# US 5,348,957 A · 5-hydroxy-2-pyrimidinylmethylene derivatives useful as antiinflammatory agents

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- Number: US 5,348,957 A
- Document ID: US5348957A
- Status: Granted
- Kind: A
- Application number: 08/103,462
- Filed: 1993-08-06
- Granted: 1994-09-20
- Earliest claimed: 1991-09-09
- Assignees: Warner-Lambert Company
- Inventors: Thomas R. Belliotti; David T. Connor; Catherine R. Kostlan
- Web page: https://patentgrep.com/patent/US5348957A

## CPC

- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention compounds are 5-hydroxy-2-pyrimidinylmethylene derivatives and pharmaceutically acceptable addition salts, bases, and base salts thereof, pharmaceutical compositions and methods of use therefor. The invention compounds are found to have activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment of, for example, inflammation and GI ulcers.

## Claims

### Claim 1

A method of treating inflammation in a human in need of such treatment which comprises administering a compound of the formula ##STR26## or a pharmaceutically acceptable acid addition or base salt thereof; wherein
R.sub.1 and R.sub.2 are tertiarybutyl;
R.sub.19 is H;
A is
1) ##STR27## wherein X is S, O, NH, or CH.sub.2 ; and
Y is S, O, or NH;
2) ##STR28## wherein X is as defined above; and
B is
i) SR.sub.7,
ii) SOR.sub.7,
iii) SO.sub.2 R.sub.7,
iv) NR.sub.15 R.sub.16,
v) NHCN,
vi) ##STR29## vii) ##STR30## viii) ##STR31## ix) N(OR.sub.6)R.sub.4, x) N(OH)COR.sub.5,
xi) NR.sub.4 W,
xii) S(CH.sub.2).sub.n CO.sub.2 R.sub.6, or
xiii) NR.sub.7 COR.sub.6
wherein
Z' is S, O, NH, or NCN;
W is CO.sub.2 R.sub.7, ##STR32## n is 1, 2, or 3; m is 1, 2, 3, 4, or 5;
R.sub.15 and R.sub.1 6 are independently H, lower alkyl, aralkyl, or (CH.sub.2).sub.n NR.sub.6 R.sub.7 wherein n is as defined above;
R.sub.3 is H, alkyl, or aryl;
R.sub.4 is H or alkyl;
R.sub.5 is alkyl, aryl, or CF.sub.3 ;
R.sub.6 is H or lower alkyl; and
R.sub.7 is lower alkyl;
3) ##STR33## wherein Z is CH.sub.2, S, O, or NR.sub.8 wherein R.sub.8 is H, lower alkyl, OH, or OMe; or
4) ##STR34## wherein p is 0, 1, or 2;
W.sub.1 is H.sub.2, O, or S;
R.sub.9 is
i) lower alkyl,
ii) lower alkenyl,
iii) SO.sub.2 CH.sub.3,
iv) OR.sub.10,
v) ##STR35## vi) NR.sub.12 R.sub.13, or vii) -(CH.sub.2).sub.n Y.sub.1
wherein
n is as defined above;
R.sub.10 is H, lower alkyl, tosyl, or ##STR36## Y.sub.1 is --CN, --OR.sub.10, SH, SR.sub.7, ##STR37## NR.sub.12 R.sub.13 wherein R.sub.12 and R.sub.13 are as defined herein, wherein
R.sub.7 and R.sub.10 are as defined above;
R.sub.11 is lower alkyl, lower alkoxy, or NH.sub.2
R.sub.14 is -OH, lower alkyl, lower alkoxy, or NH.sub.2
R.sub.12 and R.sub.13 are each independently H, lower alkyl, lower alkenyl, (CH.sub.2).sub.q OH, (CH.sub.2).sub.q NR.sub.17 R.sub.18, or (CH.sub.2).sub.q SR.sub.7, or R.sub.12 and R.sub.13 taken together form a morpholinyl, piperidinyl, piperazinyl, or an N-methyl piperazinyl ring,
wherein
R.sub.7 is as defined above;
q is an integer of 1-6;
R.sub.17 and R.sub.18 are independently lower alkyl, in unit dosage form.

### Claim 2

A method of treating Gl ulcers in a human in need of such treatment which comprises administering a compound of the formula ##STR38## or a pharmaceutically acceptable acid addition or base salt thereof; wherein
R.sub.1 and R.sub.2 are tertiarybutyl;
R.sub.19 is H;
A is
1) ##STR39## wherein X is S, O, NH, or CH.sub.2 ; and
Y is S, O, or NH;
2) ##STR40## wherein X is as defined above; and
B is
i) SR.sub.7,
ii) SOR.sub.7,
iii) SO.sub.2 R.sub.7,
iv) NR.sub.15 R.sub.16,
v) NHCN,
vi) ##STR41## vii) ##STR42## viii) ##STR43## ix) N(OR.sub.6)R.sub.4, x) N(OH)COR.sub.5,
xi) NR.sub.4 W,
xii) S(CH.sub.2).sub.n CO.sub.2 R.sub.6, or
xiii) NR.sub.7 COR.sub.6
wherein
Z' is S, O, NH, or NCN;
W is CO.sub.2 R.sub.7, ##STR44## n is 1, 2, or 3; m is 1, 2, 3, 4, or 5;
R.sub.15 and R.sub.1 6 are independently H, lower alkyl, aralkyl, or (CH.sub.2).sub.n NR.sub.6 R.sub.7
wherein n is as defined above;
R.sub.3 is H, alkyl, or aryl;
R.sub.4 is H or alkyl;
R.sub.5 is alkyl, aryl, or CF.sub.3 ;
R.sub.6 is H or lower alkyl; and
R.sub.7 is lower alkyl;
3) ##STR45## wherein Z is CH.sub.2, S, O, or NR.sub.8 wherein R.sub.8 is H, lower alkyl, OH, or OMe; or
4) ##STR46## wherein p is 0, 1, or 2;
W.sub.1 is H.sub.2, O, or S;
R.sub.9 is
i) lower alkyl,
ii) lower alkenyl,
iii) SO.sub.2 CH.sub.3,
iv) OR.sub.10,
v) ##STR47## vi) NR.sub.12 R.sub.13, or vii) -(CH.sub.2).sub.n Y.sub.1
wherein
n is as defined above;
R.sub.10 is H, lower alkyl, tosyl, or ##STR48## Y.sub.1 is --CN, --OR.sub.10, SH, SR.sub.7, ##STR49## NR.sub.12 R.sub.13 wherein R.sub.12 and R.sub.13 are as defined herein, wherein
R.sub.7 and R.sub.10 are as defined above;
R.sub.11 is lower alkyl, lower alkoxy, or NH.sub.2
R.sub.14 is --OH, lower alkyl, lower alkoxy, or NH.sub.2
R.sub.12 and R.sub.13 are each independently H, lower alkyl, lower alkenyl, (CH.sub.2).sub.q OH, (CH.sub.2).sub.q NR.sub.17 R.sub.18, or (CH.sub.2).sub.q SR.sub.7, or R.sub.12 and R.sub.13 taken together form a morpholinyl, piperidinyl, piperazinyl, or an N-methyl piperazinyl ring,
wherein
R.sub.7 is as defined above;
q is an integer of 1-6;
R.sub.17 and R.sub.18 are independently lower alkyl, in unit dosage form.