U.S. patent application number 13/003406 was filed with the patent office on 2011-05-12 for selective hydroxamic acid based mmp-12 and mmp-13 inhibitors.
Invention is credited to Leslie Wighton McQuire, Olivier Rogel, Michael Shultz, Ruben Alberto Tommasi, Sven Weiler.
Application Number | 20110112076 13/003406 |
Document ID | / |
Family ID | 41279377 |
Filed Date | 2011-05-12 |
United States Patent
Application |
20110112076 |
Kind Code |
A1 |
McQuire; Leslie Wighton ; et
al. |
May 12, 2011 |
SELECTIVE HYDROXAMIC ACID BASED MMP-12 AND MMP-13 INHIBITORS
Abstract
The present invention provides a compound of formula (I) said
compound is inhibitor of MMP-12 and/or MMP-13, and thus can be
employed for the treatment of a disorder or disease characterized
by abnormal activity of MMP-12 and/or MMP-13. Accordingly, the
compound of formula (I) can be used in treatment of disorders or
diseases mediated by MMP-12 and/or MMP-13. Finally, the present
invention also provides pharmaceutical composition that include the
compound of formula (I). ##STR00001##
Inventors: |
McQuire; Leslie Wighton;
(Cambridge, MA) ; Rogel; Olivier; (Basel, CH)
; Shultz; Michael; (Cambridge, MA) ; Tommasi;
Ruben Alberto; (Cambridge, MA) ; Weiler; Sven;
(Basel, CH) |
Family ID: |
41279377 |
Appl. No.: |
13/003406 |
Filed: |
July 13, 2009 |
PCT Filed: |
July 13, 2009 |
PCT NO: |
PCT/EP09/58932 |
371 Date: |
January 10, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61080472 |
Jul 14, 2008 |
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Current U.S.
Class: |
514/217.11 ;
514/227.5; 514/230.5; 514/235.5; 514/238.2; 514/299; 514/311;
514/312; 514/314; 514/319; 514/338; 514/354; 514/357; 514/365;
514/367; 514/412; 514/423; 514/459; 514/575; 540/604; 544/105;
544/131; 544/159; 544/59; 546/112; 546/153; 546/172; 546/206;
546/282.4; 546/323; 546/337; 548/166; 548/200; 548/452; 548/537;
549/426; 562/623 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 35/04 20180101; C07D 413/12 20130101; C07D 213/74 20130101;
C07D 487/08 20130101; A61P 19/02 20180101; C07D 295/13 20130101;
C07C 2601/02 20170501; C07C 311/46 20130101; C07D 277/06 20130101;
C07D 277/80 20130101; C07D 309/06 20130101; A61P 29/00 20180101;
A61P 43/00 20180101; C07D 279/12 20130101; A61P 1/02 20180101; A61P
9/10 20180101; C07D 213/89 20130101; C07D 401/12 20130101; C07D
453/06 20130101; A61K 31/18 20130101; C07C 2601/08 20170501; C07D
213/42 20130101; C07C 311/29 20130101; C07D 211/92 20130101; C07D
405/12 20130101; C07D 471/08 20130101; A61P 19/00 20180101; A61P
35/00 20180101; A61P 9/00 20180101; A61P 9/04 20180101; C07C 311/42
20130101; C07C 2601/14 20170501; A61P 31/00 20180101; C07D 211/96
20130101; C07D 215/36 20130101; C07D 211/60 20130101; C07C 311/19
20130101; A61P 11/06 20180101; C07D 223/06 20130101; A61P 11/08
20180101; C07C 323/60 20130101; A61P 11/02 20180101; C07D 207/48
20130101 |
Class at
Publication: |
514/217.11 ;
562/623; 546/206; 549/426; 548/200; 546/323; 546/337; 540/604;
546/153; 548/537; 546/172; 544/159; 548/452; 544/59; 546/112;
544/105; 546/282.4; 544/131; 548/166; 514/575; 514/319; 514/459;
514/365; 514/354; 514/312; 514/423; 514/357; 514/314; 514/311;
514/238.2; 514/412; 514/227.5; 514/299; 514/230.5; 514/338;
514/235.5; 514/367 |
International
Class: |
C07C 259/06 20060101
C07C259/06; C07D 211/60 20060101 C07D211/60; C07D 309/06 20060101
C07D309/06; C07D 277/06 20060101 C07D277/06; C07D 211/78 20060101
C07D211/78; C07D 213/56 20060101 C07D213/56; C07D 223/06 20060101
C07D223/06; C07D 401/12 20060101 C07D401/12; C07D 207/48 20060101
C07D207/48; C07D 215/36 20060101 C07D215/36; C07D 295/145 20060101
C07D295/145; C07D 209/52 20060101 C07D209/52; C07D 279/12 20060101
C07D279/12; C07D 221/22 20060101 C07D221/22; C07D 413/12 20060101
C07D413/12; C07D 405/12 20060101 C07D405/12; C07D 413/14 20060101
C07D413/14; C07D 277/80 20060101 C07D277/80; A61K 31/165 20060101
A61K031/165; A61K 31/445 20060101 A61K031/445; A61K 31/351 20060101
A61K031/351; A61K 31/426 20060101 A61K031/426; A61K 31/44 20060101
A61K031/44; A61K 31/55 20060101 A61K031/55; A61K 31/4709 20060101
A61K031/4709; A61K 31/40 20060101 A61K031/40; A61K 31/47 20060101
A61K031/47; A61K 31/5375 20060101 A61K031/5375; A61K 31/403
20060101 A61K031/403; A61K 31/54 20060101 A61K031/54; A61K 31/439
20060101 A61K031/439; A61K 31/536 20060101 A61K031/536; A61K
31/4433 20060101 A61K031/4433; A61K 31/5377 20060101 A61K031/5377;
A61K 31/428 20060101 A61K031/428; A61P 11/06 20060101 A61P011/06;
A61P 11/02 20060101 A61P011/02; A61P 11/08 20060101 A61P011/08;
A61P 19/02 20060101 A61P019/02; A61P 9/10 20060101 A61P009/10; A61P
35/00 20060101 A61P035/00; A61P 35/04 20060101 A61P035/04; A61P
1/02 20060101 A61P001/02; A61P 9/04 20060101 A61P009/04; A61P 9/00
20060101 A61P009/00; A61P 43/00 20060101 A61P043/00 |
Claims
1. A compound of formula (I) ##STR00217## wherein R.sub.1 is
hydrogen, alkyl, alkenyl, alkynyl, aryl-alkyl-, cycloalkyl, or
heterocycloalkyl, each of which is optionally substituted by one to
three substituents selected from aryl-alkoxy-, hydroxy, alkoxy,
HS--, alkyl-S--, alkyl-O--(O)C--, cyano, alkyl-SO.sub.2--, and
aryl; R.sub.2 is H, alkyl, alkenyl, alkynyl, aryloxy-alkyl-,
aryl-alkyl-, heteroaryl-alkyl-, or heterocycloalkyl-alkyl, each of
which is optionally substituted by one to three substituents
selected from HS--, halo, alkoxy, alkyl, and dialkylamino; X is
hydrogen, hydroxyl, alkoxy, or halo; Y is R.sub.3--NH--, wherein
R.sub.3 is hydrogen, alkyl, alkyl-C(O)--, or aryl; or Y is alkoxy,
alkyl, hydrogen, hydroxyl, alkyl-C(O)--NH--, alkenyl-O--, or
aryl-alkoxy-; R.sub.1 and R.sub.2 taken together with the carbon
atom and the nitrogen atom to which they are attached, form a 3- to
7-membered ring; or a pharmaceutically acceptable salts thereof; or
an optical isomer thereof; or a mixture of optical isomers.
2. The compound of claim 1, wherein R.sub.1 is (C.sub.1-C.sub.7)
alkyl, (C.sub.1-C.sub.7) alkenyl, (C.sub.1-C.sub.7) alkynyl, or (4-
to 7-membered) heterocycloalkyl, each of which is optionally
substituted by one to three substituents selected from hydroxy,
HS--, (C.sub.1-C.sub.7) alkyl-S--, (C.sub.6-C.sub.10) aryl, or
(C.sub.1-C.sub.7) alkyl-O--C(O)--; R.sub.2 is (C.sub.1-C.sub.7)
alkyl, (C.sub.1-C.sub.7) alkenyl, (C.sub.6-C.sub.10)
aryl-(C.sub.1-C.sub.7) alkyl-, (5- to 9-membered)
heteroaryl-(C.sub.1-C.sub.7) alkyl-, and (C.sub.6-C.sub.10)
aryloxy-(C.sub.1-C.sub.7) alkyl-; X is hydrogen, hydroxy, or
(C.sub.1-C.sub.7) alkoxy; Y is hydrogen, (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl-O--, H.sub.2N--, or (C.sub.1-C.sub.7)
alkyl-C(O)--NH--; or R.sub.1 and R.sub.2 taken together with the
carbon atom and the nitrogen atom to which they are attached, form
a 3- to 7-membered ring; or a pharmaceutically acceptable salts
thereof; or an optical isomer thereof; or a mixture of optical
isomers.
3. The compound of claim 2, wherein R.sub.1 is a (C.sub.1-C.sub.7)
alkyl, or (C.sub.1-C.sub.7) alkenyl; R.sub.2 is a (C.sub.1-C.sub.7)
alkyl, (C.sub.1-C.sub.7) alkenyl, (C.sub.1-C.sub.7) alkynyl, or
(C.sub.6-C.sub.10) aryl-(C.sub.1-C.sub.7) alkyl-; Y is H,
H.sub.2N--, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) alkyl, or
(C.sub.1-C.sub.4) alkyl-NH--; X is H, HO--, or (C.sub.1-C.sub.4)
alkoxy; or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
4. A compound of formula (II) according to claim 1: ##STR00218##
wherein R.sub.1 is hydrogen, alkyl, alkenyl, alkynyl, aryl-alkyl-,
cycloalkyl, or heterocycloalkyl, each of which is optionally
substituted by one to three substituents selected from
aryl-alkoxy-, hydroxy, alkoxy, HS--, alkyl-S--, alkyl-O--(O)C--,
cyano, alkyl-SO.sub.2--, and aryl; R.sub.2 is H, alkyl, alkenyl,
alkynyl, aryloxy-alkyl-, aryl-alkyl-, heteroaryl-alkyl-, or
heterocycloalkyl-alkyl, each of which is optionally substituted by
one to three substituents selected from HS--, halo, alkoxy, alkyl,
and dialkylamino; X is hydrogen, hydroxyl, alkoxy, or halo; Y is
R.sub.3--NH--, wherein R.sub.3 is hydrogen, alkyl, alkyl-C(O)--, or
aryl; or Y is alkoxy, alkyl, hydrogen, hydroxyl, alkyl-C(O)--NH--,
alkenyl-O--, or aryl-alkoxy-; R.sub.1 and R.sub.2 taken together
with the carbon atom and the nitrogen atom to which they are
attached, form a 3- to 7-membered ring; or a pharmaceutically
acceptable salts thereof; or an optical isomer thereof; or a
mixture of optical isomers.
5. The compound of claim 4, wherein R.sub.1 is (C.sub.1-C.sub.7)
alkyl, (C.sub.1-C.sub.7) alkenyl, (C.sub.1-C.sub.7) alkynyl, or (4-
to 7-membered) heterocycloalkyl, each of which is optionally
substituted by one to three substituents selected from hydroxy,
HS--, (C.sub.1-C.sub.7) alkyl-S--, (C.sub.6-C.sub.10) aryl, or
(C.sub.1-C.sub.7) alkyl-O--C(O)--; R.sub.2 is (C.sub.1-C.sub.7)
alkyl, (C.sub.1-C.sub.7) alkenyl, (C.sub.6-C.sub.10)
aryl-(C.sub.1-C.sub.7) alkyl-, (5- to 9-membered)
heteroaryl-(C.sub.1-C.sub.7) alkyl-, and (C.sub.6-C.sub.10)
aryloxy-(C.sub.1-C.sub.7) alkyl-; X is hydrogen, hydroxy, or
(C.sub.1-C.sub.7) alkoxy; Y is hydrogen, (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl-O--, H.sub.2N--, or (C.sub.1-C.sub.7)
alkyl-C(O)--NH--; or R.sub.1 and R.sub.2 taken together with the
carbon atom and the nitrogen atom to which they are attached, form
a 3- to 7-membered ring; or a pharmaceutically acceptable salts
thereof; or an optical isomer thereof; or a mixture of optical
isomers.
6. The compound of claim 5, wherein R.sub.1 is a (C.sub.1-C.sub.7)
alkyl, or (C.sub.1-C.sub.7) alkenyl; R.sub.2 is a (C.sub.1-C.sub.7)
alkyl, (C.sub.1-C.sub.7) alkenyl, (C.sub.1-C.sub.7) alkynyl, or
(C.sub.6-C.sub.10) aryl-(C.sub.1-C.sub.7) alkyl-; Y is H,
H.sub.2N--, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) alkyl, or
(C.sub.1-C.sub.4) alkyl-NH--; X is H, HO--, or (C.sub.1-C.sub.4)
alkoxy; or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
7. A compound of formula (IIA) according to claim 1 ##STR00219##
wherein R.sub.1 is alkyl, R.sub.2 is alkyl or aryl-alkyl-, A is
aryl-NH--, H.sub.2N--, Alkyl, hydroxyl, alkoxy, alkyl-C(O)--NH--,
alkenyl-O--, or aryl-alkyl-O--, or a pharmaceutically acceptable
salts thereof; or an optical isomer thereof; or a mixture of
optical isomers.
8. The compound of claim 7, wherein R.sub.1 is (C.sub.1-C.sub.4)
alkyl, R.sub.2 is (C.sub.1-C.sub.7) alkyl, or (C.sub.6-C.sub.10)
aryl-(C.sub.1-C.sub.7) alkyl-, A is (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl-O--, H.sub.2N--, or (C.sub.1-C.sub.7)
alkyl-C(O)--NH--, or (C.sub.6-C.sub.10) aryl-(C.sub.1-C.sub.7)
alkyl-O--; or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
9. A compound of formula (III). ##STR00220## wherein Z.sub.1 and
Z.sub.2 are independently C or N; R.sub.1 and R.sub.2 are
independently hydrogen, alkyl, alkenyl, or alkynyl; R.sub.1 and
R.sub.2 taken together with the carbon atom and the nitrogen atom
to which they are attached, form a 3- to 7-membered ring; or or a
pharmaceutically acceptable salts thereof; or an optical isomer
thereof; or a mixture of optical isomers.
10. The compound of claim 9, wherein Z.sub.1 is N, Z.sub.2 is C,
R.sub.1 and R.sub.2 are independently (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl, or (C.sub.1-C.sub.7) alkynyl; or R.sub.1
and R.sub.2 taken together with the carbon atom and the nitrogen
atom to which they are attached, form a 3- to 7-membered ring; or a
pharmaceutically acceptable salts thereof; or an optical isomer
thereof; or a mixture of optical isomers.
11. The compound of claim 9, wherein Z.sub.1 is C, Z.sub.2 is N,
R.sub.1 and R.sub.2 are independently (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl, or (C.sub.1-C.sub.7) alkynyl; or R.sub.1
and R.sub.2 taken together with the carbon atom and the nitrogen
atom to which they are attached, form a 3- to 7-membered ring; or a
pharmaceutically acceptable salts thereof; or an optical isomer
thereof; or a mixture of optical isomers.
12. A method of inhibiting activity of MMP-13 and/or MMP-12 in a
subject, comprising administering to the subject a therapeutically
effective amount of the compound according to claim 1.
13. A method of treating a disorder or a disease in a subject
mediated by MMP-13 and/or MMP-12, wherein the method comprises
administering to the subject a therapeutically effective amount of
the compound according to claim 1 or 9.
14. The method of claim 13, wherein the disorder or the disease is
selected from the group consisting of Alport syndrome, asthma,
rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis,
atherosclerosis, cancer invasion and metastasis, diseases involving
tissue destruction, loosening of hip joint replacements,
periodontal disease, diseases related to the weakening of the
extracellular matrix, heart failure, and aortic aneurysms.
15. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 or 9 and one or more
pharmaceutically acceptable carriers.
16. A pharmaceutical composition comprising a therapeutically
effective amount of the compound according to claim 1 or 9 and one
or more therapeutically active agents selected from an
antiinflamatory agent and an anitrheumatic agent.
17-20. (canceled)
Description
[0001] The invention relates to sulfonylamino hydroxamic acid
derivatives and to processes for their preparation, pharmaceutical
compositions comprising said compounds, a method of inhibiting
matrix-degrading metalloproteinase, such as matrix
metalloproteinases 12 and 13 (MMP-12 and MMP-13), in mammals using
such compounds and the use of these derivatives as medicaments.
[0002] Matrix metalloproteinases (MMPs) are proteinases that are
involved in the breakdown and remodeling of the extracellular
matrices (ECM) under a variety of physiological and pathological
conditions. Matrix metalloproteinases (MMPs), which comprise a
family of more than 20 members, use Zn.sup.2+ in the active sites
to catalyze hydrolyses of ECM. Basd on their substrate
specificities, they can be broadly classified into three
subfamilies: collagenase, stromelysins and gelatinases.
[0003] Under normal physiological conditions, these enzymes serve
many important functions, including wound healing and tissue
remodeling. However, when these enzymes are over activated, they
can over-degrade ECM, resulting in disease conditions. For example,
MMP-2 and MMP-9 (both are gelatinases) are thought to be involved
in the pathogenesis of inflammatory, infectious, and neoplastic
diseases in many organs. Excess activity of MMP-8, also known as
collagenase-2 or neutrophil collagenase, is associated with
diseases such as pulmonary emphysema and osteoarthritis. Excess
activity of MMP-12, also known as macrophage elastase or
metalloelastase, plays a key role in tumor invasion, arthritis,
atherosclerosis, Alport syndrome, and chronic obstructive pulmonary
disease (COPD). MMP-1 and MMP-13 are involved in the proteolysis of
collagen. Excessive degradation of collagen is associated with the
development of various diseases, including osteoarthritis.
[0004] Osteoarthritis is associated with excessive degradation of
type II collagen. Early work suggested that collagenase-1 (MMP-1)
may be responsible for such conditions because MMP-1 can
specifically cleave type II collagen to produce characteristic 3/4
and 1/4 fragments. Later work indicated that collagenase-3 (MMP-13)
may be more important in the development of osteoarthritis. MMP-13
can also cleave type II collagen to give the characteristic 3/4 and
1/4 fragments and does so at least 10 times faster than MMP-1. In
addition, MMP-13 is found to be expressed in osteoarthritic
cartilage. These observations suggest that MMP-13 activity may be a
significant contributor to the progression of osteoarthritis and
other diseases that are associated with cartilage collagen
degradation. See e.g., P. G. Mitchell et al., "Cloning, expression,
and type II collagenolytic activity of matrix metalloproteinase-13
from human osteoarthritic cartilage," J Clin Invest. 1996 Feb. 1;
97(3): 761-768. Therefore, MMP-13 is an attractive target for
therapeutic interventions in the management of diseases involving
excessive type II collagen degradation.
[0005] Many MMP inhibitors are known in the art. For example, U.S.
Pat. No. 6,500,983 issued to Kottirsch et al. discloses the use of
hydroxamic acid derivatives as MMP inhibitors. U.S. Pat. Nos.
6,277,987 and 6,410,580 issued to Kukkola et al. disclose sulfonyl
amino acid and sulfonylamino hydroxamic acid derivatives as MMP
inhibitors. The hydroxamic acid moiety in these inhibitors binds to
the active site Zn.sup.2+ to inhibit enzymatic activities. These
patents are assigned to the assignee of the present invention and
are incorporated by reference in their entireties.
[0006] While prior art MMP inhibitors are generally effective in
inhibiting the target enzymes, selectivity is more difficult to
achieve due to the high degree of homology among the MMPs. Because
MMPs serve important functions under normal physiological
conditions, therapeutics designed to inhibit any disease-causing
MMP preferably are selective. For example, inhibitors for use in
the prevention or treatment of osteoarthritis should preferably
have substantial selectivity for MMP-13 over other MMPs (e.g.,
MMP-2 or MMP-9).
[0007] The present invention provides inhibitors that are selective
for MMPs involved in the development of diseases, such as MMP-13
and MMP-12.
[0008] In one aspect, an inhibitor can include a compound of
formula (I):
##STR00002##
[0009] wherein
[0010] R.sub.1 is hydrogen, alkyl, alkenyl, alkynyl, aryl-alkyl-,
cycloalkyl, heterocycloalkyl, each of which is optionally
substituted by one to three substituents selected from
aryl-alkoxy-, hydroxy, alkoxy, HS--, alkyl-S--, alkyl-O--(O)C--,
cyano, alkyl-SO.sub.2--, or aryl;
[0011] R.sub.2 is H, alkyl, alkenyl, alkynyl, aryloxy-alkyl-,
aryl-alkyl-, heteroaryl-alkyl-, heterocycloalkyl-alkyl, each of
which is optionally substituted by one to three substituents
selected from HS--, halo, alkoxy, alkyl, or dialkylamino;
[0012] X is hydrogen, hydroxyl, alkoxy, or halo;
[0013] Y is R.sub.3--NH--, wherein R.sub.3 is hydrogen, alkyl,
alkyl-C(O)--, or aryl; or
[0014] Y is alkoxy, alkyl, hydrogen, hydroxyl, alkyl-C(O)--NH--,
alkenyl-O--, or aryl-alkoxy-;
[0015] R.sub.1 and R.sub.2 taken together with the carbon atom and
the nitrogen atom to which they are attached, form a 3- to
7-membered ring;
[0016] or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
[0017] Preferably, the present invention provides the compound of
formula (I), wherein R.sub.1 is (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl, (C.sub.1-C.sub.7) alkynyl, or (4- to
7-membered) heterocycloalkyl, each of which is optionally
substituted by one to three substituents selected from hydroxy,
HS--, (C.sub.1-C.sub.7) alkyl-S--, (C.sub.6-C.sub.10) aryl, or
(C.sub.1-C.sub.7) alkyl-O--C(O)--; R.sub.2 is (C.sub.1-C.sub.7)
alkyl, (C.sub.1-C.sub.7) alkenyl, (C.sub.6-C.sub.10)
aryl-(C.sub.1-C.sub.7) alkyl-, (5- to 9-membered)
heteroaryl-(C.sub.1-C.sub.7) alkyl-, or (C.sub.6-C.sub.10)
aryloxy-(C.sub.1-C.sub.7) alkyl-; X is hydrogen, hydroxy, or
(C.sub.1-C.sub.7) alkoxy; Y is hydrogen, (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl-O--, H.sub.2N--, or (C.sub.1-C.sub.7)
alkyl-C(O)--NH--; or R.sub.1 and R.sub.2 taken together with the
carbon atom and the nitrogen atom to which they are attached, form
a 3- to 7-membered ring; or a pharmaceutically acceptable salts
thereof; or an optical isomer thereof; or a mixture of optical
isomers.
[0018] More preferably, the present invention provides the compound
of formula (I), wherein R.sub.1 is a (C.sub.1-C.sub.7) alkyl, or
(C.sub.1-C.sub.7) alkenyl; R.sub.2 is a (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl, (C.sub.1-C.sub.7) alkynyl, or
(C.sub.6-C.sub.10) aryl-(C.sub.1-C.sub.7) alkyl-; Y is H,
H.sub.2N--, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) alkyl, or
(C.sub.1-C.sub.4) alkyl-NH--; X is H, HO--, or (C.sub.1-C.sub.4)
alkoxy; or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
[0019] In another aspect, an inhibitor can include a compound of
formula (II).
##STR00003##
[0020] wherein
[0021] R.sub.1 is hydrogen, alkyl, alkenyl, alkynyl, aryl-alkyl-,
cycloalkyl, heterocycloalkyl, each of which is optionally
substituted by one to three substituents selected from
aryl-alkoxy-, hydroxy, alkoxy, HS--, alkyl-S--, alkyl-O--(O)C--,
cyano, alkyl-SO.sub.2--, or aryl;
[0022] R.sub.2 is H, alkyl, alkenyl, alkynyl, aryloxy-alkyl-,
aryl-alkyl-, heteroaryl-alkyl-, heterocycloalkyl-alkyl, each of
which is optionally substituted by one to three substituents
selected from HS--, halo, alkoxy, alkyl, or dialkylamino;
[0023] X is hydrogen, hydroxyl, alkoxy, or halo;
[0024] Y is R.sub.3--NH--, wherein R.sub.3 is hydrogen, alkyl,
alkyl-C(O)--, or aryl; or
[0025] Y is alkoxy, alkyl, hydrogen, hydroxyl, alkyl-C(O)--NH--,
alkenyl-O--, or aryl-alkoxy-;
[0026] R.sub.1 and R.sub.2 taken together with the carbon atom and
the nitrogen atom to which they are attached, form a 3- to
7-membered ring;
[0027] or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
[0028] Preferably, the present invention provides the compound of
formula (I), wherein R.sub.1 is (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl, (C.sub.1-C.sub.7) alkynyl, or (4- to
7-membered) heterocycloalkyl, each of which is optionally
substituted by one to three substituents selected from hydroxy,
HS--, (C.sub.1-C.sub.7) alkyl-S--, (C.sub.6-C.sub.10) aryl, or
(C.sub.1-C.sub.7) alkyl-O--C(O)--; R.sub.2 is (C.sub.1-C.sub.7)
alkyl, (C.sub.1-C.sub.7) alkenyl, (C.sub.6-C.sub.10)
aryl-(C.sub.1-C.sub.7) alkyl-, (5- to 9-membered)
heteroaryl-(C.sub.1-C.sub.7) alkyl-, or (C.sub.6-C.sub.10)
aryloxy-(C.sub.1-C.sub.7) alkyl-; X is hydrogen, hydroxy, or
(C.sub.1-C.sub.7) alkoxy; Y is hydrogen, (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl-O--, H.sub.2N--, or (C.sub.1-C.sub.7)
alkyl-C(O)--NH--; or R.sub.1 and R.sub.2 taken together with the
carbon atom and the nitrogen atom to which they are attached, form
a 3- to 7-membered ring; or a pharmaceutically acceptable salts
thereof; or an optical isomer thereof; or a mixture of optical
isomers.
[0029] More preferably, the present invention provides the compound
of formula (I), wherein R.sub.1 is a (C.sub.1-C.sub.7) alkyl, or
(C.sub.1-C.sub.7) alkenyl; R.sub.2 is a (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl, (C.sub.1-C.sub.7) alkynyl, or
(C.sub.6-C.sub.10) aryl-(C.sub.1-C.sub.7) alkyl-; Y is H,
H.sub.2N--, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) alkyl, or
(C.sub.1-C.sub.4) alkyl-NH--; X is H, HO--, or (C.sub.1-C.sub.4)
alkoxy; or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
[0030] In another aspect, an inhibitor can include a compound of
formula (IIA)
##STR00004##
[0031] wherein
[0032] R.sub.1 is alkyl, R.sub.2 is alkyl or aryl-alkyl-, A is
aryl-NH--, H.sub.2N--, Alkyl, hydroxyl, alkoxy, alkyl-C(O)--NH--,
alkenyl-O--, or aryl-alkyl-O--, or a pharmaceutically acceptable
salts thereof; or an optical isomer thereof; or a mixture of
optical isomers.
[0033] Preferably the present invention provides the compound of
formula (IIA), wherein R.sub.1 is (C.sub.1-C.sub.4) alkyl, R.sub.2
is (C.sub.1-C.sub.7) alkyl, (C.sub.6-C.sub.10)
aryl-(C.sub.1-C.sub.7) alkyl-, A is (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl-O--, H.sub.2N--, or (C.sub.1-C.sub.7)
alkyl-C(O)--NH--, or (C.sub.6-C.sub.10) aryl-(C.sub.1-C.sub.7)
alkyl-O--; or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
[0034] In another aspect, an inhibitor can include a compound of
formula (III).
##STR00005##
[0035] wherein
[0036] Z.sub.1 and Z.sub.2 are independently C or N;
[0037] R.sub.1 and R.sub.2 are independently hydrogen, alkyl,
alkenyl, or alkynyl;
[0038] R.sub.1 and R.sub.2 taken together with the carbon atom and
the nitrogen atom to which they are attached, form a 3- to
7-membered ring; or
[0039] or a pharmaceutically acceptable salts thereof; or an
optical isomer thereof; or a mixture of optical isomers.
[0040] Preferably, the present invention provides the compound of
formula (III), wherein Z.sub.1 is N, Z.sub.2 is C, R.sub.1 and
R.sub.2 are independently (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl, or (C.sub.1-C.sub.7) alkynyl; or R.sub.1
and R.sub.2 taken together with the carbon atom and the nitrogen
atom to which they are attached, form a 3- to 7-membered ring; or a
pharmaceutically acceptable salts thereof; or an optical isomer
thereof; or a mixture of optical isomers.
[0041] Also preferably, the present invention provides the compound
of formula (III), wherein Z.sub.1 is C, Z.sub.2 is N, R.sub.1 and
R.sub.2 are independently (C.sub.1-C.sub.7) alkyl,
(C.sub.1-C.sub.7) alkenyl, or (C.sub.1-C.sub.7) alkynyl; or R.sub.1
and R.sub.2 taken together with the carbon atom and the nitrogen
atom to which they are attached, form a 3- to 7-membered ring; or a
pharmaceutically acceptable salts thereof; or an optical isomer
thereof; or a mixture of optical isomers.
[0042] The present invention provides for compounds of formula I,
pharmaceutical compositions employing such compounds and for
methods of using such compounds.
[0043] For purposes of interpreting this specification, the
following definitions will apply and whenever appropriate, terms
used in the singular will also include the plural and vice
versa.
[0044] As used herein, the term "alkyl" refers to a branched or
unbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to
20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10
carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
n-decyl and the like. When an alkyl group includes one or more
unsaturated bonds, it may be referred to as an alkenyl (double
bond) or an alkynyl (triple bond) group. Furthermore, when an alkyl
group is linked to an aryl group (defined below), it may be
referred to as an "arylalkyl" group.
[0045] The term "aryl" refers to monocyclic or bicyclic aromatic
hydrocarbon groups having 6-20 carbon atoms in the ring portion.
Preferably, the aryl is a (C.sub.6-C.sub.10) aryl. Non-limiting
examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl,
each of which may optionally be substituted by 1-4 substituents,
such as optionally substituted alkyl, trifluoromethyl, cycloalkyl,
halo, hydroxy, alkoxy, acyl, alkyl-C(O)--O--, aryl-O--,
heteroaryl-O--, optionally substituted amino, thiol, alkylthio,
arylthio, nitro, cyano, carboxy, alkyl-O--C(O)--, carbamoyl,
alkylthiono, sulfonyl, sulfonamido, heterocycloalkyl and the
like.
[0046] Furthermore, the term "aryl" as used herein, refers to an
aromatic substituent which can be a single aromatic ring, or
multiple aromatic rings that are fused together, linked covalently,
or linked to a common group such as a methylene or ethylene moiety.
The common linking group also can be a carbonyl as in benzophenone
or oxygen as in diphenylether or nitrogen as in diphenylamine.
[0047] As used herein, the term "carbamoyl" refers to
H.sub.2NC(O)--, alkyl-NHC(O)--, (alkyl).sub.2NC(O)--,
aryl-NHC(O)--, alkyl(aryl)-NC(O)--, heteroaryl-NHC(O)--,
alkyl(heteroaryl)-NC(O)--, aryl-alkyl-NHC(O)--,
alkyl(aryl-alkyl)-NC(O)-- and the like.
[0048] As used herein, the term "sulfonamido" refers to
alkyl-S(O).sub.2--NH--, aryl-S(O).sub.2--NH--,
aryl-alkyl-S(O).sub.2--NH--, heteroaryl-S(O).sub.2--NH--,
heteroaryl-alkyl-S(O).sub.2--NH--, alkyl-S(O).sub.2--N(alkyl)-,
aryl-S(O).sub.2--N(alkyl)-, aryl-alkyl-S(O).sub.2--N(alkyl)-,
heteroaryl-S(O).sub.2--N(alkyl)-,
heteroaryl-alkyl-S(O).sub.2--N(alkyl)- and the like.
[0049] As used herein, the term "heterocycloalkyl" or "heterocyclo"
refers to an optionally substituted, fully saturated or
unsaturated, aromatic or nonaromatic cyclic group, e.g., which is a
4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to
15-membered tricyclic ring system, which has at least one
heteroatom in at least one carbon atom-containing ring. Each ring
of the heterocyclic group containing a heteroatom may have 1, 2 or
3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur
atoms, where the nitrogen and sulfur heteroatoms may also
optionally be oxidized. The heterocyclic group may be attached at a
heteroatom or a carbon atom.
[0050] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl,
oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl,
thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl,
tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,
2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl,
2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl
sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl,
1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.
[0051] Exemplary bicyclic heterocyclic groups include indolyl,
dihydroindolyl, benzothiazolyl, benzoxazinyl, benzoxazolyl,
benzothienyl, benzothiazinyl, quinuclidinyl, quinolinyl,
tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl,
tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl]
or furo[2,3-b]pyridinyl), dihydroisoindolyl,
1,3-dioxo-1,3-dihydroisoindol-2-yl, dihydroquinazolinyl (such as
3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like.
[0052] Exemplary tricyclic heterocyclic groups include carbazolyl,
dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,
acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl,
xanthenyl, carbolinyl and the like.
[0053] The term "heterocycloalkyl" further refers to heterocyclic
groups as defined herein substituted with 1, 2 or 3 substituents
selected from the groups consisting of the following:
[0054] (a) alkyl;
[0055] (b) hydroxy (or protected hydroxy);
[0056] (c) halo;
[0057] (d) oxo, i.e., .dbd.O;
[0058] (e) amino (NH.sub.2), alkylamino or dialkylamino;
[0059] (f) alkoxy;
[0060] (g) cycloalkyl;
[0061] (h) carboxy;
[0062] (i) heterocyclooxy, wherein heterocyclooxy denotes a
heterocyclic group bonded through an oxygen bridge;
[0063] (j) alkyl-O--C(O)--;
[0064] (k) mercapto;
[0065] (l) nitro;
[0066] (m) cyano;
[0067] (n) sulfamoyl or sulfonamido;
[0068] (o) aryl;
[0069] (p) alkyl-C(O)--O--;
[0070] (q) aryl-C(O)--O--;
[0071] (r) aryl-S--;
[0072] (s) aryloxy;
[0073] (t) alkyl-S--;
[0074] (u) formyl, i.e., HC(O)--;
[0075] (v) carbamoyl;
[0076] (w) aryl-alkyl-; and
[0077] (x) aryl substituted with alkyl, cycloalkyl, alkoxy,
hydroxy, amino, alkyl-C(O)--NH--, alkylamino, dialkylamino or
halogen.
[0078] As used herein, the term "sulfonyl" refers to R--SO.sub.2--,
wherein R is hydrogen, alkyl, aryl, heteroaryl, aryl-alkyl,
heteroaryl-alkyl, aryl-O--, heteroaryl-O--, alkoxy, aryloxy,
cycloalkyl, or heterocycloalkyl.
[0079] As used herein, the term "alkoxy" refers to alkyl-O--,
wherein alkyl is defined herein above. Representative examples of
alkoxy include, but are not limited to, methoxy, ethoxy, propoxy,
2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy,
cyclopropyloxy-, cyclohexyloxy- and the like. As used herein, the
term "lower alkoxy" refers to the alkoxy groups having 1-7 carbons
and preferably 1-4 carbons.
[0080] As used herein, the term "acyl" refers to a group R--C(O)--,
wherein R has from 1 to 10 carbon atoms of a straight, branched, or
cyclic configuration or a combination thereof, attached to the
parent structure through carbonyl functionality. Such group may be
saturated or unsaturated, and aliphatic or aromatic. Preferably, R
in the acyl residue is alkyl, or alkoxy, or aryl, or heteroaryl.
Also preferably, one or more carbons in the acyl residue may be
replaced by nitrogen, oxygen or sulfur as long as the point of
attachment to the parent remains at the carbonyl. Examples include
but are not limited to: acetyl, benzoyl, propionyl, isobutyryl,
t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers
to acyl containing one to four carbons.
[0081] As used herein, the term "cycloalkyl" refers to optionally
substituted saturated or unsaturated monocyclic, bicyclic or
tricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-7
carbon atoms, each of which may be substituted by one or more
substituents, such as alkyl, halo, oxo, hydroxy, alkoxy,
alkyl-C(O)--, acylamino, carbamoyl, alkyl-NH--, (alkyl).sub.2N--,
thiol, alkylthio, nitro, cyano, carboxy, alkyl-O--C(O)--, sulfonyl,
sulfonamido, sulfamoyl, heterocycloalkyl and the like. Exemplary
monocyclic hydrocarbon groups include but are not limited to:
cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and
cyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups
include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl,
decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl,
2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the
like. Exemplary tricyclic hydrocarbon groups include adamantyl and
the like.
[0082] As used herein, the term "sulfamoyl" refers to
H.sub.2NS(O).sub.2--, alkyl-NHS(O).sub.2--,
(alkyl).sub.2NS(O).sub.2--, aryl-NHS(O).sub.2--,
alkyl(aryl)-NS(O).sub.2--, (aryl).sub.2NS(O).sub.2--,
heteroaryl-NHS(O).sub.2--, aralkyl-NHS(O).sub.2--,
heteroaralkyl-NHS(O).sub.2-- and the like.
[0083] As used herein, the term "aryloxy" refers to both an--O-aryl
and an--O-- heteroaryl group, wherein aryl and heteroaryl are
defined herein.
[0084] As used herein, the term "acylamino" refers to the
group--NRC(O)R' where each of R and R' is independently hydrogen,
alkyl, aryl, heteroaryl, or heterocycloalkyl, where both R and R'
groups are optionally joined to form a heterocyclic group (e.g.,
morpholino) wherein alkyl, aryl, heteroaryl and heterocycloalkyl
are as defined herein.
[0085] As used herein, the term "heteroaryl" refers to a 5-14
membered monocyclic- or bicyclic- or fused polycyclic-ring system,
having 1 to 8 heteroatoms selected from N, O or S. Preferably, the
heteroaryl is a 5-10 membered ring system. Typical heteroaryl
groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl,
2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or
5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-,
4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or
5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or
4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or
5-pyrimidinyl.
[0086] The term "heteroaryl" also refers to a group in which a
heteroaromatic ring is fused to one or more aryl, cycloaliphatic,
or heterocycloalkyl rings, where the radical or point of attachment
is on the heteroaromatic ring. Nonlimiting examples include but are
not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-,
4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-,
3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl,
1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-,
7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-,
4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or
6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-,
5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-,
3-, 4-, 5-, 6-, 7-, or 8-4-aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-,
7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl,
1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-,
4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or
9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl,
1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-,
7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-,
or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-,
8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or
thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or
11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or
7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or
8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or
5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or
54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or
8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or
6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or
9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or
11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or
7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-,
6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-,
4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or
9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-,
5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl.
Typical fused heteroary groups include, but are not limited to 2-,
3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or
8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-,
6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-,
4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or
7-benzothiazolyl.
[0087] A heteroaryl group may be mono-, bi-, tri-, or polycyclic,
preferably mono-, bi-, or tricyclic, more preferably mono- or
bicyclic.
[0088] As used herein, the term "acylamino" refers to the
group--NRC(O)R' where each of R and R' is independently hydrogen,
alkyl, aryl, heteroaryl, or heterocycloalkyl, where both R and R'
groups are optionally joined to form a heterocyclic group (e.g.,
morpholino) wherein alkyl, aryl, heteroaryl and heterocycloalkyl
are as defined herein.
[0089] As used herein, the term "halo" refers to fluoro, chloro,
bromo, and iodo.
[0090] As used herein, the term "isomers" refers to different
compounds that have the same molecular formula. Also as used
herein, the term "an optical isomer" refers to any of the various
stereo isomeric configurations which may exist for a given compound
of the present invention and includes geometric isomers. It is
understood that a substituent may be attached at a chiral center of
a carbon atom. Therefore, the invention includes enantiomers,
diastereomers or racemates of the compound. "Enantiomers" are a
pair of stereoisomers that are non-superimposable mirror images of
each other. A 1:1 mixture of a pair of enantiomers is a "racemic"
mixture. The term is used to designate a racemic mixture where
appropriate. "Diastereoisomers" are stereoisomers that have at
least two asymmetric atoms, but which are not mirror-images of each
other. The absolute stereochemistry is specified according to the
Cahn-Ingold-Prelog R--S system. When a compound is a pure
enantiomer the stereochemistry at each chiral carbon may be
specified by either R or S. Resolved compounds whose absolute
configuration is unknown can be designated (+) or (-) depending on
the direction (dextro- or levorotatory) which they rotate plane
polarized light at the wavelength of the sodium D line. Certain of
the compounds described herein contain one or more asymmetric
centers and may thus give rise to enantiomers, diastereomers, and
other stereoisomeric forms that may be defined, in terms of
absolute stereochemistry, as (R)- or (S). The present invention is
meant to include all such possible isomers, including racemic
mixtures, optically pure forms and intermediate mixtures. Optically
active (R)- and (S)-isomers may be prepared using chiral synthons
or chiral reagents, or resolved using conventional techniques. If
the compound contains a double bond, the substituent may be E or Z
configuration. If the compound contains a disubstituted cycloalkyl,
the cycloalkyl substituent may have a cis- or trans-configuration.
All tautomeric forms are also intended to be included.
[0091] As used herein, the term "pharmaceutically acceptable salts"
refers to salts that retain the biological effectiveness and
properties of the compounds of this invention and, which are not
biologically or otherwise undesirable. In many cases, the compounds
of the present invention are capable of forming acid and/or base
salts by virtue of the presence of amino and/or carboxyl groups or
groups similar thereto (e.g., phenol or hdroxyamic acid).
Pharmaceutically acceptable acid addition salts can be formed with
inorganic acids and organic acids. Inorganic acids from which salts
can be derived include, for example, hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example,
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, maleic acid, malonic acid, succinic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid, salicylic acid, and the like. Pharmaceutically acceptable
base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for
example, sodium, potassium, lithium, ammonium, calcium, magnesium,
iron, zinc, copper, manganese, aluminum, and the like; particularly
preferred are the ammonium, potassium, sodium, calcium and
magnesium salts. Organic bases from which salts can be derived
include, for example, primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines, basic ion exchange resins, and the like,
specifically such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, and ethanolamine. The
pharmaceutically acceptable salts of the present invention can be
synthesized from a parent compound, a basic or acidic moiety, by
conventional chemical methods. Generally, such salts can be
prepared by reacting free acid forms of these compounds with a
stoichiometric amount of the appropriate base (such as Na, Ca, Mg,
or K hydroxide, carbonate, bicarbonate, or the like), or by
reacting free base forms of these compounds with a stoichiometric
amount of the appropriate acid. Such reactions are typically
carried out in water or in an organic solvent, or in a mixture of
the two. Generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred, where
practicable. Lists of additional suitable salts can be found, e.g.,
in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing
Company, Easton, Pa., (1985), which is herein incorporated by
reference.
[0092] The present invention includes all pharmaceutically
acceptable isotopically-labeled compounds of the invention, i.e.
Agents of the Invention, wherein (1) one or more atoms are replaced
by atoms having the same atomic number, but an atomic mass or mass
number different from the atomic mass or mass number usually found
in nature, and/or (2) the isotopic ratio of one or more atoms is
different from the naturally occurring ratio.
[0093] Examples of isotopes suitable for inclusion in the compounds
of the invention comprises isotopes of hydrogen, such as .sup.2H
and .sup.3H, carbon, such as .sup.11C, .sup.13C and .sup.14C,
chlorine, such as .sup.36Cl, fluorine, such as .sup.18F, iodine,
such as .sup.123I and .sup.125I, nitrogen, such as .sup.13N and
.sup.15N, oxygen, such as .sup.15O, .sup.17O and .sup.18O,
phosphorus, such as .sup.32P, and sulphur, such as .sup.35S.
[0094] Certain isotopically-labeled Agents of the Invention, for
example, those incorporating a radioactive isotope, are useful in
drug and/or substrate tissue distribution studies. The radioactive
isotopes tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0095] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0096] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy.
[0097] Isotopically-labeled Agents of the Invention can generally
be prepared by conventional techniques known to those skilled in
the art or by processes analogous to those described in the
accompanying Examples and Preparations using an appropriate
isotopically-labeled reagents in place of the non-labeled reagent
previously employed.
[0098] As used herein, the term "pharmaceutically acceptable
carrier" includes any and all solvents, dispersion media, coatings,
surfactants, antioxidants, preservatives (e.g., antibacterial
agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drugs, drug stabilizers, binders,
excipients, disintegration agents, lubricants, sweetening agents,
flavoring agents, dyes, such like materials and combinations
thereof, as would be known to one of ordinary skill in the art
(see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any
conventional carrier is incompatible with the active ingredient,
its use in the therapeutic or pharmaceutical compositions is
contemplated.
[0099] The term "therapeutically effective amount" of a compound of
the present invention refers to an amount of the compound of the
present invention that will elicit the biological or medical
response of a subject, or ameliorate symptoms, slow or delay
disease progression, or prevent a disease, etc. In a preferred
embodiment, the "effective amount" refers to the amount that
inhibits or reduces expression or activity of MMP-13 or another
selected MMP.
[0100] As used herein, the term "subject" refers to an animal.
Preferably, the animal is a mammal. A subject also refers to for
example, primates (e.g., humans), cows, sheep, goats, horses, dogs,
cats, rabbits, rats, mice, fish, birds and the like. In a preferred
embodiment, the subject is a human.
[0101] As used herein, the term "a disorder" or "a disease" refers
to any derangement or abnormality of function; a morbid physical or
mental state. See Dorland's Illustrated Medical Dictionary, (W.B.
Saunders Co. 27th ed. 1988).
[0102] As used herein, the term "inhibition" or "inhibiting" refers
to the reduction or suppression of a given condition, symptom, or
disease, or a significant decrease in the baseline activity of a
biological activity or process. Preferably, the condition is
associated with or mediated by MMP-13, such as osteoarthritis.
[0103] As used herein, the term "treating" or "treatment" of any
disease or disorder refers in one embodiment, to ameliorating the
disease or disorder (i.e., arresting or reducing the development of
the disease or at least one of the clinical symptoms thereof). In
another embodiment "treating" or "treatment" refers to ameliorating
at least one physical parameter, which may not be discernible by
the patient. In yet another embodiment, "treating" or "treatment"
refers to modulating the disease or disorder, either physically,
(e.g., stabilization of a discernible symptom), physiologically,
(e.g., stabilization of a physical parameter), or both. In yet
another embodiment, "treating" or "treatment" refers to preventing
or delaying the onset or development or progression of the disease
or disorder.
[0104] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context. Recitation of ranges of values herein
is merely intended to serve as a shorthand method of referring
individually to each separate value falling within the range.
Unless otherwise indicated herein, each individual value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g. "such as") provided herein is intended
merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No
language in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0105] Any asymmetric carbon atom on the compounds of the present
invention can be present in the (R)-, (S)- or (R,S)-configuration,
preferably in the (R)- or (S)-configuration. Substituents at atoms
with unsaturated bonds may, if possible, be present in cis-(Z)- or
trans (E)-form. Therefore, the compounds of the present invention
can be in the form of one of the possible isomers or mixtures
thereof, for example, as substantially pure geometric (cis or
trans) isomers, diastereomers, optical isomers (antipodes),
racemates or mixtures thereof.
[0106] Any resulting mixtures of isomers can be separated on the
basis of the physicochemical differences of the constituents, into
the pure geometric or optical isomers, diastereomers, racemates,
for example, by chromatography and/or fractional
crystallization.
[0107] Any resulting racemates of final products or intermediates
can be resolved into the optical antipodes by known methods, e.g.,
by separation of the diastereomeric salts thereof, obtained with an
optically active acid or base, and liberating the optically active
acidic or basic compound. In particular, the hydroxamide or
sulfonamide moiety may thus be employed to resolve the compounds of
the present invention into their optical antipodes, e.g., by
fractional crystallization of a metal (e.g., Zn.sup.2+) complex
formed with an optically active co-ligand, e.g., L- or D-histidine.
Racemic products can also be resolved by chiral chromatography,
e.g., high pressure liquid chromatography (HPLC) using a chiral
adsorbent.
[0108] Finally, compounds of the present invention are either
obtained in the free form, as a salt thereof, or as prodrug
derivatives thereof.
[0109] When a basic group is present in the compounds of the
present invention (such as in a substituent group), the compounds
can be converted into acid addition salts thereof, preferably
pharmaceutically acceptable salts thereof. These may be formed,
with inorganic acids or organic acids. Suitable inorganic acids
include but are not limited to, hydrochloric acid, sulfuric acid, a
phosphoric or hydrohalic acid. Suitable organic acids include but
are not limited to, carboxylic acids, such as (C.sub.1-C.sub.4)
alkanecarboxylic acids which, for example, are unsubstituted or
substituted by halogen, e.g., acetic acid, such as saturated or
unsaturated dicarboxylic acids, e.g., oxalic, succinic, maleic or
fumaric acid, such as hydroxycarboxylic acids, e.g., glycolic,
lactic, malic, tartaric or citric acid, such as amino acids, e.g.,
aspartic or glutamic acid, organic sulfonic acids, such as
(C.sub.1-C.sub.4) alkylsulfonic acids, e.g., methanesulfonic acid;
or arylsulfonic acids which are unsubstituted or substituted, e.g.,
by halogen. Preferred are salts formed with hydrochloric acid,
methanesulfonic acid and maleic acid.
[0110] When an acidic group is present in the compounds of the
present invention, the compounds can be converted into salts with
pharmaceutically acceptable bases. Such salts include alkali metal
salts, like sodium, lithium and potassium salts; alkaline earth
metal salts, such as calcium and magnesium salts; ammonium salts
with organic bases, e.g., trimethylamine salts, diethylamine salts,
tris (hydroxymethyl)methylamine salts, dicyclohexylamine salts and
N-methyl-D-glucamine salts; salts with amino acids such as
arginine, lysine and the like. Salts may be formed using
conventional methods, advantageously in the presence of an ethereal
or alcoholic solvent, such as a lower alkanol. From the solutions
of the latter, the salts may be precipitated with diethyl ethers,
e.g., diethyl ether. Resulting salts may be converted into the free
compounds by treatment with acids. These or other salts can also be
used for purification of the compounds obtained.
[0111] When both a basic group and an acid group are present in the
same molecule, the compounds of the present invention can also form
internal salts.
[0112] The present invention also provides pro-drugs of the
compounds of the present invention that converts in vivo to the
compounds of the present invention. A pro-drug is an active or
inactive compound that is modified through in vivo reaction, such
as hydrolysis, metabolism and the like, into a compound of this
invention following administration of the prodrug to a subject. The
suitability and techniques involved in making and using pro-drugs
are well known by those skilled in the art. Prodrugs can be
conceptually divided into two non-exclusive categories,
bioprecursor prodrugs and carrier prodrugs. See The Practice of
Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San
Diego, Calif., 2001). Generally, bioprecursor prodrugs are
compounds, which are inactive or have low activity compared to the
corresponding active drug compound that contains one or more
protective groups and are converted to an active form by metabolism
or solvolysis. Both the active drug form and any released metabolic
products should have acceptably low toxicity. Typically, the
formation of active drug compound involves a metabolic process or
reaction that is one of the follow types:
[0113] 1. Oxidative reactions, such as oxidation of alcohol,
carbonyl, and acid functions, hydroxylation of aliphatic carbons,
hydroxylation of alicyclic carbon atoms, oxidation of aromatic
carbon atoms, oxidation of carbon-carbon double bonds, oxidation of
nitrogen-containing functional groups, oxidation of silicon,
phosphorus, arsenic, and sulfur, oxidative N-delakylation,
oxidative O- and S-delakylation, oxidative deamination, as well as
other oxidative reactions.
[0114] 2. Reductive reactions, such as reduction of carbonyl
groups, reduction of alcoholic groups and carbon-carbon double
bonds, reduction of nitrogen-containing functions groups, and other
reduction reactions.
[0115] 3. Reactions without change in the state of oxidation, such
as hydrolysis of esters and ethers, hydrolytic cleavage of
carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic
heterocycles, hydration and dehydration at multiple bonds, new
atomic linkages resulting from dehydration reactions, hydrolytic
dehalogenation, removal of hydrogen halide molecule, and other such
reactions.
[0116] Carrier prodrugs are drug compounds that contain a transport
moiety, e.g., that improve uptake and/or localized delivery to a
site(s) of action. Desirably for such a carrier prodrug, the
linkage between the drug moiety and the transport moiety is a
covalent bond, the prodrug is inactive or less active than the drug
compound, and any released transport moiety is acceptably
non-toxic. For prodrugs where the transport moiety is intended to
enhance uptake, typically the release of the transport moiety
should be rapid. In other cases, it is desirable to utilize a
moiety that provides slow release, e.g., certain polymers or other
moieties, such as cyclodextrins. See, Cheng et al., US20040077595,
application Ser. No. 10/656,838, incorporated herein by reference.
Such carrier prodrugs are often advantageous for orally
administered drugs. Carrier prodrugs can, for example, be used to
improve one or more of the following properties: increased
lipophilicity, increased duration of pharmacological effects,
increased site-specificity, decreased toxicity and adverse
reactions, and/or improvement in drug formulation (e.g., stability,
water solubility, suppression of an undesirable organoleptic or
physiochemical property). For example, lipophilicity can be
increased by esterification of hydroxyl groups with lipophilic
carboxylic acids, or of carboxylic acid groups with alcohols, e.g.,
aliphatic alcohols. Wermuth, The Practice of Medicinal Chemistry,
Ch. 31-32, Ed. Werriuth, Academic Press, San Diego, Calif.,
2001.
[0117] Exemplary prodrugs are, e.g., esters of free carboxylic
acids and S-acyl and O-acyl derivatives of thiols, alcohols or
phenols, wherein acyl has a meaning as defined herein. Preferred
are pharmaceutically acceptable ester derivatives convertible by
solvolysis under physiological conditions to the parent carboxylic
acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl
esters, benzyl esters, mono- or di-substituted lower alkyl esters,
such as the .omega.-(amino, mono- or di-lower alkylamino, carboxy,
lower alkoxycarbonyl)-lower alkyl esters, the .alpha.-(lower
alkanoyloxy, lower alkoxycarbonyl or di-lower
alkylaminocarbonyl)-lower alkyl esters, such as the
pivaloyloxymethyl ester and the like conventionally used in the
art. In addition, amines have been masked as arylcarbonyloxymethyl
substituted derivatives which are cleaved by esterases in vivo
releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem.
2503 (1989)). Moreover, drugs containing an acidic NH group, such
as imidazole, imide, indole and the like, have been masked with
N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier
(1985)). Hydroxy groups have been masked as esters and ethers. EP
039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid
prodrugs, their preparation and use.
[0118] In view of the close relationship between the compounds, the
compounds in the form of their salts and the pro-drugs, any
reference to the compounds of the present invention is to be
understood as referring also to the corresponding pro-drugs of the
compounds of the present invention, as appropriate and
expedient.
[0119] Furthermore, the compounds of the present invention,
including their salts, can also be obtained in the form of their
hydrates, or include other solvents used for their
crystallization.
[0120] The compounds of the present invention have valuable
pharmacological properties, they are useful as inhibitors of matrix
metalloproteinases such as matrix metalloproteinase 13 (MMP-13) or
MMP-12. MMP12, also known as macrophage elastase or
metalloelastase, is able to degrade extracellular matrix components
such as elastin and is involved in tissue remodeling processes.
MMP-12 has been indicated to be a key protein in the pathologenesis
of tumor invasineness, arthritis, atherosclerosis, Alport syndrome,
and chronic obstructive pulmonary disease (COPD). MMP-13, also
known as collagenase 3, has been indicated in (1) extracellular
matrix degradation and cell-matrix interaction associated with
metastasis especially as observed in invasive breast cancer lesions
and in malignant epithelia growth in skin carcinogenesis; and (2)
during primary ossification and skeletal remodelling (M.
Stahle-Backdahl et al., (1997) Lab. Invest. 76 (5):717-728; N.
Johansson et al., (1997) Dev. Dyn. 208(3):387-397), in destructive
joint diseases such as rheumatoid and osteo-arthritis (D. Wernicke
et al., (1996) J. Rheumatol. 23:590-595; P. G. Mitchell et al.,
(1996) J. Clin. Invest. 97(3):761-768; O. Lindy et al., (1997)
Arthritis Rheum 40(8:1391-1399); and the aseptic loosening of hip
replacements (S. Imai et al., (1998) J. Bone Joint Surg. Br.
80(4):701-710). MMP13 has also been implicated in chronic adult
periodontitis as it has been localised to the epithelium of
chronically inflamed mucosa human gingival tissue (V. J. Uitto et
al., (1998) Am. J. Pathol 152(6):1489-1499) and in remodelling of
the collagenous matrix in chronic wounds (M. Vaalamo et al., (1997)
J. Invest. Dermatol. 109(1): 96-101).
[0121] In certain embodiments, some of the compounds of the present
invention are selective MMP-13 inhibitors over MMP-2. The selective
MMP-13 inhibitors refer to the compounds for which the ratio of the
inhibitory activity for MMP-13 over that for MMP-2 is at least two,
or five, or ten, or twenty, or fifty or more. The selective MMP-13
inhibitors as used herein, also encompass the compounds in free
form or in pharmaceutically acceptable salts, carriers as well the
prodrugs, or metabolites of the compounds.
[0122] Accordingly, the compounds of the present invention are also
useful for treatment of a disorder or a disease mediated by MMP-13
or MMP-12. In particular, the compounds of the present invention
are useful for treatment of at least one disorder or disease
selected from Alport syndrome, asthma, rhinitis, chronic
obstructive pulmonary diseases (COPD), arthritis (such as
rheumatoid arthritis and osteoarthritis), cancer invasion and
metastasis, diseases involving tissue destruction, loosening of hip
joint replacements, periodontal disease.
[0123] Additionally, the present invention provides: [0124] a
compound of the present invention for use as a medicament; [0125]
the use of a compound of the present invention for the preparation
of a pharmaceutical composition for the delay of progression and/or
treatment of a disorder or disease mediated by MMP-12, and/or
MMP-13. [0126] the use of a compound of the present invention for
the preparation of a pharmaceutical composition for the delay of
progression and/or treatment of a disorder or disease mediated by
MMP-12, and/or MMP-13. [0127] the use of a compound of the present
invention for the preparation of a pharmaceutical composition for
the delay of progression and/or treatment of a disorder or disease
selected from Alport syndrome, asthma, rhinitis, chronic
obstructive pulmonary diseases (COPD), arthritis (such as
rheumatoid arthritis and osteoarthritis), cancer invasion and
metastasis, diseases involving tissue destruction, loosening of hip
joint replacements, periodontal disease.
[0128] In another aspect, the present invention provides a
pharmaceutical composition comprising a compound of the present
invention and a pharmaceutically acceptable carrier. The
pharmaceutical composition can be formulated for particular routes
of administration such as oral administration, parenteral
administration, and rectal administration, etc. In addition, the
pharmaceutical compositions of the present invention can be made up
in a solid form including capsules, tablets, pills, granules,
powders or suppositories, or in a liquid form including solutions,
suspensions or emulsions. The pharmaceutical compositions can be
subjected to conventional pharmaceutical operations such as
sterilization and/or can contain conventional inert diluents,
lubricating agents, or buffering agents, as well as adjuvants, such
as preservatives, stabilizers, wetting agents, emulsifers and
buffers etc.
[0129] Preferably, the pharmaceutical compositions are tablets and
gelatin capsules comprising the active ingredient together with
[0130] a) diluents, e.g., lactose, dextrose, sucrose, mannitol,
sorbitol, cellulose and/or glycine; [0131] b) lubricants, e.g.,
silica, talcum, stearic acid, its magnesium or calcium salt and/or
polyethyleneglycol; for tablets also [0132] c) binders, e.g.,
magnesium aluminum silicate, starch paste, gelatin, tragacanth,
methylcellulose, sodium carboxymethylcellulose and/or
polyvinylpyrrolidone; if desired [0133] d) disintegrants, e.g.,
starches, agar, alginic acid or its sodium salt, or effervescent
mixtures; and/or [0134] e) absorbents, colorants, flavors and
sweeteners.
[0135] Tablets may be either film coated or enteric coated
according to methods known in the art.
[0136] Suitable compositions for oral administration include an
effective amount of a compound of the invention in the form of
tablets, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use are prepared according to any
method known in the art for the manufacture of pharmaceutical
compositions and such compositions can contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents and preserving agents in order to provide
pharmaceutically elegant and palatable preparations. Tablets
contain the active ingredient in admixture with nontoxic
pharmaceutically acceptable excipients which are suitable for the
manufacture of tablets. These excipients are, for example, inert
diluents, such as calcium carbonate, sodium carbonate, lactose,
calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid;
binding agents, for example, starch, gelatin or acacia; and
lubricating agents, for example magnesium stearate, stearic acid or
talc. The tablets are uncoated or coated by known techniques to
delay disintegration and absorption in the gastrointestinal tract
and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate can be employed. Formulations for oral use can
be presented as hard gelatin capsules wherein the active ingredient
is mixed with an inert solid diluent, for example, calcium
carbonate, calcium phosphate or kaolin, or as soft gelatin capsules
wherein the active ingredient is mixed with water or an oil medium,
for example, peanut oil, liquid paraffin or olive oil.
[0137] Injectable compositions are preferably aqueous isotonic
solutions or suspensions, and suppositories are advantageously
prepared from fatty emulsions or suspensions. Said compositions may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively,
and contain about 0.1-75%, preferably about 1-50%, of the active
ingredient.
[0138] Suitable compositions for transdermal application include an
effective amount of a compound of the invention with carrier.
Advantageous carriers include absorbable pharmacologically
acceptable solvents to assist passage through the skin of the host.
For example, transdermal devices are in the form of a bandage
comprising a backing member, a reservoir containing the compound
optionally with carriers, optionally a rate controlling barrier to
deliver the compound of the skin of the host at a controlled and
predetermined rate over a prolonged period of time, and means to
secure the device to the skin.
[0139] Suitable compositions for topical application, e.g., to the
skin and eyes, include aqueous solutions, suspensions, ointments,
creams, gels or sprayable formulations, e.g., for delivery by
aerosol or the like. Such topical delivery systems will in
particular be appropriate for dermal application, e.g., for the
treatment of skin cancer, e.g., for prophylactic use in sun creams,
lotions, sprays and the like. They are thus particularly suited for
use in topical, including cosmetic, formulations well-known in the
art. Such may contain solubilizers, stabilizers, tonicity enhancing
agents, buffers and preservatives.
[0140] The present invention further provides anhydrous
pharmaceutical compositions and dosage forms comprising the
compounds of the present invention as active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0141] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0142] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
[0143] The invention further provides pharmaceutical compositions
and dosage forms that comprise one or more agents that reduce the
rate by which the compound of the present invention as an active
ingredient will decompose. Such agents, which are referred to
herein as "stabilizers," include, but are not limited to,
antioxidants such as ascorbic acid, pH buffers, or salt buffers,
etc.
[0144] The pharmaceutical compositions contain a therapeutically
effective amount of a compound of the invention as defined above,
either alone or in a combination with another therapeutic agent.
Such other therapeutic agents include, for example, an
anti-inflammatory agent with cyclooxygenase inhibiting activity, or
other antirheumatic agents such as methotrexate, each at an
effective therapeutic dose as reported in the art. Examples of
antiinflammatory agents with cyclooxygenase inhibiting activity are
diclofenac, naproxen, ibuprofen, and the like.
[0145] Furthermore, the combinations as described above can be
administered to a subject via simultaneous, separate or sequential
administration (use). Simultaneous administration (use) can take
place in the form of one fixed combination with two or more active
ingredients, or by simultaneously administering two or more
compounds that are formulated independently. Sequential
administration (use) preferably means administration of one (or
more) compounds or active ingredients of a combination at one time
point, other compounds or active ingredients at a different time
point, that is, in a chronically staggered manner, preferably such
that the combination shows more efficiency than the single
compounds administered independently (especially showing
synergism). Separate administration (use) preferably means
administration of the compounds or active ingredients of the
combination independently of each other at different time points,
preferably meaning that two compounds are administered such that no
overlap of measurable blood levels of both compounds are present in
an overlapping manner (at the same time).
[0146] Also combinations of two or more of sequential, separate and
simultaneous administrations are possible, preferably such that the
combination compound-drugs show a joint therapeutic effect that
exceeds the effect found when the combination compound-drugs are
used independently at time intervals so large that no mutual effect
on their therapeutic efficiency can be found, a synergistic effect
being especially preferred.
[0147] Additionally, the present invention provides: [0148] a
pharmaceutical composition or combination of the present invention
for use as a medicament; [0149] the use of a pharmaceutical
composition or combination of the present invention for the delay
of progression and/or treatment of a disorder or disease mediated
by MMP-12 and/or MMP-13. [0150] the use of a pharmaceutical
composition or combination of the present invention for the delay
of progression and/or treatment of a disorder or disease selected
from increased degradation of collagen, osteoarthritis, malignant
epithelia growth in skin carcinogenesis, tumor invasineness,
arthritis, atherosclerosis, Alport syndrome, and chronic
obstructive pulmonary disease (COPD).
[0151] The pharmaceutical composition or combination of the present
invention can be in unit dosage of about 1-1000 mg of active
ingredients for a subject of about 50-70 kg, preferably about 5-500
mg of active ingredients. The therapeutically effective dosage of a
compound, the pharmaceutical composition, or the combinations
thereof, is dependent on the species of the subject, the body
weight, age and individual condition, the disorder or disease or
the severity thereof being treated. A physician, clinician or
veterinarian of ordinary skill can readily determine the effective
amount of each of the active ingredients necessary to prevent,
treat or inhibit the progress of the disorder or disease.
[0152] The above-cited dosage properties are demonstrable in in
vitro and in vivo tests using advantageously mammals, e.g., mice,
rats, dogs, monkeys or isolated organs, tissues and preparations
thereof. The compounds of the present invention can be applied in
vitro in the form of solutions, e.g., preferably aqueous solutions,
and in vivo either enterally, parenterally, advantageously
intravenously, e.g., as a suspension or in aqueous solution. The
dosage in vitro may range between about 10.sup.-3 molar and
10.sup.-9 molar concentrations. A therapeutically effective amount
in vivo may range, depending on the route of administration,
between about 0.1-500 mg/kg, preferably between about 1-100
mg/kg.
[0153] The compounds are particularly useful for the treatment of,
for example, inflammatory conditions, osteoarthritis, rheumatoid
arthritis and tumors. Beneficial effects are evaluated in
pharmacological tests generally known in the art, and as
illustrated herein.
[0154] Antiinflammatory activity can be determined in standard
inflammation and arthritic animal models well-known in the art,
e.g. the adjuvant arthritis model in rats and the collagen II
induced arthritis model in mice (Mediators of Inflam. 1, 273-279
(1992).
[0155] Gelatinase (MMP-2) inhibitory activities can be determined
as follows: Stock solutions of substrate
(MCA-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH.sub.2) are prepared in DMSO
at a concentration of 1.4 mM. Stock solutions of inhibitors (0.03
.mu.M-3 mM) are also prepared in DMSO. The inhibitors are diluted
into the assay solutions, and the controls use an equal volume of
DMSO so that the final DMSO concentration from the inhibitor and
substrate dilutions in all assays is 1.0%. Assays are performed in
an assay buffer (100 mM sodium chloride, 10 .mu.M ZnCl. Sub 2, 10
mM CaCl.sub.2, 100 mM Tris-Cl pH7.5, 0.05% Brij-35), containing
1.0% DMSO from the substrate and inhibitor additions. The substrate
concentration used in the assays is 5 .mu.M. The assays are carried
out at 20-25.degree. C. The fluorescence changes, as a result of
substrate cleavage, are monitored using an excitation wavelength of
325 nm and an emission wavelength of 405 nm. The reaction mixtures
are added in duplicate into appropriate wells of a 384-well assay
plate. The reaction mixtures are preincubated with the inhibitors
for 60 minutes The reactions are started by the addition of MMP
substrate, and the fluorescence intensity changes are measured
after 60 minutes The apparent enzyme activity in the presence of an
inhibitor is then compared with that in the absence of any
inhibitor to determine the inhibition effect of the inhibitor.
These techniques are within the knowledge of one skilled in the
art. The inhibition results are expressed as the inhibitor
concentrations required to effect 50% inhibition (IC.sub.50) of the
enzyme activity, as compared with the control (non-inhibited)
reactions.
[0156] Illustrative of the invention, compound 80 in the Tables
below exhibits an IC.sub.50 of 55 nM.
[0157] Collagenase-3 (MMP-13) inhibitory activity is determined as
described above. Recombinant pro-collagenase-3 is activated with 1
mM APMA, and stored in the assay buffer after extensive dialysis in
the assay buffer.
[0158] Illustrative of the invention, compound 80 in the Tables
below exhibits an IC.sub.50 of about 113 nM.
[0159] MMP-12 inhibitory activity is determined as described
above.
[0160] The effect of compounds of the invention in vivo can be
determined in rats. Typically, six rats are dosed orally with a
compound up to four hours before being injected intra-articularly
in both knees (N=12) with 0.1 to 2 ug/knee of recombinant human
MMP-13 dissolved 0.05 mL of saline. Two hours later the rats are
sacrificed, synovial lavage is collected, and chondroitin sulfate
(CS) fragments released into the joint are quantitated. Chondroitin
sulfate is measured by an inhibition ELISA using a Chondrotin
Sulfate specific antibody (CS-56 (Sigma), in an analogous manner to
the methods described by Thonar (Thonar, E. J.-M. A., Lenz, M. E.,
Klinsworth, G. K., Caterson, B., Pachman, L. M., Glickman, P.,
Katz, R., Huff, J., Keuttner, K. E. Quantitation of keratan sulfate
in blood as a marker of cartilage catabolism, Arthr. Rheum. 28,
1367-1376 (1985).
[0161] The effect in protecting against cartilage degradation in
arthritic disorders can be determined e.g. in a surgical model of
osteoarthritis described in Arthritis and Rheumatism, Vol. 26,
875-886 (1983).
[0162] The effect of the compounds of the invention for the
treatment of emphysema can be determined in animal models described
in American Review of Respiratory Disease 117, 1109 (1978).
[0163] The antitumor effect of the compounds of the invention can
be determined, for example, by measuring the growth of human tumors
implanted subcutaneously in Balb/c nude mice according to
methodology well-known in the art in comparison to placebo treated
mice. Illustrative tumors are, for example, estrogen-dependent
human breast carcinoma BT20 and MCF7, human bladder carcinoma T24,
human colon carcinoma Colo 205, human lung adenocarcinoma A549, and
human ovarian carcinoma NIH-OVCAR3.
[0164] The inhibition of tumor metastasis can be determined in two
lung metastasis models. In the B16-F10 melanoma model, metastasis
is measured by counting the numbers of lung metastasized melanoma
nodules produced by intravenously injected B16-F10 melanoma cells
into BDF1 treated mice, according to methodology well known in the
art. In the HT1080 model, metastasis is quantified by measuring the
fluorescence intensity of enhanced green fluorescent protein (EGFP)
in the lung of Balb/c nude mice produced by the metastasized tumor
from intravenously injected GFP-expressing human fibrosarcoma
HT1080 cells. The inhibition is obtained by comparison of
compound-treated and placebo-treated mice in both methods. In the
HT1080 model, EGFP-expressing HT1080 cells are prepared by limiting
dilution method in the presence of geneticin after transfecting the
EGFP expression vector (pEGFP-CI) (CLONTECH Laboratories Inc., Palo
Alto, Calif.). A suspension of cells (10.sup.6 cells/0.1 mL of PBS)
is injected intravenously into Balb/c nude mice. After
administering test compounds and vehicle p.o. 3 weeks, tumor
metastasized lungs of mice are removed after sacrifice and
homogenized. After centrifugation, the cells are washed 3 times
with lysing reagent (150 mM ammonium chloride, 0.1 mM EDTA-4 Na, 10
mM KHCO.sub.3, pH 7.4) to lyse the red blood cells and 2 times with
PBS. After centrifugation, EGFP is extracted from cells by 10%
Triton in PBS and put into the wells of a 96-well multi plate. The
fluorescence intensity is determined using a fluorescence plate
reader at the excitation and emission wave lengths of 485 and 530
nm, respectively.
[0165] The effect of the compounds of the invention on
atherosclerotic conditions can be evaluated using atherosclerotic
plaques from cholesterol-fed rabbits which contain activated matrix
metalloproteinases as described by Sukhova et al, Circulation 90,
1404 (1994). The inhibitory effect on matrix metalloproteinase
enzyme activity in rabbit atherosclerotic plaques can be determined
by in situ zymography, as described by Galis et al, J. Clin.
Invest. 94, 2493 (1994), and is indicative of plaque rupture.
[0166] The compounds of the invention are particularly useful in
mammals as antiinflammatory agents for the treatment of, for
example, osteoarthritis and rheumatoid arthritis, as antitumor
agents for the treatment and prevention of tumors growth, tumor
metastasis, tumor invasion or progression, and as
antiatherosclerotic agents for the treatment and prevention of the
rupture of atherosclerotic plaques.
[0167] The present invention also relates to methods of using the
compounds of the invention and their pharmaceutically acceptable
salts, or pharmaceutical compositions thereof, in mammals for
inhibiting the matrix-degrading metalloproteinases, e.g.
stromelysin, gelatinase, collagenase and macrophage
metalloelastase, for inhibiting tissue matrix degradation, and for
the treatment of matrix-degrading metalloproteinase dependent
conditions as described herein, e.g. inflammation, rheumatoid
arthritis, osteoarthritis, also tumors (tumor growth, metastasis,
progression or invasion), pulmonary disorders, and the like
described herein. Tumors (carcinomas) include mammalian breast,
lung, bladder, colon, prostate and ovarian cancer, and skin cancer,
including melanoma and Kaposi's sarcoma.
[0168] The following Examples are intended to illustrate the
invention and are not to be construed as being limitations thereon.
Temperatures are given in degrees Centrigrade. If not mentioned
otherwise, all evaporations are performed under reduced pressure,
preferably between about 15 and 100 mmHg (20-133 mbar). The
structures of final products, intermediates and starting materials
are confirmed by standard analytical methods, e.g. microanalysis
and/or spectroscopic characteristics (e.g. MS, IR, or NMR).
Abbreviations used are those conventional in the art.
EXAMPLES
[0169] The compounds of formula (I) can be prepared by the
procedures described in the following sections. In a typical
procedure a carboxylic acid derivative is prepared according to
Method A, Method B, Method C, Method D, Method E, Method F, or
Method G. Generally, the compounds of formula (I) can be prepared
from a carboxlic acid derivivative according to Method J, Method K,
or Method L.
Method A: General Method for the Conversion of Amino Acid
tert-butyl Esters to N-Sulfonyl Amino Acid Derivatives
##STR00006##
[0170] As to the individual steps in the above scheme, step 1
involves the sulfonylation of D-valine tert-butyl ester with a
suitably substituted naphthalene-2-sulfonyl chloride to yield a
substituted N-(naphthalene-2-sulfonyl)-D-valine tert-butyl ester.
Step 2 involves the N-alkylation of the sulfonylamide, using an
appropriate alkyl halide (e.g., 1-iodo-3-methylbutane or isoamyl
iodide) between 20.degree. C. and 90.degree. C. Step 3 involves the
deprotection of the tert-butyl ester. These derivatives may be
converted into the requisite N-hydroxyamides via any of the general
methods described below.
Typical Procedure for N-sulfonylation:
N-(6-acetoxy naphthalene-2-sulfonyl)-D-valine tert-butyl ester
[0171] D-valine tert-butyl ester (6.24 g, 35.9 mmol), 6-acetoxy
naphthalene-2-sulfonyl chloride (10.2 g, 35.9 mmol) and
triethylamine (12.5 mL, 89.7 mmol) are stirred in dioxane-water
(1:1, 243 mL) at ambient tempereature for 2 hours. The reaction
mixture is acidified with a solution of aqueous citric acid (10%
w/w, 800 mL). The precipitate is collected by filtration affording
product as pale yellow crystals (10.2 g, 68% yield). LCMS (m/z):
(439.28; M+18, 420.24; M-1).
Typical Procedure for N-alkylation of sulfonamides:
N-isoamyl-N-(6-acetoxy naphthalene-2-sulfonyl)-D-valine tert-butyl
ester
[0172] To a solution of N-(6-acetoxy
naphthalene-2-sulfonyl)-D-valine tert-butyl ester (3.15 g, 7.48
mmol) in N,N-dimethylformamide (15 mL) is added potassium carbonate
(3.09 g, 22.36 mmol), followed by 1-bromo-3-methyl butane (1.79 mL,
14.94 mmol), and the reaction is allowed to stir at ambient
temperature for 16 h. Another equivalent of 1-bromo-3-methyl butane
(0.9 mL, 7.5 mmol) is added and the reaction is allowed to stir for
16 h at ambient temperature. The reaction is poured over water and
extracted three times with dichloromethane. The combined organic
extracts are washed with brine, dried over magnesium sulfate and
concentrated in vacuo. The crude product is purified by column
chromatography and eluted with a gradient of 2-7% (hexanes-ethyl
acetate) to afford the title compound as a yellow oil (2.5 g, 68%
yield), along with N-isoamyl-N-(6-(3-methylbutoxy)
naphthalene-2-sulfonyl)-D-valine tert-butyl ester as a yellow oil
(0.3 g, 7.7% yield). LCMS (m/z): (492.26; M+1).
[0173] Typical procedure for the conversion of tert-butyl esters to
carboxylic acids:
N-Isoamyl-N-(6-hydroxy naphthalene-2-sulfonyl)-D-valine
[0174] N-Isoamyl-N-(6-hydroxy naphthalene-2-sulfonyl)-D-valine
tert-butyl ester (0.33 g, 0.74 mmol) is dissolved in 4 N
hydrochloric acid in ethyl acetate (50 mL), and the reaction is
allowed to stir at ambient temperature for 16 h. The solvent is
removed in vacuo, and the residue is purified by column
chromatography (15% hexanes-ethyl acetate) to afford the title
compound as a colorless oil (0.26 g, 90% yield). LCMS (m/z):
(394.24, M+1; 392.27, M-1).
[0175] While the above procedure illustrates the synthesis of a
6-hydroxynaphthane derivative, one of ordinary skill in the art
would appreciate that other substituted naphthane derivates (having
substituents at different positions or having different
substitutents) may be similarly prepared.
Method B: General Method for the Conversion of Amino Acid
tert-butyl Carbamates to N-sulfonyl Amino Acid Derivatives
##STR00007##
[0176] As to the individual steps in method B, step 1 involves the
formation of D-isoleucine methyl ester with a concomitant removal
of the tert-butoxy carbamate. Alternatively, amino acids without
the tert-butoxy carbamate group can be converted directly to the
corresponding methyl ester under identical conditions. When the
desired methyl ester is commercially available, step 1 may be
omitted while the remainder of method B is followed. Step 2
involves the sulfonylation of D-leucine methyl ester with a
suitably substituted naphthalene-2-sulfonyl chloride to yield a
substituted N-(naphthalene-2-sulfonyl)-D-leucine methyl ester. Step
3 involves the N-alkylation of the sulfonylamide, using an
appropriate alkyl halide (e.g., 1-iodo-3-methylbutane or isoamyl
iodide). Step 4 involves the deprotection of the methyl ester via
saponification
Typical Procedure for the Formation of methyl esters:
(R)-2-Amino-4-methyl-pentanoic acidmethyl ester
[0177] To a solution of
(R)-2-tert-butoxycarbonylamino-4-methyl-pentanoic acid (2 g, 8.7
mmol) in methanol (20 mL) is added thionyl chloride (2.59 g, 21.7
mmol). The reaction mixture is refluxed for 2 h. The reaction
mixture is cooled to room temperature and concentrated in vacuo.
The crude product is carried on without any further purification.
.sup.1H NMR (400 MHz, MeOD): .delta. 1.00 (q, 6H, J=3 Hz), 1.7-1.9
(m, 3H, J=7.7 Hz), 3.85 (s, 3H), 4.0 (t, 1H).
Typical Procedure for the sulfonylation of amines:
(R)-4-Methyl-2-(naphthalene-2-sulfonylamino)-pentanoic acid methyl
ester
[0178] To a suspension of methyl ester (8.7 mmol, 1 eq) in
dioxane/water (25 mL/25 mL, 1:1) is added triethylamine (3.1 g,
30.45 mmol) followed by the addition of 2-naphthalenesulfonyl
chloride (1.97 g, 8.7 mmol). The reaction is stirred at room
temperature for 18 h, then acidified with 1 N hydrochloric acid and
extracted with dichloromethane. The combined organic extracts are
dried over sodium sulfate and concentrated to give the crude
product, which is carried on without any further purification. LCMS
(m/z): 336 (M+1).
Typical Procedure for alkylation of sulfonamides:
(R)-4-Methyl-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-pentanoic
acid methyl ester
[0179] To a mixture of the sulfonylated methyl ester (8.7 mmol, 1.0
equivalents) and potassium carbonate in N,N-dimethylformamide (20
mL) is added 1-iodo-3-methyl butane. The mixture is stirred atroom
temperaturefor 18 h. The reaction is diluted with water and
extracted with ethyl acetate. The combined organic extracts are
washed with brine, dried over sodium sulfate and concentrated to
afford the crude product (3.2 g) which is carried on without
additional purification. LCMS (m/z): 406 (M+1).
General Procedure for the Saponification of Methyl Esters:
(R)-4-Methyl-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-pentanoic
acid
[0180] To a solution of methyl ester (1.6 g, 3.95 mmol) in
tetrahydrofuran/water (21 mL/7 mL) is added lithium hydroxide (1 N,
7.9 mL). The reaction is stirred at room temperature for 18 h. The
reaction mixture is acidified 1 N hydrochloric acid and extracted
with ethyl acetate. The combined organic extracts are dried over
sodium sulfate and concentrated in vacuo. Purification by flash
chromatography yields 810 mg of the title compound as a white foam.
.sup.1H NMR (400 MHz, MeOD): .delta. 0.95 (m, 12H), 1.3-1.8 (m,
6H), 3.15-3.4 (m, 2H), 4.55 (q, 1H, J=5 Hz), 7.55-7.65 (m, 2H), 7.8
(dd, 1H), 7.91-8.05 (m, 3H), 8.40 (s, 1H). LCMS (m/z): 392 (M+1).
Analytics calculated for C.sub.21H.sub.29NO.sub.4S. C, 64.42; H,
7.47; N, 3.58. Found: C, 64.49; H, 7.33; N, 3.56.
Method C: General Method for the Conversion of Amino Acid benzyl
Esters to N-sulfonyl Amino Acid Derivatives
##STR00008##
[0181] As to the individual steps in the above scheme, step 1
involves the sulfonylation of D-valine tert-butyl ester with a
suitably substituted naphthalene-2-sulfonyl chloride to yield a
substituted N-(naphthalene-2-sulfonyl)-D-valine tert-butyl ester.
Step 2 involves the N-alkylation of the sulfonylamide, using an
appropriate alkyl halide (e.g., 1-iodo-3-methylbutane or isoamyl
iodide). Step 3 involves the deprotection of the benzyl ester via
hydrogenolysis.
[0182] The sulfonylation and alkylation steps are carried out under
analogous conditions as those described in methods A and B. The
benzyl ester is converted to a carboxylic acid derivative following
the typical procedure described below.
Typical Hydrogenation Procedure:
[0183] To a solution of 240 mg (0.44 mmol)
2-[(6-Benzyloxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-3-methyl--
butyric acid tert-butyl ester in 20 ml EtOAc is added 50 mg PdC
(10%) and the mixture is hydrogenated at 50 psi for 18 h. The
mixture is filtered through Celite and evaporated to give the
desired product.
Method D: Typical Procedure for the Conversion of napthol
Derivatives to alkyl Derivatives
##STR00009##
[0184] As to the individual steps in method D, step 1 involves the
hydrolysis of the ester to provide the phenolic intermediate, step
2 involves the activation of the naphthol group into a
trifluoromethanesulfonyl ester. Step 3 involves the displacement of
the trifluoromethanesulfonyl ester with the desired substituent,
e.g., a methyl group shown in the scheme above. Once the
substitution is completed, the product may be converted into the
desired carboxylic acid according to the steps outlined in method
A.
Typical Procedure for the Hydrolysis of Napthol Esters:
N-Isoamyl-N-(6-hydroxy naphthalene-2-sulfonyl)-D-valine tert-butyl
ester
[0185] To a solution of N-isoamyl-N-(6-acetoxy
naphthalene-2-sulfonyl)-D-valine tert-butyl ester (0.75 g, 1.53
mmol) in ethanol-water (35 mL-15 mL) is added potassium carbonate
(0.422 g, 3.05 mmol), and the reaction is heated to reflux for 16
h. The solvents are removed in vacuo, and the residue is
redissolved in water and extracted three times with
dichloromethane. The combined organic extracts are washed with
sodium bicarbonate and brine, dried over sodium sulfate, and
concentrated in vacuo. The crude product is purified by column
chromatography (10% hexanes-ethyl acetate) to afford the title
compound as a yellow oil (0.58 g, 85% yield).
N-isoamyl-N-(6-trifluoromethanesulfonyloxy
naphthalene-2-sulfonyl)-D-valine tert-butyl ester
[0186] To a solution of N-isoamyl-N-(6-hydroxy
naphthalene-2-sulfonyl)-D-valine tert-butyl ester (0.18 g, 0.35
mmol) in dichloromethane (10 mL) at 0.degree. C. is added
triethylamine (0.099 mL, 0.71 mmol), triflic anhydride (0.089 mL,
0.53 mmol), and 4-dimethylaminopyridine (0.004 g, 0.035 mmol). The
reaction is stirred at 0.degree. C. for 1 hour. The solvents are
removed in vacuo, and the residue is purified by column
chromatography (6% hexanes-ethyl acetate) to afford the title
compound (a triflate) as a yellow solid (0.14 g, 68% yield).
N-Isoamyl-N-(6-methyl naphthalene-2-sulfonyl)-D-valine tert-butyl
ester
[0187] To a solution of N-isoamyl-N-(6-trifluoromethanesulfonyloxy
naphthalene-2-sulfonyl)-D-valine tert-butyl ester (1.1 g, 1.89
mmol) in N,N-dimethylformamide (20 mL) is added lithium chloride
(0.40 g, 9.5 mmol), tetramethyl tin (0.525 mL, 3.79 mmol), and
bistriphenylphosphino palladium dichloride (0.066 g, 0.095 mmol).
The reaction is heated to 80.degree. C. for 16 h. The reaction is
allowed to cool to ambient temperature and filtered through Celite.
The filtrate is poured over water and extracted three times with
dichloromethane. The combined organic extracts were washed with
brine, dried over sodium sulfate, and concentrated in vacuo. The
residue is purified by column chromatography (4% hexanes-ethyl
acetate) to afford the title compound as a white solid (0.41 g, 50%
yield).
[0188] Alternatively, different alkoxy substituted aryl compounds
of formula (I) (where X=an alkoxy group) can be prepared from the
suitably protected phenolic intermediate (tert-butyl shown for
illustrative purposes) according to method E, which contains 1
steps. As illustrated in method E, this procedure involves the
alkylation of the phenolic intermediate described above in method D
with a suitable alkyl iodide (e.g methyl iodide). The reaction
conditions for the desired O-alkylation are analogous to the
conditions for N-alkylation described in methods A and B. The
conversion of the tert-butyl ester thus generated to the carboxylic
acid is accomplished in the same manner described in method A.
Method E: Typical Procedure for the Alkylation of Napthol
Derivatives
##STR00010##
[0190] Alternatively, cyclic N-sulfonyl amino acid analogs of
compounds of formula (I) can be prepared according to method F,
which contains 6 steps.
Method F: Typical Procedure for the Formation of Tetrahydropyridine
and Tetrahydroazepine Derivatives
##STR00011##
[0192] As to individual steps in method F, step 1 involves
sulfonylation of a suitably protected amino acid derivative
containing an olefin in the side chain. Step 2 involves the
alkylation of the sulfonamide nitrogen. Steps 1 and 2 are analogous
to the typical sulfonylation and alkylation conditions described in
methods A and B. Step 3 involves a ring closing metathesis reaction
to generate the cyclic amino acid. The resulting ester can be
converted into the corresponding carboxylic acid by steps described
in method B.
Step 3: Typical Procedure for Ring Closing Metathesis:
(R)-1-(1-Methoxy-naphthalene-2-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-car-
boxylic acid ethyl ester
[0193] A solution of
(R)-2-ally-1-(10-methoxy-naphthalene-2sulfonyl)-amino-pent-4-enoic
acid ethyl ester (141 mg, 0.35 mmol) in chloroform (5 mL) is
de-gased with agon for 5 min, then Grubb's catalyst (5 mg, 0.006
mmol) is added. The reaction is stirred at room temperature for 15
min. The reaction is then concentrated in vacuo. Purification by
flash chromatography yields the product (120 mg) as a solid.
.sup.1HNMR (400 MHz, MeOD): .delta. 0.92 (t, 3H, J=7 Hz), 2.65 (br,
2H), 3.8 (q, 1H, J=7 Hz), 3.95 (br, 2H), 4.15 (s, 3H), 5.03 (m,
1H), 5.65-5.75 (m, 2H), 7.65 (dd, 2H, J=2 Hz, J=6 Hz), 7.70 (d, 1H,
J=8 Hz), 7.9 (m, 2H), 8.15 (m, 1H). LCMS (m/z): 376 (M+1).
[0194] Alternatively, substituted cyclic N-sulfonyl amino acid
analogs of compounds of formula (I) can be prepared according to
method G, which contains 4 steps.
Method G: Typical Procedure for the Alkylation of Napthol
Derivatives
##STR00012##
[0195] As to individual steps in method G, step 1 involves the
protection of the hydroxy group as a suitable silyl ether. Step 2
involves the conversion of the ketone moiety to an olefin. Step 3
involves the deprotection of the silyl ether. Step four involves
the formation of the methanesulfonic acid ester. Typical Procedure
for the Formation of tert-butyl dimethylsilyl Ethers:
2-(tert-Butyl-dimethyl-silanyloxy)-1-phenyl-ethanone
[0196] To a well stirred solution of 2-hydroxyacetophenone (1.0 g,
7.34 mmol) in dichloromethane (15 mL) is added triethylamine (1.23
mL, 8.81 mmol), 4-dimethylaminopyridine (45 mg, 0.367 mmol) and
tert-butyldimethylsilyl chloride (1.16 g, 7.71 mmol) dissolved in
dichloromethane (2 mL). The reaction mixture is stirred at room
temperature for 1 h, then diluted with dichloromethane (50 mL),
washed with 10% citric acid, saturate sodium carbonate, brine,
dried over magnesium sulfate, filtered and concentrated in vacuo.
The residue is purified via silica gel chromatography (20% ethyl
acetate in hexanes) to yield the title compound as a yellow oil
(1.3 g, 5.19 mmol).
Typical Procedure for the Formation of Olefins from Ketones:
tert-Butyl-dimethyl-(2-phenyl-allyloxy)-silane
[0197] To a well stirred solution of methyl-triphenyl-phosphonium
bromide (3.08 g, 8.61 mmol) in tetrahydrofuran (10 mL) at 0.degree.
C. is added n-butyllithium (4.89 mL, 7.83 mmol of a 1.6 M
solution). The reaction mixture is allowed to warm to room
temperature, stirred for 1 h, then cooled to 0.degree. C.
2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethanone (980 mg, 3.91
mmol) in tetrahydrofuran (30 mL) is then slowly added. The mixture
is stirred at room temperature for 30 min then quenched by the
addition of a saturated aqueous solution of ammonium chloride and
extracted several times with ethyl acetate. The organic layers are
combined, washed with water, brine, dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue is purified via
silica gel chromatography (20% ethyl acetate in hexanes) to yield
1.3 g of the title compound as a clear oil containing ethyl acetate
and was used directly in the next step.
Typical Procedure for the Deprotection of tert-butyl dimethylsilyl
ethers
2-Phenyl-prop-2-en-1-ol
[0198] To a well stirred solution of
tert-butyl-dimethyl-(2-phenyl-allyloxy)-silane (1.3 g, 5.23 mmol)
in tetrahydrofuran (10 mL) is slowly added a solution of a 1 N
tetrabutylammonium fluoride in tetrahydrofuran (10.5 mL, 10.5
mmol). The reaction is allowed to stir for 20 min, quenched by the
addition of a saturated aqueous solution of ammonium chloride and
extracted several times with ethyl acetate The organic layers are
combined, washed with water, brine, dried over magnesium sulfate,
filtered and concentrated in vacuo. The residue is purified via
silica gel chromatography (10% ethyl acetate in hexanes) to yield
700 mg of the title compound.
Typical Procedure for the Formation of Methanesulfonic Acid
Esters
Methanesulfonic acid 2-phenyl-allyl ester
[0199] To a well stirred solution of 2-phenyl-prop-2-en-1-ol (700
mg, 5.22 mmol) in dichlorometane (10 mL) at 0.degree. C. is added
triethylamine (0.945 mL, 6.78 mmol) and methylsulfonyl chloride
(0.424 mL, 5.48 mmol). The reaction is allowed to stir for 10 min,
warmed to room temperature and is stirred for 30 min. The reaction
is quenched by the addition of a saturated aqueous solution of
ammonium chloride and extracted several times with ethyl acetate.
The organic layers are combined, washed with 1 N hydrochloric acid,
brine, dried over magnesium sulfate, filtered and concentrated in
vacuo. The residue is purified via silica gel chromatography (10%
ethyl acetate in hexanes) to yield the title compound (1.07 g, 4.95
mmol).
[0200] The resulting methanesulfonic acid esters are converted to
the desired carboxylic acid derivative by method F as shown
below.
##STR00013##
[0201] Alternatively, bicyclic N-sulfonyl amino acid analogs of
compounds of formula (I) can be prepared according to method H,
which contains 7 steps.
Method H: Typical Procedure for the Hydrogenation of
Tetrahydropiperidine and Tetrahydroazepine Analogs
[0202] To a mixture of
(R)-1-(quinoline-3-sulfonyl)-piperidine-2-carboxylic acid
hydroxyamide (110 mg) in ethanol (5 mL) is added 10% palladium on
carbon (10 mg). The reaction mixture is maintained under 1
atmosphere of hydrogen for 18 h. The reaction mixture is filtered
through Celite, and concentrated in vacuo yield a product (85 mg)
as a light beige solid.
General Methods for the Formation of Hydroxamates
Method I: General Method for the Conversion of Carboxylic Acid
Derivatives to Hydroxyamide Compounds Via Hydroxylamine
Method J: General Method for the Conversion of Carboxylic Acid
Derivatives to Hydroxyamide Compounds Via Acid Chloride
##STR00014##
[0204] As to the individual steps in the above scheme, step 1
involves activation of the carboxylic acid as the acid chloride.
Step 2 involves the substitution of the acid chloride with
hydroxylamine to yield the desired hydroxamic acid.
##STR00015##
Typical procedure for the formation of N-hydroxyamides via acid
chlorides
##STR00016##
N-Benzyl-N-(7-ethoxy-naphthalene-2-sulfonyl)-D-valine hydroxamic
acid (NVP-LBQ690) (Converted from the carboxylic acid to the
hydroxamic acid via the acid chloride)
[0205] To a solution of
N-benzyl-N-(7-ethoxy-naphthalene-2-sulfonyl)-D-valine (0.335 mg,
0.76 mmol) in dichloromethane (20 ml) is added 5 drops of DMF and 2
M oxalyl chloride (1 ml, 2 mmol). After 1 hour the reaction is
complete by TLC. The mixture is transfered dropwise to a cooled
(0.degree. C.) mixture of 50% aqueous hydroxylamine (3 ml, 2 mmol)
in THF (25 ml). After stirring for 1 hour the reaction is washed
with 1 N hydrochloric acid, saturated sodium chloride solution,
dried over MgSO.sub.4, filtered and concentrated. The crude product
is purified by column chromatography (hexane-ethyl acetate; 1:1)
and crystallized from diethyl ether affording the title compound.
Mass spectrum (457.2; M+1, 455.4; M-1). CHN Calc CHN 63.14, 6.18,
6.14 Found CHN 63.17, 6.11, 6.01.
[0206] Alternatively, compounds of the general formula I can be
prepared from the carboxylic acid intermediates as desbribed above,
according to method J, which contains 2 steps.
Method K: General Method for the Conversion of Carboxylic Acid
Derivatives to Hydroxyamide Compounds Via
O-tetrahydropyranylhyrdroxylamine
##STR00017##
[0207] Typical Procedure for Making O-tetrahydropyranyl
N-hyrdroxyamide
[0208] Following the procedure for the formation of
O-tritylhydroxylamine compounds, O-tetrahydropyranyl
N-hyrdroxyamides can be prepared by analogous methods where
O-tetrahydropyranylhyrdroxylamine is used instead of
O-tritylhydroxylamine.
General Procedure for the Deprotection of O-tetrahydropyranyl
N-hyrdroxyamide
[0209] To a solution of the tetrahydropyranyl protected hydroxamic
acid is added ethanol and 3 N hydrochloric acid and the reaction
stirred at ambient temperature for 16 hours. Water and ethyl
acetate are added, the aqueous layer neutralized with sodium
bicarbonate and the layers separated. The aqueous layer is
extracted with ethyl acetate, washed with brine, dried over
magnesium sulfate and filtered. The solvent is removed in vacuo and
the residue is purified by crystallization from diethyl ether and
hexane to give the desired product As to the individual steps in
the above scheme, step 1 involves coupling of the carboxylic acid
with tetrahydropyranyl (tetrahydropyranyl) protected hydroxylamine.
Step 2 involves removal of the tetrahydropyranyl protecting group
via acid hydrolysis to yield the desired hydroxamic acid.
Method L: General Method for the Conversion of Carboxylic Acid
Derivatives to Hydroxyamide Compounds Via
O-tritylhyrdroxylamine
##STR00018##
[0210] Tpical Procedure for Making O-trityl hydroxyamide
Compounds:
[0211] A solution of acid (460 mg, 1.18 mmol), O-tritylhydroxyamine
(485 mg, 1.76 mmol), N-methyl morpholine (594 mg, 5.88 mmol),
1-hydroxy-7-azabenzo-triazole (160 mg, 1.18 mmol), and
1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (293
mg, 1.53 mmol) in dichloromethane (20 mL) are stirred at room
temperature for 18 h. The reaction is then acidified with 1 N
hydrochloric acid and extracted with dichloromethane. The combined
organic extracts are washed with brine, dried over sodium sulfate,
and concentrated in vacuo to give 810 mg of product as white solid
which is carried on without any further purification. LCMS (m/z):
647 (M-1).
Typical Procedure for the Deprotection of O-trityl hydroxyamide
Compounds:
[0212] To a solution of trityl protected hydroxylamine compound
(400 mg, 0.62 mmol) in dichloromethane (10 mL) is added
trifluoroacetic acid (563 mg, 4.9 mmol) followed by the addition of
triethylsilane (143 mg, 1.23 mmol). The reaction is stirred at room
temperature for 5 minutes, then concentrated in vacuo to give a
crude product, which is purified by flash chromatography to afford
product (280 mg) as white solid.
[0213] Alternatively, hydroxamates may be prepared directly from
carboxylic acid derivatives and hydroxylamine (50% solution in
water) following method L except the final deprotection step is
omitted.
[0214] Generally, the compounds of formula (II) can be prepared by
methods of preparing enantiomers of the compounds known to those
skilled in the art by resolving racemic mixtures, such as by
formation and recrystallization of diastereomeric salts or by
chiral chromotagraphy or HPLC separation utilizing chiral
stationery phases.
[0215] Preferably, the compounds of formula (II) can be prepared
starting with materials in the form of the intended enantiomer and
using the schemes descrbed herein, such that the resulting final
compounds are in the form of the intended enantiomer.
[0216] In starting compounds and intermediates which are converted
to the compounds of the present invention in a manner described
herein, functional groups present, such as amino, thiol, carboxyl
and hydroxy groups, are optionally protected by conventional
protecting groups that are common in preparative organic chemistry.
Protected amino, thiol, carboxyl and hydroxyl groups are those that
can be converted under mild conditions into free amino thiol,
carboxyl and hydroxyl groups without the molecular framework being
destroyed or other undesired side reactions taking place.
[0217] The purpose of introducing protecting groups is to protect
the functional groups from undesired reactions with reaction
components under the conditions used for carrying out a desired
chemical transformation. The need and choice of protecting groups
for a particular reaction is known to those skilled in the art and
depends on the nature of the functional group to be protected
(hydroxyl group, amino group, carboxy, etc.), the structure and
stability of the molecule of which the substituent is a part and
the reaction conditions.
[0218] Well-known protecting groups that meet these conditions and
their introduction and removal are described, e.g., in McOmie,
"Protective Groups in Organic Chemistry", Plenum Press, London,
N.Y. (1973); and Greene and Wuts, "Protective Groups in Organic
Synthesis", John Wiley and Sons, Inc., NY (1999).
[0219] The above-mentioned reactions are carried out according to
standard methods, in the presence or absence of diluent,
preferably, such as are inert to the reagents and are solvents
thereof, of catalysts, condensing or said other agents,
respectively and/or inert atmospheres, at low temperatures, room
temperature or elevated temperatures, at or near the boiling point
of the solvents used, and at atmospheric or super-atmospheric
pressure.
[0220] The invention further includes any variant of the present
processes, in which an intermediate product obtainable at any stage
thereof is used as starting material and the remaining steps are
carried out, or in which the starting materials are formed in situ
under the reaction conditions, or in which the reaction components
are used in the form of their salts or optically pure
antipodes.
[0221] Compounds of the invention and intermediates can also be
converted into each other according to methods generally known.
[0222] The present invention will now be illustrated by reference
to the following examples which set forth particularly advantageous
embodiments. However, it should be noted that these embodiments are
illustrative and are not to be construed as restricting the
invention in any way.
[0223] Other analogs (e.g., ethyl, propyl, etc.) may also be
prepared by this procedure. In addition, one of ordinary skill in
the art would appreciate that the triflate intermediate may also be
displaced with other nucleophiles, such as amines (RNH.sub.2 or
RR'NH) or thiols (RSH).
[0224] The above tert-butyl ester can then be deprotected (with
TFA) to produce a free carboxylic acid. The carboxylic acid can
then be converted into a trityl hydroxamic acid, which is
subsequently deprotected to produce the desired hydroxamic acid,
according to the procedures shown in Scheme I.
Example 1
(R)--N-Hydroxy-2-[(1-hydroxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amin-
o]-3-methyl-butyramide
##STR00019##
[0226] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
1-methoxy-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. Analytical data: LCMS (m/z): 409
(M+1).
Example 2
N-Hydroxy-2-[isobutyl-(naphthalene-2-sulfonyl)-amino]-acetamide
##STR00020##
[0228] Following methods B and L, the title compound is prepared
from amino-acetic acid, naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 393.1 (M+1).
Example 3
(R)-2-(Naphthalene-2-sulfonylamino)-pent-4-enoic acid
hydroxyamide
##STR00021##
[0230] Following typical sulfonylation methods and method L, the
title compound is prepared from (R)-2-amino-pent-4-enoic acid ethyl
ester and naphthalene-2-sulfonyl chloride. LCMS (m/z): 321 (M+1).
Analytics calculated for C.sub.15H.sub.16N.sub.2O.sub.4S: C, 56.24;
H, 5.03; N, 8.74. Found: C, 56.87; H, 4.84; N, 8.42.
Example 4
(R)-2-[But-3-enyl-(naphthalene-2-sulfonyl)-amino]-pent-4-enoic acid
hydroxyamide
##STR00022##
[0232] Following typical sulfonylation and alkylation methods
followed by method L, the title compound is prepared from
(R)-2-amino-pent-4-enoic acid ethyl ester, naphthalene-2-sulfonyl
chloride and 4-bromo-but-1-ene. LCMS (m/z): 375 (M+1). Analytics
calculated for C.sub.19H.sub.22N.sub.2O.sub.4S: C, 60.94; H, 5.92;
N, 7.48. Found: C, 60.73; H, 5.87; N, 7.27.
Example 5
4-Methyl-2-(naphthalene-2-sulfonylamino)-pentanoic acid
hydroxyamide
##STR00023##
[0234] Following typical sulfonylation conditions and method J, the
title compound is prepared from (R)-2-amino-4-methyl-pentanoic acid
and naphthalene-2-sulfonyl chloride. LCMS (m/z): 337.2 (M+1),
335.33 (M-1).
Example 6
N-Hydroxy-3-methyl-2-(naphthalene-2-sulfonylamino)-butyramide
##STR00024##
[0236] Following typical sulfonylation conditions and method L, the
title compound is prepared from (R)-2-amino-3-methyl-butyric acid
tert-butyl ester and naphthalene-2-sulfonyl chloride. LCMS (m/z):
321.10 (M-1).
Example 7
(R)--N-Hydroxy-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-4-pheny-
l-butyramide
##STR00025##
[0238] Following methods B and L, the title compound is prepared
from (R)-2-amino-4-phenyl-butyric acid, naphthalene-2-sulfonyl
chloride and 1-iodo-3-methyl-butane. .sup.1HNMR (400 MHz, MeOD):
.delta. 0.88 (d, 6H, J=6 Hz), 1.45-1.60 (m, 4H), 1.61-1.72 (m, 1H),
2.05-2.20 (m, 1H), 2.35-2.55 (m, 2H), 3.55-3.70 (m, 1H), 4.25 (m,
1H), 6.92 (d, 2H, J=8 Hz), 7.10-7.20 (m, 3H), 7.60-7.75 (m, 3H)
7.98-8.07 (m, 3H), 8.38 (s, 1H). LCMS (m/z): 455 (M+1). Analytics
calculated for C.sub.25H.sub.30N.sub.2O.sub.4S: C, 66.05; H, 6.65;
N, 6.16. Found: C, 65.97; H, 6.49; N, 5.98.
Example 8
(R)-2-[Allyl-(naphthalene-2-sulfonyl)-amino]-pent-4-ynoic acid
hydroxyamide
##STR00026##
[0240] Following typical sulfonylation and alkylation methods
followed by method L, the title compound is prepared from
(R)-2-amino-pent-4-ynoic acid ethyl ester, naphthalene-2-sulfonyl
chloride and 3-bromo-propene. LCMS (m/z): 359 (M+1).
Example 9
(R)-1-(Naphthalene-2-sulfonyl)-piperidine-2-carboxylic acid
hydroxyamide
##STR00027##
[0242] Following method H, the title compound is prepared from
(R)-1-(naphthalene-2-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-carboxylic
acid hydroxyamide. LCMS (m/z): 335 (M+1). Analytics calculated for
C.sub.19H.sub.22N.sub.2O.sub.4S: C, 57.47; H, 5.43; N, 19.14.
Found: C, 53.11; H, 5.09; N, 7.24.
Example 10
2-[Benzyl-(naphthalene-2-sulfonyl)-amino]-N-hydroxy-3-methyl-butyramide
##STR00028##
[0244] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and benzyl bromide. LCMS (m/z):
411.16 (M-1).
Example 11
N-Hydroxy-2-(naphthalene-2-sulfonylamino)-2-(tetrahydro-pyran-4-yl)-acetam-
ide
##STR00029##
[0246] Following methods B and L, the title compound is prepared
from amino-(tetrahydro-pyran-4-yl)-acetic acid and
naphthalene-2-sulfonyl chloride. LCMS (m/z): 365.3 (M+1), 363.4
(M-1). CHN: Calc CHN: 56.03, 5.53, 7.69; Found CHN: 56.66, 5.71,
7.23.
Example 12
N-Hydroxy-2-methyl-2-(naphthalene-2-sulfonylamino)-propionamide
##STR00030##
[0248] Following typical sulfonylation conditions and method L, the
title compound is prepared from 2-amino-2-methyl-propionic acid and
naphthalene-2-sulfonyl chloride. LCMS (m/z): 307.21 (M-1).
Example 13
(R)--N-Hydroxy-3-methyl-2-[(naphthalene-2-sulfonyl)-phenethyl-amino]-butyr-
amide
##STR00031##
[0250] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and (2-bromo-ethyl)-benzene. LCMS
(m/z): 427 (M+1). Analytics calculated for
C.sub.23H.sub.26N.sub.2O.sub.4S: C, 64.77; H, 6.14; N, 6.57. Found:
C, 64.57; H, 6.02; N, 6.53.
Example 14
N-Hydroxy-3-methyl-2-[(naphthalene-2-sulfonyl)-(3-phenyl-propyl)-amino]-bu-
tyramide
##STR00032##
[0252] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and (3-bromo-propyl)-benzene. LCMS
(m/z): 439.15 (M-1)
Example 15
(R)-4-Methyl-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-pentanoic
acid hydroxyamide
##STR00033##
[0254] Following methods B and L, the title compound is prepared
from butane (R)-2-amino-4-methyl-pentanoic acid methyl ester,
naphthalene-2-sulfonyl chloride and 1-iodo-3-methyl-butane.
.sup.1HNMR (400 MHz, MeOD): .delta. 0.80 (q, 6H, J=3.6 Hz), 0.90
(d, 6H, J=6 Hz), 1.25 (m, 1H), 1.4-1.6 (m, 2H), 1.62-1.75 (m, 2H),
3.58-3.60 (m, 1H), 4.27-4.42 (t, 1H, J=7 Hz), 7.6-7.7 (m, 2H), 7.82
(d, 1H, J=8.5 Hz), 7.98 (d, 1H, J=8.5 Hz), 8.07 (d, 1H, J=8.5 Hz),
8.45 (s, 1H). LCMS (m/z): 407 (M+1). Analytics calculated for
C.sub.21H.sub.30N.sub.2O.sub.4S: 0, 62.04; H, 7.44; N, 6.89. Found:
C, 62.32; H, 7.34; N, 6.71
Example 16
(R)--N-Hydroxy-3-(4-hydroxy-phenyl)-2-[(3-methyl-butyl)-(naphthalene-2-sul-
fonyl)-amino]-propionamide
##STR00034##
[0256] A mixture of
(R)-3-(4-benzyloxy-phenyl)-N-hydroxy-2-[(3-methyl-butyl)-(naphthalene-2-s-
ulfonyl)-amino]-propionamide (230 mg, 0.42 mmol) and 200 mg of 10%
Pd/C in ethyl acetate (20 mL) are hydrogenated under 50 PSI for 6
h. The reaction mixture is filtered through celite, and
concentrated in vacuo. Purification by flash chromatography yields
40 mg of product. .sup.1HNMR (400 MHz, MeOD): .delta. 0.90 (d, 6H,
J=5.5 Hz), 1.5-1.7 (m, 4H), 2.4-2.5 (dd, 1H, J=5 Hz), 3.05-3.15
(dd, 1H, J=5 Hz), 3.35-3.45 (m, 1H), 3.6-3.75 (m, 1H), 4.30-4.40
(q, 1H, J=5 Hz), 6.55 (d, 2H, J=8 Hz), 6.80 (d, 2H, J=8 Hz),
7.7-7.85 (m, 3H), 7.92-8.10 (m, 3H), 8.45 (s, 1H). LCMS (m/z): 457
(M+1). Analytics calculated for C.sub.24H.sub.28N.sub.2O5.sub.4S:
C, 63.14; H, 6.18; N, 6.14. Found: C, 63.03; H, 6.30; N, 5.89.
Example 17
N-methyl-N-(naphthalene-2-sulfonyl)-D-valine hydroxamic acid
##STR00035##
[0258] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and methyl iodide. LCMS (m/z):
337.18 (M+1), 335.29 (M-1).
Example 18
N-Hydroxy-4-methanesulfonyl-2-(naphthalene-2-sulfonylamino)-butyramide
##STR00036##
[0260] Following typical sulfonylation conditions and method L, the
title compound is prepared from 2-amino-4-methanesulfonyl-butyric
acid and naphthalene-2-sulfonyl chloride. LCMS (m/z): 387.2 (M+1),
385.3 (M-1).
Example 19
1-(Naphthalene-2-sulfonylamino)-cyclohexanecarboxylic acid
hydroxyamide
##STR00037##
[0262] Following typical sulfonylation conditions and method L, the
title compound is prepared from 1-amino-cyclohexanecarboxylic acid
and naphthalene-2-sulfonyl chloride. LCMS (m/z): 349.3 (M+1), 347.3
(M-1).
Example 20
(R)--N-Hydroxy-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-4-methy-
lsulfanyl-butyramide
##STR00038##
[0264] Following methods B and L, the title compound is prepared
from (R)-2-tert-butoxycarbonylamino-4-methylsulfanyl-butyric acid,
naphthalene-2-sulfonyl chloride and 1-iodo-3-methyl-butane.
.sup.1HNMR (400 MHz, MeOD): .delta. 0.88 (d, 6H, J=6 Hz), 1.41-1.60
(m, 4H), 2.02-2.38 (m, 4H), 3.55-3.70 (m, 1H), 4.45 (t, 1H, J=7
Hz), 7.60-7.70 (m, 2H), 7.85 (dd, 1H, J=2 Hz, J=7 Hz), 7.97 (d, 1H,
J=7 Hz), 8.04 (d, 2H, J=8 Hz), 8.48 (s, 1H). LCMS (m/z): 425 (M+1).
Analytics calculated for C.sub.20H.sub.28N.sub.2O.sub.4S.sub.2: C,
56.58; H, 6.65; N, 6.60. Found: C, 55.93; H, 6.71; N, 6.32.
Example 21
(R)-3,N-Dihydroxy-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-prop-
ionamide
##STR00039##
[0266] Following methods B and L, the title compound is prepared
from (R)-2-amino-3-tert-butoxy-propionic acid methyl ester,
naphthalene-2-sulfonyl chloride and 1-iodo-3-methyl-butane.
.sup.1HNMR (400 MHz, MeOD): .delta. 0.88 (d, 6H, J=6 Hz), 1.45-1.65
(m, 4H), 3.50-3.59 (m, 1H), 3.6-3.75 (m, 2H), 3.8-3.9 (m, 1H), 4.40
(t, 1H, J=7 Hz), 7.60-7.70 (m, 2H), 7.85 (dd, 1H, J=2 Hz, J=7 Hz),
7.97-8.05 (m, 3H), 8.45 (s, 1H). LCMS (m/z): 381(M+1). Analytics
calculated for C.sub.18H.sub.24N.sub.2O.sub.5S: C, 56.83; H, 6.36;
N, 7.36. Found: C, 56.38; H, 6.40; N, 7.07.
Example 22
N-Hydroxy-3-methyl-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-but-
yramide
##STR00040##
[0268] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and 1-bromo-3-methyl-butane. LCMS
(m/z): 393.1 (M+1).
Example 23
(S)-3-(Naphthalene-2-sulfonyl)-thiazolidine-4-carboxylic acid
hydroxyamide
##STR00041##
[0270] Following typical methods for sulfonylation and method L,
the title compound is prepared from (S)-thiazolidine-4-carboxylic
acid and naphthalene-2-sulfonyl chloride. LCMS (m/z): 339 (M+1).
Analytics calculated for C.sub.14H.sub.13N.sub.2O.sub.4S.sub.2: C,
49.69; H, 4.17; N, 8.28. Found: C, 49.84; H, 4.15; N, 8.03.
Example 24
(R)-2-[Allyknaphthalene-2-sulfonylyamino]-N-hydroxy-3-methyl-butyramide
##STR00042##
[0272] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and 3-bromo-propene. Analytical
data: LCMS (m/z): 363 (M+1).
Example 25
(R)-3-(4-Benzyloxy-phenyl)-N-hydroxy-2-[(3-methyl-butyl)-(naphthalene-2-su-
lfonyl)-amino]-propionamide
##STR00043##
[0274] Following methods B and L, the title compound is prepared
from (R)-2-amino-3-(4-benzyloxy-phenyl)-propionic acid,
naphthalene-2-sulfonyl chloride and 1-iodo-3-methyl-butane.
.sup.1HNMR (400 MHz, MeOD): .delta. 0.90 (d, 6H, J=6 Hz), 1.50-1.65
(m, 4H), 2.45-2.58 (m, 1H), 3.02-3.13 (m, 1H), 3.35-3.48 (m, 1H),
3.60-3.71 (m, 1H), 4.3-4.48 (m, 1H), 4.95 (s, 2H), 6.65 (d, 2H,
J=8.5 Hz), 6.89 (d, 2H, J=8.5 Hz), 7.28-7.40 (m, 5H), 7.60-8.05 (m,
3H), 7.95-8.05 (m, 3H), 8.42 (s, 1H). LCMS (m/z): 547 (M+1).
Example 26
(R)-1-(Naphthalene-2-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-carboxylic
acid hydroxyamide
##STR00044##
[0276] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
naphthalene-2-sulfonyl chloride and 3-bromo-propene. LCMS (m/z):
333 (M+1).
Example 27
2-[Benzyl-(7-ethoxy-naphthalene-2-sulfonyl)-amino]-N-hydroxy-3-methyl-buty-
ramide
##STR00045##
[0278] Following methods A, E and J, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-hydroxy-naphthalene-2-sulfonyl chloride, chloroethane and benzyl
bromide. LCMS (m/z): 457.2 (M+1), 455.4 (M-1). CHN Calc C 63.14, H
6.18, N 6.14 Found C 63.17, H 6.11, N 6.01.
Example 28
(R)--N-Hydroxy-3-methyl-2-[(naphthalene-2-sulfonyl)-pyridin-4-ylmethyl-ami-
no]-butyramide
##STR00046##
[0280] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and 4-bromomethyl-pyridine. LCMS
(m/z): 414 (M+1). Analytics calculated for
C.sub.21H.sub.23N.sub.3O.sub.4S: C, 61; H, 5.61; N, 10.16. Found:
C, 59.29; H, 5.95; N, 9.92.
Example 29
N-isoamyl-N-(6-ethyl naphthalene-2-sulfonyl)-D-valine hydroxamic
acid
##STR00047##
[0282] Following methods A, D and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester, acetic
acid 6-chlorosulfonyl-naphthalen-2-yl ester, tetraethyl-stannane
and 1-bromo-3-methyl-butane. LCMS (m/z): 419.32 (M-1). CHN Calc C
62.04, H 7.44, N 6.89; Found C, 61.88; H, 7.38; N, 6.79.
Example 30
N-(2-phenoxyethyl)-N-(naphthalene-2-sulfonyl)-D-valine hydroxamic
acid
##STR00048##
[0284] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and (2-bromo-ethoxy)-benzene. LCMS
(m/z): 443.29 (M+1), 441.37 (M-1).
Example 31
N-Hydroxy-2-[(6-hydroxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-3--
methyl-butyramide
##STR00049##
[0286] To a solution of N-isoamyl-N-(6-hydroxy
naphthalene-2-sulfonyl)-D-valine O-trityl hydroxamic acid (0.21 g,
0.32 mmol) in dichloromethane (10 mL) is added trifluoroacetic acid
(0.199 mL, 2.58 mmol) followed by triethyl silane (0.103 mL, 0.65
mmol). The reaction is allowed to stir at ambient temperature for
30 minutes. The solvent is removed in vacuo, and the residue is
purified by column chromatography (15% hexanes-ethyl acetate),
followed by crystallization from hexane-dichloromethane to afford
the title compound as a white powder (0.04 g, 30% yield). LCMS
(m/z): 409.24 (M+1), 407.29 (M-1). CHN: Calc C, 62.04; H 7.44, N
6.89; Found C, 61.88; H 7.38, N 6.79.
Example 32
2-[(6-Amino-naphthalene-2-sulfonyl)-(3-phenyl-propyl)-amino]-N-hydroxy-3-m-
ethyl-butyramide
##STR00050##
[0288] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-acetylamino-naphthalene-2-sulfonyl chloride, chloroethane and
(3-bromo-propyl)-benzene. LCMS (m/z): 454.27 (M-1).
Example 33
(R)-1-(Naphthalene-2-sulfonyl)-azepane-2-carboxylic acid
hydroxyamide
##STR00051##
[0290] Following method H the title compound is prepared from
(R)-1-(naphthalene-2-sulfonyl)-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic
acid hydroxyamide. LCMS (m/z): 349 (M+1). Analytics calculated for
C.sub.17H.sub.20N.sub.2O.sub.4S: C, 58.6; H, 5.79; N, 8.04. Found:
C, 60.83; H, 5.99; N, 7.45.
Example 34
2-[(6-Acetylamino-naphthalene-2-sulfonyl)-(3-phenyl-propyl)-amino]-N-hydro-
xy-3-methyl-butyramide
##STR00052##
[0292] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-acetylamino-naphthalene-2-sulfonyl chloride, chloroethane and
(3-bromo-propyl)-benzene. LCMS (m/z): 498.1 (M+1), 496.3 (M-1).
Example 35
N-Hydroxy-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-2-(tetrahydr-
o-pyran-4-yl)-acetamide
##STR00053##
[0294] Following methods B and L, the title compound is prepared
from amino-(tetrahydro-pyran-4-yl)-acetic acid,
naphthalene-2-sulfonyl chloride and 1-bromo-3-methyl-butane. LCMS
(m/z): 435.4 (M+1), 433.5 (M-1) (HPLC-MS).
Example 36
N-isoamyl-N-(6-methoxy naphthalene-2-sulfonyl)-D-valine hydroxamic
acid
##STR00054##
[0296] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-methoxy-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 421.36 (M-1).
Example 37
N-isoamyl-N-(6-hydroxy naphthalene-2-sulfonyl)-D-valine hydroxamic
acid
##STR00055##
[0298] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-hydroxy-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 409.24 (M+1), 407.29 (M-1).
CHN Calc C, 62.04; H, 7.44; N, 6.89 Found C, 61.88; H, 7.38; N,
6.79.
Example 38
2-[(7-Amino-naphthalene-2-sulfonyl)-(3-phenyl-propyl)-amino]-N-hydroxy-3-m-
ethyl-butyramide
##STR00056##
[0300] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-acetylamino-naphthalene-2-sulfonyl chloride and
(3-bromo-propyl)-benzene. LCMS (m/z): 456.3 (M+1), 454.4 (M-1).
Example 39
(R)-1-(Naphthalene-2-sulfonyl)-5-phenyl-1,2,3,6-tetrahydro-pyridine-2-carb-
oxylic acid hydroxyamide
##STR00057##
[0302] Following methods B, F, G and L, the title compound is
prepared from (R)-2-amino-pent-4-enoic acid ethyl ester,
naphthalene-2-sulfonyl chloride and 2-hydroxyacetophenone. LCMS
(m/z): 409 (M+1). Analytics calculated for
C.sub.14H.sub.13N.sub.2O.sub.4S.sub.2: C, 66.10; H, 4.93; N, 6.86.
Found: C, 66.10; H, 4.94; N, 6.59.
Example 40
(R)--N-Hydroxy-2-[(7-methoxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amin-
o]-3-methyl-butyramide
##STR00058##
[0304] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-methoxy-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. Analytical data: LCMS (m/z): 423
(M+1).
Example 41
N-(2-(4-fluorophenoxy)ethyl)-N-(naphthalene-2-sulfonyl)-D-valine
hydroxamic acid
##STR00059##
[0306] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and
1-(2-bromo-ethoxy)-4-fluoro-benzene. LCMS (m/z): 461.25 (M+1),
459.33 (M-1).
Example 42
2-[(6-Ethoxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy-3-m-
ethyl-butyramide
##STR00060##
[0308] Following methods A, E and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-hydroxy-naphthalene-2-sulfonyl chloride, iodoethane and
1-bromo-3-methyl-butane. LCMS (m/z): 435.34 (M-1).
Example 43
2-[Benzyl-(6-p-tolylamino-naphthalene-2-sulfonyl)-amino]-N-hydroxy-3-methy-
l-butyramide
##STR00061##
[0310] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-p-tolylamino-naphthalene-2-sulfonyl chloride and benzyl bromide.
LCMS (m/z): 518.2 (M+1), 516.4 (M-1).
Example 44
(R)-1-(Naphthalene-2-sulfonyl)-4-vinyl-1,2,3,6-tetrahydro-pyridine-2-carbo-
xylic acid hydroxyamide
##STR00062##
[0312] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-ynoic acid ethyl ester,
naphthalene-2-sulfonyl chloride and 3-bromo-propene. LCMS (m/z):
359 (M+1). Analytics calculated for
C.sub.18H.sub.18N.sub.2O.sub.4S: C, 60.32; H, 5.06; N, 17.86.
Found: C, 59.99; H, 5.31; N, 7.82.
Example 45
N-Hydroxy-3-methyl-2-[(naphthalene-2-sulfonyl)-pyridin-3-ylmethyl-amino]-b-
utyramide
##STR00063##
[0314] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and 3-chloromethyl-pyridine. LCMS
(m/z): 414.2 (M+1), 412.2 (M-1)
Example 46
(R)--N-Hydroxy-2-[[2-(3-methoxy-phenoxy)-ethyl]-(naphthalene-2-sulfonyl)-a-
mino]-3-methyl-butyramide
##STR00064##
[0316] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and
1-(2-bromo-ethoxy)-3-methoxy-benzene. Analytical data: LCMS (m/z):
473 (M+1).
Example 47
N-Hydroxy-3-methyl-2-[[6-(3-methyl-butoxy)-naphthalene-2-sulfonyl]-(3-meth-
yl-butyl)-amino]-butyramide
##STR00065##
[0318] Following methods A, E and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-hydroxy-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 477.36 (M-1).
Example 48
2-[(7-Ethoxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy-3-m-
ethyl-butyramide
##STR00066##
[0320] Following methods A, E and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-hydroxy-naphthalene-2-sulfonyl chloride, iodoethane and
1-bromo-3-methyl-butane. LCMS (m/z): 435.32 (M-1).
Example 49
N-Hydroxy-2-[(6-isobutoxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]--
3-methyl-butyramide
##STR00067##
[0322] Following methods A, E and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-hydroxy-naphthalene-2-sulfonyl chloride, 1-iodo-2-methyl-propane
and 1-bromo-3-methyl-butane. LCMS (m/z): 463.43 (M-1).
Example 50
(R)-1-(Quinoline-3-sulfonyl)-piperidine-2-carboxylic acid
hydroxyamide
##STR00068##
[0324] Following method H the title compound is prepare from
(R)-1-(quinoline-3-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-carboxylic
acid hydroxyamide. .sup.1HNMR (400 MHz, DMSO): .delta. 1.25-1.75
(m, 5H), 1.9 (m, 1H), 3.4 (m, 1H), 3.8 (br, 1H), 4.45 (br, 1H),
7.75 (t, 1H, J=7 Hz), 7.95 (t, 1H, J=7 Hz), 8.10 (d, 1H, J=7 Hz),
8.22 (d, 1H, J=7 Hz), 8.8 (d, 1H, J=2 Hz), 9.15 (d, 1H, J=2 Hz).
LCMS (m/z): 336 (M+1).
Example 51
2-[(6-Amino-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy-3-me-
thyl-butyramide
##STR00069##
[0326] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-acetylamino-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 408.1 (M+1), 406.2 (M-1).
Example 52
1-(Naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid
hydroxyamide
##STR00070##
[0328] Following typical sulfonylation conditions and method L, the
title compound is prepared from proline and naphthalene-2-sulfonyl
chloride. LCMS (m/z): 319.18 (M-1)
Example 53
2-[(6-Benzyloxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy--
3-methyl-butyramide
##STR00071##
[0330] Following methods A, E and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-hydroxy-naphthalene-2-sulfonyl chloride, benzyl bromide and
1-bromo-3-methyl-butane. LCMS (m/z): 497.44 (M-1).
Example 54
(R)--N-Hydroxy-3-methyl-2-[(naphthalene-2-sulfonyl)-pyridin-2-ylmethyl-ami-
no]-butyramide
##STR00072##
[0332] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and 2-chloromethyl-pyridine. LCMS
(m/z): 414 (M+1). (hydrochloric acid salt) Analytics calculated for
C.sub.21H.sub.24N.sub.3O.sub.4SCl: C, 57.99; H, 5.33; N, 6.44.
Found: C, 55.97; H, 5.51; N, 6.00.
Example 55
2-[(6-Acetylamino-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydrox-
y-3-methyl-butyramide
##STR00073##
[0334] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-acetylamino-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 450.2 (M+1), 448.3 (M-1).
Example 56
N-(2-Dimethylamino-ethyl)-N-(6-methoxy
naphthalene-2-sulfonyl)-D-valine hydroxamic acid
##STR00074##
[0336] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and
(2-chloro-ethyl)-dimethyl-amine. LCMS (m/z): 394.31 (M+1), 392.34
(M-1).
Example 57
N-Hydroxy-3-methyl-2-{(3-methyl-butyl)-[7-(3-methyl-butylamino)-naphthalen-
e-2-sulfonyl]-amino}-butyramide
##STR00075##
[0338] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-acetylamino-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 478.2 (M+1), 476.3 (M-1).
Example 58
(R)-2-[[2-(4-Chloro-phenoxy)-ethyl]-(naphthalene-2-sulfonyl)-amino]-N-hydr-
oxy-3-methyl-butyramide
##STR00076##
[0340] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and
1-(2-bromo-ethoxy)-4-chloro-benzene. Analytical data: LCMS (m/z):
477 (M+1).
Example 59
(R)-3-tert-Butoxy-N-hydroxy-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-a-
mino]-propionamide
##STR00077##
[0342] Following typical methods for sulfonylation, alkylation and
method L, the title compound is prepared from
(R)-2-amino-3-tert-butoxy-propionic acid methyl ester,
naphthalene-2-sulfonyl chloride and 1-iodo-3-methyl-butane.
.sup.1HNMR (400 MHz, MeOD): .delta. 0.88 (d, 6H, J=6 Hz), 0.95 (s,
9H), 1.45-1.65 (m, 4H), 2.02-2.38 (m, 4H), 3.30-3.43 (m, 1H),
3.5-3.75 (m, 2H), 4.42 (t, 1H, J=7 Hz), 7.60-7.70 (m, 2H), 7.85
(dd, 1H, J=2 Hz, J=7 Hz), 7.97-8.05 (m, 3H), 8.45 (s, 1H). LCMS
(m/z): 437 (M+1). Analytics calculated for
C.sub.22H.sub.32N.sub.2O.sub.5S: C, 60.53; H, 7.39; N, 6.42. Found:
C, 60.19; H, 7.02; N, 6.28.
Example 60
(R)-5-Methyl-1-(naphthalene-2-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-carb-
oxylic acid hydroxyamide
##STR00078##
[0344] Following methods B, F, G and L, the title compound is
prepared from (R)-2-amino-pent-4-enoic acid ethyl ester,
naphthalene-2-sulfonyl chloride and 1-hydroxy-propan-2-one. LCMS
(m/z): 345.2 (M-1). Analytics calculated for
C.sub.17H.sub.18N.sub.2O.sub.4S: C, 58.94; H, 5.24; N, 8.09. Found:
C, 58.51; H, 5.34; N, 7.68.
Example 61
2-[(7-Acetylamino-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydrox-
y-3-methyl-butyramide
##STR00079##
[0346] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-acetylamino-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 450.4 (M+1), 448.5 (M-1).
Example 62
N-(2-(3-chlorophenoxy)ethyl)-N-(naphthalene-2-sulfonyl)-D-valine
hydroxamic acid
##STR00080##
[0348] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and
1-(2-bromo-ethoxy)-3-chloro-benzene. LCMS (m/z): 477.29 (M+1),
475.35 (M-1).
Example 63
(R)-1-(Quinoline-6-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-carboxylic
acid hydroxyamide
##STR00081##
[0350] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
quinoline-6-sulfonyl chloride and 3-bromo-propene. .sup.1HNMR (400
MHz, MeOD): .delta. 2.15-2.45 (m, 4H), 3.95-4.25 (m, 4H), 5.79 (d,
2H, J=7 Hz), 5.65 (br, 2H), 7.67 (q, 1H, J=4 Hz), 8.15 (m, 2H),
8.55 (br, 2H), 8.98 (m, 1H). LCMS (m/z): 334 (M+1).
Example 64
N-(2-(2-chlorophenoxy)ethyl)-N-(naphthalene-2-sulfonyl)-D-valine
hydroxamic acid
##STR00082##
[0352] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and
1-(2-bromo-ethoxy)-2-chloro-benzene. LCMS (m/z): 477.22 (M+1),
475.30 (M-1).
Example 65
N-Hydroxy-2-methyl-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-pro-
pionamide
##STR00083##
[0354] Following methods B and L, the title compound is prepared
from 2-amino-2-methyl-propionic acid, naphthalene-2-sulfonyl
chloride and 1-bromo-3-methyl-butane. LCMS (m/z): 377.29 (M-1).
Example 66
2-[(6-Allyloxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy-3-
-methyl-butyramide
##STR00084##
[0356] Following methods A, E and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-hydroxy-naphthalene-2-sulfonyl chloride, 3-bromo-propene and
1-bromo-3-methyl-butane. LCMS (m/z): 447.31 (M-1).
Example 67
(R)--N-Hydroxy-3-methyl-2-[(3-methyl-butyl)-(quinoline-6-sulfonyl)-amino]--
butyramide
##STR00085##
[0358] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
quinoline-6-sulfonyl chloride and 1-iodo-3-methyl-butane.
.sup.1HNMR (400 MHz, MeOD): S 0.85-0.98 (m, 12H), 1.4-1.6 (m, 2H),
1.75-1.85 (m, 1H), 2.1-2.3 (m, 1H), 3.2-3.25 (m, 1H), 3.8-3.9 (m,
2H), 7.82 (q, 1H, J=4.5 Hz), 8.62 (s, 1H), 8.75 (d, 1H, J=8 Hz),
9.10 (d, 1H, J=4.5 Hz). LCMS (m/z): 394 (M+1).
Example 68
2-[(7-Ethoxy-naphthalene-2-sulfonyl)-pyridin-3-ylmethyl-amino]-N-hydroxy-3-
-methyl-butyramide
##STR00086##
[0360] Following methods A, E and J, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-hydroxy-naphthalene-2-sulfonyl chloride, chloroethane and
3-chloromethyl-pyridine. LCMS (m/z): 458.3 (M+1), 456.3 (M-1). CHN
Calc C 60.38, H 5.95, N 9.18 Found C, 60.48; H, 5.97; N, 9.08.
Example 69
(R)--N-Hydroxy-3,3-dimethyl-2-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-a-
mino]-butyramide
##STR00087##
[0362] Following methods B and L, the title compound is prepared
from (R)-2-amino-3,3-dimethyl-butyric acid, naphthalene-2-sulfonyl
chloride and 1-iodo-3-methyl-butane. .sup.1HNMR (400 MHz, MeOD):
.delta. 0.88 (q, 6H, J=4 Hz), 1.10 (s, 9H), 1.4-1.6 (m, 4H), 1.9
(m, 1H), 3.15-3.25 (m, 1H), 4.05 (s, 1H), 7.6-7.7 (m, 2H), 7.8-7.85
(m, 1H), 7.92-8.08 (m, 3H), 8.45 (s, 1H). LCMS (m/z): 405 (M-1).
Analytics calculated for C.sub.21H.sub.30N.sub.2O.sub.4S: C, 62.04;
H, 7.44; N, 6.89. Found: C, 61.70; H, 7.27; N, 6.67.
Example 70
1-[(3-Methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-cyclopentanecarboxylic
acid hydroxyamide
##STR00088##
[0364] Following methods B and L, the title compound is prepared
from 1-amino-cyclopentanecarboxylic acid, naphthalene-2-sulfonyl
chloride and 1-bromo-3-methyl-butane. LCMS (m/z): 405.24 (M+1),
403.30 (M-1). CHN Calc C, 62.35; H, 6.98; N, 6.92; Found C, 62.27;
H, 6.85; N, 6.55.
Example 71
2-[{7-[Acetyl-(3-methyl-butyl)-amino]-naphthalene-2-sulfonyl}-(3-methyl-bu-
tyl)-amino]-N-hydroxy-3-methyl-butyramide
##STR00089##
[0366] Following methods C and K, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
7-acetylamino-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 520.2 (M+1), 518.3 (M-1).
Example 72
(R)-1-(Quinoline-3-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-carboxylic
acid hydroxyamide
##STR00090##
[0368] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
quinoline-3-sulfonyl chloride and 3-bromo-propene. .sup.1HNMR (400
MHz, DMSO): S 2.20 (br, 2H), 3.85-4.15 (m, 2H), 4.70 (m, 1H), 5.65
(br, 2H), 7.77 (t, 1H, J=7 Hz), 7.95 (t, 1H, J=7 Hz), 8.1 (d, 1H,
J=8 Hz), 8.23 (d, 1H, J=8 Hz), 8.9 (d, 1H, J=2 Hz), 9.1 (d, 1H, J=2
Hz). LCMS (m/z): 334 (M+1).
Example 73
1-[(3-Methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-cyclopropanecarboxylic
acid hydroxyamide
##STR00091##
[0370] Following methods B and L, the title compound is prepared
from 1-amino-cyclopropanecarboxylic acid, naphthalene-2-sulfonyl
chloride and 1-bromo-3-methyl-butane. LCMS (m/z): 377.06 (M+1),
375.05 (M-1). CHN Calc C, 60.62; H, 6.43; N, 7.44 Found C 60.40, H
6.06, N 7.31.
Example 74
4-[Hydroxycarbamoyknaphthalene-2-sulfonylamino)-methyl]-piperidine-1-carbo-
xylic acid tert-butyl ester
##STR00092##
[0372] Following typical sulfonylation conditions and method L, the
title compound is prepared from
4-((R)-amino-carboxy-methyl)-piperidine-1-carboxylic acid
tert-butyl ester and naphthalene-2-sulfonyl chloride. LCMS (m/z):
464.3 (M+1), 462.5 (M-1), CHN: Calc C 57.00, H 6.31, N 9.06; Found
C, 57.40; H, 6.32; N, 8.53.
Example 75
N-(2-(2,3,6-trimethyl
phenoxy)ethyl)-N-(naphthalene-2-sulfonyl)-D-valine hydroxamic
acid
##STR00093##
[0374] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and
2-(2-bromo-ethoxy)-1,3,4-trimethyl-benzene. LCMS (m/z): 485.35
(M+1), 483.38 (M-1).
Example 76
(R)--N-Hydroxy-3-methyl-2-[(3-methyl-butyl)-(quinoline-3-sulfonyl)-amino]--
butyramide
##STR00094##
[0376] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
quinoline-3-sulfonyl chloride and 1-iodo-3-methyl-butane.
.sup.1HNMR (400 MHz, MeOD): .delta. 0.80-0.90 (m, 12H), 1.3-1.7 (m,
3H), 2.05-2.15 (m, 1H), 3.15 (m, 1H), 3.80 (d, 2H, J=9 Hz), 3.8-3.9
(m, 2H), 7.80 (t, 1H, J=7 Hz), 7.98 (t, 1H, J=7 Hz), 8.10 (d, 1H,
J=7 Hz), 8.12 (d, 1H, J=7 Hz), 8.90 (d, 1H, J=10 Hz), 9.2 (d, 1H,
J=2 Hz). LCMS (m/z): 394 (M+1). Analytics calculated for
C.sub.19H.sub.27N.sub.3O.sub.4S: C, 57.99; H, 6.92; N, 10.68.
Found: C, 58.09; H, 6.65; N, 10.51.
Example 77
N-Hydroxy-3-methyl-2-[(2-morpholin-4-yl-ethyl)-(naphthalene-2-sulfonyl)-am-
ino]-butyramide
##STR00095##
[0378] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and 4-(2-chloro-ethyl)-morpholine.
LCMS (m/z): 434.54 (M-1).
Example 78
(R)-1-(1-Methoxy-naphthalene-2-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-car-
boxylic acid hydroxyamide
##STR00096##
[0380] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
1-methoxy-naphthalene-2-sulfonyl chloride and 3-bromo-propene.
.sup.1HNMR (400 MHz, DMSO): .delta. 2.20 (br, 2H), 3.95 (m, 1H),
4.05 (m, 1H), 4.60 (d, 1H, J=6 Hz), 5.60 (br, 2H), 7.65-7.75 (m,
2H), 7.80 (m, 2H), 8.05 (m, 1H), 8.15 (d, 1H, J=5.5 Hz), 8.8 (s,
1H). LCMS (m/z): 363 (M+1). Analytics calculated for
C.sub.17H.sub.18N.sub.2O.sub.5S: C, 56.34; H, 5.01; N, 7.73. Found:
C, 55.87; H, 4.99; N, 7.30.
Example 79
(R)--N-Hydroxy-2-[(1-methoxy-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amin-
o]-3-methyl-butyramide
##STR00097##
[0382] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
1-methoxy-naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. Analytical data: LCMS (m/z): 423
(M+1).
Example 80
2-[(1-Chloro-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy-3-m-
ethyl-butyramide
##STR00098##
[0384] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
1-chloro-naphthalene-2-sulfonyl chlorideand
1-bromo-3-methyl-butane. LCMS (m/z): 427 (M+1), 425 (M-1), CHN:
Calc C, 56.26; H, 6.37; N, 6.56; Found C 55.92, H 6.44, N 6.29.
Example 81
N-Hydroxy-2-(naphthalene-2-sulfonylamino)-acetamide
##STR00099##
[0386] Following typical sulfonylation methods and method L, the
title compound is prepared from amino-acetic acid and
naphthalene-2-sulfonyl chloride. LCMS (m/z): 281.0 (M+1).
Example 82
4-{Hydroxycarbamoyl-[(3-methyl-butyl)-(naphthalene-2-sulfonyl)-amino]-meth-
yl}-piperidine-1-carboxylic acid tert-butyl ester
##STR00100##
[0388] Following methods A and L, the title compound is prepared
from 4-((R)-amino-carboxy-methyl)-piperidine-1-carboxylic acid
tert-butyl ester, naphthalene-2-sulfonyl chloride and
1-bromo-3-methyl-butane. LCMS (m/z): 534.2 (M+1), 532.4 (M-1), CHN:
Calc C, 60.77; H, 7.37; N, 7.87; Found C, 59.76; H, 7.43; N,
7.74.
Example 83
7-(Naphthalene-2-sulfonyl)-7-aza-bicyclo[4.2.1]nonane-8-carboxylic
acid hydroxyamide
##STR00101## ##STR00102##
[0389]
3-((2R,5S)-3,6-Diethoxy-5-isopropyl-2,5-dihydro-pyrazin-2-yl)-cyclo-
heptanone
[0390] A solution of
(S)-3,6-diethoxy-2-isopropyl-2,5-dihydro-pyrazine (6.0 g, 28.3
mmol) in tetrahydrofuran (58 mL) is cooled to -78.degree. C.
n-butyllithium (1.6 M in hexane, 21.4 mL, 34.2 mmol) is added
slowly via syringe, and the reaction is allowed to stir at
-78.degree. C. for 30 minutes. The reaction mixture is then
transferred via canula to a solution of CuBr-Me.sub.2S (3.35 g,
16.3 mmol) in tetrahydrofuran:dimethylsulfide (90 mL, [2:1]) at
-50.degree. C. The reaction is warmed to -30.degree. C. and stirred
further for 30 minutes. The reaction is then cooled to -78.degree.
C. and cyclohept-2-eneone (5.23 mL, 46.9 mmol) is added dropwise
over 10 minutes. The reaction is maintained at -78.degree. C. until
the disappearance of the dihydropyrazine is confirmed by TLC and
quenched by the addition of a saturated aqueous solution of
ammonium chloride at -78.degree. C. The reaction is allowed to warm
to ambient temperature, diluted with water, and extracted with
diethyl ether. The organic extracts were washed with ammonium
chloride, dilute ammonium hydroxide, water and brine, dried over
magnesium sulfate, and concentrated in vacuo. The residue is
purified by column chromatography eluting with a gradient of hexane
in ether (20-25%) to afford the title compound (6.52 g, 72% yield),
slightly contaminated with cyclohept-2-enone. LCMS (m/z): 323.13
(M+1).
(R)--N-naphthalene-2-sulfonyl (3-oxo-cyclohepty)glycine ethyl
ester
[0391]
3-((2R,5S)-3,6-Diethoxy-5-isopropyl-2,5-dihydro-pyrazin-2-yl)-cyclo-
heptanone (2.0 g, 6.2 mmol) is treated with 0.25 N hydrochloric
acid (25 mL), diluted with tetrahydrofuran (40 mL) and allowed to
stir at ambient temperature for 1 hour. The solvents were removed
in vacuo, and azeotroped with toluene three times. The residue was
dissolved in dichloromethane (50 mL) and cooled to 0.degree. C. To
this solution is added triethylamine (6.73 mL, 48.3 mmol), followed
by naphthalene-2-sulfonyl chloride (4.39 g, 19.4 mmol), and the
reaction is allowed to warm to ambient temperature and stirred for
16 h. The reaction is then diluted with dichloromethane washed with
1 N hydrochloric acid, sodium bicrabonate solution, and brine, and
dried over magnesium sulfate. The solvents are removed in vacuo,
and the residue is purified by column chromatography (50%
hexanes-ethyl acetate) to afford the title compound as a yellow oil
(1.8 g, 72% yield). LCMS (m/z): 404.10 (M+1), 402.09 (M-1).
(R)--N-naphthalene-2-sulfonyl (3-hydroxy-cyclohepty)glycine ethyl
ester
[0392] To a solution of (R)--N-naphthalene-2-sulfonyl
(3-oxo-cyclohepty)glycine ethyl ester (1.05 g, 2.61 mmol) in
tetrahydrofuran-ethanol (20 mL, 1:1) at 0.degree. C. is added
sodium borohydride (0.147 g, 3.88 mmol) and the reaction is stirred
at 0.degree. C. for 1 hour. The reaction was quenched at 0.degree.
C. with citric acid (10% aqueous), and the solvents were removed in
vacuo. The residue was dissolved in water and extracted three times
with ethyl acetate. The combined organic extracts were washed with
brine, dried over magnesium sulfate, and concentrated in vacuo. The
residue is purified by column chromatography (50% hexanes-ethyl
acetate) to afford the title compound as a white solid (0.90 g, 85%
yield). LCMS (m/z): 406.14 (M+1), 404.13 (M-1).
(R)--N-naphthalene-2-sulfonyl
(3-methanesulfonyloxy-cyclohepty)glycine ethyl ester
[0393] To a solution of (R)--N-naphthalene-2-sulfonyl
(3-hydroxy-cyclohepty)glycine ethyl ester (0.90 g, 2.22 mmol) in
dichloromethane (30 mL) at 0.degree. C. is added triethylamine
(0.463 mL, 3.3 mmol), methane sulfonyl chloride (0.269 g, 2.35
mmol), 4-dimethylaminopyridine (0.015 g, 0.12 mmol), and the
reaction is allowed to warm to ambient temperature and stirred for
2 hours. The reaction is diluted with dichloromethane, washed with
water and brine, and dried over magnesium sulfate. The solvents are
removed in vacuo, and the residue is purified by column
chromatography (35% hexanes-ethyl acetate) to afford the title
compound as a colorless oil (0.95 g, 88% yield). LCMS (m/z): 484.17
(M+1), 482.16 (M-1).
(R)-7-(Naphthalene-2-sulfonyl)-7-aza-bicyclo[4.2.1]nonane-8-carboxylic
acid ethyl ester
[0394] To a solution of (R)--N-naphthalene-2-sulfonyl
(3-methanesulfonyloxy-cycloheptyl) glycine ethyl ester (0.60 g,
1.24 mmol) in N,N-dimethylformamide (5 mL) is added cesium
carbonate (1.21 g, 3.71 mmol) followed by lithium iodide (0.249 g,
1.86 mmol), and the reaction is heated to 80.degree. C. for 3
hours. The reaction is cooled to ambient temperature, diluted with
water, and extracted three times with ethyl acetate. The combined
organic extracts are washed with brine, dried over magnesium
sulfate, and concentrated in vacuo. The crude product is purified
by column chromatography (20% hexanes-ethyl acetate) to afford the
title compound as a white solid (0.37 g, 77% yield). LCMS (m/z):
388.10 (M+1).
(R)-7-(Naphthalene-2-sulfonyl)-7-aza-bicyclo[4.2.1]nonane-8-carboxylic
acid
[0395] To a solution of
(R)-7-(naphthalene-2-sulfonyl)-7-aza-bicyclo[4.2.1]nonane-8-carboxylic
acid ethyl ester (0.55 g, 1.42 mmol) in tetrahydrofuran (15 mL) is
added a solution of lithium hydroxide (1.2 g, 28.6 mmol) in water
(15 mL). The reaction is heated to 80.degree. C. for 16 h, and the
solvent is removed in vacuo The residue is dissolved in water and
washed with diethyl ether. The aqueous layer is then acidified with
6 N hydrochloric acid to pH less than 4 and extracted three times
with ethyl acetate. The combined organic extracts are washed with
brine, dried over magnesium sulfate, and concentrated to afford the
title compound as a yellow solid (0.50 g, 98% yield). LCMS (m/z):
360.07 (M+1), 358.12 (M-1).
[0396] This product is then converted into a hydroxamate according
to the general protocols outlined in method L. LCMS (m/z): 375.04
(M+1), 373.02 (M-1). CHN Calc C, 60.94; H, 5.92; N, 7.48. Found C,
59.97; H, 5.92; N, 7.27
Example 84
2-[(7-Amino-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy-3-me-
thyl-butyramide
##STR00103##
[0398]
2-[(7-Acetylamino-naphthalene-2-sulfonyl)-(3-methyl-butyl)-amino]-N-
-hydroxy-3-methyl-butyramide (100 mg, 0.22 mmol) (example 61), 3 N
hydrochloric acid (2 mL) and methanol (5 mL) are combined and
stirred at reflux for 4 hours. The mixture is stirred at room for
60 hours. The solvent is partially removed in vacuo and a red
precipitate forms. This precipitate is collected by filtration and
air dried. LCMS (m/z): 408.2 (M+1), 406.3 (M-1).
Example 85
N-isoamyl-N-(6-methyl naphthalene-2-sulfonyl)-D-valine hydroxamic
acid
##STR00104##
[0400] Following methods A, D and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester, acetic
acid 7-chlorosulfonyl-naphthalen-2-yl ester, tetramethyl-stannane
and 1-bromo-3-methyl-butane. LCMS (m/z): 407.26 (M+1), 405.31
(M-1).
Example 86
(R)--N-Hydroxy-3-methyl-2-[[7-(3-methyl-butoxy)-naphthalene-2-sulfonyl]-(3-
-methyl-butyl)-amino]-butyramide
##STR00105##
[0402] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester, acetic
acid 7-chlorosulfonyl-naphthalen-2-yl ester and
1-bromo-3-methyl-butane. Analytical data: LCMS (m/z): 479
(M+1).
Example 87
N-Hydroxy-3-methyl-2-[(3-methyl-butyl)-(6-propoxy-naphthalene-2-sulfonyl)--
amino]-butyramide
##STR00106##
[0404] Following methods A, E and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
6-hydroxy-naphthalene-2-sulfonyl chloride, 1-iodo-butane and
1-bromo-3-methyl-butane. LCMS (m/z): 449.36 (M-1).
Example 88
(R)-1-(Naphthalene-2-sulfonyl)-2,3,6,7-tetrahydro-1H-azepine-2-carboxylic
acid hydroxyamide
##STR00107##
[0406] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
naphthalene-2-sulfonyl chloride and 4-bromo-but-1-ene. LCMS (m/z):
347 (M+1). Analytics calculated for
C.sub.17H.sub.18N.sub.2O.sub.4S: C, 58.94; H, 5.24; N, 8.09. Found:
C, 58.60; H, 5.24; N, 7.94.
Example 89
(R)-2-[Butyl-(naphthalene-2-sulfonyl)-amino]-3,N-dihydroxy-butyramide
##STR00108##
[0408] Following typical methods for sulfonylation, alkylation and
method L, the title compound is prepared from
(2R,3S)-2-amino-3-tert-butoxy-butyric acid, naphthalene-2-sulfonyl
chloride and 1-iodo-3-methyl-butane. .sup.1HNMR (400 MHz, DMSO): S
0.80 (d, 6H, J=4 Hz), 1.05 (d, 3H, J=8 Hz), 1.45 (m, 1H), 1.55 (m,
2H), 3.20 (m, 1H), 3.62 (m, 1H), 3.90 (br, 1H), 4.02 (d, 1H, J=7
Hz), 4.70 (br, 1H), 7.68 (m, 2H), 7.82 (d, 1H, J=7 Hz), 8.05 (t,
2H, J=7 Hz), 8.12 (d, 1H, J=7 Hz), 8.45 (s, 1H). LCMS (m/z): 395
(M+1). Analytics calculated for C.sub.19H.sub.26N.sub.2O.sub.5S: C,
57.85; H, 6.64; N, 7.10. Found: C, 57.58; H, 6.74; N, 6.94.
Example 90
2,2-Dimethyl-4-(naphthalene-2-sulfonyl)-thiomorpholine-3-carboxylic
acid
##STR00109##
[0410] Following typical sulfonylation conditions and method L, the
title compound is prepared from
(S)-2,2-dimethyl-thiomorpholine-3-carboxylic acid and
naphthalene-2-sulfonyl chloride. LCMS (m/z): 381.2 (M+1), 379.3
(M-1), CHN: Calc CHN: 53.66, 5.30, 7.36; Found CHN: 593.51, 5.20,
7.07.
Example 91
(R)-2-(Naphthalene-2-sulfonyl)-2-aza-bicyclo[2.2.2]octane-3-carboxylic
acid hydroxyamide
##STR00110##
[0412] Following typical metthods for sulfonylation and method L,
the title compound is prepared from
(R)-2-aza-bicyclo[2.2.2]octane-3-carboxylic acid and
naphthalene-2-sulfonyl chloride. LCMS (m/z): 361.30 (M+1), 359.36
(M-1). CHN Calc C, 59.98; H, 5.59; N, 7.77 Found C, 59.68; H, 5.49;
N, 7.60.
Example 92
(R)--N-Hydroxy-3,3-dimethyl-2-(quinoline-6-sulfonylamino)-butyramide
##STR00111##
[0414] Following typical methods for sulfonylation and method L,
the title compound is prepared from
(R)-2-amino-3,3-dimethyl-butyric acid and quinoline-6-sulfonyl
chloride. .sup.1HNMR (400 MHz, MeOD): .delta. 0.99 (s, 9H), 3.45
(s, 1H), 7.68 (q, 1H, J=4 Hz), 8.15 (s, 2H), 8.5 (m, 2H), 9.0 (d,
1H, J=2 Hz). LCMS (m/z): 338 (M+1).
Example 93
(R)--N-Hydroxy-3,3-dimethyl-2-(naphthalene-2-sulfonylamino)-butyramide
##STR00112##
[0416] Following typical methods for sulfonylation and method L,
the title compound is prepared from
(R)-2-amino-3,3-dimethyl-butyric acid and naphthalene-2-sulfonyl
chloride. .sup.1HNMR (400 MHz, MeOD): .delta. 1.25 (s, 9H), 3.73
(s, 1H), 7.94 (m, 2H), 8.13 (d, 1H, J=7 Hz), 8.25 (d, 1H, J=7 Hz),
8.3 (m, 2H), 8.7 (s, 1H). LCMS (m/z): 335 (M-1).
Example 94
(R)-1-(4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-1,2,3,6-tetra-
hydro-pyridine-2-carboxylic acid hydroxyamide
##STR00113##
[0418] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl chlorideand
3-bromo-propene. .sup.1HNMR (400 MHz, CDCl.sub.3): .delta. 2.05 (m,
1H), 2.75-2.80 (m, 1H), 3.3 (t, 2H, J=5 Hz), 3.82 (d, 1H, J=16 Hz),
4.10 (d, 1H, J=16 Hz), 4.35 (t, 2H, J=5 Hz), 4.69 (d, 1H, J=6.5
Hz), 5.5-5.8 (m, 2H), 6.8 (d, 1H, J=8 Hz), 6.97 (d, 1H, J=2 Hz),
7.05 (dd, 1H, J=2 Hz, J=8 Hz). LCMS (m/z): 354 (M+1).
Example 95
(R)-1-(2,3,4a,8a-Tetrahydro-benzo[1,4]dioxine-6-sulfonyl)-1,2,3,6-tetrahyd-
ro-pyridine-2-carboxylic acid hydroxyamide
##STR00114##
[0420] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
2,3-dihydro-benzo[1,4]dioxine-6-sulfonyl chloride and
3-bromo-propene. .sup.1HNMR (400 MHz, MeOD): .delta. 2.10-2.20 (m,
1H), 2.40-2.50 (m, 1H), 3.9-4.1 (m, 2H), 4.30 (d, 4H, J=4 Hz), 4.60
(d, 2H, J=6 Hz), 5.65 (br, 2H), 6.95 (d, 1H, J=9 Hz), 7.34 (m, 2H).
LCMS (m/z): 341 (M-1).
Example 96
(R)-1-(6-Morpholin-4-yl-pyridine-3-sulfonyl)-1,2,3,6-tetrahydro-pyridine-2-
-carboxylic acid hydroxyamide
##STR00115##
[0422] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
6-morpholin-4-yl-pyridine-3-sulfonyl chloride and 3-bromo-propene.
.sup.1HNMR (400 MHz, DMSO): .delta. 2.25-2.45 (br, 4H), 3.63 (t,
4H, J=5 Hz), 3.77 (t, 4H, J=5 Hz), 4.0 (dd, 2H), 4.7 (d, 1H, J=7
Hz), 5.60 (br, 2H), 6.85 (d, 1H, J=8 Hz), 7.85 (dd, 1H, J=8 Hz),
8.45 (d, 1H, J=2 Hz). LCMS (m/z): 369 (M+1).
Example 97
(R)-1-(3,4-Dimethoxy-benzenesulfonyl)-1,2,3,6-tetrahydro-pyridine-2-carbox-
ylic acid hydroxyamide
##STR00116##
[0424] Following methods B, G and L, the title compound is prepared
from (R)-2-amino-pent-4-enoic acid ethyl ester,
3,4-dimethoxy-benzenesulfonyl chloride and 3-bromo-propene.
.sup.1HNMR (400 MHz, DMSO): .delta. 2.10-2.25 (m, 1H), 2.30-2.45
(m, 1H), 3.84 (s, 3H), 3.86 (s, 3H), 3.95-4.15 (m, 2H), 4.60 (d,
1H, J=6 Hz), 5.65 (br, 2H), 7.05 (d, 1H, J=8.5 Hz), 7.82 (d, 1H,
J=2 Hz), 7.45 (dd, 1H, J=2 Hz, J=8 Hz). LCMS (m/z): 343 (M+1).
Example 98
(R)-2-[(Benzothiazole-2-sulfonyl)-(3-methyl-butyl)-amino]-N-hydroxy-3-meth-
yl-butyramide
##STR00117##
[0426] Following methods A and L, the title compound is prepared
from (R)-2-amino-3-methyl-butyric acid tert-butyl ester,
naphthalene-2-sulfonyl chloride and 1-iodo-3-methyl-butane.
.sup.1HNMR (400 MHz, MeOD): .delta. 0.85-0.95 (m, 12H), 1.4-1.75
(m, 4H), 2.2-2.3 (m, 1H), 3.4-3.5 (m, 1H), 3.7-3.8 (m, 1H),
3.9-4.05 (d, 1H, J=9 Hz), 7.55-7.7 (m, 2H), 8.08 (d, 1H, J=7 Hz,),
8.22 (d, 1H, J=7 Hz). LCMS (m/z): 400 (M+1).
Benzothiazole-2-sulfonyl chloride
##STR00118##
[0428] A suspension of 2-mercapto-benzothiazole (2 g, 11.98 mmol)
in 30% acetic acid/water is stirred at 0.degree. C. as chlorine gas
is bubbled for 15 min, then the reaction mixture is filtered, the
filter cake is washed with water, and used in the next step without
any additional purification.
TABLE-US-00001 MMP2 MMP13 IC.sub.50 IC.sub.50 MW # Structure
Structure Name [.mu.M] [.mu.M] (Calc'd) LCMS 1 ##STR00119##
N-Hydroxy-2-[(1- hydroxy-naphthalene- 2-sulfonyl)-(3-methyl-
butyl)-amino]-3-methyl- butyramide >3 0.672 408.52 409 (M + 1) 2
##STR00120## N-Hydroxy-2-[isobutyl- (naphthalene-2-
sulfonyl)-amino]- acetamide 0.133 0.0184 336.41 337.1 (M + 1) 3
##STR00121## 2-(Naphthalene-2- sulfonylamino)-pent-4- enoic acid
hydroxyamide 0.0222 0.0356 320.37 321 (M + 1) 4 ##STR00122##
2-[But-3-enyl- (naphthalene-2- sulfonyl)-amino]-pent- 4-enoic acid
hydroxyamide 0.0507 0.0007 374.46 375 (M + 1) 5 ##STR00123##
4-Methyl-2- (naphthalene-2- sulfonylamino)- pentanoic acid
hydroxyamide 0.0575 0.0405 336.41 335.33 (M - 1) 6 ##STR00124##
N-Hydroxy-3-methyl-2- (naphthalene-2- sulfonylamino)- butyramide
0.0960 0.033 322.39 321.10 (M - 1) 7 ##STR00125## N-Hydroxy-2-[(3-
methyl-butyl)- (naphthalene-2- sulfonyl)-amino]-4-
phenyl-butyramide 0.458 0.0259 454.59 455 (M + 1) 8 ##STR00126##
2-[Allyl-(naphthalene- 2-sulfonyl)-amino]- pent-4-ynoic acid
hydroxyamide 0.125 0.0035 358.42 359 (M + 1) 9 ##STR00127##
1-(Naphthalene-2- sulfonyl)-piperidine-2- carboxylic acid
hydroxyamide 0.0488 0.0049 334.4 335 (M + 1) 10 ##STR00128##
2-[Benzyl- (naphthalene-2- sulsulfonyl)-amino]-N- hydroxy-3-methyl-
butyramide 0.706 0.0281 412.51 411.16 (M - 1) 11 ##STR00129##
N-Hydroxy-2- (naphthalene-2- sulfonylamino)-2-
(tetrahydro-pyran-4-yl)- acetamide 0.0927 0.0509 364.42 363.4 (M -
1) 12 ##STR00130## N-Hydroxy-2-methyl-2- (naphthalene-2-
sulfonylamino)- propionamide 0.793 0.761 308.36 307.21 (M - 1) 13
##STR00131## N-Hydroxy-3-methyl-2- [(naphthalene-2-
sulfonyl)-phenethyl- amino]-butyramide 0.200 0.0024 426.54 427 (M +
1) 14 ##STR00132## N-Hydroxy-3-methyl-2- [(naphthalene-2-
sulfonyl)-(3-phenyl- propyl)-amino]- butyramide 0.798 0.0242 440.57
439.15 (M - 1) 15 ##STR00133## 4-Methyl-2-[(3-methyl-
butyl)-(naphthalene-2- sulfonyl)-amino]- pentanoic acid
hydroxyamide 0.128 0.0006 406.55 407 (M + 1) 16 ##STR00134##
N-Hydroxy-3-(4- hydroxy-phenyl)-2-[(3- methyl-butyl)-
(naphthalene-2- sulfonyl)-amino]- propionamide 0.174 0.0258 456.57
457 (M + 1) 17 ##STR00135## N-Hydroxy-3-methyl-2-
[methyl-(naphthalene- 2-sulfonyl)-amino]- butyramide 0.0542 0.0029
336.41 335.3 (M - 1) 18 ##STR00136## N-Hydroxy-4-
methanesulfonyl-2- (naphthalene-2- sulfonylamino)- butyramide 0.157
0.153 386.45 385.3 (M - 1) 19 ##STR00137## 1-(Naphthalene-2-
sulfonylamino)- cyclohexanecarboxylic acid hydroxyamide 0.451 0.727
348.42 347.3 (M - 1) 20 ##STR00138## N-Hydroxy-2-[(3-
methyl-butyl)- (naphthalene-2- sulfonyl)-amino]-4- methylsulfanyl-
butyramide 0.0121 0.0003 424.59 425 (M + 1) 21 ##STR00139##
3,N-Dihydroxy-2-[(3- methyl-butyl)- (naphthalene-2-
sulfonyl)-amino]- propionamide 0.0825 0.0013 380.47 381 (M + 1) 22
##STR00140## N-Hydroxy-3-methyl-2- [(3-methyl-butyl)-
(naphthalene-2- sulfonyl)-amino]- butyramide 0.384 0.0031 392.52
393.1 (M + 1) 23 ##STR00141## (S)-3-(Naphthalene-2-
sulfonyl)-thiazolidine-4- carboxylic acid hydroxyamide 338.41
339.17 (M + 1) 24 ##STR00142## 2-[Allyl-(naphthalene-
2-sulfonyl)-amino]-N- hydroxy-3-methyl- butyramide 0.0904 0.0034
362.45 363 (M + 1) 25 ##STR00143## 3-(4-Benzyloxy-
phenyl)-N-hydroxy-2- [(3-methyl-butyl)- (naphthalene-2-
sulfonyl)-amino]- propionamide 1.96 0.0441 546.69 547 (M + 1) 26
##STR00144## 1-(Naphthalene-2- sulfonyl)-1,2,3,6-
tetrahydro-pyridine-2- carboxylic acid hydroxyamide 0.0186 0.0017
332.38 333 (M + 1) 27 ##STR00145## 2-[Benzyl-(7-ethoxy-
naphthalene-2- sulfonyl)-amino]-N- hydroxy-3-methyl- butyramide
4.40 0.535 456.57 455.37 (M - 1) 28 ##STR00146##
N-Hydroxy-3-methyl-2- [(naphthalene-2- sulfonyl)-pyridin-4-
ylmethyl-amino]- butyramide 0.200 0.0068 413.5 414 (M + 1) 29
##STR00147## 2-[(6-Ethyl- naphthalene-2- sulfonyl)-(3-methyl-
butyl)-amino]-N- hydroxy-3-methyl- butyramide 0.0447 <0.0003
420.58 419.32 (M - 1) 30 ##STR00148## N-Hydroxy-3-methyl-2-
[(naphthalene-2- sulfonyl)-(2-phenoxy- ethyl)-amino]- butyramide
0.0612 0.0021 442.54 441.4 (M - 1) 31 ##STR00149## N-Hydroxy-2-[(6-
hydroxy-naphthalene- 2-sulfonyl)-(3-methyl- butyl)-amino]-3-methyl-
butyramide 0.178 0.0010 408.52 407.29 (M - 1) 32 ##STR00150##
2-[(6-Amino- naphthalene-2- sulfonyl)-(3-phenyl- propyl)-amino]-N-
hydroxy-3-methyl- butyramide 0.0822 0.0010 455.58 454.27 (M - 1) 33
##STR00151## 1-(Naphthalene-2- sulfonyl)-azepane-2- carboxylic acid
hydroxyamide 0.0745 0.0087 348.42 349 (M + 1) 34 ##STR00152##
2-[(6-Acetylamino- naphthalene-2- sulfonyl)-(3-phenyl-
propyl)-amino]-N- hydroxy-3-methyl- butyramide 2.90 1.31 497.62
496.3 35 ##STR00153## N-Hydroxy-2-[(3- methyl-butyl)-
(naphthalene-2- sulfonyl)-amino]-2- (tetrahydro-pyran-4-yl)-
acetamide 0.0810 0.0119 434.56 433.5 (M - 1) 36 ##STR00154##
N-Hydroxy-2-[(6- methoxy-naphthalene- 2-sulfonyl)-(3-methyl-
butyl)-amino]-3-methyl- butyramide 0.180 0.0013 422.55 421.36 (M -
1) 37 ##STR00155## N-Hydroxy-2-[(7- hydroxy-naphthalene-
2-sulfonyl)-(3-methyl- butyl)-amino]-3-methyl- butyramide 3.286
0.242 408.52 407.3 (M - 1) 38 ##STR00156## 2-[(7-Amino-
naphthalene-2- sulfonyl)-(3-phenyl- propyl)-amino]-N-
hydroxy-3-methyl- butyramide >0.3 0.190 455.58 454.37 (M - 1) 39
##STR00157## 1-(Naphthalene-2- sulfonyl)-5-phenyl-
1,2,3,6-tetrahydro- pyridine-2-carboxylic acid hydroxyamide 0.0278
0.0014 408.48 409 (M + 1) 40 ##STR00158## N-Hydroxy-2-[(7-
methoxy-naphthalene- 2-sulfonyl)-(3-methyl- butyl)-amino]-3-methyl-
butyramide 4.37 0.480 422.55 423 (M + 1) 41 ##STR00159##
2-[[2-(4-Fluoro- phenoxy)-ethyl]- (naphthalene-2-
sulfonyl)-amino]-N- hydroxy-3-methyl- butyramide 1.13 0.0387 460.53
459.3 (M - 1) 42 ##STR00160## 2-[(6-Ethoxy- naphthalene-2-
sulfonyl)-(3-methyl- butyl)-amino]-N- hydroxy-3-methyl- butyramide
0.307 0.0036 436.57 435.34 (M - 1) 43 ##STR00161## 2-[Benzyl-(6-p-
tolylamino- naphthalene-2- sulfonyl)-amino]-N- hydroxy-3-methyl-
butyramide >0.3 0.118 517.65 516.32 (M - 1) 44 ##STR00162##
1-(Naphthalene-2- sulfonyl)-4-vinyl- 1,2,3,6-tetrahydro-
pyridine-2-carboxylic acid hydroxyamide 0.0301 0.0018 358.42 359 (M
+ 1) 45 ##STR00163## N-Hydroxy-3-methyl-2- [(naphthalene-2-
sulfonyl)-pyridin-3- ylmethyl-amino]- butyramide 0.0255 0.0147
413.5 412.2 (M - 1) 46 ##STR00164## N-Hydroxy-2-[[2-(3-
methoxy-phenoxy)- ethyl]-(naphthalene-2- sulfonyl)-amino]-3-
methyl-butyramide 0.655 0.0139 472.56 473 (M + 1) 47 ##STR00165##
N-Hydroxy-3-methyl-2- [[6-(3-methyl-butoxy)- naphthalene-2-
sulfonyl]-(3-methyl- butyl)-amino]- butyramide 0.931 0.176 478.66
477.36 (M - 1) 48 ##STR00166## 2-[(7-Ethoxy- naphthalene-2-
sulfonyl)-(3-methyl- butyl)-amino]-N- hydroxy-3-methyl- butyramide
9.20 0.603 436.57 435.32 (M - 1) 49 ##STR00167## N-Hydroxy-2-[(6-
isobutoxy- naphthalene-2- sulfonyl)-(3-methyl-
butyl)-amino]-3-methyl- butyramide 0.102 0.0134 464.63 463.43 (M -
1) 50 ##STR00168## 1-(Quinoline-3- sulfonyl)-piperidine-2-
carboxylic acid hydroxyamide 0.975 0.132 335.38 336 (M + 1) 51
##STR00169## 2-[(6-Amino- naphthalene-2- sulfonyl)-(3-methyl-
butyl)-amino]-N- hydroxy-3-methyl- butyramide 1.13 0.0900 407.54
406.2 (M - 1) 52 ##STR00170## 1-(Naphthalene-2-
sulfonyl)-pyrrolidine-2- carboxylic acid hydroxyamide 0.350 0.293
320.37 319.18 (M - 1) 53 ##STR00171## 2-[(6-Benzyloxy-
naphthalene-2- sulfonyl)-(3-methyl- butyl)-amino]-N-
hydroxy-3-methyl- butyramide 1.61 0.165 498.65 497.44 (M - 1) 54
##STR00172## N-Hydroxy-3-methyl-2- [(naphthalene-2-
sulfonyl)-pyridin-2- ylmethyl-amino]- butyramide 0.232 0.0022 413.5
414 (M + 1) 55 ##STR00173## 2-[(6-Acetylamino- naphthalene-2-
sulfonyl)-(3-methyl- butyl)-amino]-N- hydroxy-3-methyl- butyramide
0.0813 0.0031 449.57 448.3 (M - 1) 56 ##STR00174##
2-[(2-Dimethylamino- ethyl)-(naphthalene-2- sulfonyl)-amino]-N-
hydroxy-3-methyl- butyramide 0.607 0.0324 393.51 392.3 (M - 1) 57
##STR00175## N-Hydroxy-3-methyl-2- {(3-methyl-butyl)-[7-(3-
methyl-butylamino)- naphthalene-2- sulfonyl]-amino}- butyramide
>3 1.58 477.67 476.3 (M - 1) 58 ##STR00176## 2-[[2-(4-Chloro-
phenoxy)-ethyl]- (naphthalene-2- sulfonyl)-amino]-N-
hydroxy-3-methyl- butyramide 2.65 0.116 476.98 477 (M +1) 59
##STR00177## 3-tert-Butoxy-N- hydroxy-2-[(3-methyl-
butyl)-(naphthalene-2- sulfonyl)-amino]- propionamide 0.199 0.0023
436.57 437 (M +1) 60 ##STR00178## 5-Methyl-1- (naphthalene-2-
sulfonyl)-1,2,3,6- tetrahydro-pyridine-2- carboxylic acid
hydroxyamide 0.0125 0.0009 346.41 345.2 (M - 1) 61 ##STR00179##
2-[(7-Acetylamino- naphthalene-2- sulfonyl)-(3-methyl-
butyl)-amino]-N- hydroxy-3-methyl- butyramide 0.0228 0.0005 449.57
448.40 (M - 1) 62 ##STR00180## 2-[[2-(3-Chloro- phenoxy)-ethyl]-
(naphthalene-2- sulfonyl)-amino]-N- hydroxy-3-methyl- butyramide
3.89 0.138 476.98 475.4 (M - 1) 63 ##STR00181## 1-(Quinoline-6-
sulfonyl)-1,2,3,6- tetrahydro-pyridine-2- carboxylic acid
hydroxyamide 0.0547 0.0105 333.37 334 (M + 1) 64 ##STR00182##
2-[[2-(2-Chloro- phenoxy)-ethyl]- (naphthalene-2-
sulfonyl)-amino]-N- hydroxy-3-methyl- butyramide 0.898 0.0161
476.98 475.3 (M - 1) 65 ##STR00183## N-Hydroxy-2-methyl-2-
[(3-methyl-butyl)- (naphthalene-2- sulfonyl)-amino]- propionamide
2.86 2.26 378.49 377.29 (M - 1) 66 ##STR00184## 2-[(6-Allyloxy-
naphthalene-2- sulfonyl)-(3-methyl- butyl)-amino]-N-
hydroxy-3-methyl- butyramide 0.128 0.0073 448.59 447.31 (M - 1) 67
##STR00185## N-Hydroxy-3-methyl-2- [(3-methyl-butyl)-
(quinoline-6-sulfonyl)- amino]-butyramide 0.306 0.0121 393.51 394
(M + 1) 68 ##STR00186## 2-[(7-Ethoxy- naphthalene-2-
sulfonyl)-pyridin-3- ylmethyl-amino]-N- hydroxy-3-methyl-
butyramide 0.976 0.0287 457.55
456.26 (M - 1) 69 ##STR00187## N-Hydroxy-3,3-
dimethyl-2-[(3-methyl- butyl)-(naphthalene-2- sulfonyl)-amino]-
butyramide 3.67 0.0344 406.55 405 (M - 1) 70 ##STR00188##
1-[(3-Methyl-butyl)- (naphthalene-2- sulfonyl)-amino]-
cyclopentanecarboxylic acid hydroxyamide 0.940 0.212 404.53 403.3
(M - 1) 71 ##STR00189## 2-[{7-[Acetyl-(3-methyl- butyl)-amino]-
naphthalene-2- sulfonyl}-(3-methyl- butyl)-amino]-N-
hydroxy-3-methyl- butyramide >30 >30 519.71 518.28 (M - 1) 72
##STR00190## 1-(Quinoline-3- sulfonyl)-1,2,3,6-
tetrahydro-pyridine-2- carboxylic acid hydroxyamide 0.853 0.0957
333.37 334 (M + 1) 73 ##STR00191## 1-[(3-Methyl-butyl)-
(naphthalene-2- sulfonyl)-amino]- cyclopropanecarboxylic acid
hydroxyamide 0.402 0.035 376.48 375.1 (M - 1) 74 ##STR00192##
4-[Hydroxycarbamoyl- (naphthalene-2- sulfonylamino)-
methyl]-piperidine-1- carboxylic acid tert- butyl ester 0.0004
0.0004 463.56 462.5 (M - 1) 75 ##STR00193## N-Hydroxy-3-methyl-2-
{(naphthalene-2- sulfonyl)-[2-(2,3,6- trimethyl-phenoxy)-
ethyl]-amino}- butyramide 3.11 0.0673 484.62 483.4 (M - 1) 76
##STR00194## N-Hydroxy-3-methyl-2- [(3-methyl-butyl)-
(quinoline-3-sulfonyl)- amino]-butyramide 6.91 0.361 393.51 394 (M
+ 1) 77 ##STR00195## N-Hydroxy-3-methyl-2- [(2-morpholin-4-yl-
ethyl)-(naphthalene-2- sulfonyl)-amino]- butyramide 0.144 0.0183
435.55 434.54 (M - 1) 78 ##STR00196## 1-(1-Methoxy- naphthalene-2-
sulfonyl)-1,2,3,6- tetrahydro-pyridine-2- carboxylic acid
hydroxyamide 0.0199 0.0021 362.41 363 (M + 1) 79 ##STR00197##
N-Hydroxy-2-[(1- methoxy-naphthalene- 2-sulfonyl)-(3-methyl-
butyl)-amino]-3-methyl- butyramide 0.0518 0.0011 422.55 423 (M + 1)
80 ##STR00198## 2-[(1-Chloro- naphthalene-2- sulfonyl)-(3-methyl-
butyl)-amino]-N- hydroxy-3-methyl- butyramide 0.779 0.118 426.97
425 (M - 1) 81 ##STR00199## N-Hydroxy-2- (naphthalene-2-
sulfonylamino)- acetamide 0.199 0.395 280.3 281.0 (M + 1) 82
##STR00200## 4-{Hydroxycarbamoyl- [(3-methyl-butyl)-
(naphthalene-2- sulfonyl)-amino]- methyl}-piperidine-1- carboxylic
acid tert- butyl ester <0.0003 <0.0003 533.69 532.4 (M - 1)
83 ##STR00201## 7-(Naphthalene-2- sulfonyl)-7-aza-
bicyclo[4.2.1]nonane- 8-carboxylic acid hydroxyamide 0.770 0.135
374.46 373.0 (M - 1) 84 ##STR00202## 2-[(7-Amino- naphthalene-2-
sulfonyl)-(3-methyl- butyl)-amino]-N- hydroxy-3-methyl- butyramide
>1 0.0521 407.54 406.3 (M - 1) 85 ##STR00203##
N-Hydroxy-3-methyl-2- [(3-methyl-butyl)-(7- methyl-naphthalene-2-
sulfonyl)-amino]- butyramide 3.35 0.134 406.55 405.3 (M - 1) 86
##STR00204## N-Hydroxy-3-methyl-2- [[7-(3-methyl-butoxy)-
naphthalene-2- sulfonyl]-(3-methyl- butyl)-amino]- butyramide
>10 3.25 478.66 479 (M + 1) 87 ##STR00205##
N-Hydroxy-3-methyl-2- [(3-methyl-butyl)-(6- propoxy-naphthalene-
2-sulfonyl)-amino]- butyramide 0.197 0.0098 450.61 449.36 (M - 1)
88 ##STR00206## 1-(Naphthalene-2- sulfonyl)-2,3,6,7-
tetrahydro-1H-azepine- 2-carboxylic acid hydroxyamide 0.0635 0.0162
346.41 347 (M +1) 89 ##STR00207## 3,N-Dihydroxy-2-[(3-
methyl-butyl)- (naphthalene-2- sulfonyl)-amino]- butyramide 0.111
0.0032 394.49 395 (M + 1) 90 ##STR00208## 2,2-Dimethyl-4-
(naphthalene-2- sulfonyl)- thiomorpholine-3- carboxylic acid
hydroxyamide 0.0507 <0.0003 380.49 379.3 (M - 1) 91 ##STR00209##
2-(Naphthalene-2- sulfonyl)-2-aza- bicyclo[2.2.2]octane-3-
carboxylic acid hydroxyamide 22.2 6.95 360.44 359.4 (M - 1) 92
##STR00210## N-Hydroxy-3,3- dimethyl-2-(quinoline-
6-sulfonylamino)- butyramide 0.765 0.225 337.40 338 (M + 1) 93
##STR00211## N-Hydroxy-3,3- dimethyl-2- (naphthalene-2-
sulfonylamino)- butyramide 0.6 0.09 336.41 335 (M - 1) 94
##STR00212## (R)-1-(4-Methyl-3,4- dihydro-2H- benzo[1,4]oxazine-7-
sulfonyl)-1,2,3,6- tetrahydro-pyridine-2- carboxylic acid
hydroxyamide 0.037 353.40 354 (M + 1) 95 ##STR00213##
(R)-1-(2,3-Dihydro- benzo[1,4]dioxine-6- sulfonyl)-1,2,3,6-
tetrahydro-pyridine-2- carboxylic acid hydroxyamide 0.0026 342.37
341 (M - 1) 96 ##STR00214## (R)-1-(6-Morpholin-4-
yl-pyridine-3-sulfonyl)- 1,2,3,6-tetrahydro- pyridine-2-carboxylic
acid hydroxyamide 0.326 368.4 369 (M + 1) 97 ##STR00215##
(R)-1-(3,4-Dimethoxy- benzenesulfonyl)- 1,2,3,6-tetrahydro-
pyridine-2-carboxylic acid hydroxyamide 10.2 342.3 343 (M + 1) 98
##STR00216## (R)-2-[(Benzothiazole- 2-sulfonyl)-(3-methyl-
butyl)-amino]-N- hydrox-3-methyl- butyramide 0.713 0.063 399.53 400
(M + 1)
Other Embodiments
[0429] Other embodiments will be evident to those of skill in the
art. It should be understood that the foregoing detailed
description is provided for clarity only and is merely exemplary.
The spirit and scope of the present invention are not limited to
the above examples, but are encompassed by the following
claims.
* * * * *