Hydroxamic and carboxylic acid derivatives having MMP and...

Details Hydroxamic and carboxylic acid derivatives having MMP and... Hydroxamic and carboxylic acid derivatives having MMP and...

1998-11-12

2001-02-13

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C514S254100, C514S336000, C514S341000, C514S348000, C514S397000, C514S398000, C514S451000, C514S534000, C514S575000, C546S194000, C546S207000, C546S210000, C546S216000, C546S224000, C548S315400, C548S319500, C549S425000, C560S012000, C562S621000, C562S622000

Reexamination Certificate

active

06187924

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to hydroxamic and carboxylic acid derivatives, and to their use in medicine.
BACKGROUND 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 the 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 THF 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
m is 0-2;
X is S(O)
t-2
;
Y is OH or NHOH;
R
1
H or a group (optionally substituted with R
7
) selected from C
1-6
alkyl C
2-4
alkenyl, aryl, C
1-6
alkyl-aryl, heteroaryl, C
1-6
alkyl-heteroaryl, heterocycloalkyl, C
1-6
alkyl-heterocycloalkyl, cycloalkyl and C
1-6
alkyl-cycloalkyl, and R
2
H or C
1-6
alkyl;
or CR
1
R
2
is a cycloalkyl or heterocycloalkyl ring optionally substituted with R
7
or a group (optionally substituted with R
7
) selected from C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl and C
1-6
alkyl-heteroaryl;
each B is the same or different and H is or a group selected from C
1-6
alkyl-aryl, C
1-6
alkyl, cycloalkyl, C
1-6
alkyl-cycloalkyl, cycloalkenyl, heterocycloalkenyl, C
1-6
alkyl-heteroaryl, heterocycloalkyl, C
1-6
alkyl-heterocycloalkyl, aryl or heteroaryl, any of which groups is optionally substituted by a substituent selected from R
3
, C
1-6
alkyl-R
3
, C
2-6
alkenyl-R
3
, aryl (optionally substituted with R
3
), aryl-C
1-6
alkyl-R
3
, C
1-6
alkyl-aryl (optionally substituted with R
3
), C
1-6
alkyl-heteroaryl (optionally substituted with R
3
), aryl-C
2-6
alkenyl-R
5
, heteroaryl (optionally substituted with R
3
), heteroaryl-C
1-6
alkyl-R
3
, cycloalkyl (optionally substituted with R
3
) and heterocycloalkyl (optionally substituted with R
3
), provided with NB
2
is not NH
2
,
or B—N—B is a heterocycloalkyl ring substituted with ═O or ═NOR
4
,
or, when neither R
1
or R
2
is H, B—N—B is a heterocycloalkyl or heterocycloalkenyl ring optionally substituted by a substituent selected from R
3
, C
1-6
alkyl-R
3
, C
2-6
alkenyl-R
3
, aryl (optionally substituted with R
3
), aryl-C
1-6
alkyl-R
3
, C
1-6
alkyl-aryl (optionally substituted with R
3
), C
1-6
alkyl-heteroaryl (optionally substituted with R
3
), aryl-C
2-6
alkenyl-R
5
, heteroaryl (optionally substituted with R
3
), heteroaryl-C
1-6
alkyl-R
3
, cycloalkyl (optionally substituted with R
3
), and heterocycloalkyl (optionally substituted with R
3
);
R
3
is C
1-6
alkyl, C
2-6
alkenyl-R
5
, halogen, CN, NO
2
, N(R
4
)
2
, OR
4
, C(═NOR
6
)R
4
, CON(R
4
)
2
, COR
4
, CO
2
R
8
, NR
4
R
5
, S(O)
0-2
N(R
4
)
2
;
R
4
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
6
, COR
6
, SO
0-2
R
6
, CO
2
R
6
, OR
6
, CONR
8
R
6
, NR
8
R
6
, halogen, CN, SO
2
NR
8
R
6
or NO
2
, and for each case of N(R
4
)
2
the R
4
groups are the same or different or N(R
4
)
2
is heterocycloalkyl optionally substituted with R
6
, COR
6
, SO
0-2
R
6
, CO
2
R
6
, OR
6
, CONR
8
R
6
, NR
8
R
6
, halogen, CN, SO
2
NR
8
R
6
or NO
2
;
R
5
is COR
4
, CON(R
4
)
2
, CO
2
R
6
or SO
2
R
6
;
R
6
is C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl or C
1-6
alkyl-heteroaryl; and
R
7
is OR
4
, COR
4
, CO
2
R
8
, CON(R
4
)
2
, NR
4
R
5
, S(O)
0-2
R
6
, SO
2
N(R
4
)
2
, halogen, CN or cycloimidyl (optionally substituted with R
8
); and
R
8
is H or C
1-6
alkyl;
and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy, or 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 and CR
1
R
2
is CH
2
or NB
2
is NH
2
, N(Ph)H, N(Ph)CH
3
, N(C
6
HG
11
)CH
3
or N(4-methoxybenzoyl)
2
.
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
;
B is not H;
B is optionally substituted C
1-6
alkyl, cycloalkyl, heterocycloalkyl, C
1-6
alkyl-aryl or C
1-6
alkyl-heteroaryl;
B—N—B is an optionally substituted heterocycloalkyl ring;
B—N—B is a heterocycloalkyl ring substituted with ═NOR
4
;
R
1
is optionally substituted C
1-6
alkyl, C
1-6
alkyl-heteroaryl, C
1-6
alkyl-aryl or C
1-6
alkyl-heterocycloalkyl;
CR
1
R
2
is the said optionally substituted cycloalkyl or heterocycloalkyl ring;
R
3
is C
1-6
alkyl, C
2-6
alkenyl-R
5
, halogen, CN, NO
2
, N(R
4
)
2
, OR
4
, COR
4
, NR
4
R
5
, S(O)
0-2
R
6
or SO
2
N(R
4
)
2
; and
R
7
is CON(R
4
)
2
, NR
4
R
5
, SO
2
N(R
4
)
2
or cycloimidyl.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon and sulfur 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 enantiomners and diastereomers, and mixtures including racemic mixtures thereof.
It will further be appreciated that the compounds according to the invention may contain an oxime. This oxime can give rise to geometrical isomers, and in each case the invention is to be understood to extend to all such isomers and 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 is 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 heteroatoms selected from N, O, S and oxidised verisons thereof, and which is optionally benzofused at any available position. This term includes, for example, azetidinyl, pyrrolidinyl, tetrahydrof

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