzenesulfonyl-N-hydroxy-1-[(2,2,5-trimethyl-1,3--
dioxan-5-yl)carbonyl]4-piperdinecarboxamide;
[0102]
Tert-butyl-4-{[4-2-butynyloxy)phenyl]sulfonyl)}[(hydroxyamino)carbo-
nyl]-1-piperidinecarboxalate;
[0103]
4-{([4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperidinecarboxa-
mide hydrochloride;
[0104]
Methyl({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbo-
nyl]-1-piperidinyl}methyl)benzoate hydrochloride;
[0105]
4-({4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxyamino)carbonyl]-
-1-piperidinyl}methyl)benzoic acid hydrochloride;
[0106]
1-[4-(Aminocarbonyl)benzyl]-4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N--
hydroxy-4-piperidinecarboxamide hydrochloride;
[0107] Tert-butyl
4-{[4-(but-2-ynyloxy)phenyl]sulfinyl}-4-[(hydroxyamino)--
carbonyl]piperidine-1-carboxalate;
[0108] 4-(4-But-2-ynyloxy-benzenesulfinyl)-piperidin-4-carboxylic
acid hydroxamide hydrochloride; and
[0109]
1-(4-Bromo-benzyl)-4-(4-But-2-ynyloxy-benezenesulfinyl)-piperidine--
4-carboxylic acid hydroxamide hydrochloride;
[0110] and pharmaceutical salts thereof.
[0111] Heteroaryl, as used throughout, is a 5-10 membered mono- or
bicyclic aromatic ring having from 1-3 heteroatoms selected from N,
NR7, S and O.
[0112] Heteroaryl is preferably 9
[0113] wherein K is defined as O, S or --NR.sub.7, and R.sub.7 is
hydrogen, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl of 1-6
carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 1-6 carbon
atoms, cycloalkyl of 3-6 carbon atoms, --C(O)--R.sub.1,
--SO.sub.2--R.sub.1, --C(O)--NHR.sub.1, --C(O)--NR.sub.5R.sub.6,
--C(O)R.sub.1, NR.sub.5R.sub.6, --C(O)--OR.sub.1,
--C(NH)--NH.sub.2.
[0114] Preferred heteroaryl rings include pyrrole, furan,
thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole,
pyrazole, imidazole, isothiazole, thiazole, isoxazole, oxazole,
indole, isoindole, benzofuran, benzothiophene, quinoline,
isoquinoline, quinoxaline, quinazoline, benzotriazole, indazole,
benzimidazole, benzothiazole, benzisoxazole, and benzoxazole.
Heteroaryl groups of the present invention may be mono or
disubstituted
[0115] --C.sub.4-C.sub.8-cycloheteroalkyl is defined as 10
[0116] wherein K is O, S or NR7 and R7 is as defined before.
Preferred heterocycloalkyl rings include piperidine, piperazine,
morpholine, tetrahydropyran, tetrahydrofuran or pyrrolidine.
Heterocycloalkyl groups of the present invention may optionally be
mono- or di-substituted.
[0117] Aryl, as used herein refers to phenyl or naphthyl aromatic
rings which may, optionally be mono- or di-substituted.
[0118] Alkyl, alkenyl, alkynyl, and perfluoroalkyl include both
straight chain as well as branched moieties. Alkyl, alkenyl,
alkynyl, and cycloalkyl groups may be unsubstituted (carbons bonded
to hydrogen, or other carbons in the chain or ring) or may be mono-
or poly-substituted.
[0119] Aralkyl as used herein refers to a substituted alkyl group,
-alkyl-aryl wherein alkyl is lower alkyl and preferably from 1-3
carbon atoms, and aryl is as previously defined.
[0120] Heteroaralkyl as used herein refers to a substituted alkyl
group, alkyl-heteroaryl wherein alkyl is lower alkyl and preferably
from 1-3 carbon atoms, and heteroaryl is as previously defined.
[0121] Halogen means bromine, chlorine, fluorine, and iodine.
[0122] Suitable substituents of aryl, aralkyl, heteroaryl,
heteroaralkyl, alkyl, alkenyl, alkynyl and cycloalkyl include, but
are not limited to halogen, alkyl of 1-6 carbon atoms; alkenyl of
2-6 carbon atoms; alkynyl of 2-6 carbon atoms, cycloalkyl of 3-6
carbon atoms, --OR.sub.5, .dbd.O, --CN, --COR.sub.5, perfluoroalkyl
of 1-4 carbon atoms, --O-perfluoroalkyl of 1-4 carbon atoms,
--CONR.sub.5R.sub.6, --S(O).sub.nR.sub.5, --OPO(OR.sub.5)OR.sub.6,
--PO(OR.sub.5)R.sub.6, --OC(O)OR.sub.5, --OR.sub.5NR.sub.5R.sub.6,
--OC(O)--NR.sub.5R.sub.6, --C(O)--NR.sub.5OR.sub.6, --COOR.sub.5,
--SO.sub.3H, --NR.sub.5R.sub.6,
--N[(CH.sub.2).sub.2].sub.2NR.sub.5, --NR.sub.5COR.sub.6,
--NR.sub.5COOR.sub.6, --SO.sub.2NR.sub.5R.sub.6, --NO.sub.2,
--N(R.sub.5)SO.sub.2R.sub.6, --NR.sub.5CONR.sub.5R.sub.6,
--NR.sub.5C(.dbd.NR.sub.6)--NR.sub.5R.sub.6,
--NR.sub.5C(.dbd.NR.sub.6)--- N(SO2R.sub.5)R.sub.6,
--NR.sub.5C(.dbd.NR.sub.6)--N(C.dbd.OR.sub.5)R.sub.6- ,
-tetrazol-5-yl, --SO.sub.2NHCN, --SO.sub.2NHCONR.sub.5R.sub.6,
phenyl, heteroaryl or --C.sub.4-C.sub.8-cycloheteroalkyl;
[0123] wherein --NR.sub.5R.sub.6 may form a pyrrolidine,
piperidine, morpholine, thiomorpholine, oxazolidine, thiazolidine,
pyrazolidine, piperazine, or azetidine ring;
[0124] R.sub.5 and R.sub.6 are each, independently, hydrogen, alkyl
of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl aralkyl
heteroaryl, heteroaralkyl or
--C.sub.4-C.sub.8-cycloheteroalkyl;
[0125] R.sub.7 is hydrogen, aryl heteroaryl, alkyl of 1-6 carbon
atoms or cycloalkyl of 3-6 carbon atoms, --C(O)--R.sub.1,
--SO.sub.2--R.sub.1, --C(O)--NHR.sub.1, --C(O)--OR.sub.1,
C(NH)--NH.sub.2; and n is 0-2.
[0126] When a moiety contain more than substituent with the same
designation each of those substituents may be the same or
different.
[0127] 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.
[0128] 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 steamers substantially free of
the other are disclosed and claimed as well.
[0129] 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 metastasis, tissue ulceration, abnormal wound healing,
periodontal disease, graft rejection, insulin resistance, bone
disease and HIV infection. In particular, the compounds of the
invention provide enhanced levels of inhibition of the activity of
TACE in vitro and in cellular assay and/or enhanced selectivity
over MMP-1 and are thus particularly useful in the treatment of
diseases mediated by TNF.
[0130] Also according to the present invention, there are provided
processes for producing the compounds of the present invention.
Process of the Invention
[0131] The compounds of the present invention may be prepared
according to one of the general processes outlined below.
[0132] The compounds of the present invention, where n=0, X=O, S,
or NR.sup.7, and R.sup.8 and R.sup.9 taken with the carbon atom to
which they are attached, form a six membered heterocyclic ring
containing N--R.sup.7, S or O and A=S, SO or SO.sub.2 may be
prepared according to one of the general processes outlined
below.
[0133] As outlined in scheme 1, the appropriately substituted
mercaptan derivative was alkylated using .alpha.-bromo acetic acid
ester derivative in refluxing chloroform using
N,N-disopropylethylamine as base. The sulfide derivative thus
obtained was reacted with appropriately substituted propargyl
bromide derivative in refluxing acetone using K.sub.2CO.sub.3 as
base. In the case of X=--N--R.sup.7 the N-alkylation can be carried
out in DMF/NaH at room temperature. The sulfide derivative thus
obtained was oxidized using m-chloroperbenzoic acid in
CH.sub.2Cl.sub.2 or by using Oxone in methanol/water. The sulfone
thus obtained can be converted to the corresponding piperidine
derivative by reacting it with bis(2-chloroethyl)-N-substituted
amine derivative. 11
[0134] a. Diisopropylethyamine/CHCl.sub.3/RT/3 Hr; b.
K.sub.2CO.sub.3/Acetone/Prpargyl bromide derivative; c.
Oxone/MeOH:THF/THF/RT; d:
K.sub.2CO.sub.3/18-Crown-6/(C.sub.4H.sub.9)-4NB-
r/Acetone/Bis-2-chloroethyl N-substituted amine derivative/Reflux;
e: NaOH/THF:MeOH/RT and
(COCl).sub.2/NH.sub.2OH.HCl/Et.sub.3N/THF/DMF.
[0135] Bis-2-chloroethyl N-substituted amines can be prepared from
the substituted diethanolamine and thionyl chloride. (Scheme 2).
The cyclic product obtained by the above mentioned operation, can
be hydrolyzed to carboxylic acid and subsequently converted to the
hydroxamic acid as outlined in scheme 1. 12
[0136] The corresponding sulfides and sulfoxides can be prepared
starting from the corresponding saturated heterocyclic carboxylic
acid derivative. (Scheme-3). N-Boc protected isonipecotic acid can
be lithiated using tert-butyllithium and the resulting anion was
reacted with appropriately substituted disufides. The sufide
derivative can be converted to hydroxamic acids by the procedure
outlined above. 13
[0137] These sulfides subsequently can be converted to the
sulfoxides using 30% hydrogen peroxide at room temperature. The
required disulfides can be prepared from the appropriately
substituted thiol and DMSO/HCl oxidation. This procedure can be
applied to any saturated, fused or non-fused heterocyclic
carboxylic acid derivative. (Scheme 4) 14
[0138] Alternatively, sulfone derivatives can also be lithiated and
carbonylated Using either dry ice or CO.sub.2 gas. (Scheme 5). The
sulfone derivative can be a mono heterocyclic, bicyclic, benzo
fused or hetero aryl such as pyridyl, thienyl, furanyl, pyrazinyl,
pyrimidyl, thiazolyl fused ring systems. 15
[0139] The oxygen analogue can be prepared (Scheme 6) from the
appropriately substituted alkynyloxy-benzenesulfonyl acetic acid
ethyl ester and 2-chloroethyl ether. The corresponding pyran
derivative can be hydrolyzed to carboxylic acid, which can be
converted to the hydroxamic acid derivative. 16
[0140] The thiols used as intermediates for the synthesis of
compounds of the invention can be made according to Scheme 7. Thus,
sulfonic acid salts 1, where XR.sub.50 is a hydroxy, thiol or
substituted amino moiety may be alkylated with acetylenes 2, where
J is a suitable leaving group such as halogen mesylate, tosylate,
or triflate to give 3. Acetylenes 2 are commercially available or
known compounds, or they may be synthesized by known methods by
those skilled in the art. The sulfonic acid salts 3 may be
converted into the corresponding sulfonyl chloride or other
sulfonylating agent 4 by known methods, such as reaction with
oxalyl chloride, phosphorus oxychloride or other reagent compatible
with substituents R.sub.1, R.sub.2 and R.sub.3 and the acetylene.
The sulfonyl chloride 4 can then be reduced to the corresponding
thiol 5 using triphenylphosphine in a suitable solvent mixture such
as dichloromethane/DMF at a temperature of between -20.degree. C.
and 30.degree. C. 17
[0141] Alternatively, disulfide 6 may be converted into
di-acetylene 7 by reaction with compounds 2, followed by reduction
of the disulfide bond to provide the desired thiols 5,
Bisacetylenes 7 may also be converted into thiols 5 via sulfonyl
chlorides 4. Alkylation of the phenol, thiophenol, aniline or
protected aniline 8 with 2 to give 9, followed by reaction with
chlorosulfonic acid provides sulfonic acids 10 which are readily
converted into 4 with oxalyl chloride or similar reagents and
subsequently reduced to thiols 5. Thiophenols 11 are also
precursors to 5 via protection of the thiol with a triphenylmethyl
or other suitable protecting group, alkylation of XH, where X is O,
N or S, and deprotection of the sulfur. 18
[0142] Compounds of the invention wherein X is N, O, S, SO or
SO.sub.2, can be synthesized according to Scheme 8 and Scheme 9.
Alkylation of the para-disubstituted aryl 14, or its protected
equivalent, with acetylene 2 in the presence of a base such as
potassium carbonate in a polar aprotic solvent such as acetone or
DMF at a temperature of between 20.degree. C. and 120.degree. C.
provides the mono-propargylic ether 15. Those skilled in the art
will recognize that protecting groups may be required to avoid
undesirable side reactions and increase the yield of the reaction.
The need and choice of protecting group for a particular reaction
is known to those skilled in the art. Reaction of this compound
with .-propiolactone, or a substituted propiolactone derivative
(wherein the substituents are defined as before), in the presence
of a base such as potassium t-butoxide in a polar solvent, or
solvent mixture, such as THF or DMF affords the carboxylic acid 16.
Conversion of carboxylic acid 16 into the corresponding hydroxamic
acid, 17, is accomplished via formation of an activated ester
derivative such as an acid chloride or acid anhydride followed by
reaction with hydroxylamine. It is understood by those skilled in
the art that when A is sulfur, in Scheme 8 and all relevant
subsequent Schemes, the sulfur can be oxidized to the corresponding
sulfoxide or sulfone at any stage after formation of the thioether,
using a suitable oxidant such as oxone, air, m-chloroperbenzoic
acid or hydrogen peroxide.
[0143] Compounds 18 are also accessible from the Michael addition
of compound 15 to a cyclic acrylate ester, or substituted acrylate
ester (substituents are defined as before), to provide 18, in which
R.sub.30 is hydrogen or a suitable carboxylic acid protecting
group. Deprotection of the ester moiety then provides carboxylic
acid, which can be converted into the analogous hydroxamic acid.
Similarly, Michael addition of mono-protected 1,4-disubstituted
aryl 19, where XR.sub.25 is hydroxy or protected hydroxy, thiol or
amine, gives compound 20. Unmasking of the protecting group gives
thiol, aniline or phenol 21 which can be alkylated with propargyl
derivative 2 to provide 18. Mono protected compound 19 can also be
reacted with .beta.-propionolactone to provide 22. Alternatively,
22 can be deprotected followed by alkylation to give 16 and 17.
[0144] Synthesis of compounds of the invention wherein X is N, O,
S, SO or SO.sub.2, and the linker between the proximal heteroatom
and the hydroxamic acid is a one or three carbon chain can be
synthesized according to Scheme 9. Compound 19, where XR.sub.25 is
hydroxy or protected hydroxy, thiol or amine, can react with ester
24 or lactone 24a, in which R.sub.30 is hydrogen or a suitable
carboxylic acid protecting group, with an appropriately substituted
leaving group such as halogen, tosylate, mesylate or triflate, to
provide 25. Unmasking of the heteroatom X of compound 25 then
provides 26, which may next be alkylated with propargylic
derivative 2 to give acetylene-ester 27. Ester 27 can be converted
into the corresponding hydroxamic acid 28 through conversion of the
ester into the carboxylic acid by acid or base hydrolysis, followed
by conversion into the hydroxamic acid as described in Scheme 1.
Alternatively, compound 15, prepared as shown in Scheme 8, can be
alkylated directly with ester 24 or lactone 24a to give 27 and then
28. Substituents on the carbon alpha to the hydroxamic are defined
as before. 19
[0145] Compounds of the invention wherein A is a methylene or
substituted methylene group, and X is oxygen, can be obtained
according to Scheme 10. Esters or carboxylic acids 29, commercially
available or known in the literate can be converted into the
corresponding phenols, 30. Allylation of the phenol with acetylene
2 gives the propargylic ethers, 31, which can be converted into the
corresponding carboxylic acids and thence the hydroxamic acids, 33,
as described in Scheme 1. Substituents on the carbon alpha to the
hydroxamic, are defined as before. 20
[0146] Compounds of the invention wherein A is --SO.sub.2--, and
R.sub.8 and R.sub.9 are not hydrogen, are available starting from
4-fluorobenzenethiol 34 as shown in Scheme 11. Deprotonation of the
thiol followed by reaction with e-propiolactone, or an acrylate
ester, or ester deriavtive 24, and subsequent oxidation of the
resulting thioether provides sulfone-acid 35. Displacement of the
4-fluoro substituent of 35, or its corresponding ester, with
propargyl derivative 36, wherein X is N, O or S, then provides
sulfone 16. Compound 16 can be converted into the compounds of the
invention according to Scheme 1. Fluoroaryl 35 can also react with
a masked hydroxyl, thiol or amino group (HXR.sub.40, wherein
R.sub.40 is a suitable protecting group) in the presence of a base
such as sodium hydride in a polar aprotic solvent such as DMF to
provide 36. Deprotection of 36 followed by alkylation with
acetylenic derivative 2 then gives 16. 21
[0147] Compounds of the invention wherein X is NH are also
available starting from the appropriate commercially available
nitro aryl compound 38 (Scheme 12). Thus, the anion of compound 38
can be used to alkylate .beta.-propiolactone, or a substituted
derivative, or a cyclic acrylate ester to provide 40 and 39
respectively. Reduction of the nitro group followed by alkylation
of the resulting aniline then gives 16. Compound 38 can also be
alkylated with ester derivative 24 to afford nitro-ester 40,
followed by reduction to give the corresponding aniline, analogous
to compound 26 of Scheme 9. 22
[0148] Compounds of the invention wherein R.sub.11, alpha to the
hydroxamic acid, is a hydroxy group can be obtained via epoxides
41, as shown in Scheme 13. These epoxides are available through the
oxidation of the corresponding acrylate esters or by the Darzens
reaction of an alpha-halo ester with a ketone. Reaction of the
epoxide with thiol, phenol or aniline 19 in the presence of base or
Lewis acid catalyzed epoxide ring opening, provides alpha-hydroxy
ester 42. Deprotection of 42 followed by alkylation with propargyl
derivative 2 gives 44. Conversion of the ester of 44 into the
analogous hydroxamic acid as described in Scheme 1 then provides
45. Compounds 45, wherein A is sulfur, may be converted into the
analogous sulfoxides or sulfones through oxidation with hydrogen
peroxide, air, Oxone or other suitable reagent at this point.
Similarly, thiol, phenol or aniline 15 can be reacted with 41 to
give 44. The hydroxyl group of compound 43 can also be manipulated
through its conversion into a suitable leaving group, such as
halide or sulfonate ester, followed by displacement with various
nucleophiles including amines to provide 44. 23
[0149] Another route to alpha-hydroxy hydroxamic acids of the
invention is shown in Scheme 14. Compound 15 can be alkylated with
alcohol 46 to give 47. Oxidation of the alcohol, with or without
concomitant oxidation of the thioether (for A=S), gives the
aldehyde 48. Reaction of aldehyde 48 with trimethylsilyl cyanide or
other suitable reagent then provides the cyanohydrin 49. Hydrolysis
of the nitrile 49 into the corresponding carboxylic acid followed
by conversion into the hydroxamic acid as described in Scheme 1
gives 50. 24
[0150] Compounds described in the present invention (from Example
30 to 63) were prepared as per the Schemes 15 and Scheme 16. In
scheme 15, the t-Boc-protected ethyl isonipecotate 51 was carefully
alkylated using diiodomethane to yield the monoiodo compound 52.
This was subsequently converted to different hydroxamic acid
derivatives as depicted in Scheme 15. In scheme 16, the N-Boc group
was selectively removed using TMSOTf/2,6-Lutidine. After the
derivatisation of the nitrogen, the O-tBu was removed using TFA in
methylene chloride. 25 26
[0151] Alternatively, compounds (wherein A=SO, and n=0) described
in examples 64 to 74 and 80 were prepared as depicted in Scheme 17.
27
EXPERIMENTAL
Example 1
1-(4-Bromo-benzyl)-4-(4-but-2-ynyxoy-benzenesulfonyl)-piperdine-4-carboxyl-
ic acid hydroxyamide
[0152] Step 1:
[0153] To a stirred solution of 4-mercapto phenol (12.6 g. 100
mmol) and N,N-diisopropylethylamine (13.0 g, 100 mmol) in
chloroform (200 ml), ethyl bromoacetate (17.0 g, 100 mmol) in
chloroform (30 ml) solution was added slowly at room temperature.
After the addition was complete, the reaction mixture was refluxed
for 1 hr and cooled to room temperature. The reaction mixture was
washed well with water, dried over anhydrous MgSO.sub.4; filtered
and concentrated. The oily product obtained was taken to next step
without purification.
[0154] Step 2:
[0155] A mixture of K.sub.2CO.sub.3 (15 gm, excess),
(4-hydroxy-phenylsulfanyl)-acetic acid ethyl ester (5 g, 23.6 mmol)
and 1-bromo-2-butyne (9.34 g, 35.4 mmol) was refluxed with stirring
for 8 hrs. The reaction mixture was then cooled to room temperature
and filtered. The filtrate was concentrated and extracted with
chloroform. The chloroform layer was washed with water, dried over
anhydrous MgSO.sub.4, filtered and concentrated. The product
obtained was taken to next step with out purification. Yield 6.0 g
(96%); yellow oil; MS: 264.0 EI (M.sup.+H).
[0156] Step 3:
[0157] To a stirred solution of (4-but-2-ynyloxy-phenyl
sulfanyl)-acetic acid ethyl ester (101 g, 380 mmol) in MeOH: THF
(3:1) (1000 ml), Oxone (670.0 g, excess) in water (1000 ml) was
added at room temperature. The reaction mixture was stirred at room
temperature for 8 hrs. The reaction mixture was then diluted with
chloroform (600 ml) and filtered. The organic layer was separated
and washed once with a saturated solution of NaHSO.sub.3 (400 ml).
The chloroform layer was washed well with water, dried and
concentrated. The oily product was dissolved in MeOH (100 ml) and
hexane (600 ml) was added. The separated colorless solid was
filtered and washed with hexane. Yield 108 g (96%); mp.
91-93.degree. C.; MS: 297 (M.sup.+H).sup.+.
[0158] Step 4:
[0159] A mixture of diethanolamine (22.5 g, 150 mmol),
4-bromobenzyl bromide (25 g, 100 mml) and N,N-diisopropylethylamine
(19.0 g, 150 mmol) was refluxed for 24 hrs in chloroform (500 ml)
solution. The reaction mixture was then concentrated and the
residue was extracted with chloroform. It was washed well with
water, dried over anhydrous MgSO.sub.4, filtered and concentrated.
The crude product obtained was taken to next step with out
purification. Yield 33.6 g (99%); Yellow oil, MS: 273.8
(M+H).sup.+.
[0160] Step 5:
[0161] 2-[(4-Bromobenzyl)-(2-hydroxy-ethyl)-amino]-ethanol (33.28
g, 122 mmol) was dissolved in methanolic hydrogen chloride (100 ml)
at 0.degree. C. Methanol was removed in vacuo and the hydrochloride
salt was suspended in C (300 ml). To a stirred solution of the
above mentioned suspension, thionyl chloride (30 g, excess) was
added slowly at room temperature. The reaction mixture was brought
to gentle reflux for 3 hrs. The reaction mixture was then
concentrated and the (4-bromobenzyl)-bis-(2-chloro-ethyl- -amine
was used in the next step with out purification. Yield: 47 g (99%);
brown solid; mp 125.degree. C.; MS: 309.8 (M+H).sup.+.
[0162] Step 6:
[0163] A stirred mixture of anhydrous K.sub.2CO.sub.3 (10 g,
excess), 18-crown-6 (1 g), tetrabutylammonium bromide (1.0 g),
(4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2.8 g,
9.46 mmol) and (4-bromo-benzyl)bis-(2-chloro-ethyl)-amine (4.9 g,
14.2 mmol) in anhydrous acetone (200 ml) was refluxed for 24 hrs.
The reaction mixture was then cooled and filtered and the filtrate
was concentrated. The crude product was extracted with chloroform,
washed well with water, dried and concentrated. The brown colored
material was purified by column chromatography on silica gel by
eluting with 50% ethylacetate:hexane. Yield 1.36 g (27%); brown
oil; MS: 534 (M+H).sup.+
[0164] Step 7:
[0165]
1-(4-Bromo-benzyl)-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4--
carboxylic acid was prepared starting from
1-(4-bromo-benzyl)-(4-but-2-yny- loxybenzenesulfonyl)-piperdine
carboxylic acid ethyl ester (1.36 g, 2.54 mmol) dissolved in
THF:methanol (100:50 ml) and 10 N NaOH (15 ml). The reaction
mixture was stirred at room temperature for 24 hrs. The reaction
mixture was then concentrated and residue was cooled and
neutralized with concentrated HCl. The separated solid was
extracted with chloroform:methanol (3:1) (300 ml) and washed with
water. The chloroform layer was dried and concentrated. The product
was crystallized from methanol. Yield 800 mg (62%); off white
solid; mp 197.degree. C.; MS: 507.9 (M+H).sup.+
[0166] Step 8:
[0167] To a stirred solution of
1-(4-bromo-benzyl)-4-(4-but-2-ynyxoy-benze- nesulfonyl)piperdine
carboxylic acid (750 mg, 1.5 mmol) and DMF (1 ml) in
CH.sub.2Cl.sub.2 (100 ml), oxalyl chloride (508 mg, 4.0 mmol) in
methylene chloride (2 ml) was added dropwise at 0.degree. C. After
the addition, the reaction mixture was warmed to room temperature
and stirred for 1 hr. The acid chloride thus formed was
concentrated to remove excess oxalyl chloride and redissolved in
CH.sub.2Cl.sub.2 (30 ml). In a separate flask hydroxylamine
hydrochloride (690 mg, 10 mmol) was dissolved in DMF (10 ml) and
triethylamine (10 g, 10 mmol) was added. The reaction mixture was
further diluted with acetonitrile (25 ml) and stirred at 0.degree.
C. The acid chloride was slowly added into the hydroxylamine and
after the addition was complete, the reaction mixture was brought
to room temperate and stirred for 24 hrs. The reaction mixture was
concentrated and the residue was e with chloroform, washed well
with water and dried over anhydrous Na.sub.2SO.sub.4. The product
was purified by silica gel column chromatography by eluting it with
10% methanol:ethyl acetate. 270 mg of
1-(4-bromo-benzyl)-4-(but-2-ynyloxy-ben-
zenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide was isolated
as a hydrochloride salt, a white powder. Yield 52%; mp 153.degree.
C.; MS: 522.9 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 1.85 (t, J=2.04 Hz, 3H), 2.23 (m. 2H), 2.49 (m, 2H), 2.83
(m, 2M, 3.36 (m, 2H), 4.28 (s, 21) 4.89 (d, J=2.2 Hz, 2H), 7.18 (d,
J=9 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.68 (m, 4H), 9.37 (s, 1H),
10.25 (s, 1H)
Example 2
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carbo-
xylic acid hydroxyamide
[0168] 2-[2-Hydroxy-ethyl(4-methoxy-benzyl)-amino]ethanol was
prepared according to the general method as outlined in Example 1
(Step 4). Starting from diethanolamine (10.5 g, 100 mmol) and
4-methoxy benzyl chloride (15.6 g, 100 mmol). Yield 21 g, (98%);
yellow oil; MS: 226 (M+H).sup.+
[0169] Bis(2-chloro-ethyl)(4-methoxy-benzyl)-amine was prepared
according to the 20.1 general method as outlined in Example 1 (Step
5). Starting from
2-[(2-hydroxyethyl)-(4-methoxy-benzyl)amino]-ethanol (11.2 g, 50
mmol). Yield 14 g, (99%); dark brown low melting solid; MS: 263
(M+H).sup.+
[0170]
4-(4-but-2-ynyloxy-benzenesulfonyl)1-(4-methoxy-benzyl)piperdine-4--
carboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1. Starting from
(4-but-2-ynyloxy-benzenesulfonyl)- acetic acid ethyl ester (2 g,
6.73 mmol) and bis-(2 chloro-ethyl)-(4-methoxy-benzyl)-amine (2.61
g, 8.75 mmol) and following the procedure as outlined in Example 1
(Step 6) 2.5 g of the product was isolated. Yield 2.5 g (77%);
yellow oil; MS: 486 (M+H).sup.+
[0171]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzyl)-piperdine--
4 carboxylic acid was prepared starting from
4-(4-but-2-ynyloxy-benzenesul-
fonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylic acid ethyl ester
(2.5 g, 5.15 mmol) dissolved in THF:methanol (3:1, 200 ml) and 10 N
NaOH (15 ml). The resulting reaction mixture was worked up as
outlined in Example 1 (Step 7). Yield 1.26 g (54%); off white
solid; mp 223.degree. C.; MS: 458 (M+H).sup.+
[0172] Stating from
4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-methoxy-benzy-
l)piperdine-4-carboxylic acid (1 g, 2.19 mmol) and following the
procedure as outlined in Example 1, (Step 8), 350 mg of
4-(4-but-2-ynyloxy-benzenes-
ulfonyl)-1-(4-methoxy-benzyl)-piperdine-4-carboxylic acid
hydroxyamide was isolated as a hydrochloride salt, an off white
solid. Yield 31%; mp 162.degree. C.; MS: 473 (M+H).sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6): .delta. 1.86 (t, 3=2.13 Hz, 3H), 2.23
(m, 2H), 2.49 (m, 2H), 2.73 (m, 2H), 3.39 (m, 2H), 3.77 (s, 3H),
4.21 (d, 3=4.26 Hz, 2H), 4.89 (d, J=2.28 Hz, 2H), 6.99 (d, J=8.7
Hz, 2H), 7.17 (d, J=9 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.68 (d, J=9
Hz, 2H), 9.37 (s, 1H), 10.21 (s, 1H), 11.17 (s, 1H).
Example 3
4-(4-But-2-ynyloxyl-benzensulfonyl)-1-(4-chloro-benzyl)-piperdine-4-carbox-
ylic acid hydroxyamide
[0173] 2-[(4-chlorobenzyl)(2-hydroxyethyl)-amino]-ethanol was
prepared according to the general method as outlined in Example 1
(Step 4). Starting from diethanolamine (14.3 g, 95 mmol) and
4-chlorobenzyl chloride (10.2 g, 63 mmol). Yield 12.1 g, (84%);
yellow oil; MS: 230 (M+H).sup.+
[0174] (4-chloro-benzyl)-bis-(2-chloro-ethyl)amine was prepared
according to the general method as outlined in Example 1 (Step 5).
Starting from 2-[(4 -chlorobenzyl)(2-hydroxy-ethyl)amino]ethanol
(12 g, 52.4 mmol). Yield 41.27 g, (90%); yellow powder; mp
115.degree. C.; MS: 303 (M+H).sup.+
[0175]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-chlorobenzyl)-piperdine-4--
carboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1 (Step 6). Starting from
(4-but-2-ynyloxy-benzene- sulfonyl)-acetic acid ethyl ester (4 g,
13.5 mmol) and (4-chloro-benzyl)-bis-(2-chloro-ethyl)-amine (4.9 g,
16.2 mmol). Yield 3.5 g (53%); white crystals; MP 91.8.degree. C.;
MS: 490 (M+H).sup.30
[0176]
4-(4-But-2-ynyloxy-benzenesulfonyl)1-(4-chloro-benzyl)-piperdine-4--
carboxylic acid was prepared starting from
4-(4-but-2-ynyloxy-benzenesulfo-
nyl)-1-(4-chloro-benzyl)piperdine-4-carboxylic acid ethyl ester
(3.14 g, 6.42 mmol) dissolved in THF:methanol 3:1 (100 ml) and 10 N
NaOH (10 ml). The resulting reaction mixture was worked up as
outlined in Example 1 (Step 7). Yield 2.37 g (80%); white solid; mp
205.degree. C.; MS: 461.9 (M+H).sup.30
[0177] Starting from
4-(4-but-2-ynyloxy-benzenesulfonyl)1-(4-chloro-benzyl-
)piperdine-4-carboxylic acid (2.31 g, 5.01 mmol) and following the
procedure as outlined in Example 1 (Step 8), 790 mg of
4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-chloro-benzyl)-piperdine
carboxylic acid hydroxyamide was isolated as a hydrochloride salt,
a yellow solid. Yield 31%; mp 130.degree. C.; MS: 476.9
(M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 1.856 (s,
3H), 2.23 (m, 2H), 2.73-2.89 (m, 4H), 3.37 (d, 2H), 4.28 (m, 2H),
4.89 (d, 21), 7.18 (d, J=8.94 Hz, 2H). 7.54 (s, 4H). (d, J=8.88 Hz,
2H), 9.40 (s, 1H), 103 (s, 1H).
Example 4
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic
acid hydroxyamide
[0178] Bis-(2-Chloro-ethyl)benzyl amine was prepared according to
the general method as outlined in Example 1 (Step 5). Starting from
N-benzyldiethanolamine (164.6 g, 844 mmol). Yield 178.5 g (79%);
brown solid; MS: 231.9 (M+H).sup.30
[0179] 1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine
carboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1 (Step 6). Starting from
(4-but-2-ynyloxy-benzenesulfonyl)-ac- etic acid ethyl ester (2 g,
6.73 mmol) and bis-(2-chloro-ethyl)-benzyl amine (2.3 g, 8.8 mmol).
Yield 3.33 g (99%); yellow oil; MS: 455.9 (M+H).sup.30
[0180]
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic
acid was prepared starting from
1-benzyl-4-(4-but-2-ynyloxy-benzenesulfon-
yl)piperdine-4-carboxylic acid ethyl ester (3 g, 6.6 mmol)
dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The
resulting reaction mixture was worked up as outlined in Example 1
(Step 7). Yield 1.65 g (59%); off white powder, mp 191.degree. C.;
MS: 428 (M+H).sup.+
[0181] Staring from
1-benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperdine-
-4-carboxylic acid (1.55 g, 3.63 mmol) and following the procedure
as outlined in Example 1 (Step 8), 1.08 g of
1-benzyl-4-(4-but-2-ynyloxy-ben-
zenesulfonyl)piperdine-4-carboxylic acid hydroxyamide was isolated
as a hydrochloride salt, an off white powder. Yield 62%; mp
175.degree. C.; MS: 443 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 1.85 (t, J=2.16 Hz, 3H), 2.25 (m, 2H), 2.49
(m, 4H), 2.77 (m, 2H), 4.28 (d, J=4.3 Hz, 4.89 (d, 3=2.28, 2H),
7.18 (ma, 2H), 7.46 (m, 5H), 7.73 (m, 2H), 9.36 (s, 1H), 10.27 (s,
1H), 11.08 (s, 1H).
Example 5
1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)piperdine-4-carboxy-
lic acid hydroxyamide
[0182] (4-Pent-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester
was prepared according to the general method as outlined in Example
1 (Step 2). Starting from (4 hydroxy-phenylsulfanyl)acetic acid
ethyl ester (5 g, 30 mmol) and 2-pentynyl chloride (3.7 g, 36.6
mmol) 7.15 g of the product isolated. Yield 7.15 g (86%); brown
oil; MS: 278 EI (M+H).sup.30
[0183] (4-Pent-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester
was prepared according to the general method as outlined in Example
1 (Step 3). Starting from (4 pent-2-ynyloxy-phenylsulfanyl)-acetic
acid ethyl ester (7.04 g, 25.3 mmol) and oxone (25 g)
(4-Pent-2-ynyloxy-benzenesulfo- nyl)-acetic acid ethyl ester was
isolated. Yield 8 g (99%); yellow oil; MS: 310.9 (M+H).sup.30
[0184]
1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperidine--
4 carboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1 (Step 6). Starting from
(4-pent-2-ynyloxy-benzen- esulfonyl)-acetic acid ethyl ester (4 g,
12.9 mmol) and (4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (5.83 g,
16.8 mmol, 2.85 g of the product was isolated. Yield 2.85 g (31%);
low melting white solid; MS: 549.9 (M+H).sup.30
[0185] 1-(4-Bromo-benzyl)
(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4-c- arboxylic acid
was prepared starting from 1-(4-bromo-benzyl)-4-(4-pent-2-y-
nyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester
(2.64 g 4.8 mmol) dissolved in THF methanol (100:50 ml) and 10 N
NaOH (10 ml). The resulting reaction mixture was worked up as
outlined in Example 1 (Step 7). Yield 1.6 g (65%); off white solid;
mp 217.degree. C.; MS: 521.9 (M+H).sup.30
[0186] Starting from
1-(4-bromo-benzyl)(4-pent-2-ynyloxy-benzenesulfonyl)
piperdine-4-carboxylic acid (1.55 g, 2.98 mol) and following the
procedure as outlined in Example 1 (Step 8), 200 mg of
1-(4-bromo-benzyl)
(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid
hydroxyamide was isolated as a HCl salt, a yellow solid Yield 12%;
mp 62.degree. C.; MS: 536.9 (M+H).sup.+; .sup.1H NMR (300 MHz
DMSO-d.sub.6): .delta. 1.069 (t, J=7.47 Hz, 3H), 2.26 (m, 2H), 2.49
(m, 2H), 2.73 (m, 2H), 2.89 (s, 2H), 3.40 (d, 2H), 4.26 (d, 2H),
4.9 (m, 2H) 7.18 (m, 2H), 7.48 (d, J=8.4 Hz, 2H, 7.66 (m, 4H),
10.39 (s, 1H), 11.19 (s, 1H).
Example 6
1-(4-Bromo-benzyl)-(4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-carbox-
ylic acid hydroxyamide
[0187] (4-oct-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester was
prepared according to the general method as outlined in Example 1
(Step 2). Starting from (4-hydroxy-phenyl-sulfanyl)-acetic acid
ethyl ester (5 g, 30 mmol) and 1-bromo-2-octyne (6.9 g, 36.6 mmol)
8.9 g of (4-oct-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester
was isolated Yield 8.9 g (92%); yellow oil; MS: 320 EI
(M+H).sup.30
[0188] (4-Oct-2-ynyloxy-benzenesulfonyl)acetic acid ethyl ester was
prepared according to the general method as outlined in Example 1
(Step 3). Starting from (4-oct-2-ynyloxy-phenylsulfanyl)-acetic
acid ethyl ester (8.8 g, 27.5 mmol) 8.45 g of
(4-oct-2-ynyloxy-phenylsulfonyl)-aceti- c acid ethyl ester was
isolated Yield 8.45 g (87%); yellow oil; MS: 352 EI
(M+H).sup.30
[0189]
1-(4-Bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4--
carboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1 (Step 6). Starting from
(4-oct-2-ynyloxy-benzene- sulfonyl)-acetic acid ethyl ester (4 g,
11.4 mmol) and 1-(4-bromo-benzyl)-bis-(2-chloro-ethyl)-amine (5.13
g, 14.8 mmol) 1.47 g of
1-(4-bromo-benzyl)-4-(4-oct-2-ynyloxy-benzenesulfonyl)
-piperdine-4-carboxylic acid ethyl ester was isolated. Yield 1.47 g
(22%); yellow solid; MS: 591.9 (M+H).sup.30
[0190]
1-(4-Bromobenzyl)-(4-oct-2-ynyloxy-benzenesulfonyl)-piperdine-4-car-
boxylic acid was prepared starting from
1-(4-bromobenzyl)-4-(4-oct-2-ynylo-
xybenzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (1.36 g,
2.3 mmol) dissolved in THF:methanol (50:50 ml) and 10 N NaOH (10
ml). The resulting reaction mixture was worked up as outlined in
Example 1 (Step 7). Yield 660 mg (51%); off white solid; mp
199.degree. C.; MS: 562 (M+H).sup.30
[0191] Starting from
1-(4-bromo-benzyl)-(4-oct-2-ynyloxy-benzenesulfonyl)p-
iperdine-4-carboxylic acid (570 mg, 1.01 mmol) and following the
procedure as outlined in Example 1 (Step 8), 100 mg of
1-(4-bromo-benzyl)-4-(4-(oct-
-2-ynyloxybenzenesulfonyl)-piperdine-4-carboxylic acid hydroxyamide
was isolated as a hydrochloride salt, a white powder. Yield 17%; mp
140.degree. C.; MS: 579 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 0.828 (t, J=7.14 Hz, 3H), 1.25 (m, 6H), 1.38
(m, 2H), 2.27 (m, 2H), 2.49 (m, 4H), 2.73 (m, 2H), 4.03 (m, 2H),
4.91 (s, 2H), 7.18 (d, J=9 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.68
(m, 4H), 9.43 (s, 1H), 10.25 (s, 1H), 11.19 (s, 1H).
Example 7
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine-4-carbo-
xylic acid hydroxyamide
[0192] 2-[(4-Fluoro-benzyl)-(2-hydroxy-ethyl)-amino]-ethanol was
prepared according to the general method as outlined in Example 1
(Step 4). Staring from diethanolamine (15.7 g, 150 mmol) and
4-fluoro-benzyl chloride (14.4 g, 100 mmol) 20 g of the product was
isolated. Yield 20 g, (93%%); yellow oil; MS: 215 (M+H).sup.30
[0193] (4-Flouro-benzyl)-bis-(2-chloro-ethyl)-amine was prepared
according to the general method as outlined in Example 1 (Step 5).
Starting from 2-[(4-fluoro-benzyl)-(2-hydroxy-ethyl)-amino]-ethanol
(23.6 g, 110 mmol) 28 gms of the product was isolated. Yield 28 g,
(96%); brown solid; mp 98-99.degree. C.; MS: 251 (M+H).sup.+
[0194]
4-(4-But-2-ynyloxy-benzenesulfonyl-(4-fluoro-benzyl)-piperidine-4-c-
arboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1 (Step 6). Starting from
(4-but-2-ynyloxy-benzenesul- fonyl)-acetic acid ethyl ester (5 g,
16.9 mmol) and (4-fluoro-benzyl)-bis-(2-chloro-ethyl)-amine (5.8 g,
20.1 mmol) 5.3 g of the product was isolated. Yield 5.3 g (67%);
Brown oil; MS: 474 (M+H).sup.30
[0195]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperidine--
4 carboxylic acid was prepared starting from
4-(4-but-2-ynyloxy-benzenesul-
fonyl)-1-(4-fluoro-benzyl)-piperidine-4-carboxylic acid ethyl ester
(9.5 g, 20 mmol) dissolved in THF:methanol 3:1 (100 ml) and 10 N
NaOH (20 ml). The resulting reaction mixture was worked up as
outlined in Example 1 (Step 7). Yield 5.7 g (63%); white solid; mp
106-106.degree. C.; MS: 447 (M+H).sup.30
[0196] Starting from
4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzy- l)
piperidine-4-carboxylic acid (5.7 g, 13 mmol) and following the
procedure as outlined in Example 1 (Step 8), 4.1 g of
4-(4-but-2-ynyloxy-benzenesulfonyl)-1-(4-fluoro-benzyl)-piperdine-4-carbo-
xylic acid hydroxyamide was isolated as a HCl salt, a yellow solid
Yield: 64%; mp 162-4.degree. C.; MS: 461 (M+H).sup.+; .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 1.92 (so 3H), 2.02-2.32 (m, 6H),
2.86 (m, 2H), 3.41 (d, 2H), 4.84 (d, 1H), 7.01 (d, J=8.94 Hz, 2H},
7.15 (d, J=8.88 Hz, 2H), 7.25 (d, 1=Hz, 2H), 7.74 (d, 3=9.0 Hz,
2H), 9.4-9.7 (bs, 1H).
Example 8
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carbox-
ylic acid hydroxyamide
[0197] 4-{[Bis-(2-hydroxyethyl)-amino]-methyl)benzonitrile was
prepared according to the general method as outlined in Example 1
(Step 4) starting from diethanolamine (10.2 g, 97 mmol) and
.alpha.-bromo-p-tolunitrile (15.8 g, 81 mmol). Yield, (68%); white
solid; mp 163.degree. C. MS: 221.2 (M+H).sup.30
[0198] 4-([Bis-(2-chloroethyl)-amino]-methyl)benzonitrile was
prepared according to the general method as outlined in Example 1
(Step 5) starting from
4-{[bis-(2-hydroxyethyl)-amino]-methyl}benzonitrile (33.28 g, 122
mmol). Yield g, (%); brown solid; mp .degree. C.; MS:
(M+H).sup.30
[0199]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-
-carboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1 (Step 6). Starting from
4-(4-but-2-ynyloxy-benze- nesulfonyl)-acetic acid ethyl ester (5.86
g, 19.8 mmol) and 4-cyano-benzyl-bis-(2-chloro-ethyl)-amine (5.4 g,
18 mmol) 4.7 g of the product was isolated. Yield (52%); amber oil;
MS: 481.0 (M+H).sup.30
[0200]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-
-carboxylic acid was prepared starting from
4-(4-But-2-ynyloxy-benzenesulf-
onyl)-1-(4-cyano-benzyl-piperidine-4-carboxylic acid ethyl ester (4
g, 8.3 mmol) dissolved in THF:Methanol (60:30 ml) and 10 N NaOH (10
ml). The resulting reaction mixture was worked up as outlined in
Example 1 (Step 7). Yield 1.8 g (48%); off white solid; MS: 441.9
(M+H).sup.30
[0201] Starting from
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl-
)-piperidine-4-carboxylic acid (1.8 g, 4 mmol) and following the
procedure as outlined in Example 1 (Step 8), 0.20 g of
4-(4-But-2-ynyloxy-benzenesu- lfonyl)-1-(4-cyano-benzyl)-piperidine
4-carboxylic acid hydroxamide was isolated as a hydrochloride salt,
white solid. Yield 20%; mp 109.6.degree. C.; MS: 468.0 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 1.86 (m, 3H), 2.25 (m,
4H), 2.5 (m, 2H), 2.85 (d, 2H), 4.39 (s, 2H), 4.88 (s, 21H),
7.15-7.19 (d, J=13.2, 2H), 7.67-7.70 (d, J=13.5, 2H), 7.78 (m, 2H),
7.96-7.99 (d, J=9.6, 2H), 9.42 (s, 1H), 10.14 (s, 1H), 11.20 (s,
1H)
Example 9
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4-carbo-
xylic acid hydroxamide
[0202] 2-[(2-Hydroxy-ethyl)(4-methyl-benzyl)-amino]-ethanol was
prepared according to the general method as outlined in Example 1
(Step 4). Starting from diethanolamine (4.84 g, 46 mmol) and
4-methylbenzyl bromide (8.5 g, 46 mmol), 8.2 g of the product was
isolated Yield, (85%); white solid; MS: 210.1 (M+H).sup.30
[0203] 4-Methyl-benzyl-bis-(2-chloro-ethyl)-amine was prepared
according to the general method as outlined in example 1 (Step 5).
Starting from 2-[(2-Hydroxyethyl)(4-methyl-benzyl)-amino]-ethanol
(6.0 g, 20 mmol) 5.2 g of the product was isolated. Yield: (84%);
yellow solid; mp 145-147.degree. C.; MS: 245.9 (M+H).sup.30
[0204]
4-(4-But-2-ynyloxy-benzenesulfonyl-1-(4-methyl-benzyl)-piperidine-4
carboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1 (Step 6). Staring from
4-(4-but-2-ynyloxy-benzen- esulfonyl)-acetic acid ethyl ester (5.75
g, 19.0 mmol) and 4-methyl benzyl-bis-(2-chloro-ethyl)amine (6.04,
208 mmol) 6.47 g of the product was isolate. Yield (72%); amber
oil; MS: 470 (M+H).sup.30
[0205]
4-(4-But-2-ynyloxy-benzenesulfonyl-1-(4-methyl-benzyl)-piperidine-4-
-carboxylic acid was prepared starting from
4-(4-But-2-ynyloxy-benzenesulf-
onyl)-1-(4-methyl-benzyl)-piperidine-4-carboxylic acid ethyl ester
ester (6.4 g, 13.6 mmol) dissolved in THF:Methanol (30:20 ml) and
10 N NaOH (15 ml). The resulting reaction mixture was worked up, as
outlined in Example 1 (Step 7). Yield 2.3 g (48%); off white solid;
mp 213.degree. C. MS: 441.9 (M+H).sup.30
[0206] Starting from
4-But-2-ynyloxy-benzenesulfonyl)-1-(4-methyl-benzyl) piperidine
4-carboxylic acid (2.0 g, 5.0 mmol) and following the procedure as
outlined in Example 1 (Step 8), 3.6 g of
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4
methyl-benzyl)piperidine-4-carbo- xylic acid hydroxamide was
isolated as a HCl salt, off-white solid. Yield 1.2 g (28%); mp
188.degree. C.; MS: 457.0 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 1.86 (s, 3H), 2.27 (m, 2H), 2.56 (m, 4H),
2.64 (m, 2H), 4.23-4.24 (d, J=4.5, 2H), 4.89 (d, J=1.8, 2H),
7.16-7.19 (d, J=9 2H), 7.247.26 (d, J=7.5, 2H), 7.37-7.40 (d,
J=0.1, 2H), 9.36 (s, 1H), 10.11 (s, 1H), 11.20 (s, 1H)
Example 10
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-c-
arboxylic acid hydroxyamide
[0207] 2-[(2-Hydroxy-ethyl)(3,4-diclor-benzyl)-amino]-ethanol was
prepared according to the general method as outlined in Example 1.
(Step 4). Starting from diethanolamine (4.84 g, 46 mmol) and
3,4-dichlorobenzyl chloride (8.97 g, 46 mmol). 9.4 g of the product
was isolated. Yield, (78%); white solid; MS: 264.3 (M+H).sup.30
[0208] 3,4-Dichloro-benzyl-bis-(2-chloro-ethyl)-amine was prepared
according to the general method as outlined in Example 1 (Step 5).
Starting from
2-[(2-Hydroxyethyl)-(3,4-dichloro-benzyl)-amino]-ethanol (10.7 g,
41 mmol), 10.7 g of the product was isolated Yield: (84%); yellow
solid; mp 218-220.degree. C.; MS: 301.8 (M+H).sup.30
[0209]
4-(4-But-2-ynyloxy-benzenesulfonyl-(3,4-dichloro-benzyl)-piperidine-
-4 carboxylic acid ethyl ester was prepared according to the
general method as outlined in Example 1 (Step 6). Starting from
4-(4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (6.1 g,
23 mmol) and 3,4-dichloro-benzyl-bis-(2-chloro-ethyl)-amine (8.6 g,
25 mmol), 4.9 g of the product was isolated. Yield: (41%); amber
oil; MS: 523.8 (M+H).sup.30
[0210]
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl-piperidi-
ne-4-carboxylic acid was prepared starting from
4-(4-But-2-ynyloxy-benzene-
sulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4-carboxylic acid
ethyl ester ester (8.6 g, 16.4 mmol) dissolved in THF:Methanol
(40:30 ml) and 10 N NaOH (15 ml). The resulting reaction mixture
was worked up as outlined in Example 1 (Step 7). Yield 2.1 g (38%);
off white solid; mp 232.degree. C. MS: 495.9 (M+H).sup.30
[0211] Starting from
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(3,4-dichloro-b-
enzyl-piperidine-4-carboxylic acid (2.06 g, 4.0 mmol) and following
the procedure as outlined in Example 1 (Step 8}, 1.2 g of
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(3,4-dichloro-benzyl)-piperidine-4--
carboxylic acid hydroxamide was isolated as a HCl salt, off-white
solid Yield 1.2 g (56%); mp 213.degree. C.; MS: 510.9 (M+H).sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 1.86 (s, 3H), 2.30 (m,
2H), 2.50 (m, 41), 2.80 (m, 21), 4.40 (5' 2H), 4.90 (s, 21),
7.16-7.19 (d, J=9 2H), 751-7.54 (d, J=8.4, 2H), 7.66-7.69 (d,
J=0.0, 2H), 7.75-7.86 (d, J=11.7, 2H), 7.88 (s, 1H), 938 (s, 1H),
10.44 (s, 1H), 11.19 (s, 1H).
Example 11
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-carbox-
ylic acid hydroxyamide
[0212] Step 1:
[0213] (4-Prop-2-ynyloxy-phenylsulfanyl)-acetic acid ethyl ester
was prepared according to the general method as outlined in Example
1 (Step 2). Starting from (4-hydroxy-phenylsulfanyl)-acetic acid
ethyl ester (example 1, 1.sup.st paragraph) (2.12 g, 10 mmol) and
propargyl bromide (1.8 g, 15 mol) 2.4 g of the product was
isolated. Yield: (96%); amber oil; MS: 251(M+H).sup.+
[0214] Step 2:
[0215] (4-Prop-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester
was prepared according to the general method as outlined in Example
1 (Step 3). Starting from (4-prop-2-ynyloxy-phenyl sulfanyl)-acetic
acid ethyl ester (2.5 g, 10 mmol) 2.8 g of
(4-Prop-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester was
isolated. Yield (99%); brown oil; MS: 283 (M+H).sup.30
[0216] Step 3:
[0217]
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-
-carboxylic acid ethyl ester was prepared according to the general
method as outlined in Example 1 (Step 6). Starting from
(4-prop-2-ynyloxy-benzen- esulfonyl)-acetic acid ethyl ester (21.62
g, 76.7 mmol) and (4-bromo-benzyl)-bis(2-chloro-ethyl)-amine (31.9
g, 92 mmol), 23 g of the ester derivative was isolated. Yield:
(58%); yellow oil; MS: 521.9 (M+H).sup.+.
[0218] Step 4:
[0219]
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdine-4-
-carboxylic acid was prepared starting from
1-(4-bromo-benzyl)-4-(4-prop-2-
-ynyloxy-benzene-sulfonyl)-piperdine-4-carboxylic acid ethyl ester
(5 g, 9.59 mmol) dissolved in THF:methanol (150:50 ml) and 10 N
NaOH (15 ml). The resulting reaction mixture was worked up as
outlined in Example 1 (Step 7). Yield 3.4 g (72%); brown low
melting solid; MS: 491.9 (M-H).sup.31
[0220] Step 5:
[0221] Starting from
1-(4-Bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfony- l)
piperdine-4-carboxylic acid (3 g, 6.1 mmol) and following the
procedure as outlined in Example 1 (Step 8), 580 mg of
1-(4-bromo-benzyl-4-(4-prop--
2-ynyloxy-benzene-sulfonyl)piperdine-4-carboxylic acid hydroxyamide
was isolated as an HCl salt, off white powder. Yield 18%; mp
155.degree. C.; MS: 508.8 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 2.22 (m, 2H), 2.50 (m, 2H>, 2.79 (m, 2H),
3.45 (m, 2H), 4.27 (m, 2H), 4.96 (d, J=2.3 Hz, 21, 7.2 (d, J=39 Hz,
2H), 7.48 (m, 2H), 7.68 (m, 4H), 9.37 (s, 1H), 10.36 (s, 1H), 11.19
(s, 1H).
Example 12
1-(4-Bromo-benzyl)-4-[4-(4-piperdin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-p-
iperdine-4-carboxylic acid hydroxyamide
[0222] To a stirred solution of piperidine (1.63 g, 19.2 mmol)
diluted in dioxane (100 mL) acetic acid (5 mL) was added. The
reaction fumed and stirred for 5 minutes.
1-(4-bromo-benzyl)-4-(4-prop-2-ynyloxy-benzenesulf-
onyl)piperdine-4-carboxylic acid ethyl ester (5.0 g, 9.6 mmol),
paraformaldehyde (0.29 g, 9.6 mmol) and the copper(I)chloride (0.35
g) was added to the piperidine solution. The reaction turned green
and was heated at reflux for 1 hour turned brown. It was then
concentrated and diluted in ice water then brought to pH 8 with
NH.sub.4OH and extracted in CHCl.sub.3. The organic layer was
washed 4 times with water then dried over NaO.sub.4 then
concentrated. The product was purified by silica gel column
chromatography by eluting it with 5% methanol:chloroform
solution.
[0223] Yield 5.15 g (87%); brown oil; MS: 309.9 (M+2H), 618.8
(M+H).sup.30
[0224]
1-(4-Bromo-benzyl)4[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfo-
nyl]-piperdine carboxylic acid was prepared starting from
1-(4-bromo-benzyl)4[4-(4
piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-p-
iperidine-4-carboxylic acid ethyl ester (4.64 g, 7.5 mmol)
dissolved in THF methanol (50:150 ml) and 10 N NaOH (20 ml). The
resulting reaction mixture was worked up as outlined in Example 1
(Step 7). Yield 3.35 g (76%); off white solid; mp 180.degree. C.;
MS: 295.9 (M+2H).sup.2+ 590.9 (M+H).sup.+
[0225] Starting from
1-(4-bromo-benzyl)[4-(4-piperidin-1-yl-but-2-ynyloxy)-
benzene-sulfonyl]-piperidine-4-carboxylic acid (1.9 g, 3.2 mmol)
and following the procedure as outlined in Example 1 (Step 8), 810
mg of
1-(4-bromo-benzyl)-4-[4-(4-piperidin-1-yl-but-2-ynyloxy)-benzenesulfonyl]-
-piperidine-4-carboxylic acid hydroxyamide was isolated as a
hydrochloride salt, a pale yellow solid. Yield 40%; mp 209.degree.
C.; MS: 303.4 (M+2M 605.9 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 1.70 (m, 2H), 2.29 (m, 2H), 2.76 (m, 4H),
3.40 (m, 10H), 4.14 (s, 2H), 4.26 (2H), 7.24 (d, J=9 Hz, 2H), 7.51
(d, J=8.4 Hz, 2H), 7.67 (m, 4H), 9.39 (s, 1H), 10.45 (s, 1H).
Example 13
1-(4-Bromo-benzyl)-4-[4-(4-morpholin-4-yl
but-2-ynyloxy)-benzenesulfonyl]-- piperdine-4-carboxylic acid
hydroxyamide
[0226] To a stirred solution of morpholine (1.68 g, 19.2 mmol)
diluted in dioxane (100 mL) acetic acid (5 mL) was added. The
reaction fumed and stirred for 5 minutes.
1-(4-bromo-benzyl)-4-4-prop-2-ynyloxy-benzenesulfo-
nyl)-piperidine-4-carboxylic acid ethyl ester (5.0 g, 9.6 mmol),
paraformaldehyde (0.29 g, 9.6 mmol) and the copper(I)chloride (0.35
g) was added to the piperidine solution. The reaction turned green
and was heated at reflux for 1 hour turned brown. It was then
concentrated and diluted in ice water then brought to pH 8 with
NH.sub.4OH and extracted in CHCl.sub.4. The organic layer was
washed 4 times with water then dried over Na.sub.2SO.sub.4 then
concentrated. The product,
1-(4-Bromo-benzyl)-4-[4-morpholin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-pi-
peridine-4-carboxylic acid ethyl ester was purified by silica gel
column chromatography by eluting it with. 5% methanol:chloroform
solution. Yield 3.0 g (50%); colorless solid; mp 110.degree. C.;
MS: 311 (M+2H).sup.2+, 621 (M+H).sup.+
[0227] 1-(4-Bromo-benzyl)-4-[4-morpholin-4-yl-but-2-ynyloxy)
benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting
from
1-(4-bromo-benzyl-4[4-(4-morpholin-4-yl-but-2-ynyloxy)benzenesulfonyl]-pi-
peridine-4-carboxylic acid ethyl ester (2.87 g, 4.6 mmol) dissolved
in THF:methanol (3:1, 150 ml) and 10 N NaOH (10 ml). The resulting
reaction mixture was worked up as outlined in Example 1 (Step 7).
Yield 2.26 g (83%); white powder, mp 198.degree. C.; MS: 593.1
(M+H).sup.+
[0228] Starting from
(4-bromo-benzyl)-4-[4-(morpholin-4-yl-but-2-ynyloxy)--
benzenesulfonyl]-piperidine-4-carboxylic acid (2.1 g, 3.55 mmol)
and following the procedure as outlined in example 1, 1.8 g of
1-(4-bromo-benzyl)-4-[4-(4-morpholin-4-yl-but-2-ynyloxy)-benzenesulfonyl]-
-piperidine-4-carboxylic acid hydroxyamide was isolated as a
hydrochloride salt, a white solid. Yield 80%; mp 94.degree. C.; MS:
304.4 (M+2H) 607.9 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 2.38 (m, 2H), 2.46 (m, 2H), 2.75 (m, 2H),
3.35 (m, 2H), 3.87, (m, 8H), 4.21 (s, 2H), 4.26 (s, 2H), 5.10 (s,
2H), 7.24 (d, J=9 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.67 (m, 4H),
9.42 (S. 1H), 10.69 (s, H), 11.13 (s, 1H)
[0229] Examples of compound where A=S or S=O.
Example 14
4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1-carboxy-
lic acid tert-butyl ester
[0230] To a solution of triphenylphosphine (24.7 g, 94.2 mmol) and
dimethylformamide (0.6 mL) in dichloromethane (25 mL) was added a
solution of 4-but-2-ynyloxy-phenylsulfonyl chloride (7.69 g, 31.4
mmol) in dichloromethane dropwise over 30 min. After an additional
2 h, 1N aqueous hydrochloric acid (20 mL) and water was added. The
organic layer was separated and concentrated in vacuo. Aqueous
sodium hydroxide (1N, 50 mL) was added and the solid removed by
filtration. The aqueous phase was washed with diethyl ether
(3.times.), treated with 1N aqueous hydrochloric acid (50 mL) and
extracted with ether (3.times.) the combined organic extracts were
dried over anhydrous magnesium sulfate and concentrated to give the
thiol as an oil (3.77 g). This material was dissolved in
dimethylsulfoxide (40 mL) and concentrated hydrochloric acid was
added (2 mL). After 18 h, diethyl ether was added and the organic
phased was washed with water (5.times.) and dried over anhydrous
magnesium sulfate. Concentration in vacuo gave a yellow solid which
was filtered through silica gel with hexane:ethyl acetate to give
bis(4-but-2-ynyloxy phenyl)disulfide as a yellow solid (3.0 g,
80%). .sup.1HNMR (CDCl3: 300 MHz): 1.86 (s, --CH3, 3H), 4.63 (s,
--CH2, 2H), 6.90 (d, ArH, 2 J=9 Hz), 7.40 (d, ArH, 2, J=9 Hz).
[0231] To a solution of N-BOC-isonipecotic acid (0.62 g, 2.7 mmol)
in tetrahydrofuran (20 mL) at -78.degree. C. was added
tert-butyllithium (3.4 mL, 0.7M in hexane, 5.7 mmol). After 10 min
at -78.degree. C. the yellow solution was warmed to 0.degree. C. in
an ice bath. After 30 min the colorless solution was cooled to
-78.degree. C. whereupon bis (4-but-2-ynyloxy phenyl) disulfide
(1.0 g, 2.8 mmol) was added as a solution in tetrahydrofuran (6
mL). The reaction mixture was allowed to warm to 25.degree. C.
After 1.5 h ethyl acetate was added followed by 6 mL of 1N aqueous
hydrochloric acid in 20 mL of water. The organic layer was washed
with water and brine, dried over anhydrous magnesium sulfate and
concentrated in vacuo. Chromatography on silica gel
(methanol/methylene chloride) gave the product (0.55 g). .sup.1H
NMR (DMSO-d6): 1.38 (s, OtBu, 9H), 1.5-1.6 (m, CHH, 2H), 1.84 (s,
CH3, 3H), 1.89-1.99 (m, CHH, 2H), 2.95-3.05 (m, CHH, 2H), 3.6-3.7
(m, CHH, 2H), 4.8 (s, CH2, 2H), 6.95 (d, ArH, 2H, J=9 Hz), 7.38 (d,
ArH, 2H, J=9 Hz).
[0232] Dimethylformamide (0.163 mL) was added to a solution of
oxalyl chloride (1.06 mL of a 2.0M solution in dichloromethane) in
dichloromethane (2 mL) at 0.degree. C. After 15 min a solution of
the acid in dimethylformamide (5 mL) was added and the reaction
mixture was allowed to warm to room temperature. After 1 h the an
mixture was added to a mixture of hydroxylamine hydrochloride
(0.737 g), triethylamine (2.22 mL), water (5.7 mL) and
tetrahydrofuran (22.8 mL) that had been stirring at 0.degree. C.
for 15 min. The reaction was held at 0.degree. C. for 18 h then
diluted with dichloromethane and washed with saturated aqueous
sodium bicarbonate (3.times.), then dried over potassium carbonate
and concentrated in vacuo to give 480 mg of
44-but-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1-carboxyl-
ic acid tert-butyl ester. .sup.1H NMR (DMSO-d6): 1.37 (s, OtBu,
9H), 1.5-1.6 (m, CHH, 2H), 1.84 (s, CH.sub.3, 3H), 1.9-2.0 (m, CHH,
2H), 3.05-3.15 (m, CHH, 2H), 3.5-3.6 (m, CHH, 2H), 4.8 (s,
CH.sub.2, 2H), 6.9 (d, ArH, 2H), 7.4 (d, ArH, 2H), 8.8 (s, NHOH,
1H), 10.7 (d, NHOH, 1H).
Example 15
4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic acid
hydroxyamide
[0233]
4-(4-But-2-ynyloxy-phenylsulfanyl)-4-hydroxycarbamoyl-piperidine-1--
carboxylic acid tert-butyl ester, prepared by the method outlined
in Example 14 (Step 3) (0.175 g, 0.4 mmol), was t with 4N
hydrochloric acid in dioxane (5 mL) at 25.degree. C. for 1 h 15
min. The reaction mixture was concentrated in vacuo, diethyl ether
was added and the resulting precipitate isolated by filtration to
give 4-(4-but-2-ynyloxy-phenylsulfa- nyl)-piperidine 4-carboxylic
acid hydroxyamide as a white solid (0.12 g). Electrospray Mass
Spectroscopy: ((M+H).sup.+=321)
Example 16
1-(4-Bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxy-
lic acid hydroxyamide
[0234] 4-(4-But-2-ynyloxy-phenylsulfanyl)-piperidine-4-carboxylic
acid hydroxyamide (prepared by the procedure outlined in example
15) (0.15 g, 0.5 mmol) in methanol (5 mL) and dimethylformamide
(2.5 mL) was treated with triethylamine (0.15 mL, 1.1 mmol)
followed by 4-bromobenzylbromide (0.13 g, 0.53 mmol). After 6 h the
solution was diluted with ethyl acetate, acidified to pH=6 with 1N
aqueous hydrochloric acid, washed sequentially with water, aqueous
sodium bicarbonate and brine and dried over anhydrous sodium
sulfate. Concentration in vacuo gave
1-(4-bromo-benzyl)-4-(4-but-2-ynyloxy-phenylsulfanyl-piperidine-4-carboxy-
lic acid hydroxyamide. .sup.1H NMR (DMSO-d6): 1.5-1.6 (m, CHH, 2H),
1.8 (s, CH3, 3H), 1.9-2.2 (m, CHH, 4H), 2.5-2.6 (m, CHH, 2H), 3.4
(s, CH2, Ar, 2H), 4.75 (s, CH2, 2H), 6.9 (d, ArH, 2H), 7.2 (d, ArH,
2H), 7.3 (d, ArH, 2H), 7.5 (d, ArH, 2H), 8.8 (s, NHOH, 1H), 10.6
(d, NHOH, 1H). Electrospray Mass Spectroscopy:
((M+H).sup.+=489/491)
[0235] Examples of compounds, where n=1 and A=S, S=O or
SO.sub.2
Example 17
4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic
acid hydroxyamide
[0236] 4-But-2-ynyloxy-benzenesulfonic acid sodium salt
[0237] 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 700
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.
[0238] 4-But-2-ynyloxy-benzenesulfonyl chloride
[0239] To a 0.degree. solution of 43.8 mL (0.087 mol) of oxalyl
chloride in 29 mL of dichloro-methane was dropwise added 6:77 mL
(0.087 mol) of DMF followed by 7.24 g (0.029 mol) of
4-but-2-ynyloxy-benzenesulfonic acid sodium salt. 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. 6365.degree. C. EI Mass
Spec: 243.9 (M.sup.+).
[0240] But-2-ynyloxy-benzene
[0241] To a solution of 6.14 g (23.40 mmol) of triphenylphosphine
dissolved in 100 mL of benzene and 50 mL of THF was added 1.75 mL
(23.40 mmol) of 2-butyn-1-ol. After five minutes 2.00 g (21.28
mmol) of the phenol, dissolved in 10 mL of THF, was added to the
reaction followed by 3.69 mL (23.40 mmol) of diethyl
azodicarboxylate. The resulting reaction mixture was stirred for 18
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 desired
propargylic ether as a clear liquid. EI Mass Spec: 146.0
M.sup.+
[0242] 4-But-2-ynyloxy-benzenesulfonyl chloride
[0243] To a solution of 0.146 g (1.0 mmol) of the
but-2-ynyloxy-benzene in 0.3 mL of dichloromethane in an
acetone/ice bath under N, 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 g (53%) of the desired
product as a light brown solid.
[0244] 4-But-2-ynyloxy-benzenethiol
[0245] To a solution of 11.8 g (0.045 mol) of triphenylphosphine
dissolved in 10 mL of dichloromethane and 0.3 mL of DMF was added
3.67 g (0.015 mol) of the 4-but-2-ynyloxy-benzenesulfonyl chloride,
dissolved in 15 mL of dichloromethane and the resulting mixture was
stirred for 2 h at room temperature. After the addition of 5 mL of
1N HCl solution the reaction was stirred for 0.5 h followed by the
addition of 15 mL of brine. The organics were separated and
concentrated in vacuo and the residue was diluted with ether and
2.5N sodium hydroxide solution. The resulting precipitate was
filtered off and the aqueous layer was acidified to pH2 and
extracted with ether. The combined organics were washed with brine,
dried over Na.sub.2 SO.sub.4, filtered through Magnesol.RTM. and
concentrated in vacuo. The residue was chromatographed on silica
gel eluting with hexanes/ether (4:1) to provide 1.13 g (42%) of the
thiol as a yellow oil. CI Mass Spec: 179 (M+H).
[0246]
4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxy-
lic acid
[0247] To a solution of 0.112 g (2.81 mmol) of 60% sodium hydride
in 2 mL of THF, cooled to 0.degree. C., was added a solution of
0.500 g (2.81 mmol) of 4-but-2-ynyloxy-benzenethiol dissolved in 3
mL of THF. The resulting mixture was stirred for 0.5 h at room
temperature, then cooled to 5.degree. C., followed by the addition
of 0.518 g (3.65 mmol) of neat 2,7-dioxaspiro[3,5]nonane-1-one
while keeping the reaction temperature below 10.degree. C. The
reaction was allowed to warm to room temperature and stirred for an
additional 0.5 h and then quenched with 3 mL of 3N HCl solution and
3 mL of water. The resulting mixture was extracted with
dichloromethane and the combined organics were washed with water
and brine, dried over Na.sub.2SO.sub.4, filtered through a plug of
silica gel and concentrated in vacuo. The residue was triturated
with hexanes and acetonitrile and filtered to give 0.72 g of the
carboxylic acid as a semi-solid. Electrospray Mass Spec: 319
(M-H).sup.-.
[0248]
4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxy-
lic acid hydroxyamide
[0249] To a 0.degree. C. solution of 0.74 g (2.31 mmol) of the
product of
4-(4-but-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic
acid, dissolved in 7 mL of dichloromethane and 0.175 mL of DMF was
added 1.27 mL (2.54 mmol) of a 2M solution of oxalyl chloride. The
reaction was warmed to room temperature and stirred for 2 h and
then recooled to 0.degree. C. A mixture of 0.875 mL (14.2 mmol) of
a 50% hydroxylamine solution, 5.0 mL of THF and 2.0 mL of t-butanol
were then added to the reaction. The reaction was stirred at room
temperature for 1 h and then concentrated in vacuo. The residue was
extracted with dichloromethane and the combined organics were
washed with water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo. The residue was chromatographed on
silica gel eluting with dichloromethane/methanol (92:8) to provide
0.212 g of the sulfide-hydroxamic acid as a white solid; m.p.
135-137.degree. C. Electrospray Mass Spec: 336 (M+H).sup.30
Example 18
4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-tetrahydro-pyran-4-carboxylic
add hydroxyamide
[0250] To a 0.degree. C. solution of 0.186 g (0.56 mmol) of the
product of
4-(4-but-2-ynyloxy-phenylsulfanylmethyl)-tetrahydro-pyran-4-carboxylic
acid hydroxyamide, dissolved in 1.2 mL of THF and 4.8 mL of
methanol was dropwise added a solution of 0.619 g (1.008 mmol) of
Oxone.RTM. in 3 mL of water, while keeping the temperature below
20.degree. C. After the addition was complete the reaction was
stirred at room temperature for 3 h. The reaction mixture was then
poured into a cooled solution of 2.5 mL of toluene and 5 mL of
ethyl acetate and the precipitate was filtered off. The filtrate
was extracted with ethyl acetate/toluene and the combined organic
layers were washed with water, dried over Na2SO4 and concentrated
in vacuo. The residue was triturated with ethyl acetate/toluene
(5:2), filtered and dried in vacuo to provide 0.12 g (55%) of the
sulfone-hydroxamic acid as a white solid; m.p. 184185.degree. C.
Electrospray Mass Spec: 368 (M+H).sup.30
Example 19
4-(4-But-2-ynyloxy-benzenesulfinylmethyl)-tetrahydro-pyran-4-carboxylic
acid hydroxyamide
[0251] To a 0.degree. C. solution of 0.288 g (0.80 mmol) of the
product of
4-(4-but-2-ynyloxy-benzenesulfanylmethyl)-tetrahydro-pyran-4-carboxylic
acid hydroxyamide dissolved in 20 mL of methanol was added 7.0 mL
of 30% hydrogen peroxide solution. The reaction was allowed to warm
to room temperature and stirred for 24 h. The reaction mixture was
then recooled to 0.degree. C., quenched with saturated
Na.sub.2SO.sub.3 and concentrated in vacuo. The residue was diluted
with water and dichloromethane. The organics were washed with water
and brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo. The residue was chromatographed on silica gel eluting
with dichloromethane/methanol (95:5) to provide 0.050 g of the
sulfoxide as a white solid. Electrospray Mass Spec: 351.9
(M+H).sup.30
Example 20
4-([4-(2-butynyloxy)phenyl]sulfonyl)-N-hydroxytetrahydro-2H-pyran 4
carboxamide
[0252] Step 1:
[0253] Ethyl
4-([4-(2-butynyloxy)phenyl]sulfonyl)tetrahydro-2H-pyran-4-car-
boxylate
[0254] (4-but-2-ynyloxy-benzenesulfonyl) acetic acid ethyl ester
(10 g, 33.8 mmol) was added to a stirring solution of potassium
carbonate (12 g), 18-crown-6 (0.5 g), 2-chloroethyl ether (4.75 ml,
40.5 mmol), and tetrabutyl ammonium bromide (0.5 g) in methyl ethyl
ketone (200 ml). The mixture was heated at reflux overnight before
the salts were filtered off and the filtrate was concentrated. The
residue was dissolved in chloroform and washed with water. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated. The compound was isolated using silica-gel column
chromatography by eluting it with 20% ethyl acetate:hexane
solution. Ethyl 4-{[4-(2-butynyloxy)phenyl]sulfonyl}tetrah-
ydro-2H-pyran-4-carboxamide was isolated as a yellow oil (10.06 g).
Yield 80%; MS: 367.2 (M+H).sup.30
[0255]
4-([4-2-butynyloxy)phenyl]sulfonyl)tetrahydro-2H-pyran-4-carboxylic
acid was prepared according to the general method as outlined in
example 1 (step 7), starting from ethyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}tetra- hydro-2H-pyran
carboxylate (10 g, 27.3 mmol); 2.7 g white solid mp: 197.degree.
C.; Yield 30%; MS: 337.2 (M-H).sup.-
[0256] Starting from a crude mixture of
([4-(2-butynyloxy)phenyl]sulfonyl) tetrahydro-2H-pyran-4-carboxylic
acid (2.59 g, 7.66 mmol), and following the procedure as outlined
in Example 1 (step 8), 1.51 g of
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxytetrahydro-2H-pyran-4-carbo-
xamide was isolated as off white crystals Mp: 210.degree. C.;
Yield: 58%; MS: 354.2 (M+H).sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 1.85 (t, J=2.28H, 3H), 1.92 (m, 2H), 2.20
(d, J=13.1H; 2H), 3.15 (t, J=11.52, 2H), 3.86 (d of d, 2H), 4.88
(d, J=2.34 Hz, 2H), 7.16 (d, J=8.7H 2H), 7.66 (d, J=8.91H, 2H),
9.16 (s, 1H), 11 (s, 1H).
Example 21
1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperdine
carboxamide
[0257] Ethyl [(3-hydroxyphenyl)sulfanyl]acetate was prepared
according to the general method as outlined in example 1 (step 1),
starting from ethyl bromoacetate (7.95 g, 47.6 mmol) and
3-hydroxythiophenol (7.95 g, 47.6 mmol); 4.21 g yellow oil. Yield
41%; MS: 211.2 (M-H).sup.31
[0258] Ethyl{[3-(2-butynyloxy)phenyl]sulfanyl}acetate was prepared
according to the general method as outlined in example 1 (step 2),
starting from ethyl [(3-hydroxyphenyl)sulfanyl]acetate (3.87 g,
18.3 mmol) and 4-bromo-2-butyne (2.66 g, 20 mmol) 5.16 g yellow
oil. Yield 100%; MS(EI): 264.1 (M+M).sup.30
[0259] Ethyl{[3-(2-butynyloxy)phenyl]sulfonyl)acetate was prepared
according to the general method as outlined in example 1 (step 3),
staring from ethyl([3-(2-butynyloxy)phenyl]sulfanyl}acetate (5 g,
18.9 mmol) and oxone (23.3 g, 37.9 mmol); 6.19 g yellow oil. Yield
100%; MS(EI): 296.1 (M+H).sup.30
[0260] Ethyl
1-benzyl-4-([3-(2-butynyloxy)phenyl]sulfonyl-4-piperdine-carb-
oxylate was prepared according to the general method as outlined in
example 1 (step 6), starting from
ethyl{[3-(2-butynyloxy)phenyl]sulfonyl}- acetate (3 g, 10.1 mmol)
and Benzyl-bis-(2-chloro-ethyl)amine hydrochloride (2.88 g 10.7
mmol); 2.91 g yellow oil. Yield 63%; MS: 456.3 (M+H).sup.30
[0261] 1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-4-piperdine
carboxylic acid was prepared according to the general method as
outlined in example 1 (step 7), starting from ethyl
1-benzyl-4-{[3-(2-butynyloxy)p- henyl]sulfonyl}-4-piperdine
carboxylate (2.9 g 6.37 mmol), 1.10 g off white powder mp:
171.degree. C.; Yield 40%/0; MS: 428.4 (M+H).sup.30
[0262] Starting from
1-benzyl-4-{[3-(2-butynyloxy)phenyl]sulfonyl}-4-piper- dine
carboxylic acid (1 g, 12.34 mmol), and following the procedure as
outlined in Example 1 (step 8), 460 mg of
1-benzyl-4-{[3-(2-butynyloxy)ph- enyl]sulfonyl}-N-hydroxy-4
piperdine carboxamide was isolated as an off white solid mp:
91.4.degree. C.; Yield: 41%; MS: 443.4 (M+H).sup.+; .sup.1H NMR
(300 MHz, DMSO d6): .delta. 1.83 (t, 3H), 2.23-2.27 (m, 2H),
2.73-2.89 (m, 2H), 3.29 (m, 2H), 3.68 (q, 2H), 4.31 (m, 1H), 4.39
(d, J=5 Hz, 1H), 4.85 (d, J=2.25, 2H), 7.25-7.61 (m, 9H), 9.1 (s,
1H), 11.2 (s, 1H).
Example 22
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-1-isopropyl-4-piperidine
carboxamide
[0263] Ethyl
4-([4-2-butynyloxy)phenyl]sulfonyl)-1-isopropyl-4-piperidine
carboxylate was prepared according to the general method as
outlined in example 1 (step 6), starting from
(4-but-2-ynyloxy-benzenesulfonyl)acetic acid ethyl ester (6 g, 20.3
mmol) and isopropyl[bis(2-chloroethyl)]amine hydrochloride (4.88 g,
22.3 mmol), 5.28 g brown oil. Yield 64%; MS: 408.2 (M+H).sup.30
[0264] 4-[4-(2-butynloxy)phenyl]sulfonyl-1-isopropyl 4-piperdine
carboxylic acid was prepared according to the general method as
outlined in example 1 (step 7), starting from ethyl
4-([4-(2-butynyloxy)phenyl]sul- fonyl)-1-isopropyl-4-piperdine
carboxylate (5.25 g 13 mmol); 2.06 g yellow solid mp: 233.degree.
C.; Yield 42%; MS: 380.1 (M+H).sup.30
[0265] Starting from
4-{([4-(2-butynyloxy)phenylsulfonyl)-1-isopropyl-4-pi- peridine
carboxylic acid (1.9 g, 5 mmol), and following the procedure as
outlined in Example 1 (step 8), 107 mg of
4-([4-2-butynyloxy)phenyl]sulfo- nyl}-N-hydroxy-1-isopropyl-4
piperidine carboxamide was isolated as an brown solid mp:
105.degree. C.; Yield: 5%; MS: 395.2 (M+H).sup.+; .sup.1H NMR (300
MHz, DMSO-d.sub.4): .delta. 1.2 (n, 6H), 1.85 (t, 3H), 2.27 (m,
2H), 2.73 (m, 2H), 3.06 (ma, 2H), 3.52 (m, 2H), 3.57 (m, 1H), 4.89
(m, 210, 7.19 (m, 2H), 7.71 (m, 2H), 9.3 (s, 1H), 11.4 (s, 1H).
Example 23
4-([4-(2-butynyloxy)phenyl]sulfonyl)-N-hydroxyl-(3-pyridinylmethyl)-4-pipe-
ridine carboxamide
[0266] Ethyl
4-([4-(2-butynyloxy)phenyl]sulfonyl)-1-(3-pyridinylmethyl)-4--
piperidine carboxylate was prepared according to the general method
as outlined in example 1 (step 6), starting from
(4-but-2-ynyloxy-benzenesul- fonyl)-acetic acid ethyl ester (4 g,
16.9 mmol) and 3-pyridyl methyl[bis(2-chloroethyl)]amine
hydrochloride (4.18 g, 18.6 mmol); 370 mg brown oil. Yield 5%; MS:
457.4 (M+H).sup.+
[0267] 4-([4-(2-butynyloxy)phenyl]sulfonyl)-1-(3-pyridinyl
methyl)-4-piperidine carboxylic acid was prepared according to the
general method as outlined in example 1 (step 6), starting from
ethyl
4-{[4-butynyloxy)phenyl]sulfonyl}-1-(3-pyridinylmethyl)-4-piperidine
carboxylate (320 mg, 0.7 mmol); 150 mg yellow solid. Yield 50%; MS:
429.2 (M+H).sup.30
[0268] Starting from
4-{[4{2-butynyloxy)phenyl]sulfonyl}-1-(3-pyridinyl
methyl)-4-piperidine carboxylic acid (860 mg, 2 mmol), and
following the procedure as outlined in Example 1 (step 8), 800 mg
of
4-{[4{2-butynyloxy)phenyl]sulfonyl}-N-hydroxyl(3-pyridinylmethyl)-4-piper-
idine carboxamide was isolated as a white solid mp: 115.degree. C.;
Yield: 84%; MS: 444.1 (M+H).sup.+; .sup.1H NMR (300 MHz, DMSO-d6):
.delta. 1.86 (t, J=1.98 Hz, 31, 2.32 (in 21, 2.46 (s, 2H), 2.84 (m,
2H), 3.46 (d, J=12 Hz, 2H), 4.45 (s, 2H), 4.89 (d, 2.1 Hz, 2H),
7.17 (d, J=8.9 Hz, 2H), 7.68 (d, J=8.85 Hz, 2H), 7.9 (t, J=5.6 Hz,
1H), 8.0 (s, 1H), 8.51 (d, J=7.9H, 1), 8.87 (d, J=4.6 Hz, 1H), 8.99
(s, 1H), 11.4 (s, 1H).
Example 24
3-{[4-(2-Butynyloxy)phenylsulfonyl)-1-ethyl-N-hydroxy-3-piperidinecarboxam-
ide
[0269] Step 1: Piperidine-1,3-dicarboxylic acid 1-tert-butyl
3-ethyl ester
[0270] To a stirred solution of ethyl nipecotate (5.1 g, 33 mmol)
in CH.sub.2Cl.sub.2 (75 ml) and triethylamine (3.7 g, 36 mmol) was
added portionwise di-t-butyldicarbonate (7.1 g, 33 mmol). The
reaction mixture was stirred at room temperature for 18 h, quenched
with ice water and extracted with chloroform. The organic layer was
dried over sodium sulfate, filtered, concentrated and
chromatographed on a silica-gel column with 20:80 ethyl
acetate:hexane. Piperidine 1,3-dicarboxylic acid 1-tert-butyl
ester-3-ethyl ester was isolated as a waxy solid. Yield 6.86 g
(82%). MS (ES): m/z 258.2 (M+H).sup.+.
[0271] Step 2: 1 tert-Butyl) 3 et
3-{[4-2-butynyloxy)phenyl]sulfonyl)-1,3-- piperidine
dicarboxylate
[0272] To a stirred solution of diisopropylamine (7.2 g, 28 mmol)
in THF (25 ml) at -78.degree. C. was added n-butyllithium (1.6 m
solution in hexanes, 19.0 ml, 30.8 mmol). The mixture was stirred
for 30 min at 0.degree. C. The mixture was then cooled to
-78.degree. C. and piperidine-1,3-dicarboxylic acid 1-tert-butyl
ester 3-ethyl ester (5.3 g 28 mmol) in THF (20 ml) was added
slowly. The reaction mixture was stirred for 30 min then
4-but-2-ynyloxy-benzenesulfonyl fluoride (6.4 g, 28 mmol) in THF
(15 ml) was added slowly. The reaction was warmed to room
temperature and after 4 hrs quenched with ice water and exacted
with chloroform. The organic layer was dried over sodium sulfate,
filtered, concentrated and chromatographed on a silica-gel column
with 20% ethyl acetate:hexane to afford 1-(tert-Butyl)
3-3-([4-2-butynyloxy)phenyl]sulfo- nyl)-1,3-piperidine
dicarboxylate as a white solid. Yield 9.8 g (76%); mp 103.4.degree.
C.; MS (ES): m/z 466.4 (M+H).sup.+. .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 1.07 (t, 3H), 1.34 (s, 9H), 3.31 (s, 3H),
3.84 (m, 2H), 4.00 (m, 4M, 4.53 (d, 2H), 4.91 (m, 4H), 7.22 (d,
2H), 7.71 (d, 2H).
[0273] Step 3: To a stirred solution of 1-(tert-Butyl) 3 ethyl
3-{(4-2-butynyloxy) phenyl]sulfonyl)-1,3-piperidine dicarboxylate
(5.45 g, 11.7 mmol) in methylene chloride (25 ml) at 0.degree. C.
was added a saturated solution of hydrogen chloride in methylene
chloride (25 ml). After 5 hours the solution was concentrated to
afford ethyl
3-{[4-(2-butynyloxy)phenyl]sulfonyl}-3-piperidinecarboxylate
hydrogen chloride and is stored under nitrogen. White hygroscopic
solid; Yield 3.47 g (74%); MS ES): m/z 366.2 (M+H).sup.+
[0274] Step 4: (Ethyl
3-([4-(2-butynyloxy)phenyl]sulfonyl)-1-ethyl-3-piper-
idinecarboxylate)
[0275] 3-([4-(2-Butynyloxy)phenyl]sulfonyl)-3-piperidinecarboxylate
hydrogen chloride (2.97 g, 8.0 mmol), ethyl iodide (1.28 g, 8 mmol)
and dry powdered potassium carbonate (3.8 g) in dry acetone (60 ml)
was heated to reflux for 18 hours. The mixture was allowed to cool
and the potassium salts were filtered and concentrated. The residue
was extracted with chloroform and washed with H.sub.2O, dried over
sodium sulfate and concentrated to afford ethyl
3-([4-2-butynyloxy)phenyl]sulfonyl)-1-ethyl--
3-piperidinecarboxylate. This product was used without further
purification. Amber gum, yield 3.47 g (99%); MS (ES): m/z 394
(M+H).sup.+.
[0276] Step 5: 3-{[4-(2-butynyloxy)phenyl]sulfonyl)-1
ethyl-3-piperidine-4-carboxylic acid
3-([4-(2-butynyloxy)phenyl]sulfonyl}-
-1-yl-3-piperidine-4-carboxylic acid was prepared starting from
ethyl
3-([4-(2-butynyloxy)phenyl]sulfonyl}-1]-3-piperidine-4-carboxylate
(3.2 g, 8.0 mmol) dissolved in THF:Methanol (15:25 ml) and NaOH (15
ml). The resulting reaction mixture was worked up as outlined in
example 1 (step 7). Yield 2.11 g (71%), white solid: mp
159.2.degree. C.; MS (ES): m/z 366.3 (M+H).sup.30
[0277] Step 6:
3-{[4-(2-butynyloxy)phenyl]sulfonyl)-1-ethyl-N-hydroxy-3-pi-
peridinecarboxamide Starting from
3-([4-2-butynyloxy)phenyl]sulfonyl)-1
ethyl-3-piperidine-4-carboxylic acid (2.0 g, 5.5 mmol) and and
following the procedure as outlined in example 1 (step 8), 0.193 g
of
3-([4-(2-butynyloxy)phenyl]sulfonyl)-1-ethyl-N-hydroxy-3-piperidinecarbox-
amide hydrogen chloride was isolated as a white solid. Yield 10%;
mp 190.3.degree. C.; MS (ES): m/z 405.3 (M+H).sup.+; .sup.1H NMR
(300 MHz DMSO d6): .delta. 1.18 (m, 3H), 1.97 (m, 2H), 2.55 (m,
2H), 3.21 (m, 5H), 3.52 9S, 3H), 3.82 (d, 1H), 4.91 (m, 2H), 7.19
(d, 2H), 7.51 (s, 5H), 8.67 (s, 1H), 9.48 (s, 1H}.
Example 25
3-{[4-(2-butynyloxy)phenyl]sulfonyl)-1-(4-chlorobenzyl)-N-hydroxy-3-piperi-
dinecarboxamide
[0278] Step 1: Ethyl
3-{[4-(2-butynyloxy)phenyl]sulfonyl)-1-(4-chlorobenzy-
l-3-piperidinecarboxylate
[0279] Stating from ethyl
3-([4-(2-butynyloxy)phenyl]sulfonyl)-3-piperidin- ecarboxylate
hydrogen chloride (1.1 g, 2.7 mmol) and 4-chlorobenzyl chloride
(0.485, 3.0 mmol) in dry acetone (50 ml) and following the
procedure outlined in example 24, (step 4)) Ethyl
3-{[4-(2-butynyloxy)phe-
nyl]sulfonyl}-1(4-chlorobenzyl)3-piperidinecarboxylate was isolated
as a brown oil. This product was taken to the next step without
further purification. Yield 1.66 g (99%); MS (ES): m/z: 4913
M+H).sup.30
[0280] Step 2:
3-([4-(2-butynyloxy)phenyl]sulfonyl}1-(4-chlorobenzyl)-3-pi-
peridinecarboxylic acid
[0281]
3-([2-butoxy)phenyl]sulfonyl)-1-(4-chlorobenzyl)-1-3-piperidinecarb-
oxylic acid was prepared starting from ethyl
3-{[4-2-butynloxy)phenyl]sulf-
onyl)-1-(4-chlorobenzyl)-3-piperidinecarboxylate (1.64 g, 3.3 mmol)
dissolved in THF:Methanol (15:50 ml) and NaOH (15 ml). The
resulting reaction mixture was worked up as outlined in example 1
(step 7); Yield 1.11 g (75%), white solid: mp 115.2.degree. C.; MS
(ES): m/z 462.1 (M+H).sup.30
[0282] Step 3:
3-{[2-butynyloxy)phenyl]sulfonyl)-1-(chlorobenzyl)-N-hydrox-
y-3-piperidinecarboxamide
[0283] Starting from
3-([4-2-butoxy)phenyl]sulfonyl)-1-4-chlorobenzyl)-3-p-
iperidinecarboxylic acid (1.1 g, 2.4 mmol) and and following the
procedure as outlined in example 1, (step 8), 0.48 g of
3-{([4-(2-butynyloxy)phenyl-
]sulfonyl}-1-(4-chlorobenzyl)-3-N-hydroxy-3-piperidinecarboxamide
hydrogen chloride was isolated as a white solid. Yield 43%; mp
124.4.degree. C.; MS (ES): m/z: 477.1 (M+H).sup.+; .sup.1H NMR (300
MD, DMSO d.sub.6): 52.0 (m, 2H), 3.39 (m, 5H), 4.27 (d, 2H), 4.89
(m, 2H), 7.14 (d, 2H), 7.15 (m, 4H), 7.61 (d, 2H), 8.95 (s, 1H),
9.46 (s, 1H).
Example 26
4-([4-(2-Butynyloxy)phenyl]sulfonyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl-
]-piperidine-4-carboxylic acid hydroxyamide
[0284] A mixture of diethanolamine (2.1 g, 20 mmol),
4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol) and
K.sub.2CO.sub.3 (10 g, excess) was refluxed in acetone (100 ml) for
24 hrs At the end, reaction mixture was cooled to room temperature
and filtered. It was concentrated to dryness and redissolved in
touene (200 ml) and thionyl chloride (6.75 g, 50 mmol). It was
heated to 80.degree. C. for 1 hr and the separated brown solid,
bis-(2-chloro-ethyl)-[4-(2-pip- eridin-1-yl-ethoxy-benzyl]-amine
was filtered and dried. The crude product was taken to next step
with out purification. Yield: 7.0 g, (89%).
[0285]
4-([4-(2-Butynyloxy)phenyl]sulfonyl)-1-[4-(2-piperidin-1-yl-ethyl)--
benzyl]-piperdine-4-carboxylic acid ethylester was was prepared
according to the general method as outlined in example 1 (step 6),
star from ethyl([4-(2-butynyloxy)phenyl]sulfonyl)acetate (2.9 g,
10.0 mmol) and
bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine
dihydrochloride (4.3 g, 10 mmol), 2.8 g of product (brown oil) was
isolated. Yield 48%; MS: 583. (M+1).sup.30
[0286]
4-{[4-2-Butynyloxy)phenyl]sulfonyl}-1-[4-2-piperidin-1-yl-ethoxy)-b-
enzyl]-piperidine-4-carboxylic acid was prepared according to the
general method as outlined in example 1 (step 7), starting from
4-{([42-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-
-piperidine carboxylic acid ethylester (3.0 g, 5.15 mmol); 2.2 g of
white powder mp: 172.degree. C.; Yield 77%; MS: 555
(M+H).sup.30
[0287] Starting from 4-55
[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperi-
din-1-yl-ethoxy)benzyl]-piperidine-4-carboxylic acid (5.0 g, 9.0
mmol), and following the procedure as outlined in Example 1 (step
8), 1.8 g of
4-([4-{2-Butynyloxy)phenyl]sulfonyl}-1-[4-2-piperidin-1-yl-ethoxy)-benzyl-
]-piperidine-4 carboxylic acid hydroxyamide was isolated as an
yellow spongy solid. The dihydrochloride salt was prepared by
dissolving the free amine with methanolic hydrochloric acid. mp:
124.degree. C.; Yield: 1.8 g (32%); MS: 570 (4M+H).sup.+.
Example 27
4-(14-(2-Butynyloxy)phenyl-0-sulfonyl)-1-3-pentanyl)-piperdine-4-carboxyli-
c acid hydroxyamide
[0288]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl)-1-(3-pentanyl)-piperidin-4-car-
boxylic acid ethyl ester was was prepared according to the general
method as outlined in example 1 (step 6), starting from
ethyl{[4-(2-butynloxy)ph- enyl]sulfonyl}acetate (8.8 g, 30.0 mmol)
and bis-(2-chloro-ethyl)(3-pentan- yl)amine dihydrochloride (7.4 g,
30 mmol), 3.5 g of product (brown oil) was isolated. Yield 26%; MS:
436 (M+H).sup.30
[0289]
4-{[2-Butnyloxy)phenyl]sulfonyl}-1-3-pentanyl)-piperidin-4-carboxyl-
ic acid was prepared according to the general method as outlined in
example 1 (step 7), starting from
4{[(4-(2-Butnyloxy)phenyl]sulfonyl}-1-3- -pentyl)-piperdine-4
carboxylic acid ethyl ester (3.0 g, 6.8 mmol); 2.5 g of spongy
yellow solid. mp: 98.degree. C.; Yield 90%; MS: 408
(M+H).sup.30
[0290] Starting from
4-{[4-(2-Butynloxy)phenyl]sulfonyl}-1-3-pentanyl)-pip- eridine
carboxylic acid (2.5 g, 6.1 mmol), and following the procedure as
outlined in Example 1 (step 8), 1.8 g of
4-([4-(2-Butynyloxy)phenyl]sulfo-
nyl)-1-3-pentanyl)-piperidine-4-carboxylic acid hydroxyamide was
isolated as an yellow spongy solid. The hydrochloride salt was
prepared by dissolving the free amine with methanolic hydrochloric
acid. mp: 101-103.degree. C.; Yield: 1.1 g (42%); MS: 460
(M+H).sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 1.8 (t,
6H), 1.5-1.7 (m, 6H), 1.9 (s, 3H), 2.3-2.7 (m, 8H), 3.0 (m, 2H),
3.4 (s, 3H), 3.6 (d, 2H), 4.9 (s, 2H), 7.21 (d, 2H), 7.8 (d, 2H),
9.3 (s, 1H), 9.8 (s, 1H), 11.2 (s. 1H).
Example 28
1-(4-Methoxy-benzyl)-4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-carbox-
ylic acid hydroxyamide
[0291] 1-(4-Methoxy benzyl)4-prop-2-ynyloxy
benzenesulfonyl)-piperidine-4-- carboxylic acid ethyl ester was
prepared according to the general method as outlined in example 1
(step 6), starting from (4-prop-2-ynyloxybenzene- sulfonyl)-acetic
acid ethyl ester (prepared as described in example 11, step 1 and
2)(10.0 g, 35.0 mmol) and 4-methoxy-benzyl)bis-(2-chloro-amine
hydrochloride (10.5 g, 35 mmol), 6.0 g of product (brown oil) was
isolated. Yield 36%; MS: 472 (M+H).sup.30
[0292]
1-(4-Methoxy-benzyl)}-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperdin-
e-4-carboxylic acid was prepared according to the general method as
outlined in example 1 (step 7), starting from
1-4-Methoxy-benzyl)-4-(4-pr-
op-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl
ester (6.0 g, 12.73 mmol); 5.0 g of spongy yellow solid. mp:
208.degree. C.; Yield 92%; MS: 444 (M+H).sup.30
[0293] Starting from 1
(4-Methoxy-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfo-
nyl)-piperidine-4 carboxylic acid (6.0 g, 13.5 mmol), and following
the procedure as outlined in Example 1 (step 8), 2.0 g of
1-4-Methoxy-benzyl)-4-4-prop-2-ynyloxy-benzenesulfonyl)piperidine-4-carbo-
xylic acid hydroxyamide was isolated as an yellow spongy solid. The
hydrochloride salt was prepared by dissolving the free amine with
methanolic hydrochloric acid. mp: 150.degree. C.; Yield: 2.0 g
(29%); MS: 459 (M+H).sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 2.3-2.8 (m, 6H), 3.3 (d, 2H), 3.5 (s, 3H), 4.2 (s, 2H), 5.0
(s, 2H), 7.3 (d, 2H), 7.5 (d, 2H), 7.6 (d. 2H), 7.7 (d, 2H), 10.9
(s, 1H), 11.2 (s, 1H).
Example 29
1-(4-Chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-carb-
oxylic acid hydroxyamide
[0294]
1-4-Chloro-benzyl-4-(4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-
-carboxylic acid ethyl ester was prepared according to the general
method as outlined in example 1 (step 6), starting from
(4-prop-2-ynyloxy-benzen- esulfonyl)-acetic acid ethyl ester
(prepared as described in example 11, step 1 and 2.times.10.0 g,
35.0 mmol) and 4-chloro-benzyl)-bis-(2-chloro-- ethyl)-amine
hydrochloride (10.5 g, 35 mmol), 8.0 g of product (brown oil) was
isolated. Yield 48%; MS: 475 (M+H).sup.30
[0295] 1 (4-Chloro-benzyl
4-prop-2-ynyloxy-benzenesulfonyl)-piperidine-4-c- arboxylic acid
was prepared according to the general method as outlined in example
1 (step 7), staring from 1-4-chloro-benzyl)-4-prop-2-ynyloxy-benz-
enesulfonyl) piperidine carboxylic acid ethyl ester (6.0 g, 12.63
mmol); 5.0 g of spongy yellow solid. mp: 205.degree. C.; Yield 92%
o; MS: 448 (M+H).sup.30
[0296] Starting from
1-(4-chloro-benzyl)-4-(4-prop-2-ynyloxy-benzenesulfon- yl)
piperidine-4-carboxylic acid (6.0 g, 13.4 mmol), and following the
procedure as outlined in Example 1 (step 8), 2.0 g of
1-4-chloro-benzyl)4-(4-prop-2-ynyloxy-b piperidine 1-carboxylic
acid hydroxyamide was isolated as an yellow spongy solid. The
hydrochloride salt was prepared by dissolving the free amine with
methanolic hydrochloric acid. mp: 146.degree. C.; Yield: 4.0 g
(59%/0); MS: 499 (M+H).sup.+. .sup.1H NMR (300 M, DMSO-d.sub.6):
.delta. 2.0-2.5 (m, 6H), 3.2 (d, 2H), 4.18 (s, 2H), 4.9 (s, 2H),
7.42 (d, 2H), 7.61 (d, 7.71 (d, 2H), 7.85 (d, 2H), 11.0 (s, 1H),
11.2 (s, 1H).
Example 30
tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl)methyl)-4-[(hydroxyamino)c-
arbonyl]-1-piperidinecarboxylate
[0297] Step 1: Piperidine-1,4-dicarboxylic acid tert-butyl ester
ethyl ester
[0298] To a solution of of ethyl isonipecotate (4.72 g, 0.03 mmol)
in 30 mL of THF was added slowly di-tert-butyl dicarbonate (7.2 g,
0.03 mmol) at room temperature. The resulting mixture was stirred
for two hours and diluted with EtOAc. The organics were washed with
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with ethyl
acetate:hexanes (1:9) to provide 7.52 g (97%) of the desired
product as a colorless oil. Electrospray Mass Spec: 258.3
(M+H).sup.30
[0299] Step 2: 1-(tert-Butyl) 4-ethyl
4-iodomethyl)piperidine-1,4-dicarbox- ylate
[0300] To a solution of piperidine-1,4-dicarboxylic acid tert-butyl
ester ethyl ester (12.8 g, 49.74 mmol) in 73 mL of dry THF under
N.sub.2 atmosphere at -42.degree. C. was added 24.87 mL (49.74
mmol) of 2M Lithium diisopropylamine in heptane/THF/ethylbenzene
dropwise to not exceed -40.degree. C. After one hour, 4.0 mL (49.74
mmol) of diiodomethane was added and the solution was warmed to
ambient temperature overnight. The resulting solution was diluted
with H.sub.2O and extracted with ethyl acetate. The organics were
washed with brine, dried over MgSO.sub.4, filtered and concentrated
in vacuo to provide 18.84 g (95%) of the desired product as a brown
oil. Electrospray Mass Spec: 398.2 (M+H).sup.30
[0301] Step 3: 4-But-2-ynyloxy-benzenesulfonic acid sodium
salt:
[0302] To a solution of 4-hydroxybenzenesulfonate sodium salt
(52.35 g, 0.225) 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 45.08 g (81%)
of the desired product as a white solid.
[0303] Step 4: 4-But-2-ynyloxy-benzenesulfonyl chloride
[0304] To a stirred solution of oxalyl chloride (47.8 ml, 0.545
mol) at 6.degree. C. in 240 mL of CH.sub.2Cl.sub.2 was added a DMF
(43.0 ml) solution of 4-but-2-ynyloxy-benzenesulfonic acid sodium
salt in a drop wise manner. The reaction mixture was stirred at
0.degree. C. for 30 min and then let warm to room temperature and
stirred for 18 h The reaction was then poured into ice and
extracted with hexanes. The organics were washed with water and
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo to
provide 42.0 g (95%) of the desired product as yellow solid.
[0305] Step 5: 4-But-2-ynyloxy-benzenethiol
[0306] To a solution of 11.8 g (0.045 mol) of triphenylphosphine in
10 mL of CH.sub.2Cl.sub.2 and 0.3 mL of DMF was added dropwise a
solution of 4-but-2-ynyloxy-benzenesulfonyl chloride in 15 mL
CH.sub.2Cl.sub.2. Stirred at room temperature for two hours, added
5 mL of 1N HCl, stirred for 30 min., and then added 15 mL of brine.
The organics were separated and concentrated in vacuo. The residue
was diluted with ether and filtered the insolubles. The filtrate
was washed with 2.5N NaOH and the aqueous solution separated,
acidified and extracted with ether. The organics were washed with
H.sub.2O, brine, dried over MgSO.sub.4, filtered and concentrated
in vacuo to give 1.54 g (58%) of the desired product as a pale
yellow oil.
[0307] Step 6: 1-(tert-butyl) 4-ethyl
4-({[4-(2-butynyloxy)phenyl]sulfanyl-
}methyl)-1,4-piperidinedicarboxylate
[0308] A mixture of 0.294 g (0.74 mmol) of 1-tert-Butyl) 4-ethyl
4-(iodomethyl)piperidine-1,4-dicarboxylate, 0.145 (0.814 mmol) of
4-but-2-ynyloxy-benzenethiol and 0.204 g (1.48 mmol) of
K.sub.2CO.sub.3 in 2.0 mL of DMF was stirred at room temperature
for 18 h. The resulting mixture was diluted with EtOAc, washed with
H.sub.2O, brine, dried over MgSO.sub.4 and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with
EtOAc:Hexanes (1:19) to provide 0.328 g (99%) of the desired
product as a colorless oil. Electrospray Mass Spec 448.3
(M+H).sup.30
[0309] Step 7:
4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-piperidin-1,4-dica-
rboxylic acid mono-tert-butyl ester
[0310] A mixture of 0.288 g (0.0643 mmol) of 1-tert-butyl) 4-ethyl
4-([4-2-butynyloxy)phenyl]sulfanyl}methyl)-1,4
piperidinedicarboxylate, 3.25 mL of 1N NaOH 3.25 mL of THF and 3.25
mL of MeOH was heated to reflux for 3 h The organics were removed
and the residue was diluted with H.sub.2O, acidified and extracted
with EtOAC. The organics were washed with H.sub.2O, brine, dried
over mgSO.sub.4, filtered and concentrated in vacuo to provide
0.241 g (89%) of the desired product as an off white gum
Electrospray Mass Spec: 464.3 (M+FA-H).sup.31
[0311] Step 8: WAY 173665
tert-butyl-4-([4-(2-butynyloxy)phenyl]sulfanyl}m-
ethyl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate
[0312] To a solution of 0.204 g (0.49 mmol) of
4-(4-But-2-ynyloxy-phenylsu-
lfonylmethyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl
ester, 0.079 g (0.58 mmol) of 1-hydroxybenzotriazole in 2.5 mL of
DMF was added 0.112 g (0.84 mmol) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and
stirred at room temperature for 1 h. Then added 0.3 mL of 50%
aqueous hydroxylamine and stirred for 18 h. The resulting mixture
was diluted with EtOAc, washed with H.sub.2O, brine, dried over
MgSO.sub.4, filtered and concentrated in vacuo. The residue was
chromatographed on silica gel eluting with 1.5%
MeOH/CH.sub.2Cl.sub.2 to provide 0.077 g (36%) of the desired
product as a white solid. Electrospray Mass Spec: 435.2
(M+H).sup.30
Example 31
4-({[4-(But-2-ynyloxy)phenyl]thio}methyl)-N-hydroxypiperidine-4-carboxamid-
e
[0313] To a solution of 0, 143 g (0.033 mmol) of
tert-butyl-4-({[4-(2-buty- nyloxy)
phenyl]sulfanyl)methyl)-4[(hydroxyamino)carbonyl]-1-piperidinecarb-
oxylate in 5 mL of C and 1 mL of MeOH was added 5 mL of 4M HCl in
dioxane and stirred for 1 h. The reaction was concentrated in vacuo
and the residue was triturated with ether and filtered to provide
0.093 g (76%) of the desired product as a pale orange solid.
Electrospray Mass Spec: 335.3 (M+H)
Example 32
tert-Butyl-4-({[4-(2-butynyloxy)phenyl]sulfinyl}methyl)-4-[(hydroxyamino)c-
arbonyl]-1-piperidinecarboxylate
[0314] To a slurry of
tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl}meth-
yl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.24 g,
0.55 mmol) at 0.degree. C. in 7 mL of MeOH was added dropwise 3.5
mL of 30% hydrogen peroxide. The reaction was allowed to warm to
room temperature and stirred for 18 h. The reaction was cooled to
0.degree. C. and quenched with 3.5 mL of a saturated solution of
Na.sub.2SO.sub.3. The organics were removed and the aqueous
solution was extracted with CH.sub.2Cl.sub.2. The organics were
washed with H.sub.2O, brine, dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was triturated with ether to
provide 0.166 g (67%) of the desired product as an off white solid.
Electrospray Mass Spec: 451.3 (M+H).sup.30
Example 33
4-[[[4-(2-Butynyloxy)phenyl]sulfinyl]methyl]-N-hydroxy-4-piperidinecarboxa-
mide
[0315]
4-{[4-2-Butynyloxy)phenyl]yl}methyl)-N-hydroxy-4-piperidinecarboxam-
ide was prepared according to the general method as outlined in
Example 31. Starting from
tert-butyl-4-(([{4-2-butynyloxy)phenyl]sulfinyl)methyl)-
-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.082 g, 0.18
mmol), 0.066 g (95%) of the desired product was isolated as a white
solid Electrospray Mass Spec: 351.2 (+H).sup.30
Example 34
tert-Butyl({([4-(but-2-ynyloxy)phenyl]sulfonyl)methyl)-4-[(hydroxyamino)ca-
rbonyl]piperidine-1-carboxylate
[0316] To a solution of
tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfanyl)me-
thyl)4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate (0.422 g,
0.97 mmol) in 8 mL of MeOH, 4 mL of CH.sub.2Cl.sub.2 and 2 mL of
THF was added a solution of 1.79 g (2.91 mmol) of OXONE in 8 mL of
H.sub.2O and stirred at room temperature for 18 h. The solid was
filtered and the filtrate was concentrated in vacuo. The residue
was diluted with EtOAc, washed with H.sub.2O, brine, dried over
MgSO.sub.4, filtered, and concentrated to provide 0.351 g (77%) of
the desired product as a white solid Electrospray Mass Spec: 467.3
(M+H).sup.30
Example 35
tert-butyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)c-
arbonyl]-1-piperidinecarboxylate
[0317]
tert-Butyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxy-
amino)carbonyl]-1-piperidinecarboxylate was prepared according to
the general method as outlined in Example 31. Starting from
tert-Butyl-4-({[4-but-2-ynyloxy)phenyl]sulfonyl}methyl)-4-[(hydroxyamino)-
carbonyl]piperidine-1-carboxylate (0.10 g, 0.214 mmol) 0.074 g
(86%) of the desired product was isolated as white solid.
Electrospray Mass Spec: 367.3 (M+H).sup.30
Example 36
1-Acetyl
4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4-piperidi-
necarboxamide
[0318] Step 1:
4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-1,4-piperidine
dicarboxylic acid, 1-tert-butyl 4-ethyl ester
[0319] To a solution of 1-(tert-butyl) 4-ethyl
4-({[4-(2-butynyloxy)phenyl-
]sulfanyl}methyl)-1,4-piperidinedicarboxylate (1.66 g, 3.7 mmol)
(prepared in example 30, step 6) in 20 mL of CH.sub.2Cl.sub.2 was
added tetrabutylammonium oxone (17.38 g, 14.7 mmol) and stirred at
room temperature for 18 h. The reaction was concentrated in vacuo
and the residue was diluted with EtOAc, washed with H.sub.2O, 5%
KHSO.sub.4, brine, dried over MgSO.sub.4, filtered and concentrated
to provide 1.69 g (95%) of the desired product as a pale yellow
gum. Electrospray Mass Spec: 480.3 (M+H).sup.30
[0320] Step 2
4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]4-piperidinecarb-
oxylic acid, ethyl ester
[0321]
4-[[[42-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic
acid ethyl ester was prepared according to the general method as
outlined in Example 31. Starting from
4-[[[4-(2-Butynyloxy)phenyl]sulfinyl]methyl]-
-1,4-piperidinedicarboxylic acid 1-tert-butyl 4-ethyl ester (1.62 g
3.4 mmol), 1.335 g (95%) of the desired product was isolated as a
tan solid. Electrospray Mass Spec: 380.2 (M+H).sup.30
[0322] Step 3:
1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl)]piper-
idinecarboxylic acid, ethyl ester
[0323] To a solution of
4-[[[4-2-Butynyloxy)phenyl]sulfonyl]methyl]-4-pipe-
ridinecarboxylic acid ethyl ester (0.24 g, 0.576 mmol),
triethylamine (0.32 ml) and catalytic amount of
4-Dimethylaminopyridine in 6.0 mL of CH.sub.2Cl.sub.2 was added a
solution of acetyl chloride (0.068 ml, 0.864 mmol) in 11.0 mL of
CH.sub.2Cl.sub.2. The reaction stirred at room temperature for 4 h
and washed with H.sub.2O, brine, dried over MgSO.sub.4, filtered
through a pad of silica gel and concentrated to provide 0.242 g
(100%) of the desired product as a colorless gum. Electrospray Mass
Spec: 422.2 (M+H).sup.30
[0324] Step 4:
1-Acetyl-4-(4-but-2-ynyloxy-benzenesulfonylmethyl)-piperidi-
ne-4-carboxylic acid
[0325] 1-Acetyl(but-2-ynyloxy-benzenesulfonylmethyl piperidine-4
carboxylic acid was prepared according to the general method as
outlined in Example 30, (step 7). Starting from
1-Acetyl-4-[[[4-(2-butynyloxy)phen-
yl]sulfonyl]methyl]piperidinecarboxylic acid, ethyl ester (0.22 g,
0.524 mmol), 0.141 g of the desired product was isolated as a pale
yellow solid. Electrospray Mass Spec: 438.2 (M+FA-H).sup.31
[0326] Step 5:
1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hyd-
roxy-4-piperidinecarboxamide
[0327]
1-Acetyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]-N-hydroxy-4-p-
iperidinecarboxamide was prepared according to the general method
as outlined in Example 30 (step 8). Starting from
1-Acetyl-4-(4-But-2-ynylox-
y-benzenesulfonylmethyl)-piperidine-4-carboxylic acid, (0.122 g,
0.31 mmol) 0.048 g (38%) of the desired product was isolated as a
pale yellow solid. Electrospray Mass Spec: 409.2 (M+H).sup.30
Example 37
1-2-Butynyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4
piperidinecarboxamide hydrochloride
[0328] Step 1:
1-(2-Butynyl-4-[[[4-(2-butynyloxy)phenyl]sulfonyl]methyl]4--
piperidinecarboxylic acid, ethyl ester
[0329] A mixture of 4-[[[4-2-Butynyloxy)phenyl]sulfonyl]methyl]4
piperidinecarboxylic acid ethyl ester (0.208 g, 0.5 mmol),
1-bromo-2-butyne (0.044 ml, 0.53 mmol) and K.sub.2CO.sub.3 (0.138
g, 1.0 mmol) in 5.0 mL of DMF was stirred at room temperature for 6
h. The reaction was diluted with EtOAc and washed with H.sub.2O,
brine, dried over MgSO.sub.4, filtered, and concentrated in vacuo.
The residue was chromatographed on silica gel eluting with
EtOAc:hexanes (1:1) to provide 0.183 g (85%) of the desired product
as a pale yellow gum. Electrospray Mass Spec: 432.2
(M+H).sup.30
[0330] Step 2:
1-2-Butynyl)-4-[4-2-butynyloxy)benzenesulfonylmethyl]-piper-
idine-4 carboxylic acid
[0331]
1-(2-Butynyl-4[4-(2-butynyloxy)benzenesulfonylmethyl]-piperidine-4
carboxylic acid was prepared according to the general method as
outlined in example 30 (step 7). Starting from
1-(2-Butynyl)4-[[[4-(2-butynyloxy)p-
henyl]sulfonyl]methyl]-4-piperidinecarboxylic acid, ethyl ester,
(0.153 g, 0.354 mmol), 0.12 g (84%) of the desired product was
isolated as a white solid. Electrospray Mass Spec: 404.2
(M+H).sup.+
[0332] Step 3:
1-2-Butynyl)-4-([4-2-butynyloxy)phenyl]sulfonyl}methyl)-N-h-
ydroxy-4 piperidinecarboxamide hydrochloride
[0333]
1-(2-Butynyl)-4-({[4-2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-
-4-piperidinecarboxamide hydrochloride was prepared according to
the general method as outlined in Example 30 (step 8). Starting
from
1-(2-butynyl)-4-[4-(2-butynyloxy)benzenesulfonylmethyl]-piperidine-4-carb-
oxylic acid, (0.15 g, 0.34 mmol), 0.05 g of the desired product,
which was dissolved in 11.0 mL of CH.sub.2Cl.sub.2 and treated with
0.225 mL of 1M HCl in CH.sub.2Cl.sub.2. The solution was stirred
for 1 h, and concentrated in vacuo. The residue was triturated with
ether to provide 0.044 g (280%) of the hydrochloride of the desired
product as a beige solid. Electrospray Mass Spec: 419.2
(M+H).sup.30
Example 38
N-1-(tert-Butyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1,-
4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1,4-1]sulfonyl}meth-
yl)-N-hydroxy-1,4-piperidinedicarboxamide
[0334] Step
1:1-tert-Butylcarbamoyl-4-(4-but-2-ynyloxy-benzenesulfonylmeth-
yl)-piperidine-4-carboxylic acid ethyl ester
[0335] To a solution of tert-butylisocyanate (0.097 ml, 0.85 mmol)
in 8.0 mL of CH.sub.2Cl.sub.2, was added
4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]me- thyl]J
piperidinecarboxylic acid ethyl ester (prepared from example 36,
step 2) (0.337 g, 0.81 mmol) and triethylamine (0.135 ml, 0.97
mmol) and stirred at room-temperature for 2 h. The reaction was
diluted with CH.sub.2Cl.sub.2 and washed with H.sub.2O) brine,
dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
residue was triturated with ether:hexanes (1:1) to provide 0.284 g
(73%) of the desired product as a white solid. Electrospray Mass
Spec: 479.2 (M+H).sup.30
[0336] Step 2:
1-[(tert-Butylamino)carbonyl]4-({[4-(2-butynyloxy)phenyl]su-
lfonyl}methyl)-4-onyl]-4-({[4-(2-butoxy)phenyl]sulfonyl}methyl)-4-piperidi-
necarboxylic acid
[0337]
1-[(tert-Butylamino)carbonyl]4-({[4-(2-butynyloxy)phenyl]sulfonyl}m-
ethyl)-4-onyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl]methyl)-4-piperidine
carboxylic acid was prepared according to the general method as
outlined in Example 30 (step 7). Starting from
1-tert-butylcarbamoyl-4-(4-but-2-yn-
yloxy-benzenesulfonylmethyl)-piperidine-4-carboxylic acid ethyl
ester (0.259 g, 0.54 mmol), 0.169 g, (69%) of the desired product
was isolated as white solid. Electrospray Mass Spec: 451.4
(M+H).sup.30
[0338] Step 3:
N-1-(tert-Butyl)-4-({[(4-(2-butynyloxy)phenyl]sulfonyl}meth-
yl)-N-4-hydroxy-1,4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl-N-4-hydroxy-1,-
4-1]sulfonyl}methyl-N-hydroxy-1,4-piperidinedicarboxamide
[0339]
N-1-(tert-Butyl)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-h-
ydroxy-1,4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-1,4-1]sulf-
onyl}methyl)-N-4-hydroxy-1,4-piperidinedicarboxamide was prepared
according to the general method as outlined in Example 30 (step 8).
Starting from
1-[(tert-Butylamino)carbonyl-4-({[4-(2-butynyloxy)phenyl]su-
lfonyl)methyl)-4-onyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-pipe-
ridinecarboxylic acid (0.149 g, 0.33 mmol), 0.077 g of the desired
product was isolated as pale yellow solid. Electrospray Mass Spec:
466.3 (M+H).sup.30
Example 39
Methyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-[hydroxyamino)carbon-
yl]-1-piperidinecarboxylate
[0340] Step 1:
4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4 dicarboxylic
acid ethyl ester methyl ester
[0341] To a solution of
4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-pip-
eridinecarboxylic acid ethyl ester (0.354 g, 0.85 mmol) in 1.0 mL
of CH.sub.2Cl.sub.2 under N.sub.2 atmosphere was added dropwise a
solution of N,O-bis(trimedysilyl)acetamide (0.462 ml, 1.87 mmol) in
0.5 mL of CH.sub.2Cl.sub.2 and stirred for 1 h. The reaction was
cooled to 0.degree. C. and added dropwise a solution of 0.079 mL
(1.02 mmol) of methylchloroformate in 0.5 mL of CH.sub.2Cl.sub.2.
The reaction was allowed to stir at room temperature for 1 h and
cooled to 0.degree. C., quenched with pH7 buffer solution and
extracted with EtOAc. The organics was washed with H.sub.2O, brine,
dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
residue was chromatographed on silica gel eluting with
EtOAc:hexanes (1:2) to provide 0.315 g (85%) of the desired product
as a colorless oil. Electrospray Mass Spec: 438.3 (M+H).sup.30
[0342] Step 2:
4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4-di-
carboxylic acid monomethyl ester
[0343]
4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4-dicarboxyl-
ic acid monomethyl ester was prepared according to the general
method as outlined in Example 30 (step 7). Starting from
4-(4-But-2-ynyloxy-benzene-
sulfonylmethyl)piperidine-1,4-dicarboxylic acid ethyl ester methyl
ester (0.277 g, 0.633 mmol), 0.175 g (67%) of the desired product
was isolated as white solid. Electrospray Mass Spec: 410.2
(M+H).sup.30
[0344] Step 3: Methyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-4-[(hyd-
roxyamino)carbonyl]-1-piperidinecarboxylate
[0345] Methyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)[(hydroxyamino)
carbonyl]-1-piperidinecarboxylate was prepared according to the
general method as outlined in Example 30 (step 8). Starting from
4-(4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4-dicarboxylic
acid monomethyl ester (0.15 g, 0.366 mmol), 0.053 g (34%) of the
desired product was isolated as a white solid Electrospray Mass
Spec: 425.3 (M+H).sup.30
Example 40
Benzyl
4-({[4-2-butynyloxy)phenyl]sulfonyl)methyl)-4-[(hydroxyamino)carbon-
yl]-1-piperidinecarboxylate
[0346] Step 1:
4-4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4-dic-
arboxylic acid benzyl ester ethyl ester
[0347]
4-4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4-dicarboxyli-
c acid benzyl ester ethyl ester was prepared according to the
general method as outlined in Example 39 (step 1). Starting from
4-[[[4-2-Butynyloxy)phenyl]sulfonyl]methyl]4 piperidinecarboxylic
acid ethyl ester (0.312 g, 0.75), 0.337 g (87%) of the desired
product was isolated as colorless oil. Electrospray Mass Spec:
514.2 (M+H0+
[0348] Step 2:
44-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4-dica-
rboxylic acid monobenzyl ester
[0349]
4-4-But-2-ynyloxy-benzenesulfonylmethyl)-piperidine-1,4-dicarboxyli-
c acid monobenzyl ester was prepared according to the general
method as outlined in Example 30 (step 7). Starting from
4-(4-But-2-ynyloxy-benzene-
sulfonylmethyl)piperidine-1,4-dicarboxylic acid-benzyl ester ethyl
ester (0.32 g, 0.623 mmol), 0.2 g of the desired product was
isolated as white solid. Electrospray Mass Spec: 484.2
(M-H).sup.31
[0350] Step 3: Benzyl-4-[4-2-butynyloxy)phenyl]sulfonyl
methyl)-4-[(hydroxyamino)carbonyl]-1-piperidinecarboxylate
[0351] Benzyl 4-([[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-4
[(hydroxyamino) carbonyl]-1-piperidinecarboxylate was prepared
according to the general method as outlined in Example 30, (step
8). Start from 4-(4-But-2-ynyloxy-benzene
sulfonylmethyl)-piperidine-1,4-dicarboxylic acid monobenzyl ester
(0.18 g, 0.37 mmol), 0.106 g (57%) of the desored product was
isolated as off-white solid. Electrospray Mass Spec: 501.3
(M+H)
Example 41
1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-butynylo-
xy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide
[0352] Step 1:
Ethyl-1-benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-
-4-4-2-butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxylate
[0353]
Ethyl-1-benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-4-(2--
butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxylate was
prepared according to the general method as outlined in Example 37
(step 1). Starting from
4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]4-piperidinecar-
boxylic acid ethyl ester (prepared in Example 36, step 2) (0.312 g,
0.75 mmol), 0.265 g of the desired product was isolated as white
solid. Electrospray Mass Spec: 470.2 (M+H).sup.30
[0354] Step 2:
1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-pip-
eridinecarboxylic-benzyl-4-({[4-(2-butynloxy)phenyl]sulfonyl}methyl)-4-pip-
eridinecarboxylic acid
[0355]
1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)piperidinecarb-
oxylic
benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-4-piperidinecar-
boxylic acid was prepared according to the general method as
outlined in Example 30 (step 7). Starting from
Ethyl-1-benzyl-4-({[4-(2-butynyloxy)ph-
enyl]sulfonyl}methyl)4-4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-piperidin-
ecarboxylate (0.25 g, 0.53 mmol), 0.227 g (90%) of the desired
product was isolated as a white solid. Electrospray Mass Spec.
442.2 (M+H).sup.30
[0356] Step 3:
1-Benzyl-4-({[4-2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydr-
oxy-4-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide
[0357]
1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-b-
utynyloxy)
phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide was
prepared according to the general method as outlined in Example 30
(step 8). Starting from
1-Benzyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-
-piperidinecarboxylic-benzyl-4-({([4-(2
butynyloxy)phenyl]sulfonyl}methyl)- -4-piperidinecarboxylic acid
(0.211 g, 0.44 mmol), 0.108 g of the desired product was isolated
as white solid. Electrospray Mass Spec: 457.2 (M+H).sup.30
Example 42
4-({[4-(2-Butynyloxy)phenyl]sulfonyl)methyl-N-hydroxy-1-[(2,2,5-trimethyl--
1,3-dioxan-5-yl)carbonyl]-piperidinecarboxamide
[0358] Step 1: Ethyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-1-[(2,2,-
5-trimethyl-1,3-dioxan-5-yl)carbonyl]-piperidinecarboxylate
[0359] Ethyl
4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-[2,2,5-trimeth-
yl-1, dioxan-5-yl)carbonyl]-4-piperidinecarboxylate was prepared
according to the general method as outlined in Example 30 (step 8).
Starting from
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxylic
acid ethyl ester (0.333 g, 0.8 mmol) and
2,2,5-trimethyl-(1,3)dioxane-5-carbox- ylic acid (0.168 g, 0.96
mmol), 0.339 g (79%) of the desired product was isolated as a white
solid. Electrospray Mass Spec: 536.1 (M+H).sup.30
[0360] Step 2: 4-({[4-(2-Butynyloxy)phenyl]sulfonyl}m
1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]4-piperidinecarboxylic
acid
[0361]
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-1-[(2,2,5-trimethyl-1,-
3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylic acid was prepared
according to the general method as outlined in Example 30 (step 7).
Starting from ethyl
4-({[4-(2-butynyloxy)phenyl]sulfonylmethyl)-1-[(2,2,5-trimethyl-1,3-
-dioxan-5-yl)carbonyl]-4-piperidinecarboxylate (0.299 g, 0.558
mmol), 0.235 g (83%) of the desired product was isolated as white
solid. Electrospray Mass Spec: 506.2 (M-H).sup.31
[0362] Step 3:
4-({[4-(2-Butnyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(2-
,2,5-trimethyl-1,3
dioxan-5-yl)carbonyl]-4-piperidinecarboxamide
[0363]
4-{[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[(2,2,5-tri-
methyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide was
prepared according to the general method as outlined in Example 30
(step 8). Starting from
4-([4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-1-((2,2,5-trime-
thyl-1,3-dioxan-5-yl)carbonyl]-4 piperidinecarboxylic acid (0.22 g,
0.433 mmol), 0.16 g of the desired product was isolated as white
solid. Electrospray Mass Spec: 523.2 (M+H).sup.30
Example 43
4-({[4-(2-Butynyloxy)phenyl]sulfonylmethyl)-N-hydroxy-1-[3-hydroxy-2-(hydr-
oxymethyl-2-methylpropanoyl]-4-piperdinecarboxamide
[0364] A mixture of
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-
-1-[(2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]-4-piperdinecarboxamide
(0.106 g, 0.2 mmol) and 2 mL of 1N HCl in 2 mL of THF was stirred
at room temperature for 4 h. The reaction was diluted with EtOAc,
washed with H.sub.2O, saturated NaHCO.sub.3, brine, dried over
MgSO.sub.4, filtered, and concentrated in vacuo. The residue was
triturated with ether to provide 0.67 g (71%) of the desired
product as an off white solid Electrospray Mass Spec: 483.2
(M+H).sup.30
Example 44
1-[Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydr-
oxy-4-1]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-oxy)phen-
yl]sulfonyl}methyl)-N-hydroxy-4-piperidinecarboxamide
[0365] Step 1: N,N'-t-Boc-protected thiourea: To a stirred solution
of thiourea (0.57 g, 7.5 mmol) in 150 mL of THF under N.sub.2 at
0.degree. C. was added 60%/NaH (1.35 g, 33.8 mmol) in mineral oil.
After 5 minutes, the ice bath was removed and the reaction mixture
was allowed to stir at room temperature for 10 minutes. The
reaction mixture was cooled to 0.degree. C. and 3.6 g (16.5 mmol)
of di-tert-butyl dicarbonate was added. After 30 minutes, the ice
bath was removed and the reaction was stirred for 2 h The reaction
was then quenched with saturated NaHCO.sub.3 solution, poured into
water and extracted with 3.times.EtOAc. The organics were washed
with H.sub.2O, brine, dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was triturated with hexane to
provide 1.72 g (83%) of the desired product as a white solid.
[0366] Step 2:
tert-Butyl-4-[(tert-butoxyamino)carbonyl]-4-({[4-(2-yloxy)p- henyl
sulfonyl}methyl)-1-piperidinecarboxylate
[0367]
tert-Butyl-4-[(tert-butoxyamino)carbonyl]-4-({[4-(2-yloxy)phenyl]su-
lfonyl}methyl)-1-piperidinecarboxylate was prepared according to
the general method as outlined in Example 30 (step 8). Starting
from 4-(4-but-2-ynyloxy-benzenesulfonyl
methyl)piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.53
g, 5.6 mmol) and O-tert-butyl-hydroxylam- ine hydrochloride (1.4 g,
11.2 mmol), 2.31 g (79%) of the desired product was isolated as a
white solid. Electrospray Mass Spec: 523.2 (M+H).sup.30
[0368] Step 3:
N-(tert-Butoxy)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl-
)-4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxamide
[0369] To a solution of
tert-Butyl-4-[(tert-butoxyamino)carbonyl]4-({[4-(2-
-yloxy)phenyl]sulfonyl)methyl)-1-piperidinecarboxylate (3.0 g, 5.5
mmol) in 6 mL of CH.sub.2Cl.sub.2 was added of
trimethylsilyltrifluoromethylsul- fonate (1.1 ml, 6.05 mmol)
followed by 0.7 mL of 2,6-lutidine. The reaction was stirred for 1
h and diluted with The organics were washed with H.sub.2O,
saturated NaHCO.sub.3, brine dried over MgSO.sub.4, filtered, and
concentrated in vacuo to provide 2.01 g (86%) of the desired
product as an off white solid. Electrospray Mass Spec: 423.2
(M+H).sup.30
[0370] Step 4:
([4[(tert-Butoxyamino)carbonyl]4-[[[4-(2-[2-butynyloxy)
phenyl]sulfonyl}ethyl)-4-piperidinecarboxamide
butoxycarbonyl)amino]methy- lene]carbamic acid, tert-butyl
ester
[0371] To a mixture of
N-(tert-Butoxy)-4-({[4-(2-butynyloxy)phenyl]sulfony- lmethyl)-4-4
(2-butynyloxy)phenyl]sulfonyl)methyl)-4-piperidinecarboxamide
(0.127 g, 0.3 mmol), the di-t-boc-protected thiourea (obtained from
step 1) (0.091 g, 0.33 mmol) and triethylamine (0.092 ml) in 3 mL
of DMF was added mercury(II) chloride (0.09 g, 0.33 mmol) and
stirred for 1 h at 0.degree. C. The reaction was diluted with EtOAc
and filtered through a pad of celite. The organics were washed with
H.sub.2O, brine, dried over MgSO.sub.4, filtered, and concentrated
in vacuo. The residue was triturated with hexanes to provide the
desired product as a white solid. Electrospray Mass Spec: 665.5
(M+H).sup.+
[0372] Step 5:
1-[Amino(imino)methyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl-
}methyl)-N-hydroxy)-4-oxy)phenyl]sulfonyl}methyl)-N-hydroxy-4-piperidineca-
rboxamide
[0373] A mixture of
[[4-[(tert-Butoxyamino)carbonyl]-4-[[[4-(2-[442-[4-(2--
butynyloxy)phenyl]sulfonyl}methyl)-4-piperidinecarboxamide
butoxycarbonyl)amino]methylene]carbamic acid, tert-butyl ester
(0.135 g, 0.2 mmol) and 3 mL of trifluoroacetic acid in 2 mL of
CH.sub.2Cl.sub.2 was heated at 60.degree. C. for 24 h. The reaction
was concentrated in vacuo and was prep HPLC to provide 0.032 g
(31%) of the desired product as a beige solid. Electrospray Mass
Spec: 409.3 (M+H).sup.30
Example 45
4-({[4-(2-Butynyloxy)phenyl]sulfonyl)methyl)-N-hydroxy-1-(4-hydroxy-2
butynyl)-phenyl]sulfonyl}methyl)-N-hydroxy-1-(4-hydroxy-2-butynyl)-4-pipe-
ridinecarboxamide
[0374] Step 1:
Ethyl({[4-(2-butynyloxy)phenyl]sulfonyl}methyl)-4-{[(3-chlo-
roanilino)carbonyl]oxy).sub.2-butynyl)-4-piperidinecarboxylate
[0375] Ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl]methyl)-1-(4-{((3
chloroanilino)carbonyl]oxy)-2-butynyl)-piperidinecarboxylate was
prepared according to the general method as outlined in Example 37
(step 1). Starting from
4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl])-4-piperidinec-
arboxylic acid ethyl ester (0.291 g, 0.7 mmol) and
4-chloro-2-butynyl-(3-c- hlorophenyl)carbamate (0.19 g, 0.735),
0.27 g (64%) of the desired product was isolated as pale yellow
oil. Electrospray Mass Spec: 601.3 (M+H).sup.30
[0376] Step 2:
Ethyl-4-({[(4-(2-butynyloxy)phenyl]sulfonyl}methyl)-1-(4-hy-
droxy-2-butynyl)-4-nyloxy)phenyl]sulfonyl}methyl)-1-4-hydroxy-2-butynyl-4--
piperidine carboxylate
[0377] A solution of
ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl}methyl-1-(-
4-{[(3-chloroanilino)carbonyl]oxy}-2-butynyl)-4-piperidinecarboxylate
(from step 1) 0.22 g, 0.366 mmol) and lithiumhydroxide hydrate
(0.019 g, 0.44 mmol) in 4 mL MeOH was heated to reflux for 3 h. The
reaction was concentrated, diluted with H.sub.2O, acidified to pH3
and extracted with CH.sub.2Cl.sub.2. The organics were washed with
H.sub.2O, brine, dried over MgSO.sub.4, filtered, and concentrated
in vacuo. The residue was chromatographed on silica gel eluting
with 3% MeOH/CH.sub.2Cl.sub.2 to provide 0.12 g (73%) of the
desired product as an yellow oil. Electrospray Mass Spec: 448.3
(M+H).sup.30
[0378] Step 3:
4-({[4-2-Butynyloxy)phenyl]sulfonyl}methyl)-1-(4-hydroxy-2--
butynyl-4-nyl]sulfonyl}methyl-1-(4-hydroxy-2-butynyl)-4-piperidinecarboxyl-
ic acid
[0379]
4-({[4-(2-Butynyloxy)phenyl]sulfonyl}methyl)1-(4-hydroxy-2-butynyl)-
-4
nyl]sulfonyl-}methyl)-1-(4-hydroxy-2-butyl)-4-piperidinecarboxylic
acid was prepared according to the general method as outlined in
Example 30 (step 7). Staring from
ethyl-4-({[4-(2-butynyloxy)phenyl]sulfonyl)methyl)-
-1-(4-hydroxy-2-butynyl)-4-piperidinecarboxylate (0.115 g, 0.257
mmol), 0.08 g (74%) of the desired product was isolated as white
solid. Electrospray Mass Spec: 420.4 (M+H).sup.30
[0380] Step 4:
4-({[442-Butynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-(4-hy-
droxy-2-butynyl)-phenyl]sulfonyl}methyl)-N-hydroxy-yl-4-hydroxy-2-but)-4-p-
iperidinecarboxamide
[0381]
4-({[4-(2-Butynyloxy)phenyl]sulfonylmethyl)-N-hydroxy-[(4-hydroxy-2-
-butynyl)-phenyl]sulfonyl}methyl)-N-hydroxy-(4-hydroxy-2-2
piperidinecarboxamide was prepared according to the general method
as outlined in Example 30 (step 8). Starting from
4-({[4-(2-Butynyloxy)pheny-
l]sulfonyl}methyl)-1-(4-hydroxy-2-butynyl)-4-nyl]sulfonyl}methyl)-1-(4-hyd-
roxy-2-butynyl)-4-piperidinecarboxylic acid (0.073 g, 0.174 mmol),
0.026 g (34%) of the desired product was isolated as white solid.
Electrospray Mass Spec: 435.3 (M+H).sup.30
[0382] Methods for the solution phase synthesis of the compounds of
the present invention is as shown in the following scheme. 28
Example 46
4-({[4{But-2-ynyloxy)phenyl]sulfonyl}methyl)-1-ethyl-N-hydroxypiperidine-4-
-carboxamide triflouroacetic acid salt
[0383] Step A: A solution of
N-tert-butoxy)-4-({[4-2-butynyloxy)phenyl]sul- fonyl)
methyl)-4-[4-(2-butynyloxy)phenyl]sulfonyl}methyl-4-piperidinecarbo-
xyamide (0.097 g, 0.23 mmol), ethyl iodide (0.019 mL, 0.24 mmol)
and triethylamine (0.096 mL, 0.69 mmol) in 2 mL of CH.sub.2Cl.sub.2
was shaken at room temperature for 18 h and then concentrated in
vacuo.
[0384] Step B: A solution of the residue from Step A in 1 mL of
CH.sub.2Cl.sub.2 and 1 mL of trifluoroacetic acid was heated at
50.degree. C. for 2 h and then concentrated in vacuo to provide the
desired product.
[0385] The following hydroxamic acids were synthesized according to
the procedures of
4-([4-But-2-ynyloxy)phenyl]sulfonyl)methyl)-ethyl-N-hydroxy-
piperidine-4 carboxamide triflouroacetic acid salt using the
appropriate reagents.
Example 47
Reagent--0.029 mL (0.24 mmol) of 2-chloro-5-(chloromethyl)
thiophene-4-([4-But-2-ynyloxy)phenyl]sulfonyl}methyl)-1-[(5-chlorothien-2-
-yl)methyl]-N-hydroxypiperidine-4-carboxamide triflouroacetic acid
salt
Example 48
Reagent--0.0496 g (0.24 mmol) of 4-picolyl chloride hydrochloride
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-4-ylme-
thyl)piperidine-4-carboxamide triflouroacetic acid salt
Example 49
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(pyridin-3
ylcarbonyl)piperidine-4-carboxamide triflouroacetic acid salt
[0386] Step A: A solution of
N-tert-butoxy)-4-({[4-92-butynyloxy)phenyl]su-
lfonyl}methyl)-4-[4-(2-butynyloxy)phenyl]sulfonyl)methyl-4-piperidine
carboxyamide (0.097 g, 0.23 mmol), triethylamine (0.064 mL, 0.64
mmol), nicotinoyl chloride hydrochloride (0.061 g, 0.34 mmol), and
4-dimethylaminopyridine (0.002 g) in 2 mL of CH.sub.2Cl.sub.2 was
shaken at room temperature for 18 h and then concentrated in
vacuo.
[0387] Step B: same as Step B of Example 46.
[0388] The following hydroxamic acids were synthesized according to
the procedures of 4
({([(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(p-
yridin-3-ylcarbonyl)piperidinecarboxamide triflouroacetic acid salt
using the appropriate reagents.
Example 50
Reagent--0.04 mL (0.276 mmol) of benzoyl chloride
1-Benzoyl-4-({[4-(but-2--
ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxypiperidine-4-carboxamide
Example 51
Reagent--0.037 mL (0.276 mmol) of 2-thiophenecarbonyl chloride
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(thien-2-ylcarb-
onyl)piperidine-4 carboxamide
Example 52
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-1-ethyl-N-4-hydroxypiperid-
ine-1,4-dicarboxamide
[0389] Step A: A solution of
N-(tert-butoxy)-4-({[492-butynyloxy)phenyl]su-
lfonyl}methyl)-4-[4-(2-butynyloxy)phenyl]sulfonyl)methyl-4-piperidine
carboxyamide (0.097 g, 0.23 mmol), triethylamine (0:064 mL, 0.64
mmol) and ethyl isocyanate (0.02 mL, 0.253 mmol) in 2 mL of
CH.sub.2Cl.sub.2 was shaken at room temperature for 18 h and then
concentrated in vacuo.
[0390] Step B: same as Step B of Example 46.
[0391] The following hydroxamic acids were synthesized according to
the procedures of Example 52 using the appropriate reagents.
Example 53
Reagent--0.275 mL (0.253 mmol) of phenylisocyanate
4-({[4-(But-2-ynyloxy)p-
henyl]sulfonyl}methyl)-N-4-hydroxy-N-1-phenylpiperidine-1,4-dicarboxamide
Example 54
Reagent--0.32 mL (0.253 mmol) of diethylcarbamyl chloride
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-1-,N-1-diethyl-N-4-hydrox-
ypiperidine-1,4-dicarboxamide
Example 55
Reagent-0.0295 mL (0.253 mmol) of morpholine carbonyl chloride
4-({([4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-(morpholin-4-y-
lcarbonyl)piperidine-4-carboxamide
Example 56
Reagent--0.043 g (0.253 mmol) of methylphenylcarbamoyl chloride
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-4-hydroxy-N-1-methyl-N-1--
phenylpiperidine-1,4-dicarboxamide
Example 57
Octyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl}methyl)-[(hydroxyamino)carbony-
l]piperidine-4-carboxylate
[0392] Step A: A solution of 0.097 g (0.23 mmol) of
N-(tert-butoxy)-4-({[4-92-butynyloxy)phenyl]sulfonylmethyl)[42-butynyloxy-
)phenyl]sulfonyl}methyl-4-piperidinecarboxyamide (0.097 g, 0.23
mmol), octyl chloroformate (0.0495 ml, 0.253 mmol) and
diisopropylethylamine (0.08 ml, 0.46 mmol) in 2 mL of
CH.sub.2Cl.sub.2 was shaken at room temperature for 18 h and then
concentrated in vacuo.
[0393] Step B: same as Step B of Example 46.
[0394] The following hydroxamic acids were synthesized according to
the procedures of Example 57 using the appropriate reagents.
Example 58
Reagent--0.038 mL (0.253 mmol) of 4-methoxyphenyl chloroformate
4-Methoxyphenyl-4-({[4-(but-2-ynyloxy)phenylsulfonylmethyl-4-(hydroxyamin-
o)carbonyl]piperidine-1-carboxylate
Example 59
Reagent--0.0323 mL (0.253 mmol) of benzenesulfonyl chloride
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl)methyl)-N-hydroxy-1-(phenylsulfonyl-
) piperidine carboxamide
Example 60
Reagent--0.0457 g (0.253 mmol) of 1-methylimidazole-sulfonyl
chloride
4-({[(4-(But-2-ynyloxy)phenyl]sulfonyl)methyl)-N-hydroxy-[4-[(1-methyl-1H-
-imidazol-4-yl)sulfonyl]piperidine-carboxamide
Example 61
1-12
(Benzylamino)acetyl-4-({[4-(but-2-ynyloxy)phenyl]sulfonyl)methyl)-N-h-
ydroxypiperidine-4-carboxamide
[0395] Step A: A solution of
N-tert-butoxy)-4-([42-butynyloxy)phenyl]sulfo-
nyl}methyl)-4-[4-(2-butynyloxy)phenyl]sulfonylmethyl-4 piperidine
carboxyamide (0.097 g, 0.23 mmol), triethylamine (0.064 mL, 0.64
mmol), chloroacetyl chloride (0.064 ml, 0.64 mmol), and
4-dimethylaminopyridine (0.002 g) in 2 mL of CH.sub.2Cl.sub.2 was
shaken at room temperature for 18 h The solution was then treated
with benzyl amine (0.075 mL, 0.69 mmol) and was shaken for 18 h and
then concentrated in vacuo.
[0396] Step B: same as Step B of Example 46.
[0397] The following hydroxamic acids were synthesized according to
the procedures of Example 61 using the appropriate amine
reagents.
Example 62
Reagent --0.060 mL (0.69 mmol) of morpholine
4-({[4-(But-2-ynyloxy)phenyl]-
sulfonyl}methyl)-N-hydroxy-1-(2-morpholin 4
ylacetyl)piperidine-4-carboxam- ide
Example 63
Reagent--0.076 mL (0.69 mmol) of N-methylpiperazine
4-({[4-(But-2-ynyloxy)phenyl]sulfonyl}methyl)-N-hydroxy-1-[2-(4
methylpiperazin-1-yl)acetyl]piperidine 4-carboxamide
[0398]
1 Example # HPLC retention time (min.).sup.1 MS.sup.2 (M + H).sup.+
46 1.85 395 47 2.20 498 48 1.71 458 49 2.11 472 52 2.30 438 53 2.85
486 57 3.80 523 58 2.98 517 54 2.87 466 55 2.33 480 56 2.84 500 59
2.92 507 60 2.40 511 50 2.67 471 51 2.64 477 61 2.14 514 62 1.86
494 63 1.84 507 .sup.1LC conditions: Hewlett Packard 1100; YMC
ODS-A 4.6 mm .times. 50 mm 5u 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: 98% A; Post time 1 min. Flow rate 2.5 mL/min; Detection:
220 and 254 nm DAD .sup.2Mass Spec conditions: API-electrospray
Example 64
1-Acetyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic
add hydroxamide
[0399] Step 1: 4-But-2-ynyloxybenzenesulfonyl fluoride:
[0400] To a solution of 4-but-2-ynyloxybenzenesulfonyl chloride
(prepared from Example 30, step 4) (2.0 g, 8.18 mmol) in
acetonitrle (10 ml) was added KF--CaF.sub.2 (2.85 g, 16.3 mmol) and
the resulting mixture was stirred for 4 hours at room temperature.
The reaction mixture was filtered and the filterate was
concentrated. The crude product was dissolved in EtOAc and washed
with water. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and the solvent was removed to obtain 1.5 g (80%)
of the product as solid.
[0401] Step 2:
4-(4-But-2-ynyloxybenzenesulfonyl)-piperidine-1,4-dicarboxy- lic
acid tert-butyl ester methyl ester
[0402] To a solution of diisopropylamine (1.58 mL, 11.3 mmol) in
THF (25 mL) at 0.degree. C. was added 2.5M n-BuLi (4.68 mL, 11.7
mmol) and the resulting mixture was stirred for 15 min at that
temperature. The reaction mixture was cooled to -78.degree. C. and
a solution of 1-(tert-butyl)methyl 1,4-piperidinecarboxylate
(prepared from example 30, step 1) (2.67 g, 11.0 mmol) in THF (40
mL) was added. The resulting mixture was stirred for 1 h and a
solution of 4-but-2-ynyloxy benzenesulfonyl fluoride (2.5 g, 11.0
mmol) in THF (25 mL) was added into it. After stirring for 4 h at
rt, the reaction was quenched with satd. aqueous NH.sub.4Cl
solution and extracted with EtOAc, dried over anhydrous
Na.sub.2SO.sub.4. The crude product was purified by silica gel
chromatography to obtain 2.6 g (53%) of the product as a solid;
.sup.1H NMR (300 Mk, CDCl.sub.3) .delta. 1.44(s, 9H), 1.87(m, 3H),
1.98(m, 2H), 2.32(m, 2H), 2.62(m, 2H), 3.74(s, 3H), 4.17(m, 2H),
4.74(m, 2H), 7.09(d, 2K J=7.2 Hz), 7.71(d, 2H, J=7.2 Hz).
[0403] Step 3:
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid
methyl ester:
[0404] To a solution of product from step 2 (500 mg, 1.11 mmol) in
methylene chloride (10 ml) was added 4M HCl (2 ml) and the
resulting mixture was stirred for 2 hours at room temperature. The
solid was filtered, washed with ether to obtain 410 mg (95%) of the
product as a solid .sup.1H NMR (300 MD, CDCl.sub.3):.delta. 1.86(m,
3H), 2.52(m, 4H), 2.89(m, 2H), 3.52(m, 2H), 3.74(s, 3H), 4.74(m,
2H), 7.10(d, 2H, J=8.7 Hz), 7.69(d, 2H, J=8.7 Hz).
[0405] Step 4:
1-Acetyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine carboxylic
acid methyl ester
[0406] To a solution of product from step 3 (105 mg, 0.23 mmol) in
methylene chloride (1 ml) was added triethylamine (93 mg, 0.92
mmol), acetyl chloride (18 mg, 0.23 mmol) followed by a catalytic
amount of dimethylaminopyridine. The resulting mixture was stirred
for 8 hours at room temperature, quenched with water and extracted
with methylene chloride. The organic layer was dried over anhydrous
sodium sulfate and concentrated to give 75 mg (80%) of the product
as a solid.
[0407] Step 5:
1-Acetyl(but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxyl- ic
acid:
[0408] A solution of the ester, from step 4 (240 mg, 0.61 mmol))
and lithium hydroxide (18 mg, 0.75 mmol)) in
tetrahydrofuran/methanol/water (3:3:2) mixture was stirred at room
temperature for 15 hours. The mixture was concentrated, acidified
to pH 3-5 with 1N aqueous hydrochloric acid, and exacted with ethyl
acetate. The organic layer was washed with brine and dried over
anhydrous sodium sulfate. Removal of the solvent under vacuo gave
the acid. Yield 200 mg, (87%). .sup.1H NMR(300 MHz,
acetone-d.sub.6):.delta. 1.84(t, 3H J=2.8 Hz) 1.90-2.05(m, 2H),
2.06(s, 3H), 2.25-2.51(m, 3H), 3.06(m, 1H), 4.04(m, 1H), 4.63(m,
1H), 4.86(q, 1H, J=2.0).
[0409] Step 6:
1-Acetyl(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carbox- ylic
acid hydroxamide:
[0410] To a solution of
1-acetyl(4-but-2-ynyloxybenzenesulfonyl)piperidine- -4 carboxylic
acid (180 mg, 0.48 mmol) in dimethylformamide was added
hydroxybenzotriazol (77 mg, 0.57 mmol) followed by
1-3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (127 mg,
0.66) and N-methylmorpholine (0.078 ml, 0.71 mmol). The resulting
mixture was stirred for 1 h at room temperature when 50% aqueous
hydroxylamine solution (0.145 ml, 2.37 mmol) was added and the
mixture was stirred for 15 h at that temperature. The solvent was
removed in vacuo and ethyl acetate/water was added to the crude
product. The organic layer was separated and washed successively
with 1N aqueous hydrochloric acid, water, saturated aqueous sodium
bicarbonate, and water. The organic layer was dried over anhydrous
sodium sulfate and the solvent was removed in vacuo to obtain 100
mg (53%) of the product as a solid. .sup.1H NMR(300 MHz,
CDCl.sub.3):.delta. 1.64(m, 1H), 1.85(m, 3H), 1.99(s, 3H), 2.31(m,
4H), 2.83(m, 1H), 3.88(m, 1H), 4.41(m, 1H), 4.88(m, 2H), 7.16(d,
2H, J=9.0 Hz), 7.66(d, 21-t 3=9.0 Hz), 9.26(m, 1H), 1.00(m, 1H);
MS-ES: m/z 395.2 (M+H).sup.+.
Example 65
1-Benzo-(4-but-2-ynyloxybenzenesulfonyl)piperidino 4-carboxylic
acid hydroxamide
[0411] Step 1: 1-Benzoyl(4-but-2-ynyloxybenzenesulfonyl)piperidine
4-carboxylic acid methyl ester
[0412] To a solution of
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-c- arboxylic acid
methyl ester, (400 mg, 1.03 mmol) in chloroform (10 ml) was added
triethylamine (416 mg, 4.12 mmol), benzoyl chloride (144 .mu.l,
1.24 mmol) followed by a catalytic amount of dimethylaminopyridine.
The resulting mixture was stirred for 15 hours at room temperature,
quenched with water and exacted with methylene chloride. The
organic layer was dried over anhydrous sodium sulfate and
concentrated to give 375 mg (80%) of the product as a solid. MS-ES:
m/z 456.1 (M+H).sup.+.
[0413] Step 2:
1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-ca-
rboxylic acid
[0414]
1-Benzoyl(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic
acid was prepared, starting from
1-benzoyl-4-(4-but-2-ynyloxybenzenesulfo-
nyl)piperidine-4-carboxylic acid methyl ester (300 mg, 0.66 mmol)
and lithium hydroxide (18 mg, 0.75 mmol). The resulting reaction
mixture was worked up as outlined in Example 64, (step 5). Yield:
250 mg (86%) of the acid. HR-MS: m/z Calculated for
C.sub.23H.sub.23NO.sub.6S 442.1319; Found 442.1317.
[0415] Step 3:
1-Benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-ca-
rboxylic acid hydroxamide
[0416] The general procedure for step 6 (Example 64) was followed
using
1-benzoyl-4-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-carboxylic
acid (100 mg, 0.23 mmol) in dimethylformamide (2 ml),
1-hydroxybenzotriazole (36 mg, 0.27 mmol),
1-[3-(dimethylamino)propyl]-3-thylcarbodiimide hydrochloride (62
mg, 0.32 mmol), N-methylmorpholine (0.038 ml, 0.35 mmol), and
hydroxylamine (0.083 ml, 1.15 mmol) to obtain 40 mg (38%) of the
product as a solid. MS-ES: m/z 457.2 (M+H).sup.+.
Example 66
1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxy
benzenesulfonyl)piperidine-4 carboxylic acid hydroxamide
[0417] Step 1:
1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl)pipe-
ridine-4 carboxylic acid methyl ester
[0418] To a solution of
4-(4-but-2-ynyloxy-benzenesulfonyl)piperidine-4-ca- rboxylic acid
methyl ester (260 mg, 0.77 mmol) in chloroform (7 ml) was added
triethylamine (311 mg, 3.08 mmol), 4-methoxybenzoyl chloride (158
g, 0.92 mmol) followed by a catalytic amount of
dimethylaminopyridine. The resulting mixture was stirred for 15
hours at room temperature, quenched with water and extracted with
methylene chloride. The organic layer was dried over anhydrous
sodium sulfate and concentrated to give 280 mg (75%) of the product
as a solid. HR-MS: m/z Calculated for C.sub.25H.sub.27NO.sub.7S
486.1581; Found 486.1576.
[0419] Step 2:
1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl)pipe-
ridine-4-carboxylic acid.
[0420]
1-(4-Methoxybenzoyl)-(4-but-2-ynyloxybenzenesulfonyl)piperidine-4-c-
arboxylic acid was prepared following the procedure of Example 64
(step 5). Starting from
1-(4-methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl)- piperidine
4-carboxylic acid methyl ester 250 mg, 0.52 mmol) in 4 ml of
tetrahydrofuran: methanol (1:1) and 1N sodium hydroxide (1.03 ml,
1.03 mmol) 150 mg of (62%) of the acid was isolated. HR-MS: m/z
Calculated for C.sub.24H.sub.25NO.sub.7S 472.1425; Found
472.1426.
[0421] Step 3:
1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl)pipe-
ridine-4-carboxylic acid hydroxamide:
[0422]
1-(4-Methoxybenzoyl)-4-(4-but-2-ynyloxybenzenesulfonyl)piperdine-4
carboxylic acid-hydroxamide was prepared following the procedure
Example 64 (step 6). Starting from
1-(4-methoxybenzoyl-(4-but-2-ynyloxybenzenesul- fonyl)
piperidinecarboxylic acid (90 mg, 0.19 mmol) in dimethylformamide
(2 ml), 1-hydroxybenzotriazole (31 mg, 0.23 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (51
mg, 0.27 mmol), N-methylmorpholine (0.031 ml, 0.28 mmol), and
hydroxylamine (0.068 ml 0.95 mmol), 70 mg (76%) of the product was
isolated as solid. HR-MS: m/z Calculated for
C.sub.24H.sub.26N.sub.2O.sub.7S 487.1534; Found 487.1531.
Example 67
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(pyrrolidine-1-carbonyl)-4--
piperidinecarboxamide
[0423] Step 1:
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbony-
l)-piperidine-4-carboxylic acid methyl ester
[0424] To a solution of
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-c- arboxylic acid
methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added
triethylamine (208 mg, 2.06 mmol), pyrrolidinecarbonyl chloride
(206 mg, 1.54 mmol) followed by a catalytic amount of
dimethylaminopyridine. The resulting mixture was stirred for 15
hours at room temperature, quenched with water and extracted with
methylene chloride. The organic layer was dried over anhydrous
sodium sulfate and concentrated to give 400 mg (87%) of the product
as a solid; MS-ES: m/z 449.3 (M+H).sup.+.
[0425] Step 2:
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1-carbony-
l)-piperidinecarboxylic acid:
[0426] 4-(4-But-2-ynyloxybenzenesulfonyl)-1-(pyrrolidine-1
carbonyl)-piperidinecarboxylic acid was prepared following the
procedure of Example 64 (step 5). Starting from
4-(4-but-2-ynyloxybenzenesulfonyl)--
1-(pyrrolidine-1-carbonyl)-piperidine-4-carboxylic acid methyl
ester (250 mg, 0.52 mmol) in 4 ml of tetrahydrofuran: methanol
(1:1) and 1N sodium hydroxide (1.03 ml, 1.03 mmol), 150 mg of (62%)
of the acid was isolated. HR-MS: m/z Calculated for
C.sub.24H.sub.25NO.sub.7S 472.1425; Found 472.1426.
[0427] Step 3:
4-(4-(But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(pyrrolidin-
e-1-carbonyl)-4-piperidinecarboxamide was prepared following the
procedure Example 64 (step 6). Starting from
4-(4-But-2-ynyloxybenzenesulfonyl)-N-h-
ydroxy-1-(pyrrolidine-1-carbonyl)-4-piperidinecarboxalic acid (255
mg, 0.23 mmol) in dimethylformamide (6 ml), 1-hydroxybenzotriazole
(96 mg, 0.71 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (157 mg, 0.82 mmol), N-methylmorpholine (0.099 ml,
0.84 mmol), and hydroxylamine (0.181 ml, 2.8 mmol), 150 mg (60%) of
the product was isolated as a solid. HR-MS: m/z Calculated for
C.sub.21H.sub.27N.sub.3O.s- ub.6S 450.1693; Found 450.1692.
Example 68
Ethyl
4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-1-pipe-
ridinecarboxylate
[0428] Step 1: 1-Ethyl 4-methyl
4-(4-but-2-ynyloxybenzenesulfonyl)-1,4-pip-
eridinedicarboxylate
[0429] To a solution of
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-c- arboxylic acid
methyl ester (400 mg, 1.03 mmol) in chloroform (10 ml) was added
sodium bicarbonate (865 mg, 10.3 mmol), ethylchloroformate (0.147
ml, 1.54 mmol). The resulting mixture was stirred for 15 hours at
room temperature, quenched with water and extracted with methylene
chloride. The organic layer was dried over anhydrous sodium sulfate
and concentrated to give 425 mg (98%) of the product as a solid.
MS-ES: m/z 424.4 (M+H).sup.+.
[0430] Step 2:
1-(Ethylcarbonyl)-4-(4-but-2-ynyloxybenzenesulfonyl)-1-pipe-
ridinecarboxylic acid
[0431]
1-(Ethylcarbonyl)-4-(4-but-2-ynyloxybenzenesulfonyl)-1-piperidineca-
rboxylic acid was prepared following the procedure of Example 64
(step 5). Starting from 1-Ethyl 4-methyl
4-(4-but-2-ynyloxybenzenesulfonyl)-1,4-pip- eridinedicarboxylate
(400 mg, 0.95 mmol) in 8 ml of tetrahydrofuran:methanol:water
(1:1:0.5) and lithium hydroxide (50 mg, 2.04 mmol), 340 mg of (88%)
of the acid was isolated. HR-MS: m/z Calculated for
C.sub.19H.sub.23NO.sub.7S 408.1122; Found 408.1126.
[0432] Step 3: Ethyl
4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)c-
arbonyl]-1-piperidinecarboxylate
[0433] Ethyl
4-(4-but-2-ynyloxybenzenesulfonyl)-4-[(hydroxyamino)carbonyl]-
-1-piperidinecarboxylate was prepared following the procedure
Example 64 (step 6). Starting from
1-(Ethylcarbonyl)-4-(4-but-2-ynyloxybenzenesulfon-
yl)-1-piperidinecarboxylic acid (225 mg, 0.55 mmol) in
dimethylformamide (6 ml), 1-hydroxybenzotriazole (89 mg, 0.66
mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (148 mg, 0.77 mmol), N-methylmorpholine (0.091 ml,
0.86 mmol), and hydroxylamine (0.168 ml, 2.75 mmol), 150 mg (64%)
of the product was isolated as a solid. HR-MS: m/z Calculated for
C.sub.19H.sub.24N.sub.2O.sub.7S 425.1377; Found 425.1375.
Example 69
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydro-1-[(trifluoromethyl)sulfonyl].s-
ub.u piperidinecarboxamide
[0434] Step 1: Methyl
4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(trifluorometh-
yl)sulfonyl]+piperidinecarboxylate
[0435] To a solution of
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-c- arboxylic acid
methyl ester (350 mg, 0.90 mmol) in chloroform (10 ml) was added
triethylamine (182 mg, 1.81 mmol), trifluoromethanesulfonyl
chloride (0.125 ml, 1.17 mmol) followed by a catalytic amount of
dimethylaminopyridine. The resulting mixture was stirred for 15
hours at room temperature, quenched with water and extracted with
methylene chloride. The organic layer was dried over anhydrous
sodium sulfate and concentrated to give 245 mg (56%) of the product
as a solid. HR-MS: m/z Calculated for
C.sub.18H.sub.20F.sub.3NO.sub.7S.sub.2 484.0706; Found
484.0700.
[0436] Step 2:
4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl)sulf-
onyl]-4-piperidinecarboxylic acid
[0437]
4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(trifluoromethyl)sulfonyl]-pi-
peridinecarboxylic acid was prepared following the procedure of
Example 64 (step 5). Starting from Methyl
4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(tri- fluoromethyl)
sulfonyl]-piperidinecarboxylate (225 mg, 0.47 mmol) in 8 ml of
tetrahydrofuran:methanol:water (1:1:0.5) and lithium hydroxide (24
mg, 0.98 mmol), 175 mg of (80%) of the acid was isolated. MS-ES:
m/z 468.1 (M-H).sup.-.
[0438] Step 3:
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(trifluorom-
ethyl)sulfonyl]-4 piperidinecarboxamide.
[0439] 4-(4-but-2-ynyloxy
benzenesulfonyl)-N-hydroxy-1-[(trifluoromethyl) sulfonyl]4
piperidinecarboxamide was prepared following the procedure Example
64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[-
(trifluoromethyl) sulfonyl]-4-piperidinecarboxylic acid (145 mg,
0.31 mmol) in dimethylformamide (3 ml), 1-hydroxybenzotriazole (50
mg, 0.37 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (83 mg, 0.47 mmol), N-methylmorpholine (0.051 ml,
0.47 mmol), and hydroxylamine (0.095 ml, 1.55 mmol), 90 mg (60%) of
the product was isolated as a solid. HR-MS: m/z Calculated for
C.sub.17H.sub.19N.sub.2O.s- ub.7S.sub.2 485.0659; Found
485.0666.
Example 70
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)-4-pip-
eridinecarboxamide
[0440] Step 1: Methyl
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcar-
bonyl)-4-piperidinecarboxylate
[0441] To a solution of
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-c- arboxylic acid
methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was
added triethylamine (443 mg, 4.39 mmol), nicotinyl chloride (276
ml, 1.55 mmol) followed by a catalytic amount of
dimethylaminopyridine. The resulting mire was stirred for 15 hours
at room temperature, quenched with water and exacted with methylene
chloride. The organic layer was dried over anhydrous sodium sulfate
and concentrated to give 460 mg (78%) of the product as a solid.
HR-MS: m/z Calculated for C.sub.23H.sub.24N.sub.2O.sub.6S 457.1428;
Found 457.1428.
[0442] Step 2:
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)--
4-piperidinecarboxylic acid
[0443]
4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperi-
dine carboxylic acid was prepared following the procedure of
Example 64 (step 5). Starting from Methyl
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(3-py- ridinylcarbonyl)
4-piperidinecarboxylate (430 mg, 0.94 mmol) in 8 ml of
tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml,
1.89 mmol) to obtain 235 mg (57%) of the acid. HR-MS: m/z
Calculated for C.sub.22H.sub.22N.sub.2O.sub.6S 443.1271; Found
443.1270.
[0444] Step 3:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinyl-
carbonyl)-4-piperidinecarboxamide was prepared following the
procedure Example 64 (step 6). Starting from
4-But-2-ynylobenzenesulfonyl)-1-(3-pyr-
idinylcarbonyl)4-piperidinecarboxylic acid (195 mg, 0.44 mmol) in
dimethylformamide (4 ml), 1-hydroxybenzotriazole (72 mg, 0.53
mmol), 1-(3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (119 mg, 0.62 mmol), N-methylmorpholine (0.072 ml,
0.66 mmol), and hydroxylamine (0.135 mL 2.2 mmol), 65 mg (32%) of
the product was isolated as a solid. HR-MS: m/z Calculated for
C.sub.22H.sub.23N.sub.3O.sub.6S 458.1380; Found 458.1373.
Example 71
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)-4-piper-
idinecarboxamide
[0445] Step 1: Methyl
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbo-
nyl)-4-piperidinecarboxylate
[0446] To a solution of
4-4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4 carboxylic acid
methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was
added triethylamine (261 mg, 2.58 mmol), thiophenylcarbonyl
chloride (227 mg, 1.55 mmol) followed by a catalytic amount of
dimethylaminopyridine. The resulting mixture was stirred for 15
hours at room temperature, quenched with water and extracted with
methylene chloride. The organic layer was dried over anhydrous
sodium sulfate and concentrated to give 480 mg (81%) of the product
as a solid. HR-MS: m/z Calculated for
C.sub.22H.sub.23NO.sub.6S.sub.2 462.1040; Found 462.1039.
[0447] Step 2:
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4--
piperidinecarboxylic acid
[0448] 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4
piperidinecarboxylic acid was prepared following the procedure of
Example 64 (step 5). Starting from Methyl
4-(4-but-2-ynyloxybenzenesulfonyl)1-(2-- thienylcarbonyl)
4-piperidinecarboxylate (435 mg, 0.94 mmol) in 8 ml of
tetrahydrofuran:methanol (1:1), and 1N sodium hydroxide (1.89 ml
1.89 mmol) to obtain 360 mg (86%) of the acid. HR-MS: m/z
Calculated for C.sub.21H.sub.21NO.sub.6S 448.0883; Found
448.0882.
[0449] Step 3:
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylca-
rbonyl) 4-piperidinecarboxamide
[0450]
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)--
4-piperidinecarboxamide was prepared following the procedure
Example 64 (step 6). Starling from
4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylca- rbonyl)-4
piperidinecarboxylic acid (335 mg, 0.75 mmol) in dimethylformamide
(7 ml), 1-hydroxybenzotriazole (121 mg, 0.90 mmol),
1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (201
mg, 1.05 mmol), N-methylmorpholine (0.124 ml, 1.13 mmol), and
hydroxylamine (0.229 ml, 3.75 mmol), 216 mg (62%) of the product
was isolated as a solid. HR-MS: m/z Calculated for
C.sub.21H.sub.22N.sub.2O.sub.6S.sub.2 463.0992; Found 463.0988.
Example 72
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl)sulfonyl]-
-4-piperidinecarboxamide
[0451] Step 1: Methyl 4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(4
methoxyphenyl)sulfonyl]piperidinecarboxylate
[0452] To a solution of
4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-c- arboxylic acid
methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was
added triethylamine (261 mg, 2.58 mmol), 4-methoxyphenylsulfonyl
chloride (320 mg, 1.55 mmol) followed by a catalytic amount of
dimethylaminopyridine. The resulting mixture was stirred for 15
hours at room temperature, quenched with water and extracted with
methylene chloride. The organic layer was dried over anhydrous
sodium sulfate and concentrate to give 590 mg (88%) of the product
as a solid. HR-MS: m/z Calculated for C.sub.24H.sub.72NO.sub.8S
522.1251; Found 522.1252.
[0453] Step 2:
4-(4-But-2-ynyloxybenezenesulfonyl)-1-[(4-methoxyphenyl)sul-
fonyl]-4-piperidinecarboxylic acid
[0454]
4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(4-methoxyphenyl)sulfonyl]-pi-
peridine carboxylic acid was prepared following the procedure of
Example 64 (step 5) Starting from methyl-(4-but-2
ynloxybenzenesulfonyl)-[(4-meth-
oxyphenyl)sulfonyl]4-piperidinecarboxylate (545 mg, 1.04 mmol) in 8
ml of tetrahydrofuran methanol (1:1>, and 1N sodium hydroxide
(2.091 mL 2.09 mmol) to obtain 446 mg (85%) of the acid. HR-MS: m/z
Calculated for C.sub.23H.sub.25NO.sub.8S.sub.2 508.1094; Found
508.1073.
[0455] Step 3:
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyp-
henyl)sulfonyl]4-piperidinecarboxamide
[0456]
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(4-methoxyphenyl)su-
lfonyl]-4-piperidinecarboxamide was prepared following the
procedure Example 64 (step 6). Starting from 4
(But-2-ynyloxybenzenesulfonyl)-1-[(4-
-methoxyphenyl)sulfonyl]-4-piperidinecarboxylic acid (402 mg, 0.79
mmol) in dimethylformamide (8 ml), 1-hydroxybenzotriazole (128 mg,
0.95 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (212 mg, 1.11 mmol), N-methylmorpholine (0.130 ml,
1.19 mmol), and hydroxylamine (0.242 ml, 3.95 mmol), 396 mg (96%)
of the product was isolated as a solid. HR-MS: m/z Calculated for
C.sub.23H.sub.26N.sub.2O.sub.8S.sub.2 523.1203; Found 523.1198.
Example 73
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-ethyl-1,3-dioxan-5--
yl)carbonyl]-4-piperidinecarboxamide
[0457] Step 1: Methyl
4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimeth-
yl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxylate
[0458] Methyl
4-4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-di-
oxan-5-yl)carbonyl]4-piperidine-4-carboxylate was prepared
following the procedure Example 64 (step 6). Starting from
4-(4-but-2-ynyloxy-benzenesu- lfonyl)-piperidine-4-carboxylic acid
methyl ester (500 mg, 1.29 mmol) in dimethylformamide (10 ml),
(2,2,5-trimethyl-1,3-dioxan-5-yl)carboxylic acid (224 mg, 1.29
mmol), 1-hydroxybenzotriazole (209 mg, 1.56 mol),
1-3-(dimethylamino)propyl]-3-ethlcarbodiimide hydrochloride (346
mg, 1.81 mol), and N-methylmorpholine (0.212 ml, 1.94 mmol), to
obtain 385 mg (59%) of the product as a solid. HR-MS: m/z
Calculated for C.sub.25H.sub.33NO.sub.8S 508.2000; Found
508.1998.
[0459] Step 2:
4-(4-but-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3--
dioxan-5-yl)carbonyl]-4-piperidinecarboxylic acid
[0460]
4-(4-But-2-ynyloxybenzenesulfonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-
-yl)carbonyl]-4-piperidinecarboxylic acid was prepared following
the procedure of Example 40 (step 5). Starting from Methyl
4-(4-but-2-ynyloxybenzenesulfonyl-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)car-
bonyl]-4-piperidinecarboxylate (335 mg, 0.66 mmol) in 4 ml of
tetrahydrofuran: methanol (1:1), and 1N sodium hydroxide (1.3 ml,
1.3 mmol) to obtain 315 mg (97%) of the acid. HR-MS: m/z Calculated
for C.sub.24H.sub.33NO.sub.8S 494.1843; Found 494.1835.
[0461] Step 3:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trim-
ethyl-1,3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide:
[0462]
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[(2,2,5-trimethyl-1,-
3-dioxan-5-yl)carbonyl]-4-piperidinecarboxamide was prepared
following the procedure Example 64 (step 6). Starting from
4-(4-but-2-ynyloxybenzenesul-
fonyl)-1-[(2,2,5-trimethyl-1,3-dioxan-5-yl)carbonyl]piperidinecarboxylic
acid (280 mg 0.57 mmol) in dimethylformamide (6 ml),
1-hydroxybenzotriazole (92 mg, 0.57 mmol),
1-[(3-dimethylamino)propyl]-3-- ethylcarbodiimide hydrochloride
(153 mg, 0.80 mmol), N-methylmorpholine (0.094 ml, 0.85 mmol), and
hydroxylamine (0.174 ml, 2.85 mmol), 180 mg (62/e) of the product
was isolated as a solid. HR-MS: m/z Calculated for
C.sub.24H.sub.32N.sub.2O.sub.3S 531.1771; Found 531.1768.
Example 74
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-[3-hydroxy-2-(hydroxymethyl-
)-2-methylpropanoyl]-4-piperidinecarboxamide
[0463] To a solution of product from Example 73 (150 mg, 0.29 mmol)
in tetrahydrofuran (2 ml) was added 1N aqueous hydrochloric acid (2
ml) and the resulting mixture was stirred for 4 hour. The organic
layer was washed with sodium bicarbonate, brine and dried over
anhydrous sodium sulfate. Solvent was removed to obtain 40 mg (29%)
of the product HR-MS: m/z Calculated for
C.sub.21H.sub.28N.sub.2O.sub.8S 469.1639; Found 469.1637.
Example 75
Tert-butyl
4-([4-(2-butynyloxy)phenyl]sulfonyl)-4-[(hydroxyamino)carbonyl]-
-1-piperidinecarboxalate
[0464] Step 1:
1-(tert-butoxycarbonyl)-4-{([4-(2-butynyloxy)phenyl]sulfony-
l)piperidinecarboxylic acid
[0465] A solution of
4-(4-but-2-ynyloxybenzenesulfonyl)-piperidine-1,4-dic- arboxylic
acid tert-butyl ester methyl ester (from example 64, step 2) (15 g,
33.2 mmol) in water (100 mL), methanol (50 mL) and tetrahydrofuran
(50 mL) was treated with lithium hydroxide hydrate (2.73 g, 66.4
mmol) and heated at red for 8 h. The reaction mixture was
concentrated in vacuo and filtered through celite. To the filtrate
was added aqueous 1N hydrochloric acid. A thick gum was obtained
which was dissolved in dichloromethane and washed with water.
Concentration of the organic phase gave a foam (14.9 g).
Trituration with diethyl ether gave
1-(tert-butoxycarbonyl-4-([4-(2-butnyloxy)phenyl]sulfonyl}4-piperidinecar-
boxylic acid as a white powder. Electrospray MS m/z 482
(M-H).sup.-
[0466] Step 2: Tert-butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(hydroxy- amino)
carbonyl]-1-piperidinecarboxalate
[0467] Dimethylformamide (3.53 mL, 46 mmol) was added to a solution
of oxalyl chloride (22.9 mL of a 2.0M solution in dichloromethane)
in dichloromethane (25 mL) at 0.degree. C. After 15 min a solution
of
1-(tert-butoxycarbonyl-4-([4-(2-butynyloxy)phenyl]sulfonyl}4-piperidineca-
rboxylic acid (10 g, 22.9 mmol) in dimethylformamide was added and
the reaction mixture was allowed to warm to room temperature. After
1 h the reaction mixture was added to a mixture of hydroxylamine
hydrochloride (16 g 229 mmol), triethylamine (48 mL, 344 mmol),
water (123 mL) and tetrahydrofuran (500 mL) that had been stirring
at 0.degree. C. for 15 min. The reaction was allowed to warm to
room temperature. After 18 h it was then diluted with ethyl acetate
and washed with saturated aqueous sodium bicarbonate (3.times.),
then dried over potassium carbonate and concentrated in vacuo.
Trituration with diethyl ether gave tert-butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl)-4[(hydroxyamino)carbonyl]-1-piperidi-
necarboxalate as a white powder (6.3 g). .sup.1H NMR (dmso d6, 300
MHz) .delta. 1.38 (s, 9H, t-butyl), 1.6-1.7 (m, 2H, CHH), 1.85 (t,
3H, CH3, J=2.2 Hz), 2.2-2.3 (m, 2H, CHH, 2.5-2.7 (m, 2H, NCHH),
3.9-4.0 (m, 2H, NCHH), 4.87 (q, 2H, OCH2, J=2.2 Hz), 7.1-7.7 (m,
4H, ArH). Electrospray MS m/z 453 (M+H).sup.30
Example 76
4-{[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydroxy-4-piperidinecarboxamide
hydrochloride
[0468] To tert-butyl
4-{[4-(2-butynyloxy)phenyl]sulfonyl})[(hydroxyamino)
carbonyl]-1-piperidinecarboxalate (prepared from Example 75) (6.3
g, 13.9 mmol) was added 4N hydrochloric acid in dioxane. After 6 h
the reaction mixture was concentrated in vacuo. Methanol was added
and the resulting mixture concentrated in vacuo. Dichloromethane
was added and removed in vacuo (2.times.). Trituration with diethyl
ether gave 4-([4-2
yloxy)phenyl]sulfonyl}-N-hydroxy-4-piperidinecarboxamide
hydrochloride as a white powder (5.14 g). .sup.1H NMR (dmso d6, 300
MHz) .delta. 1.86 (t, 3H, CH3, J=2.2 Hz), 2.0-2.7 (m, 8H, CH2),
4.89 (q, 2 OCH2, J=2.2 Hz), 7.1-7.8 (m, 4H, ArH), 8.8-11.0 (m, 4H,
NH2, NHOH). Electrospray MS m/z 353 (M+H).sup.30
Example 77
Methyl({4-{[4-(2-butynyloxy)phenyl]sulfonyl}4[(hydroxyamino)carbonyl]-1-pi-
peridinyl)methyl)benzoate hydrochloride
[0469] To
4-{[4-(2-butynyloxy)phenyl]sulfonyl)-N-hydroxy-4-piperidinecarbo-
xamide hydrochloride (prepared from Example 76) (2.5 g, 6.43 mmol)
and methyl 4-(bromomethyl)benzoate (1.62 g, 7.07 mmol) in methanol
(100 mL) at 50.degree. C. was added triethylamine (2.25 mL, 16.1
mmol). After 30 min additional methanol (50 mL) was added. After 18
h the reaction mixture was concentrated in vacuo and 1N aqueous
hydrochloric acid (10 mL) and water was added. The resulting solid
was isolated and to it was added methanol (20 mL) and 1N
hydrochloric acid in diethylether (15 mL). To the resulting
solution was added diethyl ether. Trituration of the precipitate
gave methyl((4-([4-(2-butynyloxy)phenyl]sulfonyl-4[(hydroxyam-
ino)carbonyl]-1-piperidinyl)methyl)benzoate hydrochloride as a
white powder (2.4 g). .sup.1H NMR (dmso d6, 300 MHz) .delta. 1.85
(t, 3H, CH3, J=2.2 Hz), 2.1-3.5 (m, 8H, CH2), 3.87 (S, 3H, OCH3),
4.40 (bd s, 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J=2.2 Hz), 7.1-8.1 (in
8H, ArH), 9.3-11.2. (r, 311, NH, NHOH). Electrospray MS m/z 501.5
(M+H).sup.30
Example 78
4-(4-([4-(2-butynyloxy)phenyl]sulfonyl}-4[(hydroxyamino)carbonyl]-1-piperi-
dinyl}methyl)benzoic acid hydrochloride
[0470] To
methyl({4[4-(2-butnyloxy)phenyl]sulfanyl}-4-[hydroxyamino)-carbo-
nyl]-1-piperidinyl)methyl)benzoate hydrochloride (Prepared from
example 77) (0.072 g, 0.134 mmol) in methanol (1 mL) was added 1N
aqueous sodium hydroxide (0.5 mL). After 18 h 1N aqueous
hydrochloric acid (0.5 mL) was added and the reaction mixture
concentrated in vacuo. Water was added and the precipitate
triturated to give 4-((4-([4-(2-butynyloxy)phenyl]sulfony-
l)-4-[(hydroxyamino)-carbonyl]-1-piperidinyl)methyl)benzoic acid
hydrochloride as an off-white solid (0.040 g). .sup.1H NMR (dmso
d6, 300 MHz) .delta. 1.85 (t, 3H, CH3, J=2.2 Hz), 2.1-3.5 (m, 8H,
CH2), 4.37 (bd s, 2H, NCH2Ar), 4.89 (q, 2H, OCH2, J=2.2 Hz),
7.0-8.1 (m, 8H, ArH), 9.3-11.2 (mA, 3H, NH, NHOH), 13.1 (bd s, 1H
COOH). Electrospray MS m/z 487.1 (4+H).sup.30
Example 79
1-[4-(Aminocarbonyl)benzyl]-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-N-hydrox-
y-4-piperidinecarboxamide hydrochloride
[0471] To
methyl((4-([4-(2-butynyloxy)phenyl]sulfonyl}4[(hydroxyamino)
carbonyl]-1-piperidinyl}methyl)benzoate hydrochloride (from example
77) (0.20 g) in methanol (10 mL) was added concentrated aqueous
ammonium hydroxide (4 mL). After several weeks the reaction mixture
was concentrated in vacuo and chromatographed on silica gel
(methanol/dichloromethane) to give a white powder which was
dissolved in dichloromethane and methanol 1N Hydrochloric acid in
diethylether was added followed by additional diethylether.
Titration gave
1-[4-(aminocarbonyl)benzyl]{[4-2-butynyloxy)phenyl]sulfonyl)-N-hydroxy-4--
piperidinecarboxamide hydrochloride as a white powder (0.106 g).
.sup.1H NMR (Dmso d6, 300 MHz) .delta. 1.85 (t, 3H, CH3, J=2.2 Hz),
2.2-3.5 (m, 8H, CH2), 4.33 (bd s, 2H, NCH2Ar), 4.89 (q, 2H, OCH2,
J=2.2 Hz), 7.1-8.0 (m, 8H ArH), 7.47 (s, 1H, CONH), 8.04 (s, 1H,
CONH), 9.35 (bd s, 1H, NHOH), 10.44 (bd s, 1H NHOH), 11.1 (s, 1H,
NH). Electrospray MS m/z 486.3 (M+H).sup.30
Example 80
Tert-butyl
4[4-(but-2-ynyloxy)phenyl]sulfinyl)-4-[(hydroxyamino)carbonyl]p-
iperidine-1-carboxalate
[0472] To tert-butyl
4-([4-(but-2-ynyloxy)phenyl]sulfanyl}-4[(hydroxyamino- )
carbonyl]piperidine-1-carboxalate (0.30 g) (obtained from example
14) in methanol (10 mL) was added 30% aqueous hydrogen peroxide (3
mL). After 3 days water and dichloromethane were added and the
organic phase washed with aqueous Na2SO3. Concentration of the
organic phase gave material which was dissolved in methanol (8 mL)
and treated with 30% aqueous hydrogen peroxide. After several days
workup as above gave tert-butyl
4-{[but-2-ynyloxy)phenyl]sufinyl}-4[(hydroxyamino)
carbonyl]piperidine-1-carboxalate as a colorless foam (0.26 g).
.sup.1H NMR (dmso d6, 300 MHz) .delta. 1.38 (s, 9H t-butyl),
1.5-1.7 (m, 2H, CHH), 1.85 (t, 3H CH3, J=2.2 Hz), 2.1-2.2 (m, 2H,
CHH), 2.5-2.7 (m, 2H, NCHH, 3.8-4.0 (m, 2H, NCHH), 4.81 (q, 2H,
OCH2, J=2.2 Hz), 7.1-7.4 (m, 4H, ArH), 9.1 (s, 1H, NHOH); 10.8 (s,
1H, NHOH). Electrospray MS m/z 437.2 (M+H).sup.30
Example 81
4-(4-(But-2-ynyloxy-benzenesulfinyl-piperidine-4-carboxylic acid
hydroxamide hydrochloride
[0473] To tert-butyl
4-([4{but-2-ynyloxy)phenyl]sulfinyl}-4-[hydroxyamino)
carbonyl]piperidine-1-carboxalate (prepared from example 80) (0.26
g) was added 4N hydrochloric acid in dioxane (4 mL). After 1 h the
reaction mixture was concentrated in vacuo. Methanol was added and
removed in vacuo. Dichloromethane was added and removed in vacuo
3.times. to give
4-4-(But-2-ynyloxy-benzenesulfinyl)piperidine-4-carboxylic acid
hydroxamide hydrochloride as a yellow solid (0.19 g). .sup.1H NMR
(dmso d6, 300 MHz) .delta. 1.86 (t, 31 CH3, J=2.2 Hz), 1.7-2.8 (m,
8H, CH2), 4.82 (q, 2H, OCH2, J=2.2 Hz), 7.1-7.5 (m, 4 ArH),
8.4-11.0 (m, 4H, NH2, NHOH). Electrospray MS m/z 337.2
(M+H).sup.+
Example 82
1-4-Bromo-benzyl-4-But-2-ynyloxy-benzenesulfinyl)-piperidine-4-carboxylic
acid hydroxamide hydrochloride
[0474] To a solution of
4-(4-(But-2-ynyloxy-benzenesulfinyl-piperidine carboxylic acid
hydroxamide hydrochloride (prepared from example 81) (0.162 g,
0.434 mmol) and 4-bromobenzylbromide (0.120 g, 0.478 mmol) in
methanol was added triethylamine (0.13 mL, 0.91 mmol). After 4 h
the reaction mixture was concentrated in vacuo and chromatographed
on silica gel (methanol/dichloromethane) to give an oily solid
which was dissolved in dichloromethane. To the solution was added
1N hydrochloric acid in ether (1 mL). Concentration in vacuo gave
1-(4-Bromo-benzyl)-4-4-But-2-yn- yloxy-benzenesulfinyl)-piperidine
carboxylic acid hydroxamide hydrochloride as a tan solid (0.102 g).
.sup.1H NMR (dmso d6, 300 MHz) .delta. 1.85 (t, 31, CH3, J=2.2 Hz),
1.9-3.5 (m, 81, CH2), 3.87 (S, 31, OCH3), 4.3 (bd s, 21, NCH2Ar),
4.82 (q, 2, --OCH2, J=2.2 Hz), 7.0-7.8 (m, 8K, ArH), 9.2-11.1 (m,
3H, NH, NHOH). Electrospray MS m/z 505.1/507.2 (M+H).sup.+
Pharmacology
[0475] 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
[0476] 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.
[0477] 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 mm and the increase in fluorescence over time is plotted
as a linear line.
[0478] 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
[0479] 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.
[0480] 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.
[0481] 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 Monocyte THP-1 Cell Differentiation Assay for Soluble
Proteins (THP-1 Soluble Protein Assay)
[0482] Mitogenic-stimulation of THP-1 cells cause differentiation
into macrophage like cells with concomitant secretion of tumor
necrosis factor (TNF-a) and TNF receptor (INF-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 calcd 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.
[0483] 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.
[0484] 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 with
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.
[0485] 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.degree. C.
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% CO.sub.2 and at
37.degree. 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 p55160 and IL-8
ELISAs.
[0486] 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/Eq 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
PL. 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.
[0487] 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.
[0488] 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: 1 % Change
= pg / ml ( compound ) - pg / ml ( veh pos control ) pg / ml ( veh
pos control ) - pg / ml ( veh neg control ) .times. 100
[0489] For the soluble protein (INF-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: 2 % Change = pg / ml ( compound
neg control ) - pg / ml ( veh neg control pg / ml ( veh neg control
) .times. 100
[0490] IC50 values for each compound are calculated by non-linear
regression analysis using customized software utilizing the JUMP
statistical package.
[0491] 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. 3 % Change = % live cells ( compound ) % live cells
( veh pos control ) - 1 .times. 100
REFERENCES
[0492] Bjornberg, F., Lantz, M, Olsson, I., and Gullberg, U.
Mechanisms involved in the processing of the p55 and the p75 tumor
necrosis factor (INF) receptors to soluble receptor forms.
Lymphokine Cytokine Res. 13:203-211, 1994.
[0493] 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 THP-1 cells in vitro. Cellular Immun. 138:1-10, 1991.
[0494] Tsuchiya, S., Yamabe, U, Yamagughi, Y., Kobayashi Y., Konno,
T., and Tada, K. Establishment and characterization of a human
acute monocytic leukemia cell line (THP-1). Int. L Cancer.
26:1711-176, 1980.
[0495] Results of the above in vitro matrix metalloproteinase
inhibition, TACE inhibition and THP standard pharmacological test
procedures are given in Table 1 below.
2TABLE 1 Example # TACE IC.sub.50.sup.a THP @3 .mu.M.sup.b MMP1
IC.sub.50.sup.c MMP9 IC.sub.50.sup.a MMP13 IC.sub.50.sup.a 1 65 46%
3.3 385 155 2 82 68% 2.57 164 39.6 3 55 34% 9 280 90 4 90 25% 2.6
148 47.3 5 188 30% .3 400 180 6 393 NT 32.9% 58.9% 60% 7 123 21%
2.5 225 59.4 8 195 21% 4.7 218 72 9 166 12% 2.1 96.2 35.2 10 11 98
7% 0.143 5.8 3.1 12 41.8% +58 15 1000 1500 13 882 +69% 10 2000 800
14 67% NT 26% 21% 32% 15 38% NT 24% 25% 24% 16 46% NT 10 2056 1465
17 139 0 10 2296 946 18 11.4 45% 10 1276 98 19 74 4% 10 10000 1321
20 30.1 47% 2643 nM 568 121 21 509 6% >10 3504 858 22 48.4% 5%
>10 1814 1076 23 86.2 62% 3206 nM 160 64.4 24 180 41% 5671 nM
2078 463 25 695 3% >10 2740 1177 26 136 63% 1994 nM 25.1 22.1 27
168 13% >10 1542 426 28 150 13% 106 nM 15.4 5.3 29 127 13% 91 nM
16 4.7 30 102 0 >10 5899 2911 31 314 8 >10 >10000
>10000 32 100 0 >10 >10000 2752 33 327 8 >10
.about.5000 .about.10000 34 33 68 .about.10 1393 102 35 57 14
>10 >10000 .about.10000 36 4.8 58 3.9 2828 380 37 18 NT 8.6
8575 1024 38 19 53 .about.10 1443 279 39 11 NT 3.77 4275 809 40 63
41 0.707 425 36 41 37 60 2.677 1121 254 42 12 78% .about.10
>10000 1627 43 13 66 .about.10 >10000 1640 44 56 49 35% 50.6%
2381 45 25 48 3.8 3584 423 46 105 NT NT NT 55.6% 47 227 NT NT NT
275 48 66 NT NT NT 1035 49 32.6 NT NT NT 1727 50 18.3 NT NT NT 352
51 21.5 NT NT NT 403 52 41.8 NT NT NT 3710 53 20.8 NT NT NT 1165 54
32.2 NT NT NT 104 55 70.7 NT NT NT 600 56 31.1 NT NT NT 3.2 57 694
NT NT NT 458 58 21.1 NT NT NT 179 59 53.3 NT NT NT 11.2 60 38.4 NT
NT NT 8.0 61 56.4 NT NT NT 575 62 64.6 NT NT NT 64.6 63 66.6 NT NT
NT 2229 64 47 30 4.076 560 136 65 73 3 3.532 448 105 66 106 73
2.768 430 81 67 72 18 2.028 853 345 68 77 10 2.249 1333 503 69 115
14 3.999 1246 499 70 87 62 2.963 639 113 71 113 14 3.117 811 183 72
221 56 4.157 1211 369 73 NT NT NT NT NT 74 132 39 4.338 963 287 75
134 -4 2.588 1951 284 76 201 26 4.503 7886 4019 77 114 52 2.187 149
349 78 64.5 64 1.051 364 73.7 79 70 83 2.420 129 50.6 80 90 -7 186
122 40 81 277 25 1.877 1035 593 82 135 16 257 125 62 .sup.a= nM or
% inhibition .sup.b= % inhibition .sup.c= .mu.M or % inhibition,
unless otherwise indicated
[0496] 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
metastsis, tissue ulceration, abnormal wound healing, periodontal
disease, graft rejection, insulin resistance, bone disease and HIV
infection.
[0497] 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.
[0498] 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.
[0499] Applicable solid carriers can include one or more substances
which may also act as flavoring agents, lubricants, solubilizers,
suspending agents, fillers, glidants, compression aids, binders or
tablet-disintegrating agents or an encapsulating material. In
powders, the carrier is a finely divided solid which is in
admixture with the finely divided active ingredient. In tablets,
the active ingredient is mixed with a carrier having the necessary
compression properties in suitable proportions and compacted in the
shape and size desired. The powders and tablets preferably contain
up to 99% of the active ingredient. Suitable solid carriers
include, for example, calcium phosphate, magnesium stearate, talc,
sugars, lactose, dextrin, starch, gelatin, cellulose, methyl
cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,
low melting waxes and ion exchange resins.
[0500] 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., fractionated coconut oil and arachis
oil). For parenteral administration the carrier can also be an oily
ester such as ethyl oleate and isopropyl myristate. Sterile liquid
carriers are used in sterile liquid form compositions for
parenteral administration.
[0501] 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.
[0502] 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 compressed 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.
[0503] The dosage to be used in the treatment of a specific patient
suffering a MMP or TACE dependent condition must be subjectively
determined by the attending physician. The variables involved
include the severity of the dysfunction, and the size, age, and
response pattern of the patient. Treatment will generally be
initiated with small dosages less than the optimum dose of the
compound. Thereafter the dosage is increased until the optimum
effect under the circumstances is reached. Precise dosages for
oral, parenteral, nasal, or intrabronchial administration will be
determined by the administering physician based on experience with
the individual subject treated and standard medical principles.
[0504] 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.
* * * * *