Claims
- 1. A compound of the formula: ##STR5## wherein one of R.sub.1 and R.sub.2 is selected from a 4-pyrimidinyl ring, which ring is optionally substituted with one or two substituents each of which is independently selected from C.sub.1-4 alkyl, halo, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, CH.sub.2 OR.sub.8, NH.sub.2, mono- or di-C.sub.1-6 -alkylamino or N-heterocycly ring selected from pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, and pyrazolidine;
- the other of R.sub.1 and R.sub.2 is selected from an optionally substituted phenyl ring, or naphthyl ring, which ring is substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth- 1 -yl or 5-naphth-2-yl substituent, is halo, nitro, cyano, C(Z)NR.sub.7 R.sub.17, C(Z)OR.sub.23, (CR.sub.10 R.sub.20).sub.n COR.sub.36, SR5, S(O)R5, OR.sub.36, halo-substituted C.sub.1-4 alkyl, C.sub.1-4 alkyl, ZC(Z)R.sub.36, NR.sub.10 C(Z)R.sub.23, or (CR.sub.10 R.sub.20).sub.n NR.sub.10 R.sub.20 and which, for other positions of substitution, is halo, (CR.sub.10 R.sub.20).sub.n nitro, (CR.sub.10 R.sub.20).sub.n cyano, (CR.sub.10 R.sub.20).sub.n C(Z)NR.sub.16 R.sub.26, (CR.sub.10 R.sub.20).sub.n C(Z)OR.sub.18, (CR.sub.10 R.sub.20).sub.n COR.sub.25, (CR.sub.10 R.sub.20).sub.n S(O).sub.m R.sub.8, (CR.sub.10 R.sub.20).sub.n OH, (CR.sub.10 R.sub.20).sub.n OR.sub.25, halo-substituted-C.sub.1-4 alkyl, C.sub.1-4 alkyl, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)R.sub.25, (CR.sub.10 R.sub.20).sub.n NHS(O).sub.m R.sub.6, (CR.sub.10 R.sub.20).sub.n NHS(O).sub.m NR.sub.7 R.sub.17, (CR.sub.10 R.sub.20).sub.n NR.sub.6 S(O).sub.m R.sub.6, (CR.sub.10 R.sub.20).sub.n NR.sub.6 S(O).sub.m 'NR.sub.7 R.sub.17 ; (CR.sub.10 R.sub.20).sub.n ZC(Z)R.sub.18 or (CR.sub.10 R.sub.20).sub.n NR.sub.7 R.sub.17 ;
- n is 0 or an integer of 1 or 2;
- n' is 0 or an integer having a value of 1 to 10;
- m is 0 or an integer of 1 or 2;
- m' is an integer of 1 or 2;
- m" is an integer having a value of 1 to 10;
- R.sub.3 is Q-(Y.sub.1 m).sub.t ;
- Q is an aryl group;
- t is an integer having a value of 1 to 3;
- R.sub.4 is hydrogen, C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkylC.sub.1-10 alkyl, C.sub.5-7 cycloalkenyl, C.sub.5-7 cycloalkenyl-C.sub.1-10 alkyl, aryl, arylC.sub.1-10 alkyl, (CR.sub.10 R.sub.20).sub.n 'OR.sub.12, (CR.sub.10 R.sub.20).sub.n OR.sub.13, (CR.sub.10 R.sub.20).sub.n S(O).sub.m R.sub.18, (CR.sub.10 R.sub.20).sub.n NHS(O).sub.2 R.sub.18, (CR.sub.10 R.sub.20).sub.n NR.sub.16 R.sub.26, (CR.sub.10 R.sub.20).sub.n NO.sub.2, (CR.sub.10 R.sub.20).sub.n CN, (CR.sub.10 R.sub.20).sub.n 'SO.sub.2 R.sub.18, (CR.sub.10 R.sub.20).sub.n S(O).sub.m 'NR.sub.16 R.sub.26, (CR.sub.10 R.sub.20).sub.n C(Z)R.sub.13, (CR.sub.10 R.sub.20).sub.n OC(Z)R.sub.13, (CR.sub.10 R.sub.20).sub.n C(Z)OR.sub.13, (CR.sub.10 R.sub.20).sub.n C(Z)NR.sub.16 R.sub.26, (CR.sub.10 R.sub.20).sub.n C(Z)NR.sub.13 OR.sub.9, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)R.sub.11, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)NR.sub.16 R.sub.26, (CR.sub.10 R.sub.20).sub.n N(OR.sub.6)C(Z)NR.sub.16 R.sub.26, (CR.sub.10 R.sub.20).sub.n N(OR.sub.6)C(Z)R.sub.13, (CR.sub.10 R.sub.20).sub.n C(.dbd.NOR.sub.6)R.sub.13, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(.dbd.NR.sub.19)NR 16R.sub.26, (CR.sub.10 R.sub.20).sub.n OC(Z)NR.sub.16 R.sub.26, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)NR.sub.16 R.sub.26, (CR.sub.10 R.sub.20).sub.n NR.sub.10 C(Z)OR.sub.10, 5-(R.sub.18)-1,2,4-oxadizaol-3-yl or 4-(R.sub.12)-5-(R.sub.18 R.sub.19)-4,5-dihydro-1,2,4-oxadiazol-3-yl; wherein the aryl, arylalkyl, cycloalkyl, and cycloalkyl alkyl, groups may be optionally substituted by halogen, hydroxy, hydroxy C.sub.1-10 alkyl, C.sub.1-10 alkoxy, S(O).sub.m C.sub.1-10 alkyl, C.sub.1-10 alkyl, halosubstituted C.sub.1-10 alkyl, NR.sub.7 R.sub.17, optionally substituted aryl, or optionally substituted arylalkyl, and wherein the optionally substituted aryl or arylalkyl substituents are halogen, hydroxy; hydroxy substituted alkyl; C.sub.1-10 alkoxy; S(O).sub.m alkyl; amino, mono and di-substituted C.sub.1-4 alkyl amino, or halosubstituted alkyl;
- R.sub.6 is C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, aryl, or aryl C.sub.1-10 alkyl;
- R.sub.5 is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl or NR.sub.7 R.sub.17, excluding the moieties --SR.sub.5 being --SNR.sub.7 R.sub.17 and --SOR.sub.5 being --SOH;
- R.sub.16 and R.sub.26 are independently hydrogen, optionally substituted C.sub.1-4 alkyl, optionally substituted aryl, optionally substituted aryl C.sub.1-4 alkyl, or R.sub.16 and R.sub.26 together with the nitrogen to which they are attached form a heterocyclic selected from pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, and pyrazolidine;
- Y.sub.1 is independently selected from hydrogen, C.sub.1-5 alkyl, halo-substituted C.sub.1-5 alkyl, halogen, or --(CR.sub.10 R.sub.20).sub.n Y.sub.2 ;
- Y.sub.2 is hydrogen, halogen, OR.sub.8, NO.sub.2, S(O).sub.m 'R.sub.11, SR.sub.8, S(O).sub.m 'OR.sub.8, S(O).sub.m NR.sub.8 R.sub.9, NR.sub.8 R.sub.9, O(CR.sub.10 R.sub.20).sub.n 'NR.sub.8 R.sub.9, C(O)R.sub.8, CO.sub.2 R.sub.8, CO.sub.2 (CR.sub.10 R.sub.20).sub.m "CONR.sub.8 R.sub.9, ZC(O)R.sub.8, CN, --C(Z)NR.sub.8 R.sub.9, NR.sub.10 C(Z)R.sub.8, C(Z)NR.sub.8 OR.sub.9, NR.sub.10 C(Z)NR8R.sub.9, NR.sub.10 S(O).sub.m 'R.sub.11, N(OR.sub.21)C(Z)NR.sub.8 R.sub.9, N(OR.sub.21)C(Z)R.sub.8, C(.dbd.NOR.sub.21)R.sub.8, NR.sub.10 C(.dbd.NR.sub.15)SR.sub.11, NR.sub.10 C(.dbd.NR.sub.15)NR.sub.8 R.sub.9, NR.sub.10 C(.dbd.CR.sub.14 R.sub.24)SR.sub.11, NR.sub.10 C(.dbd.CR.sub.14 R.sub.24)NR.sub.8 R.sub.9, NR.sub.10 C(O)C(O)NR.sub.8 R.sub.9, NR.sub.10 C(O)C(O)OR.sub.10, C(.dbd.NR.sub.13)NR.sub.8 R.sub.9, C(.dbd.NOR.sub.13)NR.sub.8 R.sub.9, C(.dbd.NR.sub.13)ZR.sub.11, OC(Z)NR.sub.8 R.sub.9, NR.sub.10 S(O).sub.m CF.sub.3, NR.sub.10 C(Z)OR.sub.10, 5-(R.sub.18)-1,2,4-oxadizaol-3-yl or 4-(R.sub.12)-5-(R.sub.18 R.sub.19)-4,5-dihydro-1,2,4-oxadiazol-3-yl;
- R.sub.7 and R.sub.17 is each independently selected from hydrogen or C.sub.1-4 alkyl or R.sub.7 and R.sub.17 together with the nitrogen to which they are attached form a heterocyclic ring selected from pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, and pyrazolidine;
- R.sub.8 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, aryl, or aryl C.sub.1-10 alkyl;
- R.sub.9 is hydrogen, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, arylalkyl, or R.sub.8 and R.sub.9 may together with the nitrogen to which they are attached form a heterocyclic selected from pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, and pyrazolidine;
- R.sub.10 and R.sub.20 is each independently selected from hydrogen or C.sub.1-4 alkyl;
- R.sub.11 is C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, or aryl C.sub.1-10 alkyl;
- R.sub.12 is hydrogen, --C(Z)R.sub.13, optionally substituted C.sub.1-4 alkyl, optionally substituted aryl, optionally substituted aryl-C.sub.1-4 alkyl, or S(O).sub.2 R.sub.18 ;
- R.sub.13 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, aryl, or aryl C.sub.1-10 alkyl;
- R.sub.14 and R.sub.24 is each independently selected from hydrogen, alkyl, nitro or cyano;
- R.sub.15 is hydrogen, cyano, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl;
- R.sub.18 is C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, aryl, or arylC.sub.1-10 alkyl;
- R.sub.19 is hydrogen, cyano, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl;
- R.sub.21 is hydrogen, a pharmaceutically acceptable cation, C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, aryl, or aryl C.sub.1-4 alkyl;
- R.sub.22 is R.sub.10 or C(Z)-C.sub.1-4 alkyl;
- R.sub.23 is C.sub.1-4 alkyl, halo-substituted-C.sub.1-4 alkyl, or C.sub.3-7 cycloalkyl;
- R.sub.25 is C.sub.1-10 alkyl, halo-substituted C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7 cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, aryl C.sub.1-10 alkyl, (CR.sub.10 R.sub.20).sub.n OR.sub.8, (CR.sub.10 R.sub.20).sub.n S(O).sub.m R.sub.18, (CR.sub.10 R.sub.20).sub.n NHS(O).sub.2 R.sub.18, (CR.sub.10 R.sub.20).sub.n NR.sub.7 R.sub.17 ; wherein the aryl, or arylalkyl is optionally substituted by halogen, hydroxy, hydroxy C.sub.1-10 alkyl, C.sub.1-10 alkoxy, S(O)m C.sub.1-10 alkyl, C.sub.1-10 alkyl, halosubstituted C.sub.1-10 alkyl, NR.sub.7 R.sub.17, optionally substituted aryl, or optionally substituted arylalkyl, and wherein the optionally substituted aryl or alkylalkyl substituents are halogen, hydroxy; hydroxy substituted alkyl; C.sub.1-10 alkoxy; S(O).sub.m alkyl; amino, mono and di-substituted C.sub.1-4 alkyl amino, or halosubstituted alkyl;
- R.sub.36 is hydrogen or R.sub.23 ;
- Z is oxygen;
- or a pharmaceutically acceptable salt thereof.
- 2. The compound according to claim 1 wherein the R.sub.1 optional substituent is C.sub.1-4 alkyl, amino, or mono substituted C.sub.1-6 alkyl amino.
- 3. The compound according to claim 1 wherein R.sub.2 is an optionally substituted phenyl.
- 4. The compound according to claim 3 wherein one or more optional substituents are independently selected from halogen or methoxy.
- 5. The compound according to claim 1 wherein R.sub.4 is hydrogen, NR.sub.16 R.sub.26, NR.sub.10 C(Z)R.sub.11, NR.sub.10 C(Z)NR.sub.16 R.sub.26, NR.sub.(10) C(.dbd.NR.sub.19)NR.sub.16 R.sub.26 or NR.sub.10 C(Z)OR.sub.10.
- 6. The compound according to claim 5 wherein R.sub.16 and R.sub.26 are hydrogen, optionally substituted C.sub.1-4 alkyl, or R.sub.16 and R.sub.26 together with the nitrogen to which they are attached form a heterocyclic ring elected from pyrrolidine, piperidine, piperazine, morpholine, imidazolidine, and pyrazolidine.
- 7. The compound according to claim 1 wherein Q is phenyl.
- 8. The compound according to claim 7 wherein the phenyl is substituted by (CR.sub.10 R.sub.20).sub.n Y.sub.2.
- 9. The compound according to claim 8 wherein Y.sub.2 is S(O).sub.m 'R.sub.11, SR.sub.8, halogen, or CO.sub.2 R.sub.8.
- 10. The compound according to claim 8 wherein n is 0 or 1.
- 11. The compound according to claim 8 wherein Y.sub.2 is substituted in the 4-position of the phenyl ring.
- 12. The compound according to claim 4 wherein the substituent is fluoro, substituted in the 4-position of the phenyl ring.
- 13. The compound according to any of claim 1 which is 4-(2-Amino-4-pyrimidinyl)-3-(4-fluorophenyl)-1 -phenylpyrazole.
- 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to claim 1.
- 15. A method of treating arthritis, or other arthritic conditions, in a mammal in need thereof which method comprises administering to said mammal an effective amount of a compound according to claim 1.
- 16. The method according to any of claim 15 wherein the compound is 4-(2-Amino-4-pyrimidinyl)-3-(4-fluorophenyl)-1 -phenylpyrazole.
RELATED INFORMATION
This application is the .sctn.371 national stage entry of PCT/US95/06287, filed May 16, 1995 which is a continuation in part application of U.S. Ser. No. 08/242,906, filed May 16, 1994 (now U.S. Pat. No. 5,559,137) issued Sep. 24, 1996.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
102e Date |
371c Date |
PCT/US95/06287 |
5/16/1995 |
|
|
11/15/1996 |
11/15/1996 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO95/31451 |
11/23/1995 |
|
|
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5051518 |
Murray et al. |
Sep 1991 |
|
Foreign Referenced Citations (3)
Number |
Date |
Country |
9852941 |
Nov 1998 |
WOX |
9852937 |
Nov 1998 |
WOX |
9852940 |
Nov 1998 |
WOX |
Non-Patent Literature Citations (1)
Entry |
Duncan et al., J. Heterocyclic Chem., vol. 24, pp. 555-558 (1987). |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
242906 |
May 1994 |
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