Pyrimidine-2,4,6-trione derivatives, processes for their...

Details Pyrimidine-2,4,6-trione derivatives, processes for their... Pyrimidine-2,4,6-trione derivatives, processes for their...

2000-09-29

2002-12-24

Ford, John M. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S296000

Reexamination Certificate

active

06498252

ABSTRACT:

FIELD
This invention relates to derivatives of 5,5-disubstituted pyrimidine-2,4,6-triones. These compounds show a marked antitumor and antimetastatic activity.
BACKGROUND
In normal tissue there is an equilibrium between synthesis and degradation. Extracellular matrix is degraded by proteinases which belong to at least three groups of matrix metalloproteinases. These are the collagenases, gelatinases and stromelysins. Normally there are specific inhibitors for these catabolic enzymes such as &agr;
2
macroglobulines and TIMP (=tissue inhibitor of metalloproteinases (MMP)) so that an excessive degradation of extracellular matrix does not occur. Adamalysins are a related group of proteinases. A prominent member of the adamalysins is TACE (TNF-&agr;-converting enzyme).
At least 17 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 and multiple sclerosis, in the formation of tumor metastases, corneal ulceration, inflammatory diseases and invasion and in diseases of bone and teeth.
It can be assumed that the pathogenesis of these clinical pictures can be favourably influenced by the administration of matrix metalloproteinase inhibitors. In the meantime a number of compounds are known from the literature (see e.g. the review article of D. E. Levy, A. M. Ezrin Emerging Drugs 2,205-230 (1997), M. Whittaker, P. Brown, Curr. Opin. Drug Discovery Dev. (1998), 1(2), 157-164. or are described in the patent literature, mainly 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-A-489 577 by Celltech, EP-A-320 118 by Beecham, U.S. Pat. No. 459 5700 by Searle, WO 97/20824 by Agouron Pharmaceuticals, WO 96/15096 by Bayer Corporation among others).
Some of these compounds show a high activity as inhibitors of matrix metalloproteinases but their oral availability is very low. Also such compounds often show broad spectrum inhibition of metalloproteinases which may be associated to undesired side-effects and toxicity.
Pyrimidine-2,4,6-trione derivatives have been described in EP0869947 generically as inhibitors of matrix metalloproteinases. However, there is still a high need for new compounds having low toxicity, no side-effects and a marked inhibitory activity against metallo-proteinases, especially as candidates for a chronic treatment against tumor growth and metastasis.
It has now been found that the claimed pyrimidine-2,4,6-trione derivatives have improved activity as matrix metallo-proteinase inhibitors over the compounds claimed in EP0869947 and also show good oral availability.
BRIEF SUMMARY OF THE INVENTION
The present invention concerns compounds of the formula I
in which
R
1
represents a phenyl, phenoxy , phenylthio, phenylsulfmyl, phenylsulfonyl , phenylamino or phenylmethyl residue, wherein the phenyl moiety is unsubstituted or substituted by one or more halogen atoms, hydroxy, C
1
-C
6
alkoxy, C
1
-C
6
alkyl cyano, or nitro groups, and R
2
represents an unsubstituted or substituted aryl or hetaryl group.
When the phenyl moiety of R
1
is a substituted phenyl moiety, it is preferred that there are one or two substituents in the para and/or meta positions.
The present invention also encompasses pharmaceutically acceptable salts or prodrugs of the compounds of formula I as well as the use of these compounds to produce pharmaceutical agents.
It has now been found that the pyrimidine-2,4,6-trione derivatives of the present invention, have improved activity as matrix metallo-proteinase inhibitors over the compounds claimed in EP0869947 and also show good oral availability.
DETAILED DESCRIPTION OF THE INVENTION
The aryl group of R2 consists of a phenyl ring. The hetaryl group is a cyclic unsaturated or saturated ring system consisting of 5 to 7 ring atoms which can be selected from one or more carbon, nitrogen, oxygen or sulfur atoms. Preferred are electron deficient hetaryl residues such as the nitrogen containing 6 membered rings like pyridines, pyrimidines, pyrazines or 1,3,5-triazines or its N-oxides. Most preferred are the hetaryl residues pyrimidinyl or pyrazinyl.
The aryl or hetaryl rings may be substituted by one or more substituents selected from halogen, hydroxy, alkoxy, amino, dialkylamino, cyano, lower alkyl, lower alkenyl, lower alkinyl, lower acyl, lower alkylthio, lower alkylsulfonyl, lower alkylaminocarbonyl, aminocarbonyl, SO
2
NR
3
R
4
, nitro, lower alkoxycarbonyl, carboxy, wherein R3 and R4, which can be the same or different represent hydrogen; C
1
-C
6
alkyl, straight chained or branched, which can be substituted one or several times by OH, N(CH
3
)
2
or which can be interrupted by oxygen, or represent CO R
5
, wherein R
5
is an alkyl group which can be substituted by NH
2
. Preferred are substitutions in para and/or meta position by one to two of the above listed substituents.
Lower alkyl in residue R
2
as such or in combinations with other residues denotes C
1
-C
6
-alkyl, preferred are methyl, ethyl, propyl, isopropyl or tert.-butyl.
Lower alkenyl denotes C
2
-C
6
alkenyl, preferably allyl or pentadienyl. Lower alkinyl denotes C
2
-C
6
alkinyl, preferably propargyl.
Lower acyl in the residue R
2
above all denotes —C(O)—C
1
-C
6
-alkyl or —C(O)H, preferred for an acetyl group.
The alkyl residues in R
2
, can optionally be interrupted once or several times by heteroatoms (O, S, NH).
Halogen is understood as fluorine, chlorine, bromine, iodine, preferably chlorine or bromine.
If compounds of the formula I contain one or several asymmetric carbon atoms, the optically active compounds of the formula I are also a subject matter of the present invention.
Compounds of the formula I can be synthesized by well-known processes preferably in that compounds of the formula II
in which R
1
has the above-mentioned meaning and T represents a leaving group such as Hal or OSO
2
R
3
Hal denoting chlorine, bromine or iodine and R
3
, denoting an aryl or a methyl residue, are reacted with a compound of the formula III
in which R
2
has the meaning stated above and optionally converted into pharmaceutically acceptable salts.
Compounds of the formula II can be synthesized by analogy to known literature procedures. Thus for example pyrimidine-2,4,6-triones brominated in the 5-position can be synthesized by reacting the appropriate bromomalonic acid dialkyl esters with urea (e.g. Acta Chim. Acad. Sci. Hung. 107 (2), 139 (1981)). The corresponding brominated or chlorinated compounds of the formula II can be obtained by reacting pyrimidine-2,4,6-triones substituted by R
1
-Phenyl in the 5-position with bromine (analogous to J. Prakt. Chemie 136, 329 (1933) or J. Chem. Soc. 1931, 1870) or sulfuryl chloride (J. Chem. Soc. 1938, 1622) or N-bromo-succinimide or similar brominating agents. Such procedures are also described in EP0869947.
Amines of the formula III are commercially available or are usually known in the literature or in analogy to the described methods in the experimental part.
Pyrimidine-2,4,6-triones of formula II with T representing hydrogen

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