Pyrimidine-2,4,6-trione metalloproteinase inhibitors

Details Pyrimidine-2,4,6-trione metalloproteinase inhibitors Pyrimidine-2,4,6-trione metalloproteinase inhibitors

2001-10-25

2004-03-16

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S299000, C544S300000, C544S301000, C544S302000, C544S303000, C544S304000, C544S306000, C544S307000

Reexamination Certificate

active

06706723

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to pyrimidine-2,4,6-trione metalloproteinase inhibitors, and to pharmaceutical compositions and methods of treatment of inflammation, cancer and other disorders.
The compounds of the present invention are inhibitors of zinc metalloendopeptidases, especially those belonging to the class of matrix metalloproteinases (also called MMP or matrixin).
The MMP subfamily of enzymes, currently contains seventeen members (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14, MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP's are most well known for their role in regulating the turn-over of extracellular matrix proteins and as such play important roles in normal physiological processes such as reproduction, development and differentiation. In addition, the MMP's are expressed in many pathological situations in which abnormal connective tissue turnover is occurring. For example, MMP-13 an enzyme with potent activity at degrading type 11 collagen (the principal collagen in cartilage), has been demonstrated to be overexpressed in osteoarthritic cartilage (Mitchel, et al.,
J. Clin. Invest
., 97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also overexpressed in osteoarthritic cartilage and inhibition of some or all of these MMP's is expected to slow or block the accelerated loss of cartilage typical of joint diseases such as osteoarthritis or rheumatoid arthritis.
It is recognized that different combinations of MMP's are expressed in different pathological situations. As such, inhibitors with specific selectivities for individual MMP's may be preferred for individual diseases.
Matrix metalloproteinase inhibitors are well known in the literature. Hydroxamic acid MMP inhibitors are exemplified in European Patent Publication 606,046, published Jul. 13, 1994. Several pyrimidine-2,4,6 trione MMP inhibitors are referred to in PCT publication WO 98/58925, published Dec. 30, 1998. PCT publication WO 00/47565, published Aug. 17, 2000 refers to certain aryl substituted pyrimidine-2,4,6-trione MMP inhibitors. U.S. Non-provisional application Ser. No. 09/635156, filed Aug. 9, 2000 (which claims priority to U.S. Provisional application No. 60/148547 filed Aug. 12, 1999) refers to heteroaryl substituted pyrimidine-2,4,6 trione MMP inhibitors. U.S. Provisional Application entitled “Spiro-Pyrimidine-2,4,6-Trione Metalloproteinase Inhibitors”, filed Oct. 26, 2000, refers to certain 5-spiro pyrimidin-2,4,6-triones. Barbituric acids and methods for their preparation are well known in the art, see for example Goodman and Gilman's, “
The Phamacological Basis of Therapeutics
,” 345-382 (Eighth Edition, McGraw Hill, 1990). Each of the above referenced publications and applications is hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula:
wherein A is optionally substituted (C
6
-C
10
)aryl or (C
2
-C
10
)heteroaryl;
B is optionally substituted (C
6
-C
10
)aryl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)heteroaryl, (C
1
-C
10
)heterocyclic, (C
6
-C
10
)aryl-(C
1
-C
4
)alkyl, (C
3
-C
8
)cycloalkyl-(C
1
-C
4
)alkyl, (C
1
-C
10
)heteroaryl-(C
1
-C
4
)alkyl or (C
1
-C
10
)heterocyclic-(C
1
-C
4
)alkyl; wherein each of the aforesaid (C
3
-C
8
)cycloalky or (C
1
-C
10
)heterocyclic may optionally contain one or two double bonds;
wherein A and B may be independently optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or two substituents independently selected from F, Cl, Br, CN, OH, (C
1
-C
4
)alkyl, (C
1
-C
4
)perfluoroalkyl, (C
1
-C
4
)perfluoroalkoxy, (C
1
-C
4
)alkoxy, and (C
3
-C
8
)cycloalkyloxy;
X is selected from the group consisting of oxygen, >C═O, sulfur, >SO
2
, >S═O, >NR
10
, —CH
2
O—, —OCH
2
—, —CH
2
S—, —CH
2
(S═O)—, —CH
2
SO
2
—, —SCH
2
—, —SOCH
2
—, —SO
2
—CH
2
[N(R
10
)]—, —[N(R
10
)]SO
2
— and —SO
2
[N(R
10
)]—;
Y is selected from the group consisting of a bond, oxygen, sulfur, >C═O, >SO
2
, >S═O, >NR
12
, —CH
2
—, —CH
2
O—, —OCH
2
—, —CH
2
S—, —CH
2
(S═O)—, —CH
2
SO
2
—, —SCH
2
—, —(S═O)CH
2
—, —SO
2
CH
2
—, —[N(R
12
)]CH
2
—, —CH
2
[N(R
12
)]—, —CH
2
CH
2
—, —CH═CH—, —[N(R
12
)]—SO
2
— and —SO
2
[N(R
12
)]—;
R
1
is hydrogen, (R
2
)
2n+1
—(C)
n
— or (C
3
-C
8
)cycloalkyl wherein said (C
3
-C
8
)cycloalkyl may also optionally be substituted by one to two substituents independently selected from halo, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkenyl, (C
1
-C
4
)alkynyl, R
3
—, R
3
—O—, perfluoro(C
1
-C
4
)alkoxy, R
3
—(C
1
-C
4
)alkyl-O—, R
3
—(C═O)—O—, (R
3
)
2
N—(C═O)—O—, —NO
2
, (R
3
)
2
N—, R
3
—(C═O)—(NR
4
)—, R
3
—(SO
2
)—(NR
4
)—, R
3
O—(C═O)—(NR
4
)—, (R
3
)
2
—N—(C═O)—(NR
4
)—, R
3
—S—, R
3
—(S═O)—, R
3
—(SO
2
)—, (R
3
)
2
N—(SO
2
)—, —CN, R
3
—(C═O)—, R
3
—O—(C═O)— and (R
3
)
2
N—(C═O)—;
n is an integer from one to ten;
each R
2
is independently selected from the group consisting of halo, R
3
—, (C
1
-C
4
)alkenyl, (C
1
-C
4
)alkynyl, R
3
—O—, perfluoro(C
1
-C
4
)alkoxy, R
3
—(C═O)—O—, (R
3
)
2
N—(C═O)—O—, —NO
2
, (R
3
)
2
N—, R
3
—(SO
2
)—(NR
4
)—, R
3
—(C═O)—(NR
4
)—, R
3
O—(C═O)—(NR
4
)—, (R
3
)
2
—N—(C═O)—(NR
4
)—, R
3
—S—, R
3
—S═O)—, R
3
—(SO
2
)—, (R
3
)
2
N—(SO
2
)—, —CN, R
3
—(C═O)—, R
3
—O—(C═O)— and (R
3
)
2
N—(C═O)—; wherein not more than three of said R
2
substituents may be other than hydrogen and any one carbon atom of said —(C)
n
— group can contain only one bond to a heteroatom; wherein a carbon atom of any two R
2
groups may be taken together with the carbon atoms to which the R
2
groups are attached to form a four to ten membered ring;
each R
3
is independently selected from the group consisting of hydrogen, (C
1
-C
4
)alkyl, (C
6
-C
10
)aryl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)heteroaryl and (C
1
-C
10
)heterocyclyl; wherein eech R
3
may be optionally substituted on any carbon atom able to support an additional substituent, by one to three substituents per alkyl moiety or by one to three substituents per ring, independently selected from the group consisting of halo, hydroxy, amino, —CN, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkyl-NH—, [(C
1
-C
4
)alkyl]
2
—N—, (C
6
-C
10
)aryl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)heteroaryl and (C
1
-C
10
)heterocyclyl; wherein said (C
3
-C
8
)cycloalkyl and (C
1
-C
10
)heterocyclyl may also optionally be substituted by oxo; wherein said (C
1
-C
10
)heteroaryl and (C
1
-C
10
)heterocyclyl may optionally be substituted on any ring nitrogen atom able to support an additional substituent by one to two substituents per ring independently selected from the group consisting of (C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl-(C═O)—, (C
6
-C
10
)aryl, (C
3
-C
8
)cycloalkyl, (C
1
-C
10
)heteroaryl and (C
1
-C
10
)heterocyclyl;
wherein said R
3
group may optionally be taken together with an R
4
group to form a three to eight membered ring; wherein two of said R
4
groups may be taken together to form a three to eight membered ring;
R
4
wherever it occurs is independently selected from hydrogen and (C
1
-C
4
)alkyl;
G is R
5
— or R
6
—(CHR
13
)
p
—; wherein G is a substituent on any ring carbon atom of B capable of forming an additional bond and is oriented at a position other than alpha to the point of attachment of the B ring to Y;
p is an integer from one to six;
wherein R
5
is selected from the group consisting of R
7
—, R
11
—O—, R
7
—(C
1
-C
4
)alkyl-O—, R
8
—(C═O)—O—, H
2
N(C═O)—O—, R
8
—NH(C═O)—O—, (R
8
)
2
N(C═O)—O—, R
8
—S—, R
8
—(S═O)—, R
8
—(SO
2
)—, H
2
N—(SO
2
)—, R
8
—NH—(SO
2
)—, (R
8
)
2
N—(SO
2
)—, formyl, R
8
—(C═O)—, HO—(C═O)—, R
8
—O—(C═)—, H
2
N—(C═O)—, R
8
NH—(C═O)—, (R
8
)
2
N—(C═O)—, —NO
2
, NH
2
, R
8
—NH—, (R
8
)
2
N—, H(C═O)—(NR
9
)—, R
8
—(C═O)—(NR
9
)—, H
2
N—(C&

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