Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-04
2001-10-30
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S058000
Reexamination Certificate
active
06310088
ABSTRACT:
FIELD OF THE INVENTION
Metalloproteinases, including matrix metalloproteinases) MMPs), (human fibroblast) collagenase, gelatinase and TNF convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-9611209, WO-A-9712902 and WO-A-9719075, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the adamalysin family (or ADAMs) whose members include TNF convertase (TACE) and ADAM-10, which can cause the release of TNF&agr; from cells, and others, which have been demonstrated to be expressed by human articular cartilage cells and also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown, such as collagenases, stromelysins and gelatinases, have been shown to inhibit the release of TNF both in vitro and in vivo. See Gearing et al (1994), Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561; GB-A-2268934; and WO-A-9320047. All of these reported inhibitors contain a hydroxamic acid zinc-binding group, as do the imidazole-substituted compounds disclosed in WO-A-9523790. Other compounds that inhibit MMP and/or TNF are described in WO-A-9513289, WO-A-9611209, WO-A-96035687, WO-A-96035711, WO-A-96035712 and WO-A-96035714.
SUMMARY OF THE INVENTION
The invention encompasses compounds which are useful inhibitors of matrix metalloproteinases and/or TNF&agr;-mediated diseases, including degenerative diseases and certain cancers. These compounds are represented by formula (I):
wherein
n is 1-2;
X is OH or S(O)
0-2
;
Y is OH or NHOH;
W is CR
3
or, when X is SO
2
, W may alternatively be N;
R
1
is H or a group selected from C
1-6
alkyl, C
2-6
alkenyl, aryl, C
1-6
alkyl-aryly heteroaryl, C
1-6
alkyl-heteroaryl, heterocycloalkyl, C
1-6
alkyl-heterocycloalkyl, cycloalkyl and C
1-6
alkyl-cycloalkyl, wherein said group is optionally substituted with R
14
, and
R
2
is H or C
1-6
alkyl, or
CR
1
R
2
is a cycloalkyl or heterocycloalkyl ring, optionally substituted with R
14
or a group (optionally substituted with R
14
) selected from C
1-6
alkyl, aryl, C
1-6
alkyl-aryl;
R
3
, R
4
and R
5
are independently H or C
1-6
alkyl or R
3
and R
4
may together represent a bond such that CR
3
CR
4
R
5
is C═CR
5
; R
5
;
R
6
, R
7
, R
8
and R
9
are independently H, R
10
or a group (optionally substituted with R
10
) selected from C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, C
1-6
alkyl-heteroaryl, heteroaryl and heterocycloalkyl, or
R
6
and R
7
, R
7
and R
8
, R
8
and R
9
, or when n=1, R
5
and R
6
, and the carbons to which they are independently attached may alternatively form an aryl, heteroaryl, cycloalkenyl or heterocycloalkenyl ring, wherein said ring is optionally substituted with R
10
or R
11
;
R
10
is C
1-6
alkyl, halogen, CN, NO
2
, N(R
11
)
2
, OR
11
, COR
11
, CO
2
R
15
, CON(R
11
)
2
, C═NOR
11
, NR
11
R
12
, S(O)
0-2
R
11
or SO
2
N(R
11
)
2
;
R
11
is H or a group selected from C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl, C
1-6
alkyl-heteroaryl, cycloalkyl, C
1-6
alkyl-cycloalkyl, heterocycloalkyl and C
1-6
alkyl-heterocycloalkyl, wherein said group is optionally substituted with R
13
, COR
13
, SO
0-2
R
13
, CO
2
R
13
, OR
13
, CONR
15
R
13
, NR
15
R
13
, halogen, CN, SO
2
NR
15
R
13
or NO
2
, and for each case of N(R
11
)
2
the R
11
groups are the same or different or N(R
11
)
2
is heterocycloalkyl optionally substituted with R
13
, COR
13
, SO
0-2
R
13
, CO
2
R
13
, OR
13
, CONR
15
R
13
, NR
15
R
13
, halogen, CN, SO
2
NR
15
R
13
or NO
2
;
R
12
is COR
11
, CON(R
11
)
2
, CO
2
R
13
or SO
2
R
13
,
R
13
is C
1-6
alkyl, axyl, C
1-6
alkyl-aryl, heteroaryl or C
1-6
alkyl-heteroaryl; and
R
14
is OR
11
, COR
11
, CO
2
R
15
, CON(R
11
)
2
, NR
11
R
12
, S(O)
0-2
R
13
, SO
2
N(R
11
)
2
, halogen, CN, NO
2
or cycloimidyl (optionally substituted with R
15
);
R
15
is H or C
1-6
alkyl;
and salts, solvates, hydrates, N-oxides, protected amino, protected carboxy, and protected hydroxamic acid derivatives thereof.
Compounds of formula (I) are disclosed for the first time as having therapeutic utility. Compounds of formula (I) are new, except those wherein Y is OH, X is S(O)
0-2
and either CR
1
R
2
is CH
2
or X is SO
2
and R
3
and R
4
together are not a bond.
Combinations of substituents and/or variables are only permissible if such combinations result in stable compounds.
DESCRIPTION OF THE INVENTION
Preferred compounds of the invention are those wherein any one or more of the following apply:
X is SO
2
;
W is CR
3
;
n is 1;
R
1
is optionally substituted C
1-6
alkyl, C
1-6
alkyl-aryl, C
1-6
alkyl-heteroaryl, or C
1-6
alkyl-heterocycloalkyl, or CR
1
R
2
forms the said optionally substituted cycloalkyl or heterocycloalkyl ring;
R
6
, R
7
, R
8
or R
9
is R
10
or optionally substituted aryl or heteroaryl;
R
10
is OR
11
, COR
11
or C═NOR
11
;
R
11
is optionally substituted aryl, C
1-6
alkyl, C
1-6
alkyl-aryl, heteroaryl or C
1-6
alkyl-heteroaryl; and
R
14
is CO
2
R
2
, CON(R
11
)
2
, NR
11
R
12
, S(O)
0-2
R
13
, SO
2
N(R
11
)
2
, or optionally substituted cycloimidyl.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof
As used in this specification, alone or in combination, the term “C
1-6
alkyl” refers to straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
The term “C
2-6
alkenyl” refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl etc.
The term “cycloalkyl” refers to a saturated alicyclic moiety having from three to six carbon atoms and which may be optionally benzofused at any available position. This term includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl and tetrahydronaphthyl.
The term “heterocycloalkyl” refers to a saturated heterocyclic moiety having from three to six carbon atoms and one or more heteroatom from the group N, O, S (or oxidised versions thereof) and which may be optionally benzofused at any available position. This term includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, indolinyl and tetrahydroquinolinyl.
The term “cycloalkenyl” refers to an alicyclic moiety having from three to six carbon atoms and having in addition one double bond. This term would include for example cyclopentenyl or cyclohexenyl.
The term “heterocycloalkenyl” refers to an alicyclic moiety having from three to six carbon atoms and one or more heteroatoms from the group N, O, S (or oxides thereof) and having in addition one double bond. This term includes, for example, dihydropyranyl.
The term “aryl” refers to an aromatic carbocyclic radical having a single ring or two condensed rings. This term includes, for example phenyl or naphthyl.
The term “heteroaryl” refers to aromatic ring systems of five to ten atoms of which at least one atom is selected from O, N and S, and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
The term “cycloimidyl” refers to a saturated ring of five to ten atoms containing the atom sequence —C(═O)NC(═O)—. The ring may be optionally benzofused at any available position. Examples include succinimidoyl, phthalimidoyl and hydantoinyl.
The term “benzofused” refers to the ad
Baxter Andrew Douglas
Montana John Gary
Nicholson Elizabeth Jane Reed
Owen David Alan
Darwin Discovery Ltd.
Gerstl Robert
Saliwanchik Lloyd & Saliwanchik
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