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US 6,441,005 B1Granted
Oxazolidinone compounds and compositions, and methods of using the same
AssigneePharmacia & Upjohn Company
InventorsMikhail F. Gordeev, Gary W. Luehr, Dinesh V. Patel, Robert C. Gadwood
Life of this patent
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Abstract
Oxazolidinones and methods for their synthesis are provided. Further provided are methods of making biologically active oxazolidinones as well as pharmaceutically acceptable compositions comprising the oxazolidinones. Oxazolidinones as disclosed herein can be readily synthesized and used in a variety of applications including use as antimicrobial agents. In one embodiment, a variety of thioamidomethyloxazolidinones and methods for their synthesis and use are provided.
Claims60
A compound of formula 1:
- wherein:
- R6 is thioacyl, aminothiocarbonyl, alkoxythiocarbonyl, alkylthio(carbonyl), or alkylthio(thiocarbonyl);
- R7 is aryl or monocyclic heteroaryl;
- R8 is C4-C7 alkyl, C2-C7 alkynyl, O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, NRCONR′, NRC(═S)NR′, or (CH2)nO, wherein n=2-6, and wherein R and R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- and
- R9 is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, or heteroaryl, and wherein R″ and R′″ are independently H, alkyl, heteroalkyl, aryl or heteroaryl,
- with the proviso that when R7 is aryl, R6 is different from alkylthio(carbonyl).
4 more elements
A compound of formula 3:
- wherein:
- R7 is aryl or monocyclic heteroaryl;
- R8 is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 allynyl, NR, O, S, C(═O)NR, NRC(═O), C(═O), C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO2, SO2NR, NRSO2, NRCONR′, NRC(═S)NR′, or (CH2)nO, wherein n=2-6, and wherein each R and R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- R9 is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, or heteroaryl, and wherein each R″ and R′″ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- and
- R10 (is heteroalkyl, aryl, heteroaryl, or C1-4 alkyl substituted with one or more NO2.
3 more elements
A compound of formula 6:
- wherein:
- R7 is aryl or monocyclic heteroaryl;
- R8 is C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, NR, O, S, C(═O)NR, NRC(═O), C(═O), C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO2, SO2NR, NRSO2, NRCONR′, NRC(═S)NR′, or (CH2)nO, wherein n=2-6, and wherein R and R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- R9 is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, or heteroaryl, and wherein R″ and R′″ are independently H, allyl, heteroalkyl, aryl or heteroaryl;
- R10 and R11 are independently aryl or heteroaryl.
2 more elements
A compound of formula 7:
- wherein.
- R7 is aryl or monocyclic heteroaryl;
- R8 is C2-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, NR, O, S, C(═O)NR, NRC(═O), C(═O), C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO2, SO2NR, NRSO2, NRCONR′, NRC(═S)NR′, or (CH2)nO, wherein n=2-6, and wherein R and R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- R9 is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, or heteroaryl, and wherein R″ and R′″ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- and
- R10 is heteroalkyl, aryl or heteroaryl.
3 more elements
A compound of the structure 1b:
- wherein:
- R2 and R4 are, independently, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group;
- R6 is thioacyl, aminothiocarbonyl, alkoxythiocarbonyl, or alkylthio(thiocarbonyl);
- and
- R1 is:
- C(O)NR7R8, C(S)NR7R8, OC(O)NR7R8, OC(S)NR7R8, NR7C(O)NR7R8, NR7C(S)NR7R8, C(O)OR7, C(O)R7, S(O)2R7, or S(O)R7, wherein R7 and R8 are, independently, C5-12alkyl, heteroalkyl, aryl or heteroaryl;
- SR12, wherein R12 is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl;
- NR13R14 or CH2NR13R14, wherein R13 is hydrogen, acyl, methylsulfonyl, alkyl, heteroalkyl, aryl or heteroaryl,and R14 is acyl, methylsulfonyl, C5-12alkyl, heteroalkyl, aryl or heteroaryl;
- NR30C(O)R31 or NR30(SO2)R31, wherein R30 is hydrogen, alkyl, heteroalkyl, aryl, or heteroaryl, and R31 is hydrogen, C5-12alkyl, heteroalkyl, aryl, or heteroaryl;
- 2-oxazolyl comprising R15 at the 4-position and R16 at the 5-position of the oxazolyl, wherein R15 and R16 are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group;
- 2-aminothiazolyl comprising R17 at the 4-position and R18 at the 5-position of the thiazole, wherein R17 and R18, are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group;
- and
- 2-(1,3,4-thiadiazolyl) comprising R21 at the 5-position of the 1,3,4-thiadiazole, wherein R21 is hydrogen, alkyl, heteroalkyl, amino(C1-4 alkyl), acylamino(C1-4 alkyl), thioacylamino(C1-4 alkyl), sulfonamido(C1-4 alkyl), heterocarbonylamino(C1-4 alkyl), aryl, heteroaryl, an electron withdrawing group, or NR22R23, wherein R22 and R23 are, independently, acyl, thioacyl, methylsulfonyl, heteroalkyl, aryl or heteroaryl;
- CH═CHR24 or C≡CR24, wherein R24 is C(O)NR7R8, C(S)NR7R8, OC(O)NR7R8, OC(S)NR7R8, NR7C(O)NR7R8, NR7C(S)NR7R8, C(O)OR10, C(O)R11, SR12, S(O)2R12, S(O)R12, NR13R14, CH2NR13R14, alkyl, aryl, or heteroaryl;
- or
- 5,6-dihydro-1,4,2-dioxazine-3-yl, wherein R25 is at the 5-position of dioxazine, and R26 is at the 6-position of dioxazine, and wherein R25 and R26, are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group;
- wherein optionally R1 and R2 together are a quinolone heterocycle C(═O)C(COOH)═CHNR27, or R1 and R2 together are a benzotriazole heterocycle NNNR27, or NN(R27)N, wherein R27 is alkyl, aryl, or heteroaryl,
- with the proviso that when R1 is 2-(1,3,4-thiadiazolyl) and R21 is hydrogen, alkyl, heteroalkyl, amino(C1-4 alkyl), acylamino(C1-4 alkyl), sulfonamido(C1-4 alkyl), an electron withdrawing group, or NR22R23, then R2 and R4 are different from hydrogen or an electron withdrawing group.
15 more elements
A compound selected from the group consisting of:
A compound of formula 3c:
- wherein:
- R2 and R4 are, independently, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group;
- R6 is thioacyl, aminothiocarbonyl, alkoxythiocarbonyl, or alkylthio(thiocarbonyl);
- R8 is C4-C7 alkyl, C2-C7 alkynyl, O, C(═S)NR, NRC(═S), C(═S)O, OC(═O), OC(═S), NRCONR′, NRCSNR′, or (CH2)nO, wherein n=2-6, and wherein R and R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- and
- R9 is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, or heteroaryl, and wherein R″ and R′″ are independently H, alkyl, heteroalkyl, aryl or heteroaryl.
3 more elements
A compound selected from the group consisting of
A compound selected from the group consisting of
A compound of formula 5c:
- wherein:
- R2 and R4 are, independently, hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawing group;
- R6 is thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl, alkoxythiocarbonyl, alkylthio(carbonyl), or alkylthio(thiocarbonyl);
- R8 is C1-C7 alkyl, C1-C7 alkenyl, C1-C7 alkynyl, NR, O, S, C(═O)NR, C(═S)NR, NRC(═O), NRC(═S), C(═O), C(═O)O, C(═S)O, OC(═O), OC(═S), S(═O), SO2, SO2NR, NRSO2, NRCONR′, NRCSNR′, or (CH2)nO, wherein n=0-6, and wherein R and R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- and
- Het2 is a heterocyclic group.
3 more elements
A compound of formula 1:
- wherein:
- R6 is thioacyl, aminothiocarbonyl, alkoxythiocarbonyl, alkylthio(carbonyl), or alkylthio(thiocarbonyl);
- R7 is monocyclic heteroaryl;
- R8 is C4-C7 alkyl, C2-C7 alkynyl, O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, NRCONR′, NRC(═S)NR′, or (CH2)nO, wherein n=2-6, and wherein R and R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;
- and
- R9 is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, or heteroaryl, and wherein R″ and R′″ are independently H, alkyl, heteroalkyl, aryl or heteroaryl.
3 more elements
Dependencies are inferred from the claim text.