Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-02
2002-06-25
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S444000, C514S471000, C549S059000, C549S476000, C548S210000
Reexamination Certificate
active
06410580
ABSTRACT:
This application is a 371 of PCT/EP99/00646, Feb. 2, 1999.
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 sulfonylamino acid and sulfonylamino hydroxamic acid derivatives of formula I
in which
W is —OH or —NHOH;
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, tetrahydroquinazolinyl 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, heteroar ylalkyl 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;
R
4
is alkyl, heterocyclylalkyl, aralkyl, aryl or heteroaryl;
m represents an integer from one to six; and
n represents the integer one or two;
and to pharmaceutically acceptable salts thereof.
Compounds of formula I are inhibitors of matrix-degrading metalloproteinases and are useful for the treatment of conditions related thereto.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. Listed below are definitions of various terms used to describe the compounds of the instant invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances either individually or as part of a larger group).
The term “heterocyclic rad ical” refer s to an optionally substituted, fully saturated or unsaturated, aro matic or nonaromatic cyclic group, for example, which is a 4 t o 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic radicals containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, thiazolyl, isoxazolyl, isoxazolinyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, thienyl, tetrahydrofuryl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl , azepinyl, 4-piperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, and the like.
Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), pyrrolopyridyl, dihydrobenzoisothiazolyl, dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinazolinyl and the like.
Exemplary tricyclic heterocyclic groups include tetrahydroimidazo[1,5-b]isoquinolinyl, carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term “heterocyclic radical” also includes substituted heterocyclic groups. Substituted heterocyclic groups refer to heterocyclic groups substituted with 1, 2, 3, 4 or 5 of the following:
(a) alkyl;
(b) hydroxy (or protected hydroxy);
(c) halo;
(d) oxo (i.e.=O);
(e) amino, alkylamino or dialkylamino;
(f) alkoxy;
(g) cycloalkyl;
(h) carboxy;
(i) heterocyclyloxy;
(j) alkoxycarbonyl, such as unsubstituted lower alkoxycarbonyl;
(k) carbamyl, alkylcarbamyl or dialkylcarbamyl;
(l) mercapto;
(m) nitro;
(n) cyano;
(o) sulfonamido, aminosulfonyl, alkyl or dialkylsulfonyl;
(p) aryl or heteroaryl;
(q) alkylcarbonyloxy;
(r) arylcarbonyloxy;
(s) arylthio;
(t) aryloxy;
(u) alkylthio;
(v) formyl;
(w) arylalkyl; or
(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino or halo.
The term “alkyl” refers to optionally substituted straight or branched chain hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 5 carbons. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the various branched chain isomers thereof, such as isopropyl, t-butyl, isobutyl, isohexyl, 4,4-dimethylpentyl, 2,2,4-trimethylpentyl and the like. Substituted alkyl groups include said alkyl groups substituted by one or more substituents selected from halogen, alkoxy, cycloalkyl, hydroxy, amino, nitro, cyano or thiol.
The term “alkoxy” refers to any of the above alkyl groups linked to an oxygen atom.
The term “cycloalkyl” refers to saturated cyclic hydrocarbon groups containing 3 to 7 ring carbons with cyclopropyl, cyclopentyl and cyclohexyl being preferred.
The term “halogen” or “halo” refers to chlorine, bromine, iodine and fluorine.
The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, or biphenyl groups, each of which may o
Kukkola Paivi Jaana
Nakajima Motowo
Robinson Leslie Ann
Sakaki Junichi
Higel Floyd D.
Loeschorn Carol A.
Novartis AG
Small Andrea D.
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