Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-02-03
2001-08-21
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C548S477000, C548S209000, C548S317100, C514S259500, C514S373000, C514S417000, C514S389000
Reexamination Certificate
active
06277987
ABSTRACT:
SUMMARY OF THE INVENTION
The invention relates to sulfonylamino acid and sulfonylamino hydroxamic acid derivatives and to processes for their preparation, pharmaceutical compositions comprising said compounds, a method of inhibiting matrix-degrading metalloproteinases in mammals using such compounds and the use of these derivatives as medicaments.
The present invention relates to novel sulfonylamino acid and sulfonylamino hydroxamic acid derivatives of formula
and pharmaceutically acceptable salts thereof. As used in formula I, and throughout the specification, the symbols have the following meanings:
W is —OH or —NHOH;
X is a heterocycle with the proviso that when X is a nitrogen containing heterocycle, the heterocycle is attached to the (CH
2
)
m
moiety by a ring nitrogen, —CONR
2
R
3
, —NR
1
COR
2
, —NR
1
SO
2
R
2
, —NR
1
CONR
2
R
3
, —NR
1
COOR
4
, heteroarylthio, alkylthio, arylalkylthio, heteroarylalkylthio, heterocycloalkylalkylthio, heterocycloalkylthio or arylthio;
Y is carbon, nitrogen, oxygen or sulfur, provided that when Y is carbon, n is 2;
Z is alkyl, aryl, alkoxy, aryloxy, aralkoxyaryl, aralkoxyheteroaryl, heteroaryl, heterocycloalkyl, heteroaryloxy, —CONR
2
R
3
, —NR
1
COR
2
, —NR
1
CONR
2
R
3
, —OCONR
2
R
3
, —NR
1
COOR
4
, or —SO
2
R
2
;
R
1
is hydrogen, alkyl, heterocycloalkylalkyl, aralkyl or heteroarylalkyl;
R
2
and R
3
are independently R
1
, aryl or heteroaryl; or R
2
and R
3
taken together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, which may optionally contain another heteroatom selected from oxygen, nitrogen and sulfur;
R
4
is alkyl, heterocycloalkylalkyl, aralkyl, aryl or heteroaryl;
m represents an integer from one to six; and
n represents the integer one or two.
Preferably X is
a) an unsubstituted or substituted heterocyclic radical, selected from the group consisting of pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyridyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro-1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydrobenzoisothiazolyl, dihydroquinazolinyl, tetrahydro-quinazolinyl and 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring, in which each ring of the heterocyclic radical containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms; with the proviso that when X is a nitrogen containing heterocyclic radical, the heterocyclic radical is attached to the (CH
2
)
m
moiety by a ring nitrogen and the proviso that nitrogen and sulfur heteroatoms of the heterocyclic radical may also be oxidized;
b) —NR
1
SO
2
R
2
, in which
R
1
is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl and
R
2
is hydrogen, alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl;
c) heterocyclylalkylthio;
d) —CONR
2
R
3
, in which
R
2
and R
3
taken together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, which may optionally contain another heteroatom selected from oxygen, nitrogen and sulfur, or
e) —NR
1
COR
2
, in which
R
1
is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl and
R
2
is hydrogen, heterocyclylalkyl, aralkyl, heteroarylalkyl or aryl;
Y is carbon, nitrogen, oxygen or sulfur, provided that when Y is carbon, n is 2;
Z is alkyl, aryl, alkoxy, aryloxy, aralkoxyaryl, aralkoxyheteroaryl, heteroaryl, heterocyclyl, heteroaryloxy, —CONR
2
R
3
, —NR
1
COR
2
, —NR
1
CONR
2
R
3
, —OCONR
2
R
3
, —NR
1
COOR
4
, or —SO
2
R
2
, in which
R
1
is hydrogen, alkyl, heterocyclylalkyl, aralkyl or heteroarylalkyl and
R
2
and R
3
are independently hydrogen, alkyl, heterocyclylalkyl, aralkyl, heteroarylalkyl, aryl or heteroaryl; or
R
2
and R
3
taken together with the nitrogen atom to which they are attached form a 5- to 7-membered ring, which may optionally contain another heteroatom selected from oxygen, nitrogen and sulfur; and
R
4
is alkyl, heterocyclylalkyl, aralkyl, aryl or heteroaryl.
Compounds of formula I are inhibitors of matrix-degrading metalloproteinases and are useful for the treatment of conditions related thereto.
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Kukkola Paivi Jaana
Nakajima Motowo
Robinson Leslie Anne
Sakaki Junichi
Lambkin Deborah C.
Loeschorn Carol
Novartis AG
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