&agr;-hydroxy, -amino, and halo derivatives of...

Details &agr;-hydroxy, -amino, and halo derivatives of... &agr;-hydroxy, -amino, and halo derivatives of...

1998-11-20

2002-08-20

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S470000, C562S496000, C562S508000, C562S581000, C562S605000

Reexamination Certificate

active

06437177

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel &agr;-hydroxy, amino, and halo derivatives of &bgr;-sulfonyl hydroxamic acids, to pharmaceutical compositions containing them, and to the method of using them. The compounds of the invention are inhibitors of matrix metalloproteinases involved in tissue degradation.
BACKGROUND OF THE INVENTION
Loss of connective tissue integrity occurs in many disease processes, including osteoarthritis, rheumatoid arthritis, septic arthritis, osteopenias such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, inflammation, asthma and other diseases related to connective tissue degradation. Although there is a high incidence of these diseases in the developed world, there is no treatment that prevents the tissue damage that occurs. Considerable lines of scientific evidence indicate that uncontrolled connective matrix metalloproteinase (MMPs) activity is responsible for the damage, and as a consequence the inhibition of these enzymes has become the target for therapeutic intervention (see Matrisian, L. M., Bases, Vol. 14, pp 445-463 (1992); Emonard, H. et al., Cellular and Molecular Biology, Vol. 36, pp 131-153 (1990); Docherty, A J. P. et al., Annals of the Rheumatic, Vol. 49, pp 469-479 (1990)).
Hydroxamic acid derivatives are a class of known therapeutically active MMPs inhibitors and there are numerous references in the art disclosing a variety of hydroxamic acid derivatives. For example, European Patent Publication No. 0,606,046 A1 discloses arylsulfonamido-substituted hydroxamic acids useful as matrix metalloproteinase inhibitors. International Publication Nos. WO 95/35275 and WO 95/35276 disclose sulfonamide hydroxamic acid and carboxylic acid derivatives useful as matrix metalloproteinases inhibitors. All these references relate to sulfonamide hydroxamic acids. The compounds of this invention are novel and distinct from all other sulfonamide hydroxamic acids in that the usual nitrogen atom is replaced by a carbon atom. The invention provides sulfonyl hydroxamic acid derivatives.
The compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, predominantly stromelysin and gelatinase, and hence are useful for the treatment of matrix metallo endoproteinase diseases such as osteoporosis, tumor metastasis (invasion and growth), periodontitis, gingivitis, corneal ulceration, dermal ulceration, gastric ulceration, inflammation, asthma, and other diseases related to connective tissue degradation.
INFORMATION DISCLOSURE
The European Patent Application No. EP 0780 386 A1 discloses matrix metalloproteinases inhibitors useful in the treatment of mammals having disease states alleviated by the inhibition of such matrix metalloproteinases.
International Publication No. WO 97/24117 discloses substituted aryl, heteroaryl, arylmethyl or heteroarylmethyl hydroxamic acid compounds especially useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF).
International Patent Application No. PCT/US97/16348 discloses &bgr;-sulfonyl hydroxamic acids as matrix metalloproteinases inhibitors.
The compounds of the present invention are novel and distinct from the above hydroxamic acids in that they have a hydroxy, amino group or fluoro on the &agr;-position and two hydrogen atoms at the &bgr;-position of the hydroxmate group.
SUMMARY OF THE INVENTION
The present invention provides novel compounds of formula I
or pharmaceutical acceptable salts thereof wherein:
R
1
is
a) C
4-12
alkyl,
b) C
4-12
alkenyl,
c) C
4-12
alkynyl,
d) —(CH
2
)
h
—C
3-8
cycloalkyl,
e) —(CH
2
)
h
-aryl,
f) —(CH
2
)
h
-aryl substituted with C
1-4
alkyl, C
1-4
alkoxy, phenyl, C
1-4
phenoxy, het, halo, —NO
2
, —CF
3
, —CN, or —N(C
1-4
alkyl)
2
,
g) —(CH
2
)
h
-het, or
h) —(CH
2
)
h
-het substituted with C
1-4
aLkyl, phenyl, C
1-4
phenoxy, het, or halo;
R
2
is
a) C
1-2
alkyl,
b) C
1-2
alkyl substituted with one to three halo, —CN, —NO
2
, —CF
3
, —N(R
3
)
2
, —SR
3
, or OH,
c) C
2-12
alkenyl,
d) C
2-12
alkenyl substituted with one to three halo, —CN, —NO
2
, or —CF
3
,
e) C
2-12
alkynyl,
f) C
2-12
alkynyl substituted with one to three halo, —CN, —NO
2
, or —CF
3
,
g) —(CH
2
)
h
—C
3-8
cycloalkyl,
h) —(CH
2
)
h
—C
3-8
cycloalkyl substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, or halo,
i) —(CH
2
)
h
—C
3-8
cycloalkenyl,
j) —(CH
2
)
h
—C
3-8
cycloalkenyl substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, or halo,
k) —(CH
2
)
h
-aryl,
l) —(CH
2
)
h
-aryl substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, —CF
3
—OH, —NO
2
, —CN, —N(R
3
)
2
, —SR
3
, —SO
2
(C
1-4
alkoxy), —C(═O)R
3
, or —NC(═O)R
3
,
m) —(CH
2
)
h
-aryl substituted with one to five halo,
n) —(CH
2
)
h
-het,
o) —(CH
2
)
h
-het substituted with one to two C
1-4
alkyl, or halo,
p) —(CH
2
)
h
—Q,
q) —(CH
2
)
h
—Q substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, halo, or phenyl,
r) —(CH
2
)
i
—X—R
4
, optionally the —(CH
2
)
i
— chain can be substituted withg one to with C
1-4
alkyl or phenyl, which in turn can be substituted with one to three halo or C
1-4
alkyl, or
s) —(CH
2
)
h
CHR
5
R
6
;
R
3
is
a) H,
b) C
3-6
cycloalkyl,
c) C
1-4
alkyl,
d) —(CH
2
)
h
-phenyl, or
e) —(CH
2
)
h
-phenyl substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, or halo;
X is
a) —O—,
b) —S(═O)
j
—,
c) —NR
7
—,
d) —S(═O)
2
NR
8
—, or
e) —C(═O)—;
R
4
is
a) H,
b) C
1-8
alkyl,
c) —(CH
2
)
h
-phenyl,
d) —(CH
2
)
h
-phenyl substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, phenyl, C
1-4
phenoxy, het, halo, —NO
2
, or —CN, or
e) —(CH
2
)
h
-het;
R
5
is
a) C
1-4
alkyl, or
b) —C(═O)R
3
;
R
6
is
a) —C(═O)R
3
, or
b) —(CH
2
)
h
C(═O)R
3
;
R
7
is
a) H,
b) C
1-
4 alkyl,
c) —(CH
2
)
h
-phenyl,
d) —(CH
2
)
h
-phenyl substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, or halo,
e) —(C(═O)——R
3
,
f) —S(═O)
2
R
3
, or
g) —C(═O)OR
3
;
R
8
is
a) C
1-4
alkyl,
b) —(CH
2
)
h
-phenyl, or
c) —(CH
2
)
h
-phenyl substituted with one to three C
1-4
alkyl, C
1-4
alkoxy, or halo;
Y is
a) —OH,
b) —NR
9
R
10
, or
c) fluoro;
R
9
and R
10
are the same and different and are
a) H,
b) —C(═O)—R
3
,
c) —C(═O)—OR
3
, or
d) —C(═O)—
NHR
3
;
aryl is monocarbocyclic, or bicarbocyclic aromatic moiety;
het is 5- to 10-membered unsaturated monomonocyclic or bicyclic heterocyclic moiety having one to three atoms selected from the group consisting of oxygen, nitrogen, and sulfur;
Q is 5- to 10-membered saturated monocyclic or bicyclic heterocyclic moiety having one to two atoms selected from the group consisting of oxygen, nitrogen, and sulfur; aryl, het, C,
1-12
alkyl, C
1-4
alkyl C
2-12
alkenyl, C
2-12
alkynyl, —C
3-8
cycloalkyl, —C
3-6
cycloalkenyl, and phenyl being optionally substituted; h is 0, 1, 2, 3, 4, 5, or 6; i is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; j is 0, 1, or 2; and with the following provisos: a) where R
2
is C
1-6
alkyl, Y is other than —NR
9
R
10
, b) where h is 0, het and Q are attached to the &agr;-position via carbon atom of heterocyclic moiety.
The compounds of the present invention inhibit various enzymes from the matrix metalloproteinase family, predominantly stromelysin and gelatinase, and hence are useful for the treatment of matrix metallo endoproteinase diseases.
As stated above, aryl, het, C
1-4
alkyl, C
1-12
alkyl, C
2-12
alkenyl, C
2-12
alkynyl, —C
3-8
cycloalkyl, —C
3-8
cycloalkenyl, Q and phenyl may be substituted as appropriate. Aryl is preferably substituted with C
1-4
alkyl, C
1-4
alkoxy, phenyl, O-phenyl, het, O-het, halo such as fluoro, chloro, bromo, OH, —NO
2
, —CN, —CF
3
, —N(R
3
)
2
such as —N(C
1-4
alkyl)
2
, —SR
3
, —SO
2
(C
1-4
alkoxy), —(CH
2
)
h
-het; —C(═O)R
3
or —NHC(═O)R
3
; het is preferably substituted with C
1-4
alkyl, pheny, phenoxy or halo; C
1-12
alkyl is preferably su

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