Hydroxamic acid derivatives

Details Hydroxamic acid derivatives Hydroxamic acid derivatives

2001-03-28

2002-09-24

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S210170, C514S319000, C514S322000, C514S327000, C514S330000, C514S423000, C544S386000, C546S198000, C546S206000, C546S221000, C546S226000, C546S245000, C548S568000, C548S953000

Reexamination Certificate

active

06455531

ABSTRACT:

This application is a National Stage Application of International Application Number PCT/GB00/04865, filed Dec. 18, 2000 published, pursuant to PCT Article 21(2), in English.
FIELD OF THE INVENTION
This invention relates to hydroxamic acid derivatives, and to their use in medicine.
BACKGROUND OF THE INVENTION
Metalloproteinases, including matrix metalloproteinase (MMP), (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 collagenase, stromelysin and gelatinase, 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-9603571 1, WO-A-96035712 and WO-A-96035714.
Further, somewhat related compounds are disclosed in U.S. Pat. No. 5,892,112, WO-A-9724117 and FR-A-2597865.
SUMMARY OF THE INVENTION
Compounds according to the invention are of formula (I):
wherein
R
1
is a group (optionally substituted with R
3
) 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 and C
1-6
alkyl-heterocycloalkyl; and
R
2
is H or C
1-6
alkyl;
or CR
1
R
2
is cycloalkyl or heterocycloalkyl optionally substituted with R
3
or a group (optionally substituted with R
3
) selected from C
1-6
alkyl, aryl, C
1-6
alkyl-aryl, heteroaryl and C
1-6
alkyl-heteroaryl;
R
3
is OR
7
, COR
7
, CO
2
R
6
, CON(R
7
)
2
, N(R
7
)
2
, NR
7
COR
7
, NR
7
CON(R
7
)
2
, NR
7
CO
2
R
8
, NR
7
SO
2
R
8
, S(O)
0-2
R
8
and SO
2
N(R
7
)
2
; or cycloimidyl (optionally substituted with R
4
)
R
4
is C
1-6
alkyl;
B—N—B is heterocycloalkyl optionally substituted with R
5
or ═NOR
5
;
R
5
is H, R
6
or a group (optionally substituted with R
6
) 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
6
is H or a group selected from N(R
7
)
2
NR
7
COR
7
, NR
7
CON(R
7
)
2
, NR
7
CO
2
R
8
, NR
7
SO
2
R
8
, OR
7
, COR
7
, CO
2
R
4
, CON(R
7
)
2
, S(O)
0-2
R
8
and SO
2
N(R
7
)
2
;
R
7
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
8
, COR
8
, S(O)
0-2
R
8
, CO
2
R
8
, OR
8
, CONR
4
R
8
, NR
6
R
8
or SO
2
NR
4
R
8
, and for each case of N(R
7
)
2
the R
7
groups are the same or different or N(R
7
)
2
is heterocycloalkyl optionally substituted with R
8
, COR
8
, S(O)
0-2
R
8
, CO
2
R
8
, OR
8
, CONR
4
R
8
, NR
6
R
8
or SO
2
NR
4
R
8
; and
R
8
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 R
1
is C
1-6
alkyl or CR
1
R
2
is heterocycloalkyl.
The compounds of the Examples are particularly preferred.
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 centers 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 “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 “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. For the group NB
2
, which is heterocycloalkyl, the saturated heterocyclic moiety must contain at least one N atom. This includes, for example, azetidinyl, pyrrolidinyl, piperidinyl 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 selected from O, N and S, and optionally substituted with an aryl group substituent. This term includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
The term “aryl group substituent” refers to a substituent chosen from halogen, CN, CF
3
, CHF
2
, CH
2
F, OCF
3
, OCF
2
H, OCFH
2
and NO
2
.
The term “halogen” means fluorine, chlorine, bromine or iodine.
The term “benzofused” refers to the addition of a benzene ring sharing a common bond with the defined ring system.
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 “optionally substituted” means optionally substituted with one or more of the groups specified, at any available position or positions. The terms “protected amino”, “protected carboxy” and “protec

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