Hydroxamic and carboxylic acid derivatives

Details Hydroxamic and carboxylic acid derivatives Hydroxamic and carboxylic acid derivatives

2001-05-15

2003-01-14

Aulakh, C. S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S141000, C546S139000, C514S307000

Reexamination Certificate

active

06506773

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), 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.
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-93/20047. All of these reported inhibitors contain a hydroxamic acid zinc-binding group, as do the imidazole-substituted compounds disclosed in WO-A-95/23790. Other compounds that inhibit MMP and/or TNF&agr;are described in WO-A-95/13289, WO-A-96/11209, WO-A-96/035687, WO-A-96/035711, WO-A-96/035712 and WO-A-96/035714.
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 and/or TNF&agr;-mediated diseases, including degenerative diseases and certain cancers.
Novel compounds according to a first aspect of the invention are represented by formula (I):
wherein
R
1
is OH or NHOH;
R
2
is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo or heterocycloalkyl (any of which may be optionally substituted with one or more substituents selected from R
6
, W and WR
6
); and
R
3
is H or alkyl;
or R
2
, R
3
and the carbon atom to which they are attached together represent a carbocyclic or heterocyclic ring (either of which may be substituted with one or more substituents selected from R
6
, W and WR
6
);
R
4
is alkyl, cycloalkyl, OR
9
, CO
2
R
14
, COR
10
, S(O)
q
R
10
where q is 0, 1 or 2, CONR
7
R
8
, CN or S(O)
q
NR
7
R
8
; two R
4
substituents may be attached to the same carbon atom to form C(R
4
)
2
, where each R
4
may be the same or different, and C(R
4
)
2
may represent C═O;
R
5
is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, CF
3
, OR
9
, COR
10
, S(O)
q
R
10
, CO
2
R
14
, CONR
7
R
8
, S(O)
q
NR
7
R
8
, halogen, NR
10
R
11
or CN, or two adjacent R
5
substituents may be combined to form a heterocyclic ring;
R
6
is OR
9
, COR
10
, CO
2
R
15
, CONR
7
R
8
, NR
10
R
11
, S(O)
q
R
10
, S(O)
q
NR
7
R
8
, ═O, ═NOR
10
, succinimido or the group
R
7
and R
8
, which may be the same or different, are each H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl, 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, CF
3
, CHF
2
, CH
2
F, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl;
R
10
is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl; and
R
11
is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl, 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;
R
12
is OR
9
or R
13
;
R
13
is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heterarylalkyl, heterocycloalkyl or cycloalkylalkyl;
R
14
is H, alkyl or cycloalkyl;
R
15
is H, alkyl or cycloalkyl, arylalkyl or heteroarylalkyl;
R
16
is H or alkyl;
A is aryl or heteroaryl, provided that when A is phenyl, R
3
is H;
W is alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclo or heterocycloalkyl;
each k and m is independently 0, 1, 2 or 3;
n is 0, 1 or 2; and
p is 0, 1 or 2;
or a salt, solvate, hydrate, N-oxide, protected amino, protected carboxy or protected hydroxamic acid derivative thereof.
DESCRIPTION OF THE INVENTION
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. 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 “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 “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. The term alkenyl includes for example, vinyl, 1-propenyl, 1- and 2- butenyl, 2- methyl-2-propenyl and the like.
The term “alkynyl” refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one triple bond. The term alkynyl includes for example, ethynyl, 1-propynyl, 1- and 2- butynyl, 1- methyl-2-butynyl and the like.
Cycloalkyl or carbocyclic ring refers to a non-aromatic cyclic or multicyclic, saturated or partially saturated ring system having from three to ten carbon atoms which may be optionally benzofused at any available position. Thus cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydronaphthyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1 ]heptenyl, cyclopentenyl, indanyl and the like.
Heterocyclo or heterocyclic ring refers to a 3 to 10 membered saturated or partially saturated monocyclic or saturated or partially saturated multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur (or oxidised versions thereof, such as N-oxide, sulphoxide, sulphone). Examples include azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, quinuclidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, N-alkyl-piperazinyl, homopiperazinyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, benzodioxole, [2,3-dihydro]benzofuryl, [3,4-dihydro]benzopyranyl, 1,2,3,4 tetrahydroquinolinyl, 1,2,3,4 tetrahydroisoquinolinyl, 8-oxabicyclo[3.2.1]octane, indolinyl, isoindolinyl, and the like.
Aryl indicates carbocyclic radicals containing 6 to 10 carbon atoms and containing either a single ring or two condensed rings. Thus aryl includes, for example, phenyl and naphthyl.
Heteroaryl refers to a 5 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur (or oxidised versions thereof, such as N-oxide). In general, the heteroaryl groups may be for example monocyclic or bicyclic fused ring heteroaryl groups. Monocyclic heteroaryl groups include, for example, five- or six-membered heteroaryl groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaryl groups include for example eight- to ten-membered fused-ring heteroaryl groups containing one, two or mo

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