Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-06-12
2004-09-07
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S253010, C514S252120, C514S451000, C514S255050, C544S295000, C544S358000, C544S360000, C544S383000, C544S402000
Reexamination Certificate
active
06787536
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to hydroxamic acid derivatives, and to their use in medicine.
BACKGROUND TO THE INVENTION
Metalloproteinases, including matrix metalloproteinase (MMP), collagenase, gelatinase and TNF&agr; convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-96/11209, WO-A-97/12902 and WO-A-97/19075, 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 ADAM or ADAM-TS families. Members of the ADAM family include TNF&agr; 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 are also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
SUMMARY OF THE INVENTION
The invention encompasses novel compounds of formula (I) which are inhibitors of matrix metalloproteinase, ADAM or ADAM-TS enzymes, and which are useful for the treatment of diseases mediated by those enzymes, including degenerative diseases and certain cancers.
Novel compounds according to a first aspect of the invention are represented by formula (I):
wherein
R
2
is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or cycloalkyl (any of which may be optionally substituted with one or more substituents selected from R
4
, W and WR
4
);
R
3
is a hydrogen atom or an alkyl group;
or R
2
, R
3
and the carbon atom to which they are attached together represent a carbocylic or heterocyclic ring (either of which may be substituted with one or more substituents chosen from R
4
, W or WR
4
);
A is a heterocylic ring (attached to SO
2
through a nitrogen atom) optionally substituted with R
4
;
B is an aryl or heteroaryl ring, optionally substituted with one or more R
5
;
D is an aryl or heteroaryl ring, optionally substituted with one or more R
5
; or a heterocyclic ring (attached through a carbon atom) optionally substituted with R
4
at any available carbon atom or with R
14
at any available nitrogen atom;
provided that both B and D are both not phenyl;
R
4
is OR
6
, COR
10
, CO
2
R
9
, CONR
7
R
8
, NR
10
R
11
, S(O)
q
R
10
, S(O)
q
NR
7
R
8
, CN, ═O or ═NOR
10
, provided that R
4
is not ═O or ═NOR
10
if a substituent on an aromatic ring;
R
5
is alkyl, cycloalkyl, CF
3
, OR
6
, COR
10
, S(O)
q
R
10
, CO
2
R
9
, CONR
7
R
8
, S(O)
q
NR
7
R
8
, halogen, NR
10
R
11
or CN;
R
6
is H, alkyl, CF
3
, CHF
2
, CH
2
F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
R
7
and R
8
, which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl, or R
7
and R
8
and the nitrogen to which they are attached together represent a heterocyclic ring;
R
9
is H, alkyl or cycloalkyl;
R
10
is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl or cycloalkylalkyl;
R
11
is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl, COR
12
, CONR
7
R
8
, S(O)
q
R
12
or S(O)
q
NR
7
R
8
, or R
10
and R
11
and the nitrogen to which they are attached together represent a heterocyclic ring optionally substituted by R
13
;
R
12
is OR
6
or R
13
;
R
13
is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkylalkyl;
R
14
is a hydrogen atom, alkyl or cycloalkyl;
q is 0, 1 or 2;
W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo, heterocycloalkyl and
X is —O—, —CO—, S(O)
q
—, —N(R
10
)—, or is absent;
and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.
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patent: 4166452 (1979-09-01), Generales, Jr.
patent: 4256108 (1981-03-01), Theeuwes
patent: 4265874 (1981-05-01), Bonsen et al.
patent: WO 96/11209 (1995-10-01), None
patent: WO 97/12902 (1996-10-01), None
patent: WO 97/19075 (1996-11-01), None
patent: WO 98/05635 (1997-08-01), None
patent: WO 99/24399 (1998-11-01), None
patent: 9924399 (1999-05-01), None
patent: 9925687 (1999-05-01), None
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Baxter Andrew Douglas
Dyke Hazel Joan
Hannah Duncan Robert
Sharpe Andrew
Darwin Discovery Limited
Patel Sudhaker B.
Rao Deepak
Saliwanchik Lloyd & Saliwanchik
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