Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-22
2001-06-05
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S301000
Reexamination Certificate
active
06242455
ABSTRACT:
The invention concerns new pyrimidine-2,4,6-trione derivatives, the production thereof and pharmaceutical preparations containing these. These compounds inhibit metalloproteases, in particular proteases from the M2 and M3 family, the astacin subfamily of M12 and M13. These protease families are defined in N. D. Rawlings and A. J. Barret, Methods Enzym. (1995) 248, 183-277.
BMP-1 is particularly preferred in the protease group M12 as an inhibition target of compounds of the invention. ECE and NEP from the M13 family are additionally preferred as well as ACE (peptidyl-dipeptidase A) from the subgroup M2.
Metalloproteases play a major role in many physiological and pathophysiological processes. Examples of this are the angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP, EC 3.4.24.11) which are involved in the metabolism of a series of blood pressure-regulating peptides (e.g. angiotensin I and ANF (atrial natriuretic factor)). ACE catalyses the cleavage of angiotensin I to the hypertensive angiotensin II. NEP is responsible for the degradation of the vasodilating peptide ANF. Endothelin converting enzyme (ECE) cleaves the endogenous, inactive big-endothelin to the effective vasoconstrictor endothelin-1, a peptide composed of 21 amino acids. The inhibition of these enzymes is of major therapeutic significance for the treatment of high blood pressure, cardiac insufficiency, renal failure and stroke. BMP-1 (bone morphogenic factor 1) has been recognized to be a metalloprotease which plays a role in converting procollagen into fibrillary collagen. Inhibitors of this enzyme are suitable for the treatment of fibroses and sclerotic processes and can favourably influence scar formation in wound healing (Proc. Natl. Acad. Sci. USA 93, 5127 (1996); Science Vol., 271, 360 (1996)).
Whereas inhibitors of ACE have already been used therapeutically (e.g. captopril, enalapril, (Exp. Opinion Ther. Patents 6, 1147 (1996)), clinically usable active substances for metalloproteases such as NEP and ECE which are free of undesired side-effects and orally available are hitherto unknown. (Literature reviews: NEP: Pharmacol. Reviews 45, 87 (1993); ECE: Bioorg. Med. Chem. Lett. 6, 2317 (1996)) and references cited therein for inhibitors of the phosphoramidone type. There are still no known low-molecular inhibitors of BMP-1.
It has now been found that the claimed new pyrimidine-2,4,6-trione derivatives are very effective as metalloprotease inhibitors with a good oral availability.
Thus the present invention concerns substances of the general formula I,
in which
R1 and R2 can be independently of one another H, alkenyl or alkyl
R3 represents a group W-V in which W represents a bond or a linear or branched alkyl or alkenyl group which can optionally be interrupted by oxygen, sulphur or nitrogen, which can be substituted by hydroxy, amino, mercapto, alkoxy, oxo, carboxy, acyl, alkyl, aralkyl, aryl or heteroaryl groups and V can represent H, a monocyclic or bicyclic, saturated or unsaturated ring which can optionally contain 1 to 4 nitrogen, oxygen or sulphur atoms and can optionally be substituted by a hydroxy, amino, mercapto, alkoxy, oxo, carboxy, acyl, acylamido, alkyl, aralkyl, aryl or heteroaryl groups.
R4 can be a residue —N(R13)—C(O)—R5, —N(R13)—C(O)—OR5, —N(R13)—SO2—R5, —N(R13)—C(S)—R5, —N(R13)—C(S)—OR5, —N(R13)—C(O)—CR14R15(—CR15R17)
n
—C(O)—R5, or —N(R13)—CR14R15(—CR16R17)
n
—C(O)—R18 each of which is bound to the central pyrimidine ring via the nitrogen atom n equals 0 or 1
R13 has the meaning mentioned above for R3 or optionally forms a 4- or 7-membered heterocycle with R14 or R16 and
R5 represents an alkyl, cycloalkyl, aralkyl, aryl or heteroaryl residue wherein these residues can be substituted by hydroxy or amino groups or halogen. R14, R15, R16 and R17 independently of another denote hydrogen, a C&agr; residue of a proteinogenic amino acid, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R14 and R15 or alternatively R16 and
R17 can together form a 3- or 7-membered carbocycle
R18 denotes OH or N(R6R7), wherein
R6 equals H or can be alkyl, cycloalkyl, aralkyl, aryl or heteroaryl and
R7 represents a group which together with the N-atom represents a proteinogenic or non-proteinogenic &agr; or &bgr; amino acid or amino acid amide and additionally R6 and R7 together can form a 4- to 7-membered ring which optionally contains heteroatoms such as oxygen, sulphur or nitrogen, and optionally can be substituted by alkyl, aralkyl, aryl or heteroaryl.
Additionally pharmacologically tolerated salts and esters of the general structure I as well as the use of these compounds to produce pharmaceutical preparations.
R1 and R2 independently of one another are preferably H or methyl, particularly preferably H
R3 preferably represents H, alkyl, cycloalkyl or aryl, heteroaryl, aralkyl or heteroaralkyl. H or C
1
-C
6
alkyl is especially preferred.
R4 is preferably a residue of a proteinogenic or non-proteinogenic &agr; or &bgr; amino acid which is linked to the central pyrimidine ring via the nitrogen atom and whose carboxyl group is either free or linked to Rx or is a group —NH—CO—CHR14—CO—Rx wherein Rx represents hydroxy, alkoxy or the group —N(R6,R7) described above.
R13 is preferably H or alkyl.
R14 and R16 are independently of one another preferably alkyl or cycloalkyl or the C&agr; residue of a proteinogenic amino acid.
R15 and R17 are preferably hydrogen.
n is preferably 0.
A combination of the preferred compounds mentioned above is quite especially preferred.
Alkyl should in all cases be a straight-chained or branched C
1
-C
10
preferably C
1
-C
6
alkyl chain such as e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl. An alkenyl group denotes unsaturated residues with 3-6 C atoms such as e.g. allyl, but-2-enyl, hexa-2,4-dienyl. Cycloalkyl represents a 3-7-membered ring in which a CH2 group can be substituted by O or NH such as among others a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or a cycloheptyl ring, preferably a cyclopenzyl or cyclohexyl ring.
Alkoxy groups denote a combination of an alkyl group according to the above definition with an oxygen atom e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy groups, of which methoxy, ethoxy, isopropoxy and butoxy are preferred.
Aryl groups denote an aromatic carbon residue preferably one with 6-10 C atoms in particular a phenyl or naphthyl group which can in each case be linked to hydroxy or amino which can optionally be substituted by alkyl groups, or to alkyl or alkoxy groups. Heteroaryl groups are aromatic residues that are composed of unsaturated carbon atoms and heteroatoms such as nitrogen, oxygen and sulphur, wherein the sum of the ring atoms can be between 5 and 10. Examples of this are an imidazole, thiazole, triazole, pyridyl, pyrimidyl, pyrazinyl, indolyl and purinyl residue. An imidazolyl, thiazolyl, pyridyl or indolyl residue are preferred. Aralkyl groups denote residues in which one of the previously defined alkyl groups is linked to one of the previously characterized aryl residues, the benzyl residue being preferred in this case. A heteroaralkyl residue represents a combination of one of the alkyl groups defined above with one of the aryl residues described above. A pyridylmethyl, imidazolylmethyl and thiazolylmethyl residue are preferred. If not stated otherwise cycloalkyl, aryl and heteroaryl residues are substituted once to three-times independently of one another by alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, mercapto or thioalkyl.
Acyl residues are straight-chained or branched C
2
-C
10
carbonylalkyls, C
2
-C
6
acyl residues are preferred.
If R6 and R7 together with the nitrogen atom to which they are bound form a ring, then this is a 5-membered to 7-membered ring, preferably a six-membered ring. A piperidine, piperazine, tetrahydroquinoline and tetrahydroisoquinoline, bicyclo(9.4.0)pentadecyl and 1.2.3.4-tetrahydrobenzo(g)isoquinoline ring are particularly preferred.
If R14 and R15 or R16 and R17 form a carbocycle then a 4-, 5- or 6-membered ring is prefer
Grams Frank
Zimmermann Gerd
Arent Fox Plotkin Kintner Kahn PLLC.
Ford John M.
McKenzie Thomas A
Roche Diagnostics GmbH
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