Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-16
2002-10-29
Ghan, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S270000, C544S300000, C544S301000
Reexamination Certificate
active
06472396
ABSTRACT:
In normal tissue there is an equilibrium between synthesis and degradation. Extracellular matrix is degraded by proteases which belong to at least three groups of matrix metalloproteases. These are the collagenases, gelatinases and stromelysins. Normally there are specific inhibitors for these catabolic enzymes such as &agr;
2
macroglobulines and MMP (=tissue inhibitor of metalloproteases (MMP)) so that an excessive degradation of extracellular matrix does not occur. A related group of proteases is the adamalysins. A prominent member of the adamalysins is TACE (TNF-&agr;-converting enzyme).
At least 11 different and yet highly homologous MMP species have been characterized, including the interstitial fibroblast collagenase (MMP-1, HFC), the neutrophil collagenase (MMP-8, HNC), two gelatinases, stromelysins (such as HSL-1) and HPUMP (for a recent review, see Birkedal-Hansen, H., Moore, W. G. I., Bodden, M. K, Windsor, L. J., Birkedal-Hansen; B., DeCarlo, A., Engler, J. A., Critical Rev. Oral Biol. Med. (1993) 4, 197-250. These proteinases share a number of structural and functional features but differ somewhat in their substrate specificity. Only HNC and HFC are capable of cleaving type I, II and III native triple-helical collagens at a single bond with the production of fragments ¾ and ¼ of the native chain length. This lowers the collagen melting point and makes them accessible to further attack by other matrix degrading enzymes.
However, the uncontrolled excessive degradation of this matrix is a characteristic of many pathological states such as e.g. in the clinical picture of rheumatoid arthritis, osteoarthritis, multiple sclerosis, in the formation of tumour metastases, corneal ulceration, inflamative diseases and invasion and in diseases of the bone and teeth.
It can be assumed that the pathogenesis of these clinical pictures can be favourably influenced by the administration of matrix metalloprotease inhibitors. A number of compounds in the meantime are known in the literature (see e.g. the review article of Nigel R A Beeley et al. Curr. Opin. ther. Patents 4 (1), 7 (1994)) or are described in the patent literature, these mainly being peptides with a hydroxamic acid residue, a thiol or phosphine group as a zinc binding group (see e.g. WO-A-9209563 by Glycomed, EP-A-497 192 by Hoffmann-LaRoche, WO-A-9005719 by British Biotechnology, EP-A489 577 by Celltech, EP-A-320 118 by Beecham, U.S. Pat. No. 4,595,700 by Searle among others).
Some of these compounds have a high activity as inhibitors of matrix metalloproteases but only have a very low oral availability.
It has now been found that the claimed new barbituric acid derivatives are very efficacious as matrix metallo-protease inhibitors and have a good oral availability.
The present invention therefore concerns substances of the general formula I
in which
X, Y and Z are independently of one another oxygen, sulphur or NH,
R
1
represents a group W—V
W is a valence dash or a straight-chained or branched C
1
-C
8
alkyl or a C
2
-C
8
alkenyl group which is optionally once or several times substituted,
V is an optionally substituted monocycle or bicycle which can contain one or several heteroatoms, or
W—V is a C1-C20 akyl group which can be interrupted by heteroatoms, one or several carbon atoms are optionally substituted,
R
2
and R
3
represent hydrogen or one of the two represent lower alkyl or lower acyl
R
4
and R
5
denote independently of each other for A—D wherein A represents a dash alkyl, alkenyl, acyl, alkylsulfonyl, sulfonyl, alkylaminocarbonyl, aminocarbonyl, alkoxycarbonyl, oxy-carbonyl, alkylaminothiocarbonyl, aminothio-carbonyl which is optionally once or several times substituted.
D represents a hydrogen, mono or bicycle, the monocycle or bicycle is optionally once or several times interrupted by heteroatoms and the monocycle or bicycle is once or several times substituted, or
R
4
and R
5
together with the nitrogen atom to which they are bound represent a ring which optionally can be interrupted by a further N atom, said ring can be condensed to a monocycle or bicycle, said ring can optionally be substituted once or several times independently by the residues hydroxy, alkoxy, amino, alkylamino, dialkylamino, nitril or by E—G wherein E represents a dash alkyl, alkenyl, acyl, alkylsulfonyl, sulfonyl, alkylaminocarbonyl, aminocarbonyl, alkoxycarbonyl oxycarbonyl, alkylaminothiocarbonyl, aminothiocarbonyl which is optionally substituted; G represents a hydrogen, mono or bicycle, the monocycle or bicycle is optionally once or several times interrupted by heteroatoms and the monocycle or bicycle is once or several times substituted,
pharmacologically acceptable salts or prodrugs thereof as well as the use of these compounds to produce pharmaceutical agents.
The monocycle listed in the case of R
1
, R
4
and R
5
is understood as saturated or unsaturated ring systems with 3-8, preferably 5-7 carbon atoms which can optionally be interrupted one or several times by heteroatoms such as nitrogen, oxygen or sulphur in particular a cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl residue. Lower alkyl, alkoxy and halogen come above all into consideration as substituents.
The bicycle listed under R
1
, R
4
and R
5
, is understood to be a condensed bicycle or a bicycle of the type monocycle
1
-L-monocycle
2
, wherein L denotes a valence dash C
1
-C
4
-alkyl group, C
2
-C
4
an alkenyl group, an oxygen or —C(O)— group.
The bicycle is preferably a residue such as a naphthyl, tetrahydronaphthyl dekalinyl, quinolinyl, isoquinolinyl, tetrahydroquino-linyl, tetrahydroisoquinolinyl, indolyl, benzimidazoyl, indazolyl, oxindolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxazolyl, purinyl, biphenyl or (4-phenoxy)phenyl residue and in particular a naphthyl, biphenyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, indolyl or benzimidazolyl residue.
The residues listed under R
1
, R
4
and R
5
can optionally be substituted once or several times by halogen, hydroxy, thio, alkyl, hydroxyalkyl, alkoxy, alkylthio, alkylsulfinyl, alkyl-sulfonyl, amino, alkylamino, dialkylamino, nitro, carboxyl, carboxamido, alkoxycarbonyl, amino or aminocarbonyl optionally substituted once or twice by lower alkyl, nitrile, oxo, thiocarboxamido, alkoxythiocarbonyl, alkmercaptocarbonyl, phosphono, alkylphosphono, dialkylphosphono, alkylsulfonylamido, arylamino, aryl, hetaryl, aryloxy, arylthio, arylsulfinyl, arylsulfonyl or acyl.
In this case the halogen, hydroxy, oxo, thio, alkoxy, alkylthio, amino, aminocarbonyl, carboxyl and acyl groups are preferred.
Lower alkyl denotes C
1
-C
6
-Alkyl, preferred methyl, ethyl, propyl, isopropyl or tert.-butyl.
Lower acyl in the residues R
2
and R
3
above all denotes for —C(O)—C
1
-C
6
-alkyl or —C(O)H, preferred for an acetyl group.
The alkyl residues in R
1
, R
4
and R
5
can optionally be interrupted once or several time by heteroatoms (O, S, NH).
Alkyl in the residues R
4
and R
5
denotes as such or in combination with alkoxy, alkylthio, arylsulfonyl, alkylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylamino, alkoxycarbonyl, aryloxycarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl a straight-chained, branched, saturated or unsaturated residue with 1-11, preferably 1-8 carbon atoms such as e.g. a methyl, ethyl, propyl, pentyl, octyl, allyl, propargyl, 2,4-pentadienyl, isopropyl, sec. butyl, 3-methylbutyl, 2-hydroxyhexyl and in particular a methyl, propyl, isopropyl, pentyl, octyl, allyl, 3-methylbutyl, 2-hydroxyhexyl and propargyl residue.
Aryl, also in combination with aryloxy, arylthio, arylsulfonyl, arylaminocarbonyl, aryloxycarbonyl, arylaminothiocarbonyl is understood as a phenyl or naphthyl residue which can optionally be substituted in particular by halogen, lower alkyl or alkoxy.
The C
1
-C
20
alkyl group listed
Bosies Elmar
Esswein Angelika
Grams Frank
Krell Hans-Willi
Menta Ernesto
Arent Fox Kintner Plotkin & Kahn
Ghan Mukund J.
McKenzie Thomas C
Roche Diagnostics GmbH
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