Hydroxamic and carboxylic acid derivatives

Details Hydroxamic and carboxylic acid derivatives Hydroxamic and carboxylic acid derivatives

2000-08-11

2003-01-07

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252130, C514S255010, C514S255020, C544S358000, C544S359000, C544S383000, C544S392000, C544S402000

Reexamination Certificate

active

06503910

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 metalloproteinase (MMP), (human fibroblast) 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-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 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 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 collagenase, stromelysin and gelatinase, have been shown to inhibit the release of TNF&agr; 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&agr; 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 novel compounds of formula (I) which are useful inhibitors of matrix metalloproteinases, ADAM or ADAM-TS enzymes, and which are useful for the treatment of diseases indicated by those enzymes and also and/or TNF&agr;-mediated diseases, including degenerative diseases and certain cancers.
Novel compounds according to the invention are of the general type represented by formula (I):
 (B)
2
N—X—(CH
2
)
n
—CR
1
R
2
—CO—Y  (I)
wherein
n=0-2;
X is S(O)
1-2
;
Y is OH or NHOH;
CR
1
R
2
is a cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl ring substituted with a group selected from ═O, ═CR
3
R
4
and ═NOR
3
, or CR
1
R
2
is a spirocyclic system, optionally substituted with R
3
or R
5
;
R
3
is H or a group (optionally substituted with R
5
) 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;
R
4
is H or C
1-6
alkyl;
R
5
is OR
9
, OCF
3
, OCH
2
F, OCHF
2
, COR
9
, CO
2
R
4
, CON(R
9
)
2
, N(R
9
)
2
, NR
9
COR
9
, NR
9
CON(R
9
)
2
, NR
9
CO
2
R
10
, NR
9
SO
2
R
10
, S(O)
0-2
R
10
, SO
2
N(R
9
)
2
or cycloimidyl (optionally substituted with R
6
);
R
6
is C
1-6
alkyl;
B is H or a group (optionally substituted with R
7
) selected from C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, aryl, C
1-6
alkyl-aryl, heteroaryl, C
1-6
alkyl-heteroaryl, cycloalkyl, C
1-6
alkyl-cycloalkyl, heterocycloalkyl, C
1-6
alkyl-heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl; and each instance of B may be the same or different, provided that NB
2
is not NH
2
;
or B—N—B is a heterocycloalkyl or heterocycloalkenyl ring optionally substituted with a group selected from R
7
, ═CR
7
R
4
, ═O and ═NOR
7
, or a spirocyclic system optionally substituted with R
7
;
R
7
is H, R
8
or a group (optionally substituted with R
8
) 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;
R
8
is H or a group selected from N(R
9
)
2
, NR
9
COR
9
, NR
9
CON(R
9
)
2
, NR
9
CO
2
R
10
, NR
9
SO
2
R
10
, OR
9
, OCF
3
, OCH
2
F, OCHF
2
, COR
9
, CO
2
R
4
, CON(R
9
)
2
, S(O)
0-2
R
10
and SO
2
N(R
9
)
2
;
R
9
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
10
, COR
10
, SO
0-2
R
10
, CO
2
R
10
, OR
10
, OCF
3
, OCH
2
F, OCHF
2
, CONR
4
R
10
, NR
4
R
10
or SO
2
NR
4
R
10
, and for each case of N(R
9
)
2
the R
9
groups are the same or different, or N(R
9
)
2
is heterocycloalkyl optionally substituted with R
10
, COR
10
, SO
0-2
R
10
, CO
2
R
10
, OR
10
, CONR
4
R
10
, NR
4
R
10
, or SO
2
NR
4
R
10
; and
R
10
is C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl or C
1-6
alkyl-heteroaryl; and the salts, solvates, hydrates, N-oxides, protected amino, protected carboxy and protected hydroxamic acid derivatives thereof.
DESCRIPTION OF THE INVENTION
Preferred compounds of the invention are those wherein any one or more of the following apply: X is SO
2
; Y is NHOH; B—N—B is optionally substituted heterocycloalkyl; n=1; and CR
1
R
2
is the said cycloalkyl or heterocycloalkyl ring.
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.
It will further be appreciated that the compounds according to the invention may contain an oxime and/or an alkene. These groups 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
1-8
alkyl” refers to straight or branched chain alkyl moiety having from one to eight carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, octyl 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 “C
2-6
alkynyl” refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 1-methyl-2-butynyl etc.
The term “cycloalkyl” refers to a saturated alicyclic moiety having from three to six carbon atoms and includes for example cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term “cycloalkenyl” refers to an alicyclic moiety having from three to six carbon atoms and having in addition one double bond. This term includes, for example, cyclopentenyl and cyclohexenyl.
The term “heterocycloalkyl” refers to a saturated heterocyclic moiety having from two to six carbon atoms and one or more heteroatom from the group N, O, S (or oxidised versions thereof) which may be optionally benzofused at any available position. This includes for example azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, benzodioxole and the like.
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 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, optionally substituted with an aryl group substituent. 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

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