Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-15
2004-10-26
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252020, C514S253010, C514S252140, C514S275000, C544S295000, C544S335000, C544S357000, C544S383000, C544S402000
Reexamination Certificate
active
06809100
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.
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, such as N-methylpiperazinyl, homopiperazinyl, oxazolidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, benzodioxolyl, [2,3-dihydro]benzofuryl, [3,4-dihydro]benzopyranyl, 1,2,3,4 tetrahydroquinolinyl, 1,2,3,4 tetrahydroisoquinolinyl, 8-oxabicyclo[3.2.1]octanyl, indolinyl, isoindolinyl, and the like.
For the case where A represents a heterocyclic ring, the heterocyclic moiety must contain at least one nitrogen atom. This includes, for example, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, thiazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4 tetrahydroisoquinolinyl 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 t
Baxter Andrew Douglas
Dyke Hazel Joan
Hannah Duncan Robert
Sharpe Andrew
Darwin Discovery Ltd.
Patel Sudhaker B.
Raymond Richard L.
Saliwanchik Lloyd & Saliwanchik
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