Barbituric acid derivatives

Details Barbituric acid derivatives Barbituric acid derivatives

2002-02-25

2004-04-06

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S270000, C544S295000, C544S296000, C544S300000, C544S301000

Reexamination Certificate

active

06716845

ABSTRACT:

SUMMARY OF THE INVENTION
This invention relates to new derivatives of 5,5-disubstituted pyrimidine-2,4,6-triones of formula I (below). These compounds show a marked antitumor and antimetastatic activity.
BACKGROUND OF THE INVENTION
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., et al., Critical Rev. Oral Biol. Med. 4 (1993) 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 manifestation 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.
The pathogenesis of the foregoing clinical manifestations can be ameliorated by the administration of matrix metalloproteinase inhibitors. A number of such compounds are known (see e.g. the review article of Levy, D. E., Ezrin, A. M., Emerging Drugs 2 (1997) 205-230; Whittaker, M., Brown, P., Curr. Opin. Drug Discovery Dev. 1 (1998) 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 92/09563 by Glycomed, EP-A 0 497 192 by Hoffinann-La Roche, WO 90/05719 by British Biotechnology, EP-A 0 489 577 by Celltech, EP-A 0 320 118 by Beecham, U.S. Pat. No. 4,595,700 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 EP 0 869 947 (WO 97/23465) as inhibitors of matrix metalloproteinases. However, there is still a need for new compounds having reduced toxicity and side-effects and a marked inhibitory activity against metalloproteinases, especially as candidates for a chronic treatment against tumor growth and metastasis.
It has now been found that the new pyrimidine-2,4,6-trione derivatives of the present invention have improved activity as matrix metalloproteinase inhibitors as compared to the compounds disclosed in EP 0 869 947.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to compounds of formula I
wherein
R
1
is selected from the group consisting of a phenyl, phenoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, phenylamino or phenylmethyl residue in which the phenyl moiety optionally may be substituted by one or more halogen atoms, alkoxy, C
1
-C
6
alkyl, cyano, or nitro groups, preferred are substitutions in para and/or meta position by one to two substituents;
R
2
is hydrogen;
R
3
is selected from the group consisting of hydrogen and lower alkyl, said lower alkyl optionally being interrupted by one or more O, N or S atoms and optionally and independently from each other may be substituted by one or more hydroxyl and oxo groups; and
R
4
is selected from the group consisting of lower alkyl that optionally may be interrupted by one or more O, N or S atoms and independently from each other may be substituted by one or more hydroxyl, oxo, aryl, aralkyl, heteroaryl or acyl groups; or alternatively,
R
2
and R
3
or R
3
and R
4
together with the nitrogen atom to which they are bound may form a piperazine ring that optionally may be substituted at the second nitrogen atom by an aryl, aralkyl or a heteroaryl group.
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 compositions.
The aryl group option for R
4
and the piperazine ring resulting from the fusion of R
3
and R
4
consists of a phenyl ring. The heteroaryl group is understood as a cyclic unsaturated 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 heteroaryl residues such as the nitrogen containing 6-membered rings like pyridines, pyrimidines, pyrazines or 1,3,5-triazines. Most preferred heteroaryl residues are pyrimidinyl or pyrazinyl.
The aryl, alone or as part of an aralkyl group or heteroaryl rings may be substituted by one or more substituents selected from halogen, hydroxy, alkoxy, amino, dialkylamino, cyano, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkinyl, lower acyl, C
1
-C
6
alkylthio C
1
-C
6
alkylsulfonyl, C
1
-C
6
alkylaminocarbonyl, aminocarbonyl, C
1
-C
6
alkylamidosulfonyl, amidosulfonyl, nitro, C
1
-C
6
alkoxycarbonyl, and carboxy. Preferred substitutions are in the para and/or meta positions and preferred substituents are selected from one or two of the above listed substituents.
The aralkyl group is preferably benzyl.
Lower alkyl as used in the definition of R
3
and R
4
or when used in combinations with other residues denotes C
1
-C
6
-alkyl. Preferred lower alkyls are methyl, ethyl, propyl, isopropyl or tert.-butyl.
Preferred R
3
and R
4
groups are independently selected from the lower alkyl groups that are interrupted by O, N or S, most preferably —CH
2
—CH
2
—O—CH
2
—CH
2
—OH—CH
2
—CH(OH)—CH
2
—O—CH
2
—CH
3
; 2-oxo-[1,3]dioxolan-4-ylmethyl; —CH
2
—CH(OH)—CH
2
OH; —CH
2
—CH(OH)—CH
2
—O—CH
3
and CH
2
—CH
2 OH.
Acyl as used in the definition of R
4
denotes CO—(C
1
-C
6
)alkyl; —C(O)—(C
1
-C
6
)-alkylen-COOH; —CO-aryl; —CO-aralkyl or —CO-heteroaryl.
Aryl and heteroaryl as used in R
4
have the same definitions given above.
Halogen means fluorine, chlorine, bromine and 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 processes known to those skilled in the art. Preferably compounds of formula I are prepared by reacting a compound of formula II
wherein R
1
is as defined above and T represents a leaving group such as Hal or OSO
2
R
10
, Hal is chlorine, bromine or iodine, and R
10
is an aryl or a methyl residue,
with a compound of formula III
wherein R
2
, R
3
and R
4
are as defined above.
Compounds of formula I may then optionally be converted into pharmaceutically acceptable salts by conventional means known to one skilled in the art.
Compounds of the formula II can be synthesized by analogy to known literature procedures. 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) (1981) 139). The corresponding brominated or chlorinated compounds of the form

Affiliated with

Also associated with

Rating

Barbituric acid derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Barbituric acid derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Barbituric acid derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3196145