MXPA99011069A - Oxazolidinone antibacterial agents having a thiocarbonyl functionality - Google Patents

Oxazolidinone antibacterial agents having a thiocarbonyl functionality

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Publication number
MXPA99011069A
MXPA99011069A MXPA/A/1999/011069A MX9911069A MXPA99011069A MX PA99011069 A MXPA99011069 A MX PA99011069A MX 9911069 A MX9911069 A MX 9911069A MX PA99011069 A MXPA99011069 A MX PA99011069A
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MX
Mexico
Prior art keywords
alkyl
phenyl
optionally substituted
oxo
oxazolidinyl
Prior art date
Application number
MXPA/A/1999/011069A
Other languages
Spanish (es)
Inventor
B Hester Jackson
George Nidy Eldon
Charles Perricone Salvatore
Poel Tonijo
Original Assignee
Hester Jackson B Jr
George Nidy Eldon
Charles Perricone Salvatore
Pharmacia & Upjohn Company
Poel Tonijo
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Publication date
Application filed by Hester Jackson B Jr, George Nidy Eldon, Charles Perricone Salvatore, Pharmacia & Upjohn Company, Poel Tonijo filed Critical Hester Jackson B Jr
Publication of MXPA99011069A publication Critical patent/MXPA99011069A/en

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Abstract

The present invention provides compounds of Formula (I) or pharmaceutical acceptable salts thereof wherein A, G and R1 are as defined in the claims which are antibacterial agents.

Description

OXAZO IDINONE ANTIBACTERIAL AGENTS THAT HAVE A TIOCARBONIL FUNCTIONALITY BACKGROUND OF THE INVENTION The present invention relates to novel and useful oxazolidinone compounds and their preparations, and more particularly to oxazolidinone compounds in which the carbonyl functionality of -NH-C (0) -R is converted to a thiocarbonyl functionality, such as, for example, a thiourea -NH-C (S) -NH2, an alkyl thiourea -NH-C (S) -NH- (C? _ alkyl), thioamide -NH-C (S) - (alkyl) of C? -4) or -NH-C (S) -H. The replacement of the oxygen atom with a sulfur atom has unexpectedly improved antimicrobial properties of the compounds. The compounds are useful antimicrobial agents, effective against various human and veterinary pathogens, including Gram positive aerobic bacteria such as for example staphylococci and multiple resistance streptococci, Gram negative organisms such as for example H. influen za ey M. ca tar rah lis, as well as anaerobic organisms such as for example, bacteroides and clostridia species, and acid-fast organisms such as for example Mycobacterium tuberculosis and Mycobacterium avium. The compounds are particularly useful because they are effective against the most recent organisms known to be responsible for infection in people with AIDS. BRIEF DESCRIPTION OF THE INVENTION In one aspect, the object of the invention is a compound of Formula I I or acceptable pharmaceutical salts thereof where: G is Ri is a) H, b) NH2, c) NH-C4 alkyl, d) C1-4 alkyl, e) alkyl of -OC? _4, f) -S alkyl of C? -, g) alkyl of C? _4 substituted with 1-3 F, 1-2 Cl, CN or alkyl of -COOC? _4, h) Cycloalkyl of C3_6 / i) N (C? -) alkyl 2 j) N ^ CH2) 2.5; A is d) a heteroaromatic entity of members having one to three atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic entity is attached by a carbon atom, wherein the heteroaromatic entity of 5 members may additionally have a ring fused in benzene or naphthyl, wherein the heteroaromatic entity is optionally substituted with one to three R 8 e) a 6-membered heteroaromatic entity having at least one nitrogen atom, wherein the heteroaromatic entity is attached by a carbon atom, wherein the 6-membered heteroaromatic entity may additionally have a ring fused to benzene or naphthyl, wherein the heteroaromatic entity is optionally substituted with one to three R55, f) a β-carbolin-3-yl, or indolizinyl through the 6-membered ring, optionally substituted with one to three R55, wherein R2 is a) H, b) F, c) Cl, d) Br, e) alkyl of C? -3, f) N02, og) R2 and R3 taken together are -0- (CH2) h-0 -; R3 is a) -S (= 0)? R4, b) -S (= 0) 2-N = S (0) jR5R6r c) -SC (= 0) R, d) -C (= 0) R8, e) -C (= 0) R9, f ) -C (= O) NR10Rn, g) -C (= NR12) R3, h) -C (R8) (Rp) -OR13, i) -C (R9) (R ??) - OR? 3, j ) -C (R8) (Rn) -OC (= 0) R13, k) -C (R9) (Rn) -OC (= 0) R13, 1) -NRirjRn, m) -N (R10) -C ( = 0) R7, o) -C (OR? 4) (OR15) R8, p) -C (R8) (R) -NR10R11, or q) Cl-8 alkyl substituted with one or more = 0 other than those of the alpha position, -S (= 0) iR? 7, -NRirjRn, C2_5 alkenyl, or C2-s alkynyl; R4 is a) C 1 alkyl optionally substituted with one or more haloes, OH, CN, NRioRn, or -C02R? 3, b) C2_4 alkenyl, d) -N3, e) -NHC (= 0) R7, f) -NR20C (= O) R7, g) -N (R19) 2, h) -NR16Ri9, oi) -NR19R20, R5 and R6 in each case are the same or different and are a) C? _2 alkyl, or ) R5 and e taken together are - (CH2) k-; R7 is C4-4 alkyl optionally substituted with one or more haloes; Rs is a) H, or b) Ci-s alkyl optionally substituted with one or more haloes, or C3-8 cycloalkyl; R9 is C4-4alkyl substituted with one or more a) -S (= 0) Ri7, b) -OR13, c) -OC (= 0) R13, d) -NRioRn, or e) alkenyl of C? 1_-5 optionally substituted with CHO; Rio and Rn in each case are the same or different and are a) H, b) C 4 alkyl, or c) C 3 8 cycloalkyl; R 2 is a) -NRioRn, b) -OR10; or c) -NHC (= O) R10; Ri3 is a) H, or b) C1-4 alkyl; R14 and R15 in each case are the same or different and are C? -4 alkyl, or R? and Ris taken together are - (CH)? -; R? < is H, C? - alkyl, or C3_8 cycloalkyl; R17 is C4_4 alkyl, or C3-8 cycloalkyl, H, C 1 - alkyl, C 2-4 alkenyl, C 3-4 cycloalkyl, -OR 3 or -NR 21 R 22; R? < is a) Cl, b) Br, or c) I; R2o is a physiologically acceptable cation; R21 and R22 in each case are the same or different and are a) H, b) C? _ Alkyl, or -NR2iR22 taken together are - (CH2) wherein R23 and R2 < in each case they are the same and are a) H, b) F, c) Cl, d) alkyl of C? -2, e) CN f) OH, g) alkoxy of C? _2, h) nitro, oi) Not me; . What is it w- and ^ C d) * & M e) '- ) j) OT * 1) m) a dianyl group optionally substituted with X and Y, n) a triacynyl group optionally substituted with X and Y, or) a quinolinyl group optionally substituted with X and Y, p) a quinoxalinyl group optionally substituted with X and Y, q) a group na ft to go idinyl optionally substituted with X and Y, u 107 v) y) And I Q and R24 taken together are wherein Z1 is a) -CH2-, b) -CH (R104) -CH2-, c) -C (0) -, or d) -CH2CH2CH2-; wherein Z 'is a) -o2s-, b) -o-, c) -N (R107) -, d) -OS-, or e) -S-; wherein Z3 is a) -o2s-, b) -o-, c) -OS-, or d) -S-; wherein A1 is a) H-, or b) CH3; where A is a) H-, b) HO-, c) CH3-, d) CH30-. e) R102O-CH2-C (0) -NH-f) R103O-C (0) -NH-, g) (C? C2) alkyl-OC (0) -, h) H0-CH2-, i) CH3O -NH-, j) (C1-C3) alkylo-02C-k) CH3-C (0) -, 1) CH3-C (0) -CH2-, m) 0 0 Overtures together are b) or = R "4 \ c) N: wherein R102 is a H-, b) CH3-, c) phenyl-CH2-, or d) CH3C (O) -; wherein R103 is a) (C1-C3) alkyl-, or b) phenyl- wherein R104 is a) H-, or b) H0-; wherein R 105 is a) H-, b) (C1-C3) alkyl-, c) CH2 = CH-CH2-, or d) CH3-0- (CH2) 2-; wherein R 106 is a) CH3-C (0) -, b) H-C (O) -, c) C12CH-C (0) -, d) HOCH2-C (0) -, CH3S02-, F2CHC (O) -, h) N ^ N-C0O) - i) H3C-C (O) -O-CH2-C (O) -, j) H-C (O) -0-CH2-C (0) -, ) C C { 0) - 1) CH = C-CH20-CH2-C (O) -, or m) phenyl-CH2-0-CH2-C (O) -; wherein R107 is a) R10 O-C (R110) (R111) -C (O) -, b) R103O-C (O) -, c) R108-C (O) -, e) & f) H3C-C (0) - (CH2) 2-C (0) -, g) R109-SO2-, i) H0-CH2-C (0) -, j) R116- (CH2) 2-, k) R113-C (0) -0-CH2-C (O) -, 1) (CH3) 2N-CH2- C (0) -NH-, m) NC-CH2-, on) F2-CH-CH2-; R 108 is a) H-, b) (C? -C) alkyl, c) aryl- (CH2) P, d) CIH? C-, f) FH2C-, g) F2HC-, oh) (C3-C6) cycloalkyl; wherein R 109 is a -CH3, b -CH2C1 c-CH CH == CH2, d aryl, or e -CH2CH; wherein R 110 and R111 are independently H-, b CH 3 -; or wherein R 112 is a H-, b CH30-CH20-CH2-, or c H0HC2-; wherein R 113 is a CH3-, bH0CH2-, c (CH3) 2-f enyl, or d (CH3) 2N-CH2-; where R 114 is a HO-, b CH30-, c H N-, d CH30-C (O) -O-, and CH3-C (0) -0-CH2-C (0) -0-, f phenyl-CH2-0-CH2-C (0) -0-, g) HO- (CH2) 2-0-, h) CH30-CH2-0- (CH2) 2-0-, oi) CH30-CH2- 0-, wherein R 113 is a) CH3-, b) HOCH2-, c) (CH3) 2N-phenyl, or d) (CH3) 2N-CH2-, wherein R115 is a) H-, or b) C1-; wherein R116 is a) HO- b) CH30-, or B is an unsaturated 4-atom binder having one nitrogen and three carbons; M is a) H, b) C? _8 alkyl, c) C3_8 cycloalkyl, d) - (CH2) mOR13, or e) - (CH2) h-NR2? R22; Z is a) O, b) S, or c) NM; W is a) CH, b) N, or c) S u 0 when Z is NM; Y is a) H, b) F, c) Cl, d) Br, e) C 1-3 alkyl, 0 f) N 0 2; X is a) H, b) -CN, c) OR2, d) halo, e) N02, f) tetrazoyl, g) -SH, h) -S (= 0) iR4, i) -S (= 0) 2-N = S (0) jRsRe j) -SC (= 0) R7, k) -C = 0) R25, 1) "-C (-0) NR27R28, m) -C (= NR29) R25, n ) -C (R25) (R28) -OR13, o) -C (R25) (R28) -OC (= 0) R13, P) -C (R28) (0RX3) - (CH2) h-NR27R28, q) -NR27R28r r) -N (R27) C (= 0) R7, s) -N (R27) -S (= 0) ± R7, t) -C (0R? 4) (OR? 5) R28, u) -C (R25) (R) -NR27R26, ov) C? _8 alkyl substituted with one or more haloes, OH, = 0 other than in the alpha position, S (= 0) iRi7, -NR27R28, C2_5 alkenyl, C2-5 alkynyl, or C3_8 cycloalkyl; R4, R5, Re, R, R13 Ri4 Ri d r i6 and R17 are the same as defined above; R25 is a) H, b) Ci-β alkyl optionally substituted with one or more haloes, C3_s cycloalkyl, alkyl substituted with one or more of -S (= 0) iRi7, -OR13, or 0C (= 0) R ? 3, NR27R28, oc) C2-5 alkenyl optionally substituted with CHO, or C02R? 3; R26 is a) R28, or b) NR27N28; R27 and R28 in each case are the same or different and are a) H, b) C? _8 alkyl, c) C3_8 cycloalkyl, d) - (CH2) m0R? 3, e) - (CH2) h-NR21R22 , of) R27 and R28 taken together are - (CH2) 20 (CH2) 2-, - (CH2) hCH (C0R7) -, or - (CH2) 2N (CH2) 2 (R7); R29 is a) -NR27R28, b) -OR27, or c) -NHC (= 0) R28; wherein R3o is a) H, b) Ci-g alkyl optionally substituted with one or more haloes, or c) C8-8 alkyl optionally substituted with one or more OH, or C6-alkoxy; wherein E is a) NR39, b) -S (= 0) i, or c) O; R38 is a) H, b) C6_6 alkyl, c) - (CH2) q-aryl, or d) halo; R39 is a) H, b) C6-6 alkyl optionally substituted with one or more OH, halo, or -CN, c) - (CH2) q-aryl d) -CO2R40, e) -COR4 ?, f) -C (= 0) - (CH2) qC (= O) R40, g) -S (= 0) 2-alkyl of C? _6, h) -S (= 0) 2- (CH2) q-aryl, oi) - (C = 0) j-Het; R40 is a) H, b) C6_6 alkyl optionally substituted with one or more OH, halo, or -CN, c) - (CH2) q-aryl, or d) - (CH2) q-0R42; R4? is _ a) C ?_6 alkyl optionally substituted with one or more OH, halo, or -CN, b) - (CH2) q-aryl, or c) - (CH2) q-0R42; R42 is a) H, b) C6_6 alkyl, c) - (CH2) q-aryl, or d) -C (= 0) -C6 alkyl -6; aryl is a) phenyl, b) pyridyl, or c) naphthyl; from a to c optionally substituted with one or more halo, -CN, OH, SH, C? -6 alkyl, C? -6 alkoxy, or C? _6 alkylthio; wherein R43 is a) H, b) Cl-2 alkyl, c) F, or d) OH; R 4 is a) H, b) CF 3, c) C 1 -C 3 alkyl optionally substituted with one or more halo. d) phenyl optionally substituted with one or more halo, e) R44 and R45 taken together are a ring of 5-, 6-, or 7 members of the formula, f) R44 and R45 taken together are ~ (CH2) k-, when R46 is an electronic withdrawal group; R 45 and R 6 in each case are the same or different and are a) an electronic removal group, b) H, c) CF 3, d) C 1-3 alkyl optionally substituted with a halo, e) phenyl, with the proviso that that at least one of R45 or R46 is an electronic withdrawal group, of) R45 and R4e taken together are a ring of 5-, 6-, or members of the formula U is a) CH2, b) O, OR S, or d) NR47; R47 is a) H, or b) C? _5 alkyl; where R48 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, ff)) CF3, g) -NO2, h) C6-6 alkoxy, i) C6-6 alkoxycarbonyl, alkylthio of C? _6, kk)) acyl of C? _6, 1) -NR49 R50,) C? _6 alkyl optionally substituted with OH, C? _5 alkoxy, C? _5 acyl, or -NR49R50, n) optionally substituted C2_8 alkenylphenyl with one or two R51, or) phenyl optionally substituted with one or two R51, p) a saturated or unsaturated 5 or 6 member heterocyclic entity having from one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R51, or R49 and R50 in each case are the same or different and are a) H, b) C4_4 alkyl / c) C5_6 cycloalkyl, or d) R49 and R50 taken together with the nitrogen atom is a saturated heterocyclic 5, 6 members optionally having an additional heteroatom selected from the group consisting of S, N, and O, and in turn may optionally be substituted, including at the additional nitrogen atom, C1-3 alkyl, or C1-6 acyl 3; R51 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3 g) -NO2, h) C6-6 alkoxy, i) C6-6 alkoxycarbonyl, ) alkylthio of C? -6, k) acyl of Ci-e, 1) C? -6 alkyl optionally substituted with OH, C1-5 alkoxy, C? 5 acyl, or -NR49R50.-m) phenyl, n) -C (= 0) NR52 R53, O) -NR49R50, p) ~ N (R52) (-SO2R54), q) -S02-NR52R53, or) -S (= 0) → R54; Rd2 and R53 in each case are the same or different and are a) H, b) C? _6 alkyl, or c) phenyl; R 5 is a) C alquilo _ alkyl, or b) phenyl optionally substituted with C? _4 alkyl; wherein R55 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) -NC-2, h) C6-6 alkoxy, i) C6 alkoxycarbonyl 6 j) alkylthio of C? -6 k) acyl of Ci-g, 1) -NR56 R57, m) C? _6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or - R56R57 , n) C2_8 alkenyl phenyl optionally substituted with one or two R58, o) phenyl optionally substituted with one or two R58, p) a 5- or 6-membered unsaturated heterocyclic entity having from one to three carbon atoms selected from the group which consists of S, N, and O, optionally substituted with one to two Rs8, or 56 and 57 in each case are the same different and are a) H, b) formyl, c) C 4 alkyl, d) C 1 acyl, e) phenyl, f) C 3-6 cycloalkyl, o) R56 and R57 taken together with the nitrogen atom is a 5-6 membered saturated heterocyclic entity which optionally has an additional heteroatom selected from the group consisting of S, N and O, and may in turn be optionally substituted with, including on the additional nitrogen, phenyl, pyrimidyl, C1-3alkyl, or C? -3 acyl; R5s is a) carboxyl, b) halo, e) -CN, d) mercapto, e) formyl, f) CF3, g) -NO2, h) C alkoxy? -e, i) C6-6 alkoxycarbonyl, j) C6-6 alkylthio, k) C6_6 acyl, 1) phenyl, m) C6_6 alkyl optionally substituted with OH, azido, alkoxy, C? _5, acyl of C? _5, -NR55Rd6, -SR67, -0-S02R68, or n) -C (= 0) NR59 Reo, o) -NR56R57, _ p) -N (R59) (-S02R54), q) -S02-NR59R6o, r) -S (= 0) iR54, s) -CH = N-R61, ot) -CH (OH) -S03R64; R54 is the same as defined above; R59 and Reo in each case are the same or different and are a) H, b) Ci.-e alkyl, c) phenyl, or d) tolyl; Re is a) OH, b) benzyloxy, c) -NH-C (= 0) -NH2, d) -NH-C (= S) -NH2, or e) -NH-C (= NH) -NR62R63; R 2 and Rd 3 in each case are the same or different and are a) H, or b) C 4 alkyl optionally substituted with phenyl or pyridyl; Re4 is a) H, or b) a sodium ion; Res and Rβ6 in each case are the same or different and are a) H, b) formyl, c) C? _4 alkyl, d) C? - acyl, e) phenyl, f) C3_6 cycloalkyl g) R65 and Rß6 taken together are a saturated 5-6 membered heterocyclic moiety having from one to three carbon atoms selected from the group consisting of S, N, and O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C? _3, or acyl of C? _3, h) -P (0) (OR70) (OR71), oi) -S02-R72, 'Re is N -N N -N N "N (CH 3) 3 C C H R58 is C3_3alkyl; Reg is a) Ci-e alkoxycarbonyl, or b) carboxyl; R70 and R71 in each case are the same or different and are a) H, or b) C? _3 alkyl; R72 is a) methyl, b) phenyl, or c) tolyl; where K is a) 0, or b) S; R73, R74, R75, R76 and R77 in each case are the same or different and are a) H, b) carboxyl, c) halo, d) -CN, e) mercapto, f) formyl, g) CF3 h) -N02 i) Ci-e alkoxy, j) Ci-e alkoxycarbonyl, k) C? -6, 1) alkylthio C) -6 acyl, m) -NR78 R79, n) substituted C? -6 alkyl optionally with OH, C1-5 alkoxy, C1-5 acyl, -NR 8R79, N (phenyl) (CH2-CH2-OH), -O-CH (CH3) (OCH2CH3), or -O-phenyl- [para-NHC (= 0) CH3], or) C2-8 alkenylphenyl optionally substituted with R51, phenyl optionally substituted with R51? q) a saturated or unsaturated 5 or 6 membered heterocyclic entity having from one to three atoms selected from the group consisting of S, N, and 0, optionally substituted with R51; R51 is the same as defined in the above; R78 and R79 in each case are the same or different and are a) H, b) C 1-4 alkyl, c) phenyl, or d) R 78 and R 79 taken together with the nitrogen atom is a saturated, 5-6 membered heterocyclic entity which optionally has an additional heteroatom selected from the group consisting of S, N, and 0, and may in turn be optionally substituted with, including on the additional nitrogen atom, C1-3 alkyl, or C3_3 acyl; where is a) 0, b) S, or c) S02; R75, R76, and R77 are the same as defined above; R80 is a) H, b) formyl, c) carboxyl, d) C6-6 alkoxycarbonyl, e) C2-8 alkyl, f) C2_s alkenyl, wherein the substituents (e) and (f) can be optionally substituted with OH, halo, C6-6 alkoxy, C6-6 acyl, Ci-alqu alkylthio or C6-6 alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic entity that ranges from 6 to 10 carbon atoms optionally substituted with carbonyl, halo, -CN, formyl, CF3, -N02, C? -6 alkyl, C? _6 alkoxy, C? -6 acyl, C? _6 alkylthio, or Ci alkoxycarbonyl -H.H; h) -NR8? R82, i) -OR90, j) S (= 0) i-R9 ?, k) -S02-N (R92) (R93), or 1) a radical of the following formulas: Rdi and R82 in each case they are the same or different and are a) H, b) C3_6 cycloalkyl, c) phenyl, d) C6_6 acyl, e) C6_8 alkyl optionally substituted with OH, C6_6 alkoxy, can be substituted with OH, a 6-membered aromatic heterocyclic entity having from one to three atoms selected from the group consisting of S, N, and 0, phenyl optionally substituted with OH, CF3, halo, -N02, C-alkoxy? -, -NR83R84, or : tr. / ^ * V N-ÍCH,) .- ' V is a) 0, b) CH2, or c) NR87; Rs3 and s4 in each case are the same different and are a) H, or b) C? -4 alkyl; Ras is a) OH, b) C? -4 alkoxy, or c) -NR88 R89; R 86 is a) H, or b) C 1-7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazolyl, methylthio, amino, phenyl optionally substituted with OH, -C (= 0) -NH 2, -C0 2 H, or -C (= NH) -NH2; a) H, b) phenyl, or e) C? _6 alkyl optionally substituted by OH; Res and R-89 in each case are the same or different and are a) H, b) C 1-5 alkyl c) C 3-5 cycloalkyl, or d) phenyl; R9o is a) C8-8 alkyl optionally substituted with C6-6 alkoxy or C1-6 hydroxy, C3_6 cycloalkyl, a 6-membered aromatic heterocyclic entity optionally fused with benzo having from one to three nitrogen atoms, which in turn can be substituted with one or two -N02, CF3, halo, -CN, OH, C1-5 alkyl, C1-5 alkoxy, or C5-5 acyl; b) / - \ v N- (CH2), - c) feni lo, or d) pyridyl; R91 is a) C6-6alkyl, b) C2-6alkenyl, wherein the substituents (a) and (b) can be optionally substituted with C1-6alkoxycarbonyl, or an aromatic heterocyclic portion of 5-6. , 7 members having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic entity having from 6 to 10 carbon atoms, or d) an aromatic heterocyclic entity of , 6, 7 members having one to three atoms selected from the group consisting of S, N, and O, wherein substituents (c) and (d) may be optionally substituted with carboxyl, halo, CN, formyl, CF3, -N02, C? -6 alkyl, C? -6 alkoxy, C? -6 acyl, C? _6 alkylthio, or Ci_6 alkoxycarbonyl; R92 and R93 in each case are the same or different and are - a) H, b) phenyl, c) C? _6 alkyl, or d) benzyl; R94 and R95 in each case are the same or different and are a) H, b) OH, c) C? _6 alkyl optionally substituted with -NR83 R84, or d) R94 and R95 taken together are = 0; R96 is a) an aromatic entity having from 6 to 10 carbon atoms, b) a 5 or 6 member aromatic heterocyclic entity optionally fused with benzo having from one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) in turn can be substituted with one or three -N02, CF3, halo, -CN, OH, phenyl, C? _5 alkyl, C1-5 alkoxy, or C1-5 acyl, c) morpholinyl, d) OH, e) C6-6 alkoxy, f) -NR83R84, g) -C (= 0) -R97, or R97 is a) morpholinyl, b) OH, or c) C1_6 alkoxy; h is 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5; 1 is 2 or 3; m is 4 or 5; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; with the proviso that n and p together are 1, 2, 3, 4, or 5; q is 1, 2, 3, or 4; r is 2, 3, or 4; t is O, 1, 2, 3, 4, 5, 0 6; u is 1 or 2.
DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the invention can be prepared using known intermediates and compounds of oxazolidinones, isoxazolines and butyloctones as intermediates and synthetic methods known in the art. The thioamides of the invention can typically be prepared by reaction of the corresponding amide with Lawesson's reagent. The compounds described in the following publications are suitable intermediates for the preparation of the compounds of this invention and are therefore incorporated as a reference for their descriptions of suitable compounds that can be converted to the subject thiocarbonyl derivatives. U.S. Patents 5,225,565; 5,182,403; 5,164,510; 5,247,090; 5,231,188; 5,565,571; 5,547,950; and 5,523,403.
PCT Application and publications PCT / US93 / 04850, WO94 / 01110; PCT / US94 / 08904, WO95 / 07271; PCT / US95 / 02972, WO95 / 25106; PCT / ÜS95 / 10992, WO96 / 13502, PCT / ÜS96 / 05202, WO 96135691; PCT / US96 / 12766; PCT / ÜS96, 113726, PCT / US96 / 14135; PCT / US96 / 17120; PCT / US96 / 19149; PCT / US97 / 01970; PCT / US95 / 12751, WO96 / 15130; and PCT / US96 / 00718, W096 / 23788. Chemical conversion techniques for converting various intermediates having a CH2NH2 in the oxazolidinone ring to CH2NH-C (S) _ -CH3 are described by Hartke, K., Barrmeyer, S., J. prakt. Chem. 1996, 338, 251-6. Similarly, the conversion of CH2NHC (= 0) CH3 to CH2NHC (S) NHCH3 is reported by Cava M.P .; Levinson, M.I., Thionation Reactions of Lawessons' Reagents, Tetrahedron 1985, 41, 5061-87. For the purpose of the present invention, the carbon content of various hydrocarbons containing entities is indicated by a prefix designating the maximum and minimum number of carbon atoms in the entity, ie, the prefix Cj._j defines the number of carbon atoms in the entity. carbon atoms present from the integer to the whole "j inclusive C De alkyl- refers to alkyl of 1 to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and its isomeric forms. of C? _2"," C? -3 alkyl "," C? _4 alkyl ""C alquilo _5 alkyl", "C ?_6 alkyl", "C?-8 alkyl" and "C ?_6 alkyl" refer to an alkyl group having from one to two, from one to three, one to four, one to five, one to six, one to eight, or one to sixteen carbon atoms, respectively, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl , heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomeric forms. The terms "C2-4 alkenyl", "C2-5 alkenyl", "C2_8 alkenyl", "C2_4 alkenyl" and "C2-C6 alkenyl" refer to at least one double bond of the alkenyl group having two to four, two to five, two to eight, two to fourteen, or two to sixteen carbon atoms, respectively, such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptydienyl, octenyl, octdienyl, oct atienyl, nonenyl, nonedienyl, nonat rieni lo, undecenyl, undedenyl, dodecenyl, tridecenyl, tet radecenil and its isomeric forms.
The terms "C2_5 alkynyl", "C2_8 alkynyl" and "C2-" alkynyl "refer to at least one triple bond of the alkynyl group having from two to five, from two to eight, or from two to ten. carbon atoms, respectively, such as, for example, ethynyl, propynyl, butynyl, pentynyl, pentyndiinyl, hexinyl, hexdiinyl, heptinyl, heptidinyl, octynyl, octynynyl, octatriinyl, noninyl, nonediinyl, nonatriinyl and their isomeric forms. The terms "C3-4 cycloalkyl", "C3-6 cycloalkyl", "C5-6 cycloalkyl" and "C3_8 cycloalkyl" refer to cycloalkyl having from three to four, from three to six, from five to six, or from three to eight carbon atoms , respectively, such as, for example, cyclopropynyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms. The terms "C? -4 alkoxy", "Ci-β alkoxy" and "C? _8 alkoxy" refer to an alkyl group having one to four, one to six, or one to eight atoms carbon, respectively, attached to the oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms.
The terms "Ci-V alkylamino and C" -8 alkylamino refer to an alkyl group having from one to six, or from one to eight carbon atoms, respectively, attached to an amino entity, such as example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, or octoylamino and their isomeric forms The terms "dialkylamino of C? _6" and "dialkylamino of C? _8" refer to two alkyl groups having one to six, or from one to eight carbon atoms, respectively, attached to an amino entity, such as, for example, dimethylamino, methylathylamino, diethylamino, dipropylamino, methypropylamino, ethylpropylamino, dibutylamino, dipentylamino, dihexylamino, methylhexylamino, diheptylamino, or dioctyl oylamino and its isomeric forms The terms "acyl of C? _3", "acyl of C? _", "acyl of C? _5", "acyl of C? -6", "acyl of C "_8" and "C2_8 acyl" refer to a carbonyl group having an alkyl group of one to three, from one to four from one to five, from one to six, from one to eight, or from two to eight carbon atoms. The terms "C 1-4 alkoxycarbonyl", "α-β alkoxycarbonyl" and "C 8 -alkoxycarbonyl" refer to an ester group having an alkyl group of one to four, one to six, or one to eight carbon atoms. The term "C 8 alkylphenyl" refers to an alkyl group having one to eight carbon atoms and their isomeric forms which is substituted with at least one phenyl radical. The term "C2-8 alkenylphenyl" refers to at least one double bond of the alkenyl group having from two to eight carbon atoms and their isomeric forms which is substituted with at least one phenyl radical. The term "C 8 alkylpyridyl" refers to an alkyl group having one to eight carbon atoms and their isomeric forms which is substituted with at least one pyridyl radical. The term "hydroxyl of C? _8" refers to an alkyl group having from one to eight carbon atoms and their isomeric forms attached to a hydroxy group. The term "C?-8 alkylsulfonyl" refers to an alkyl group having one to eight carbon atoms and their isomeric forms attached to an -S02 entity.
The term "Ci-V alkylthio" refers to an alkyl group having from one to six carbon atoms and its isomeric forms attached to a sulfur atom.The term "Het" refers to saturated, unsaturated or heterocyclic rings. 5-10 membered aromatics containing one or more oxygen, nitrogen, and sulfur atoms forming these groups, such as, for example, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3-pi_ridi 1o, 4-pyridyl , 2-pyrimidinyl, -pyrimidinyl, - . 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4 - . 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazole, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4 -oxo-2 -oxa zolyl, 5-oxazolyl, 4, 5, -dihydrooxazole, 1, 2, 3-oxatol, 1,2,3-oxadiazole, 1, 2, 4 -oxadiazole, 1, 2, 5-oxadiazole, 1,3,4-oxadiazole, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl , 3-benzo furanyl, benzoi sot ia zol, benzi soxa zol, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl , 1, 2, 3, -oxat-iazol-1-oxide, 1, 2, 4-oxadiazol-3-yl, 1,2-oxadiazol-5-yl, 5-oxo-l, 2,4-oxadiazol- 3- i, 1, 2,4-thiadiazol-3-yl, 1,2-thiadiazol-5-yl, 3-oxo-l, 2,4-thiadiazol-5-yl, 1, 3, 4- thiadiazol-5-yl, 2-oxo-l, 3,4-thiadiazol-5-yl, 1, 2,4-triazol-3-yl, 1, 2,4-t-riazol-5-yl, 1,2 , 3,4-t et razol-5-yl, 5-oxazole ilo, 1-pyrrolyl, 1-pyrazolyl, 1, 2, 3-triazol-1-yl, 1, 2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2 -isoindolyl, 7 -oxo-2-ysoindolyl, 1-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1, 3, 4, -oxadiazol, 4 -oxo-2-t-aliazolinyl, or -methyl-1, 3,4-thiadiazol-2-yl, thiazoldione, -1,2,3,4-thiatriazole, 1, 2,4-dithiazolone. Each of these entities can be substituted as appropriate. The term "halo" refers to fluorine, chlorine, bromine, or iodine. The compounds of the present invention can be converted to their salts, when appropriate, according to conventional methods. The term "pharmaceutically acceptable salts" refers to acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydrate, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form. When Q is the structure of the dotted line in the heterocyclic ring means that this link can be either single or double. In the case where the dotted line is a double bond, the R39 group will not be present. The compounds of Formula 1 of this invention contain a chiral C5 center of the isoxazoline ring, and as such there are two enantiomers or a racemic mixture or both. This invention relates to both enantiomers, as well as to the mixtures containing these enantiomers. In addition, depending on the substitutes, additional chiral centers and other isomeric forms may be present if there are group A or R], and this invention encompasses all possible stereoisomers and geometric forms in these groups. The compounds of this invention are useful for the treatment of microbial infections in humans and other warm-blooded animals, under both parenteral and oral administration. The pharmaceutical compositions of this invention can be prepared by combining the compounds of this invention with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Compositions in solid form include powders, tablets, dispersible granules, capsules, seals and suppositories. A solid carrier can be at least one substance that can also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, agent disintegrator 'of tablet, and encapsulating agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting waxes, cocoa butter, and the like. The compositions in liquid form include solutions, suspensions and emulsions. For example, solutions of the compounds of this invention dissolved in aqueous systems and aqueous propylene glycol and aqueous polyethylene glycol optionally containing suitable conventional coloring agents, flavoring agents, stabilizers and thickening agents can be provided. Preferably, the pharmaceutical composition is provided by employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component, i.e., the compound according to this invention. The amount of the active component, i.e., the compound according to this invention, in the pharmaceutical composition and in unit dosage form can therefore be varied or adjusted broadly depending on the particular application, the potency of the particular compound, and the desired concentration. In general, the amount of the active component will vary between 0.5% to 90% by weight of the composition. In therapeutic use for the treatment, or combat, of bacterial infections in warm-blooded animals, the compounds or compositions.
Pharmaceuticals thereof will be administered orally and / or parenterally at a dose to obtain and maintain a concentration, i.e., an amount, or blood level of the active component in the animal that is being subjected to this treatment which will be effective antibacterially. In general, the effective antibacterial amount of dose of the active component will be in the range of from about 0.1 to about 100, more preferably from about 3.0 to about 50 mg / kg of body weight / day. It should be understood that the doses may vary depending on the requirements of the patient, the severity of the bacterial infection that will be treated, and the particular compound that will be used. Also, it should be understood that the initial dose administered may be increased beyond the previous maximum limit in order to quickly achieve the desired blood level or the initial dose may be less than optimal and the daily dose may be increased progressively during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, 2 to 4 times a day.
When the compounds according to this invention are administered parenterally, ie by injection, for example, by intravenous injection or by other parenteral routes of administration. Pharmaceutical compositions for parenteral administration will generally contain a pharmaceutically acceptable amount of the compound or a soluble salt (acid addition salt or basic salt) dissolved in a pharmaceutically acceptable liquid carrier, such as, for example, water for injection and a buffer to provide a isotonic solution suitably damped, for example, having a pH of about 3.5-6. Suitable buffering agents include, for example, trisodium otophosphate, sodium bicarbonate, sodium citrate, N-met ilglucamine, L (+) -lysin and L (+) - arginine to name a few of a few representative buffering agents. The compound of this invention will generally be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg / mL to about 400 mg / mL of the solution. The resulting liquid pharmaceutical composition will be administered to obtain the amount of antibacterially effective dose mentioned in the above. The compounds according to this invention are advantageously administered orally in solid and liquid dosage forms.
MIC Test Method The MIC in vitro of the test compounds were determined by a standard agar dilution method. A concentrated drug solution of each analog is prepared in the preferred solvent, usually DMSO: H20 (1: 3). Dilutions in double series of each sample are made using aliquots of 1.0 ml of sterile distilled water. For each 1.0 ml aliquot of drug, 9 ml of molten Mueller Hinton agar medium is added. The drug-supplemented agar is mixed, emptied into 15 x 100 mm petri dishes, and allowed to solidify and dry before inoculation. The vials of each of the test organisms are kept frozen in the vapor phase of a liquid nitrogen freezer. The test cultures are allowed to grow overnight at 35 ° C in the appropriate medium for the organism. Colonies are collected with a sterile swab, and cell suspensions are prepared in Trypticase Soya Broth (TSB) to equal the turbidity of a McFarland standard of 0.5. A 1:20 dilution of each TSB suspension is made. The plates containing the drug-supplemented agar are inoculated with a 0.001 ml drop of the cell suspension using a Steers replicator, yielding approximately 104 to 105 cells per site. The plates are incubated overnight at 35 ° C. After incubation, the Minimum Inhibitory Concentration (MIC μg / ml) is read and the lowest concentration of the drug that inhibits the visible growth of the organism is recorded. The data is shown in Tables I and II.
TABLE I CD * without a compound of the subject invention TABLE I (continued) Cp * without a compound of the subject invention TABLE I (continued) or SAUR SEPI aureua S. S. epidcrmidi »EFAE faecalitt SI'NE E. S. S. pneumonia OW &OB pyogenea * without a compound of the subject invention TABLE II Continuation) n Key: SAUR 9213: S. aureus SEPI 30593: S. epidermidis VA-? E 12712: E. Faecium SPNE 9912: S. pneumoniae SPYO 152: S. pyogenes HINF 30063: Haemophilus influenzae MCAT 30610: Moraxella catarrhalis Ll-? Í- 9217: Enterococcus faecalis As shown in Scheme 1, the intermediates II for the compounds of this invention are also intermediates disclosed in the oxazolidinone and published applications, previously incorporated by reference. Intermediates IV for this invention are final products (Examples) of the oxazolidinone patents and previously published applications incorporated by reference. As shown in Scheme 1, Step 1, and illustrated in Example 5, the isothiocyanates III can be conveniently prepared by allowing the amine (II) intermediates to react with 1,1'-thiocarbonyldi-2 (1H) -pyridone in solvents such as, for example, methylene chloride from 0 to 25 ° C. The thioureas (a, R '= H, alkyl 4) can then be prepared as shown in Step 2 by reaction of III with ammonium or the appropriate primary amines in solvents such as, for example, 1,4-dioxane or tetrahydrofuran at 0-50 ° C. Alternatively, as illustrated in Example 6 and shown in Step 3, the thioureas can be prepared by allowing II to react with an appropriate isothiocyanate (R'-N = C = S) in solvents such as tetrahydrofuran at 0-50 ° C. The thioamides (Ib, R "= H, alkyl? _) Are prepared by allowing II to react with an appropriate dithioester (R" 'SC (= S) -R ", from Step 4 as illustrated in the Example. This reaction is carried out in aqueous, alcoholic solvents at 0-50 ° C in the presence of an alkali metal hydroxide equivalent.This reaction, especially when R "'is methyl or ethyl, can be catalyzed by a fluoride of alkali metal The reaction of II with R "'-SC (S) -R"' (R "'= CH3, C2H5) to provide Ib (Step 4) can also be carried out in the presence of a tertiary amine base such as, for example, triethylamine in solvents such as THF, dioxane or methylene chloride at 10- 50 ° C for 3-48 hours When the reaction conditions are tolerated by the R substituents (see, for example, Examples 1-3) the thioamides (Ib R "-H, alkyl 4) can also be prepared conveniently (Step 5) by allowing the appropriate amide intermediates (IV) to react with reagents such as, for example, 2, -bis (p-methoxypheni 1) -1, 3-di tiadi fos fetano-2, 4-disulfide (reagent Esson) in 1,4-dioxane, benzene, toluene or tetrahydrofuran at 60-110 ° C; phosphorus decasulfide and sodium carbonate in tetrahydrofuran at 20-50 ° C [Brillon, D., Synthetic Communications, 2_0_, 3085 (1990)] or phosphorus decasulfide and sodium fluoride in 1,2-dimethoxyethane at 20-50 ° C C [Hartke, K., Gerber, H.-D., J. Prakt. Chem., 338, 763 (1996)]. The compounds are prepared (Step 6) by allowing II to react first with carbon disulfide and a tertiary amine base such as, for example, triethylamine in solvent mixtures containing water and methanol, ethanol or isopropanol at 10-50 ° C. for 5-24 hours. The resulting intermediates are treated with an alkylating agent (R "" X where X represents bromine, iodine, alkylsufonyloxy or arylsulfonyloxy) at 0-30 ° C to provide the le compounds. In Step 7, compounds will be allowed to react with alkali metal alkoxide such as for example, sodium methoxide or potassium ethoxide in the corresponding alkanol as solvent. This reaction is conveniently carried out at the reflux temperature of the alkanol for 1-24 hours.
SCHEME 1 R-NH, R - N = C = S STAGE 1 III S II R'- NH, R- NH-C-NH-R '(R' = H, alkyl, ^) STAGE 2 R- _N = C = S the (R '= H, alkyl, .4) STAGE 3 SS II II R' "- S- CR" R-NH-C R "(R" = H. alkyl, ^) STAGE 4 Ib (R '"= CH3, C2H5, HOOC- CH,) OR II R- NH- C- R "Ib (R" = H. alkyl,. ,,) IV STAGE 5 S I 1) CS2 / Et3N II (R "" = C1 ^ alkyl, X = Br, I, RNH-C-SR "" OS02 alkyl, OS02 aryl) 2) R "" X STAGE 6 le MOR '"'" - HOR "" RNH-C-OR "" (M = Li. + Na, + K ~) STAGE 7 Id In order to better illustrate the nature of the invention and how to practice it, The following experimental examples are presented.
EXAMPLE 1: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (I) C16H20FN3 ° 3S A stirred mixture of II (PCT / US94, 3.37 g, 10.0 mmol) in dry dioxane (100 mL), under nitrogen was treated with Lawesson's Reagent (4.04 g, 10.0 mml), heated to reflux for 1 hour and brought at reflux for 1.5 hours. The reaction was terminated by TLC in silica gel with 10% MeOH-CHCl3. It was kept at room temperature for 18 hours and concentrated in vacuo. Chromatography of the residue on gel was silicated with mixtures of acetone-methylene chloride containing 10 to 15% acetone gave the product which was crystallized from acetone-hexane to provide 1: p.f. 157.5- 158.5 ° C; HRMS in theory for C16H20FN3O3S (M +): 353.1209; found: 353.1212. Analysis calculated for C? 6H20FN3O3S: C, 54.38; H, 5.38; N, 11.89; S, 9. 07. found: C, 54.21; H, 5.58; N, 11.78; S, 8.93.
EXAMPLE 2: (S) -N- [[3- [3-Fluoro-4 - [4 - (5-methyl-1, 3, -thiadiazol-2-yl) -1-piperazinyl] phenyl] -2- oxo-5-oxazolidinyl] methyl] thioacetamide (2) 21 2 According to Example 1, for the preparation of 1:21 (PCT / ÜS97 / 01970) it was allowed to react with Lawesson's Reagent under reflux with dioxane to provide 2: p.f. 222-223 ° C; HRMS in theory for C? 9H24FN602S2 (M + H +): 451.1386; found 451.1381.
EXAMPLE 3: (S) -N- [[3 - [3-Fluoro-4 - [2 ', .5 • -dioxospiro [piperidin-4,4'-imidazolidin] -1-yl] phenyl] 2-oxo- 5-oxazolidinyl] met il] t -ioacetamide (3).
STAGE A: (S) -N- [[3- [3-Fluoro- - [2 ', 5' -dioxospiro- [piperidin-4,4'-imidazol idin] -1-yl] phenyl] -2-oxo -5-oxazolidinyl] methyl] acetamide (32).
A stirred suspension of 31 (Case 4780. P CP, 0.349 g, 1.00 mmol) in 1: 1 EtOH: H20 (5 mL), under nitrogen, was treated with potassium cyanide (0.130 g, 2.00 mmol) and ammonium carbonate (0.701 g, 7.30 mmol), was heated at 55-60 ° C for 5 hours with 15 minutes and kept at room temperature for 17 hours with 15 minutes. Then it was subjected to silica gel chromatography with mixtures of MeOH-NH40H-CHC13 containing 5-20% MEOH and 0.5% NH4OH to provide 0.280 g of 32: HRMS calculated for Ci9H22FN5? 5: 419.1605 (M +); found 419.1613; Analysis calculated for C? 9H22FN505 • 1 H20: C, 52.17; H, 5.53; N, 16.01. Found: C, 52.44; H, 5.30; N, 16.11.
STAGE B: (S) -N- [[3- [3-Fluoro-4- [2 ', 5' -dioxospiro [piperidin-4,4'-imidazolidin] -yl] phenyl] -2-oxo-5- oxazolidinyl] methyl] thioacetamide (3).
A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 L), under nitrogen was treated with Lawesson's Reagent (0.202 g, 0.500 mmol), refluxed for 4 hours and concentrated in vacuo. The residue was subjected to silica gel chromatography with mixtures of MeOH-NH4OH-CHCl3 containing 1-10% MeOH and 0.1-0.5% NH4OH and the resulting product was crystallized from MeOH-CHCl3-EtOAe to provide 0.0491 g of 3: pf 218.5 ° C - HR FAB MS in theory for C19H22FN504S (M +): 435.13-76; found 435.1370. Analysis calculated for C19H22FN504S • 0.5 H20: C, 51.34; H. 5.21; N, 15.76. Found: C, 51.69; H, 5.00; N. 15.25.
EXAMPLE 4: (S) -N- [[3- [3- Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (4) C .eHjoFNjOjS 4 A solution of 41 (148 mg, 0.500 mmol) and 0. 97 M KOH (0.515 mL) in absolute EtOH (5 mL) was added to a solution of ethyl dithioacetate (57 μL, 0.50 mmol) and sodium fluoride (20 mg, 0.47 mmol) in absolute EtOH (5 mL) and the The mixture was kept at room temperature for 3 hours with 40 minutes. Additional ethyl dithioacetate was added (5 μL) after 1 hour with 55 minutes and 0.97 M KOH (40 mL) and additional sodium fluoride (6 mg) were added to the mixture after 3 hours with 5 minutes. The reaction was followed by TLC in silica gel with 10% MeOH-CHCl3 and 30% acetone-CH2C12. The main product had an Rf on the TLC that was the same as the 4.
EXAMPLE 5: (S) -N- [[3- [3- Fluoro- - (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea (5).
STAGE A: A solution of 51 (PCT / US94 / O 8904, 2.07 g, 7. 00 mmoles) in CH2C12 was added, in drops, for 30 minutes, under nitrogen to a stirred, ice-cooled solution of 1, 1'-thiocarbonyldi-2 (1H) -pyridone (1.95 g, 8.40 mmoles) in CH2C12 ( 70 mL). The mixture was slowly heated to room temperature and maintained for 18 hours. It was then diluted with CH2C12, washed with water and aqueous NaCl, dried (Na2SO4) and concentrated. Chromatography of the residue in silica gel with 10% acetonitrile-CH2Cl2 gave 1.60 g of isothiocyanate: HRMS in theory for C? 5H? 6FN303S (M +): 337.0896; found: 337.0888.
STAGE B: C.3H, 9FN «03S 5 Anhydrous ammonia was bubbled in for 7 minutes through a stirred solution of the product of Step I (1.00 g, 2.96 mmol) in THF (10 mL) and the mixture was kept at room temperature for 3 hours with 25 minutes and concentrated in vacuo. Crystallization of the acetone-hexane residue gave 0.861 g of 5: p.f. 199-199.5 ° C; MS m / z 354 (M +). Analysis calculated for d5H? 9FN403S: C, 50.84, H, 5.40; N, 15.81. Found: C, 50.87; H, 5.39; N, 15.72.
EXAMPLE 6: (S) -N- [[3- [3-Fluoro-4 - (4-morphin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -N'-met ilt-iourea (6) - - - CllHz, FN ,, 0, S s A stirred solution of methyl isothiocyanate (93 mg, 1.27 mmol) in THF was treated with ethyl acetate. (295 mg, 1.00 mmol), was maintained at room temperature for 18 hours and concentrated in vacuo.
The residue was crystallized from EtOAc-hexane to provide 246 mg of 6: p.p. 158-160 ° C; MS m / z (M +). Analysis calculated for C? 6H2? FN403S: C, 52.16; H, 5.74; N, 15.21. Found: C. 52.20; H. 5.85 N, 15.17.
EXAMPLE 7 (S) -cis-N- [[3- [3-Fluoro-4- (tetrahydro-1-oxide-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] ethanethioamide Step 1: A mixture of (S) - (-) - N - [[3- [3-fluoro-4- (3,6-dihydro-2H-thiopyran-4-yl) phenyl] S-oxide] - 2-oxo-5-oxazolidinyl] met il] acetamide (4.50 g, can be obtained according to the procedures described in International Publication No. WO 97/09328) and platinum oxide (697 mg) in methanol (164 mL ) is stirred on the Parr apparatus under a hydrogen atmosphere at 40 psi for 18 hours. The catalyst is then removed by filtration through Ceuta, and the filtrate is concentrated under reduced pressure and the residue is subjected to silica gel chromatography (230-400 mesh, 350 g), eluting with a gradient of methanol chloride. methylene (3 / 97-7 / 93). The combination and concentration of these fractions with a Rf = 0.44 by TLC (methanol / chloroform, 10/90) provided (S) -cis - (-) - N - [[3- [3-Fluoro-4- (tetrahydro- l-oxide-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide, mp 203-204 ° C. Step 2: A mixture of the compound prepared in Step 1 (2.50 g) and hydroxylamine hydrochloride (2.36 g) in pyridine (30.6 mL) and ethanol (3.4 mL) is stirred in a bottle with screw cap at 100 ° C during 22 hours at room temperature for 16 hours, during which additional hydroxylamine hydrochloride (944 mg) and pyridine (4 mL) are added. The reaction mixture is then concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate (100 mL) and saline (50 mL), adjusted to a pH of 11 with solid sodium carbonate and extracted with methanol / methylene chloride (10/90, 5 * 100 mL). The combined organic phase is concentrated under reduced pressure and the unpurified product is subjected to silica gel chromatography (230-400 mesh, 150 g), eluting with a gradient of methanol / methylene chloride (6 / 94-10 / 90). ). The collection and concentration of these fractions with a Rf = 0.14 by TLC (methanol / chloroform, 10/90) provides (S) -cis-3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran- 4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, mp 159-161 ° C. Step 3: A solution of ethyl dithioacetate (105 mL, 0.919 mmol) and sodium fluoride (39 mg, 0.919 mmol) in ethanol (9.2 mL) under a nitrogen atmosphere was treated with a mixture of (S) -cis 3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -5-aminomet i 1-2-oxa zol idinone, as prepared in Step 2, (300 mg , 0.919 mmol) and aqueous potassium hydroxide (1M, 0.92 mL) in ethanol (46 mL). The resulting solution was stirred at room temperature for 4 hours and then diluted with methylene chloride (150 mL) and washed with water (50 mL), aqueous potassium hydrogen sulfate (1M, 50 mL) and brine (25 mL). ). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, and the crude product was triturated with methylene chloride / diethyl ether and filtered to provide the title compound, m.p. 176-177 ° C (dec.).
EXAMPLE 8 (S) -cis- [[3- [3-Fluoro-4- (tetrahydro-1-oxide-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolicinyl] methyl] thiourea Step 1: A solution of 1,1'-t -carbonyldi-2 (1H) -pyridone (235 mg, 1.01 mmol) in anhydrous methylene chloride (10 mL) at 0 ° C under a nitrogen atmosphere was treated with a solution of (S) -cis-3- [3-fluoro-4- (tetrahydro-l- or ido-2H-thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxa-idolone, as prepared in Example 7, Step 2, (375 mg, 0.843 mmol) in anhydrous methylene chloride (34 L) for 30 minutes. The resulting mixture was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour and then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine. (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (70-230 mesh, 20 g), eluting with acetonityl chloride / methylene (40/60), and these fractions with Rf = 0.07 by TLC (acetonityl chloride) methylene, 30/70) were collected and concentrated to provide (S) -cis-3- [3-Fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -5-isot iocianatomet il-2-oxazolidinona, pf 187-190 ° C (dec). Step 2: A solution of (S) -cis-3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -5-isothiocyanatomethyl-2-oxazolidinone (Stage 1 , 290 mg, 0.787 mmol) in anhydrous tetrahydrofuran (39 mL) at 0 ° C under a nitrogen atmosphere was treated (by bubbling) with a stream of ammonia gas for 5 minutes. The reaction vessel was sealed, and the resulting mixture was stirred at 0 ° C for 1 hour. The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture was concentrated in vacuo to provide the product without purification. Recrystallization from methanol chloride / methylene / diethyl ether gave the title compound, m.p. 206-208 ° C (dec).
EXAMPLE 9 (S) -trans-N- [[3- [3-Fluoro-4- (tetrahydro-1-oxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinyl] met il] Ethanethioamide Step 1: The S-oxide of (S) - (-) - N - [[3- [3-fluoro-4- (3,6-dihydro-2H-thiopyran-4-yl) phenyl] -2-oxo -5-oxazolidinyl] methyl] acetamide (described in International Publication No. WO 97/09328) can be reduced to the corresponding cis- and trans-sulfoxides by catalytic hydrogenation in the presence of a catalyst and a solvent. Alternatively, the sulfide by-product of this reduction reaction can be oxidized with an oxidizing agent such as NaI04 or meta-chloroperoxybenzoic acid in solvent to provide the cis- and trans-sulfoxides. The isomeric mixture can then be separated by chromatography to isolate the trans-sulfoxide, m.p. 211-212 ° C (dec.). A mixture of the trans-sulfoxide, (S) -trans- (-) - N - [[3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -2 - oxo-5-oxazolidinyl] methyl] acet amide, (0.90 g) and hydroxylamine hydrochloride (0.85 g) in pyridine (11.0 mL) and ethanol (1.2 mL) is stirred in a cap bottle with a screw thread at 100 ° C for 23 hours. hours at room temperature for 19 hours, during which time additional hydroxylamine hydrochloride (340 mg) and pyridine (1 mL) are added. The reaction mixture is then concentrated under reduced pressure, diluted with saturated aqueous sodium carbonate (50 mL) and saline (50 mL) and extracted with methanol / methylene chloride (10/90, 6 * 100 mL). . The combined organic phase is presented under reduced pressure and the unpurified product is subjected to chromatography on silica gel (230-400 mesh, 45 g), eluting with a gradient of methanol / methylene chloride (7.5 / 92.5-10 / 90 ). Collection and concentration of these fractions with a Rf = 0.14 by TLC (methanol / chloroform, 10/90) yields (S) -trans-3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran -4-yl) phenyl] -5-aminomethyl-2-oxazolidone, mp 138-140 ° C. Step 2: A solution of ethyl dithioacetate (105 mL, 0.919 mmol) and sodium fluoride (39 mg, 0.919 mmol) in ethanol (9.2 mL) under a nitrogen atmosphere was treated with a mixture of (S) -trans - 3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidone, as prepared in Step 1, (300 mg, 0.919 mmol) and aqueous potassium hydroxide ((1M, 0.92 mL) in 46 mL ethanol). The resulting solution was stirred at room temperature for 17 hours and then diluted with methylene chloride (150 mL), washed with water (2 x 50 mL) and brine (25 mL), dried over anhydrous sodium sulfate and filtered. concentrated in va cuo. The unpurified product was subjected to silica gel chromatography (230-400 mesh, 35 g), eluting with methanol / methylene chloride (3/97), and these fractions with an Rf = 0.56 by TLC (methanol / chloroform, 10/90) was collected and concentrated and the residue was recrystallized from methylene chloride / diethylether to provide the title compound, mp. 193-194 ° C (dec.).
EXAMPLE 10 (S) -trans- [[3- [3-Fluoro-4 - (tetrahydro-1-oxide-2H-t-yopran-4-yl) phenyl] -2-oxo-5-oxa-zolidinyl] methyl] thiourea Step 1: A solution of 1,1 '-thiocarbonyldi-2 (1H) -pyridone (192 mg, 0.827 mmol) in anhydrous methylene chloride (8.3 mL) at 0 ° C under a nitrogen atmosphere was treated with a solution of (S) -trans-3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidone, as prepared in Example 9, Step 1, (225 mg, 0.689 mmol) in anhydrous methylene chloride (28 mL) for 30 minutes. The resulting mixture was stirred at 0 ° C for 30 minutes and at room temperature for 40 minutes and then diluted with methylene chloride (20 mL), washed with water (15 mL) and brine (15 mL), dried over sulfate of anhydrous sodium and concentrated in va cuo. The crude product was subjected to chromatography on silica gel (32-63 mm, 40 g), eluting with a gradient of acetonitrile / methylene chloride (30 / 70-60 / 40) under 15 psi N2, and these fractions with a Rf = 0.12 by TLC (acetonitrile / methylene chloride, 30/70) were collected and concentrated to provide (S) -trans-3- [3-Fluoro-4- (tetrahydro-l-oxide-2H-thiopyran- 4-yl) phenyl] -5-isothiocyanate omethyl-2-oxazolidone, mp 165-167 ° C. Step 2: A solution of (S) -trans-3- [3-fluoro-4- (tetrhydro-l-oxide-2H-thiopyran-4-yl) phenyl] -5-isot-iocianatomet-il-2-oxazolidone (Stage 1, 230 mg, 0.624 mmol) in anhydrous tetrahydrofuran (31.2 mL) at 0 ° C under a nitrogen atmosphere was treated (by bubbling) with a stream of ammonia gas for 5 minutes. The reaction vessel was sealed, and the resulting mixture was stirred at 0 ° C for 1 hour. The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture was concentrated in vacuo to provide the product without purification. Trituration with methylene chloride / methylene / diethylether afforded the title compound, m.p. 209-210 ° C (dec.).
EXAMPLE 11 (S) -N- [f 3- [3-Fluoro-4- (tetrahydro-1, 1-dioxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxa zol idini 1] methyl] ethanethioamide Step 1: Start with (S) -cis- (-) -N- [[3- [3-Fluoro-4- (tetrahydro-β-oxide-2H-thiopyran-4-yl) phenyl] -2-oxo- 5-oxazolidinyl] met il] acetamide, as prepared in Example 7, Step 1, and following the general procedure of Step 2, and making noncritical variations when replacing S, S-dioxide of (S) - (-) -N - [[3- [3-fluoro-4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (described in International Publication No. WO 97 / 09328) for (S) -cis - (-) -N- [[3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -2-oxo-5- oxazolidinyl] met il] acetamide, the product (S) - (-) - 3- [3 - [- Fluoro-4- (tetrahydro-1,1-dioxide-2H-thiopyran-4-yl) phenyl] was obtained] -5-aminomethyl-2-oxazolidinone, mp 194 ° C (dec.). Step 2: A solution of ethyl dithioacetate (10 mL, 0.876 mmol) and sodium fluoride (37 mg, 0.876 mmol) in ethanol (8.8 L) under a nitrogen atmosphere was treated with a mixture of (S) - (- ) -3- [3- [-fluoro-4- (tetrahydro-1,1-dioxido-2H-thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, as prepared in Step 1 , (300 mg, 0.876 mmol) and aqueous potassium hydroxide (1M, 0.88 mL) in ethanol (43.8 mL). The resulting mixture was stirred at room temperature for 26 hours, during which ethyl dithioacetate (50 mL, 0.438 mmol), sodium fluoride (19 mg, 0.438 mmol), aqueous potassium hydroxide (1M, 0.44 Ml) and ethanol were added. (3.0 mL), and then diluted with methylene chloride (150 mL), washed with water (50 mL), with aqueous potassium hydrogen sulfate (1M, 50 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in va cuo. The crude product was recrystallized from methylene chloride / diethylether to give the title compound, m.p. 186-187 ° C (dec.).
EXAMPLE 12 (S) -N- [[3- [3-Fluoro-4- (tetrahydro-1, 1-dioxido-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinyl] ethyl] thiourea Step 1: A solution of 1,1 '-thiocarbonyldi-2 (1H) -pyridone (304 mg, 1.31 mmol) in anhydrous methylene chloride (13 L) at 0 ° C under a nitrogen atmosphere was treated with a solution of (S) - (-) -3- [3- [-fluoro-4- (tetrahydro-1, l-dioxido-2H-thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, as was prepared in Example 11, Step 1, (375 mg, 1.09 mmol) in anhydrous methylene chloride (88 mL) for 30 minutes. The resulting mixture was stirred at 0 ° C for 30 minutes and at room temperature for 30 minutes and then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine (25 mL), dried over sulfate of anhydrous sodium and concentrated in va cuo. The crude product was subjected to chromatography on silica gel (230-400 mesh, 45 g), eluting with acetonitrile / methylene chloride (7.5 / 92.5), and these fractions with an Rf = 0.64 by TLC (acetonitrile chloride / methylene, 20/80) were collected and concentrated to provide (S) - (-) - 3 - [3- [-fluoro-4- (tetrahydro-1, l-dioxide-2H-thiopyran-4-yl) phenyl] ] -5-isot-iocianatomet-il-2-oxazolidinone, mp 158-162 ° C (dec.). Step 2: A solution of (S) -3- [3- [-fluoro-4 - (tetrahydro-1, l-dioxido-2H-thiopyran-4-yl) phenyl] -5-isot-iocyanatomethyl-2-oxazolidinone ( Step 1.388 mg, 0.988 mmol) in anhydrous tetrahydrofuran (49 mL) at 0 ° C under a nitrogen atmosphere was treated (by bubbling) with a stream of ammonia gas for 5 minutes. The reaction vessel was sealed, and the resulting mixture was stirred at 0 ° C for 1 hour. The excess ammonia was then removed under a stream of nitrogen and the reaction mixture was concentrated in vacuo to provide the product without purification. Recrystallization from methanol / methylene chloride / diethyl ether gave the title compound, m.p. 196-198 ° C (dec.).
EXAMPLE 13: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2 -oxo-5-oxazolidinyl] methyl] -thioformamide (7) A stirred mixture of acetic anhydride (0.23 mL, 0.0024 mol) and 95-97% formic acid (0.10 mL, 0.0027 mL) was heated, under nitrogen at 50-55 ° C for 2 hours, cooled to room temperature and treated, in portions for 2 minutes, with 398 (0.45 g, 0.0015 moles). The suspension was maintained at room temperature for 4 hours and the resulting solution was treated with Et20 (1 mL) and maintained at room temperature for 18 hours. The mixture was diluted with additional Et20 (10 L) and the solid was collected by filtration, washed with Et20 and dried to give 0.38 g of 69: MS (ES) m / z 324 (M + H +), 346 (M + Na +); lE NMR (300 mHz, CDC13) d 3.08 (m, 4H), 3.72 (m, 2H), 3.77 (d, d, 1H), 3.89 (m, 4H), 4.04 (t, 1H), 4.80 (m, 1H), 6.33 1H) 7.05 (m, 2H) 7.45 (d, d, 1H), 8.27 (s, 1H).
A stirred mixture of 6 (0.38 g, 0.00118 mol) in dioxane (20 mL), under nitrogen was treated with 4 (0.51 g, 0.00126 mol), heated to reflux for 30 minutes and maintained at this temperature for 90 minutes. Then it was evaporated under a stream of nitrogen. The residue was subjected to silica gel chromatography with 1.25% MeOH-CH2Cl2 and the slightly impure product was re-chromatographed on silica gel with 25% EtOAc-CH2C12. The resulting product was crystallized from tert-butyl ether of EtOAc-methyl to provide 0.114 g of 7: p.f. 150-155 ° C (dec); IR (DRIFT) 3322, 1752 cm "1; MS (ES) m / z 340 (M + H"), 362 (M + Na +); XHNMR [300 MHz, (CD3) 2SO] d 2.94 (m, 4H), 3.72 (m, 4H), 3.77 (d, d, 1H), 3.94 (t, 2H), 4.12 (t, 1H), 4.93 ( m, 1H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.47 (d, d, 1H), 9.33 (d, 1H), 10.59 (s, 1H). Analysis calculated for C? 5H18FN303S: C, 53.08; "H, 5.35; N, 12.38." Found: C, 53.02; H, 5.44; N, 12.36.
EXAMPLE 14: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] thiopropionamide (9). 39 10 A stirred solution, cooled with ice, of 398 (0.395 g, 0.00134 mol) and triethylamine (0.186 mL, 0.0027 mol) in CH2C12 (20 mL), under nitrogen was treated in drops, for 2 minutes, with a solution of Pro.pionyl chloride (0.128 mL, 0.00147 moles) in CH2C12 (3 mL). The mixture was kept in the ice bath for 20 minutes and at room temperature for 1 hour. It was then diluted with CH2C12, washed with saturated ~ NaHCO3, water and brine, dried (MgSO4) and concentrated. The residue (8) 9 was used without further purification in the next reaction.
A stirred mixture of the product (8) from the previous reaction and dioxane (20 mL), under nitrogen, was treated, in portions for 1 minute, with Lawesson's reagent (0.58 g, 0.0014 mol) and refluxed for 2 hours.; then he concentrated. The residue was subjected to silica gel chromatography with 2% MeOH-CHC13 and the product was crystallized from methyl tert-butyl ether to give 0.259 g of 9: p.f. 138-139 ° C; MS (ES) m / z 368 (M + H +), 390 (M + Na +); IR (DRUT) 3284, 3266, 1748, 1744 cm "1 [a] 24 D + 20 ° (MeOH); 1 H NMR [300 MHz, (CD3) 2 SO] d 1.12 (t, 3H), 2.56 (c, 2H ), 2.94 (m, 4H), 3.72 (m, 4H), 3.78 (d, d, 1H), 3.90 (t, 2H), 4.11 (t, 1H), 4.93 (, 1H), 7.05 (t, 1H) ), 7.16 (d, d, ~ 1H), 7.47 (d, d, 1H), 10.30 (s broad, 1H) Analysis calculated for C? 7H22FN303S: C, 55.57; H, 6.03; N, 11.44. C, 55.68; H, 6.21; N, 11.37.
EXAMPLE 15: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2 -oxo-5-oxazole idini 1] methyl] -2-chlorotioacetamide (11).
A stirred solution of 39 (1.54 g, 5.2 mmol) and triethylamine (750 mg, 7.5 mmol) in CH2C12 (50 mL), under nitrogen, was treated, in drops, during minutes with a solution of chloroacetyl chloride (465 mL 5.8 mmol) in CH2C12 (30 L) and maintained at room temperature for 18 hours, then washed with saturated NaHCO3 and diluted with NaCl, dried (Na2SO4) and The residue was subjected to flash chromatography on silica gel with 20-30% acetone-CH 2 Cl 2 to provide 1.49 g of 109 which was used in the next reaction without further purification.
A stirred mixture of 10 (0.371 g, 1.0 mols) and Lawesson's reagent (0.420 mg, 1.04 mmoles) in dioxane (10 L) was brought to reflux, under nitrogen for 2 hours and concentrated under reduced pressure.
The residue was subjected to silica gel chromatography-with 3-10% acetyl-CH 2 Cl 2 to provide 0.143 g of 11: MS (Cl) m / z 388 (M + H +); X NMR (300 MHz, CDC13) d 307 (m, 4H), 377 (d, d, 1H), 3.88 (, 4H), 4.04 (m, 1H), 4.12 (t, 1H), 4.35 (m, 1H), 4.61 (s, 2H), 4.98 (m, 1H), 6.96 (t, 1H), 7.08 (d, d, 1H), 7.44 (d, d, 1H), 8.69 (s, 1H). Analysis calculated for C? 6H19ClFN303S: C, 49.55; H, 4.94; N, . 83. Found: C, 49.38; H, 5.20; N, 10.27.
EXAMPLE 16: (S) -N- [[3 - [3-Fluoro-4 - (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -a, a, at ri f luorothioacetamide (13) . 1.
A stirred, ice cold solution of 39 (0.590 g, 2.0 mmol) and triethylamine (640 L, 4.6 mmol) in CH2C12 (10 mL) was treated with trifluoroacetic anhydride (325 mL, 2.3 mmol) and kept in the bath with ice for 10 minutes and then at room temperature. The reaction was monitored by TLC in silica gel with 30% acetone-CH2Cl2. Additional trif luoroacetic anhydride and triethylamine were added after 3 d (64 mL / 125 mL) 4 d (100 mL / 220 mL) and 6 d (325 mL / 1.0 mL). The reaction was terminated 1 hour after the last addition; it was mixed with CH2C12, washed with water and diluted with NaCl, dried (Na2SO4) and concentrated. The solid residue was recrystallized from acetone-heptane to give 0.566 g of 12: p.f. 161-164 ° C (dec); MS (EI) m / z 391 (m +). Analysis calculated for C? 6H17F4N304: C, 49.11; H, 4.38; N, 10.74. Found: C, 48.99; H, 4.56; N, 10.73.
A stirred mixture of 12 (0.391 g, 1.0 mmol) and Lawesson's reagent (0.422 g, 1.1 mmol) in dioxane (10 mL) was brought to reflux, under nitrogen for 2 hours, cooled slowly to room temperature and concentrated in vacuo. empty. The residue was subjected to flash chromatography on silica gel with 5-15% acetone-CH2Cl2 and the product was crystallized from acetone-heptane to give 0.249 g of 13: p.f. 151-152 ° C; MS (EI) m / z 407 (M +), 363, 209, 151, 95; 1H NMR (300 MHz, CDC13) d 3.05 (, 4H), 3.75 (d, d, 1H), 3.87 (m, 4H), 3.95 (m, 1H), 4.14 (t, 1H), 4.32 (m, 1H ), 5.01 (m, 1H), 6.92 (t, 1H), 7.05 (d, d, 1H), 7.38 (d, d, 1H), 9.03 (s, 1H). Analysis calculated for C? 6H? 7F4N303S: C, 47.17; H, 4.21; N, 10.31. Found: C, 47.09; H, 4.35; N, 10.27.
EXAMPLE 17: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a-fluorotioacetamide (15).
An ice-cooled, stirred solution of 39 (0.590 g, 2.0 mmol) and triethylamine (611 mL, 4.4 mmol) in CH2C12 (10 mL), under nitrogen, was treated, in drops, with a solution of fluoroacetyl chloride (220 mL, 2.2 mmol) in CH2C12 (5 mL) was kept in the ice bath for 10 minutes and at room temperature for 2 hours. It was then diluted with CH2C12, washed with water and dilute NaCl, dried (Na2SO4) and concentrated. The residue was subjected to silica gel chromatography with 10-30% acetone-CH2C12 to provide 0.180 g of 14: MS (ES) m / z 356 (M + H +), 378 (M + Na +).
A solution of 14 (0.180 g, 0.507 mmol) in dioxane, under nitrogen, was treated with Lawesson's reagent (0.206 g, 0.51 mmol), heated at 90-100 ° C for 1 hour and concentrated in vacuo. The residue was subjected to chromatography on silica gel with 15% acetone-CH2Cl2 to provide 0.161 g of : MS (E1) m / z 371 (M +); H NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.78 (d, d, 1H), 3.87 (m, 4H), 4.03 (m, 1H), 4.11 (t, 1H), 4.38 (m, 1H), 4.98 (m, 1H), 5.07 (s, 1H), 5.23 (s, 1H), 6.93 (t, 1H), 7.08 (dd, 1H), 7. 42 (d, d, 1H), 8.42 (s, 1H). Analysis calculated for C 16 H 19 F 2 N 303 S: C, 51.74; H, 5.16; N, 11.31. Found: C, 51.79; H, 5.31; N, 11.02.
EXAMPLE 18: (S) -N- [[3- [3-Fluoro-4- (4-morphol ynyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a, a-dif luorothioaceta ida ( 17).
A stirred, ice cooled mixture of 39 (0.590 g, 2.0 mmol), di-fluoroacetic acid (190 mL, 2.0 mmol), and 1-hydroxybenzotria zol (0.297 g, 2.2 mmol) in DMF (5 mL) under nitrogen, it was treated with 1- (3-dimethylaminopropyl) -3-ylcarbodiimide hydrochloride (0.843 g, 4.4 mmol) and kept at room temperature for 18 hours. It was diluted with CH2C12, washed with water and dilute NaCl, dried (Na2SO4) and concentrated. The solid residue was crystallized from EtOAc-heptane to give 0.617 g of 16: p.f. 149-150 ° C; XH NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.66 (m, 2H), 3.85 (i, 5H), 4.08 (t, 1H), 4.80 (m, 1H), 5.93 (t, J = 53.9 Hz, 1H), 6.92 (t, 1H), 7.06 (m, 2H), 7.39 (d, d, lfi); MS (EI) m / z 373 (M +). Analysis calculated for C 16 H 18 F 3 N 304: C, 51.48; H, 4.86; N, 11.26. Found: C, 51.59; H, 4.91; N, 11.29.
A stirred solution of 16 (0.373 g, 1.00 min) in dioxane (10 mL), under nitrogen was treated with Lawesson's reagent (0.404 g, 1.00 mmol), heated at about 95 ° C for 1 hour and concentrated in vacuo. . Chromatography of the residue on silica gel with 10% acetonide-CH2Cl2 and crystallization of the product from EtOAc-heptane gave 0.276 g of 17: p.f. 125-127 ° C; MS (EI) m / z 389 (M +), 345, 305, 247, 209, 195, 151, 138, 123, 109, 95; XH NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.76 (d, d, 1H), 3.86 (m, 4H), 4.01 (, 1H), 4.12 (t, 1H), 4.30 (m, 1H) ), 4.99 (m, 1H), 6.20 (t, J = 55.9 Hz, 1H), 6.92 (t, 1H), 7.06 (d, d, 1H), 7.38 d, d, 1H), 8.78 (s broad, 1 HOUR) . Analysis calculated for C26Hi8F3N303S: C, 49.35; H, 4.66; N, 10.79. Found: C, 49.37; H, 4.71 N, 10.83.
EXAMPLE 19: (S) -N- [[3- [3-Fluoro-4 - (4 -mor-folin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a-cyanothioacetamide (19).
A stirred mixture, cooled with ice, of 39 (0.646 g, 2.19 mmol), cyanoacetic acid (0.179 g, 2. 1 mmol) and 1-hydroxybenzothiazole (0.351 g, 2.6 mmol) in DMF (5 mL), under nitrogen, was treated with 1- (3-dimethylaminopropyl) -3-ylcarbodiimide hydrochloride (0.997 g, 5.2 mmol) and kept at room temperature for 24 hours. It was diluted with CH2C12, washed with water and dilute NaCl, dried (Na2SO4) and concentrated. The solid residue was crystallized from EtOAc-heptane to give 0.546 g of 18: p.f. 172-174 ° C: IR (DRIFT) 3316, 2256, 1754, 1684 cm "1; MS (EI) m / z 362 (M +). Analysis calculated for C? 7H19FN 04: C, 56.35; H, 5.28; N , 15.46, Found: C, 56.33; H, 5.30; N, 15.36.
A stirred solution of 18 (0.453 mg, 1.25 mmol) in dioxane (10 mL), under nitrogen, was treated with Lawesson's reagent (0.505 g, 1.25 mmol) and heated to about 100 ° C. When the reaction proceeded (TLC with 30% acetone-CH2Cl2) the mixture was cooled and concentrated in vacuo. Chromatography of the residue in silica gel with 10-20% acetone-CH2C12 and crystallization of the product from EtOAc-hepfano gave 0. 110 g of 19: p.f. 186-187 ° C (dec); MS (ES) m / z 379 (M + H +), 401 (M + Na +); XH NMR (300 MHZ, CDC13) d 3.05 (m, 4H), 3.81 (d, d.1H), 3.86 (m, 4H), 3.89 (s, 2H), 4.09 (t, 1H), 4.14 ( m, 2H), 5.01 (m, 1H), 6.92 (t, 1H), 7.05 (d, d, 1H), 7.34 (d, d, 1H), 9.15 (s, 1H); IR (DRIFT) 3244, 2260, 1754 cm Analogous to C? 7H? 9FN403S: C, 53. 96 H, . 06; N, 14.81. Found: C, 53.88; H, 5.39; N, 14.61.
EXAMPLE 20: (S) -N- [[3 - [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -, a-dichlorothioacetamide (21).
An ice-cooled, stirred solution of 39 (0.885 g, 3.00 mmol) and triethylamine (975 mL, 7 mmol) in CH2C12 (15 mL), under nitrogen was treated, dropwise with a solution of dichloroacetic anhydride (555 mL, 3.5 mmol) in CH2C12 (5 mL) and kept in the ice bath for 15 minutes and at room temperature for 18 hours. It was diluted with CH2C12, washed with water, saturated NaHCO3 and dilute NaCl, dried (Na2SO4) and concentrated. Chromatography of the residue in silica gel with 10% acetone-CH2Cl2 and crystallization of the product from acetone-heptane gave 0.463 g of 20: p.f. 197-198 ° C (dec); MS (ES) m / z 406 (M + H +), 428 (M + Na +); 1E NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.75 (m, 3H), 3.86 (m, 4H), 4.07 (t, 1H), 4.83 (m, 1H), 5.94 (s, 1H) , 6.92 (t, 1H), 7.06 (m, 2H), 7.41 (d, d, 1H).
A stirred solution of 20 (0.305g, 0.75 mmol) in dioxane (5 ml), under nitrogen, was treated with Lawesson's reagent (0.202g, 0.5 mmol), heated to about 90 ° C for 1 hour, cooled and it was concentrated in vacuo. Chromatography of the residue in silica gel first with 30% acetone-heptane and then with 10% acetone-methylene chloride and crystallization of the product rh form methylene chloride-heptane gave 0.203 g with 21: p.p. 143-144 ° C; HR17S (El) calculated for C? 6H? 8Cl2FN303 S (M) 421.0431. Analysis calculated for C16H? 8Cl2FN303, C, 45.51; H, 4.30; N, 9.95. Found: C, 45.47; H, 4.24: H, 9.88.
EXAMPLE 21: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -a- (methoxycarbonyl) thioacetamide (23).
A stirred solution of 39 (0.955 g, 3.2 mmole) and triethylamine (650 mL, 4.5 mmole) in CH2C12 (50 mL), under nitrogen, was plotted, in drops, during -20 minutes with a solution of methylmalonyl chloride (475 mL, 4.3 mmol) in CH2C12 (10 mL) and maintained at room temperature for 3 days. It was then washed with water and dilute NaCl, dried and concentrated. The residue was subjected to silica gel chromatography with 15-30% acetone-CH2Cl2 and the product was crystallized from acetone-hexane to provide 0.873 g of 22: p.f. 150-151 ° C; ? NMR (300 MHz, CDCl 3) d 3.03 (m, 4 H), 3.34 (s, 2 H), 3.67 (s, 3 H), 3.69 (m, 2 H), 3.76 (d, d, 1 H), 3.85 (m, 4H), 4.00 (t, 1H), 4.78 (m, 1H), 6.90 (t, 1H), 7.06 (d, d, 1H), 7.41 (d, d, 1H), 7.5"(t, 1H); MS (ES) m / z 396 (M + H +), 418 (M + Na +); HRMS (FAB) calculated for C18H23FN306 (M + H +) 396.1571, found 396.1579.
Analysis calculated for C18H23FN306: C, 54.68; H, 5.61; N, 10.63. Found: C, 54.69; H, 5.68; N, 10.58.
-CHjCOOCH3 A stirred solution of 22 (0.395 g, 1.0 mmol) in dioxane (10 mL), under nitrogen, was treated with Lawesson's reagent (0.202 g, 0.5 mmol) and maintained at room temperature for 4 hours 10 minutes and at 80-90 ° C for 1.5 hours. The reaction was followed by TLC in silica gel with 10% MeOH-CHCl3. At the same time, a smaller polar product begins to form. It was kept at room temperature for 18 hours and at 80 ° C for 2 hours; Lawesson's reagent (40 mg, 0.099 mmol) is added and heating at 80 ° C continued for 2 hours; There still remains some of the starting material. The mixture was concentrated and the residue was subjected to silica gel chromatography with 15% acetone-CH2Cl2 to provide 0.348 g of 23: XH NMR (300 MHz, CDC13) d 3.0.5 (, 4H), ~ 3.71 (s). , 3H), 3.81 (d, d, 1H), 3.86 (m, 4H), 3.88 (s, 2H), 4.07 (t, 1H), 4.19m, 2H), 4.99 (m, 1H), 6.91 (t , 1H), 7.07 (d, d, 1H), 7.42 (d, d, IH: 9.52 (s, 1H); IR (DRIFT) 3269, 1743 cm -i MS (Ei) m / z 411 (M +). Analysis calculated for C? 8H22FN305S: C. 52.54; H, 5.39; N, 10.21. Found: C, 52.58; H, 5.43: N, 10.14, EXAMPLE 22: (S) -N- [[3- [4 - [1- [1, 2,4] Triazolyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (25).
A stirred mixture of 2410'11 (0.150 g, 0.470 mmol) and dioxane (12.5 mL), under nitrogen, was treated with Lawesson's reagent (0.20 g, 0.50 mmol), refluxed for 1.5 hours, maintained at room temperature. environment for 18 hours and concentrated in va cuo. Flash chromatography of the residue on silica gel with 5% MeOH-CHCl3 gave the product which was crystallized from MeOH to give 0._100 g (63.4%) of 25: p.f. 161-163 ° C; ? E NMR [300 MHz, (CD3) 2SO] d 2.43 (s, 3H), 3.87 (m, 3H), 4.22 (t, 1H), 4.99 (m, 1H), 7.51 (d, 1H), 7.77 ( m, 2H), 8.26 (s, 1H), 8.97 (d, 1H), 10.35 (broad s, 1H); IR (heating) 3259, 3226, 3044, 1752 cm "1; MS (ES) m / z 336 (M + H +), 358 (M + Na +). Analysis calculated for C? 4H? 4FN502S: C, 50.14; , 4.21; N, 20.88, Found: C, 50.18; H, 4.26; N, 20.94.
EXAMPLE 23: (S) -N- [[3- [4 - [1- [1, 2,4] Triazolyl] phenyl] -2-oxo-5-oxazolidinyl] met il] thioacetamide (25).
A stirred mixture of 2610'12 (0.26 g, 0.938 mmol), ethyl dithioacetate (0.12 g, 0.998 mmol), sodium fluoride (0.040 g, 0.953 mmol) and absolute EtOH (10 mL), under nitrogen, were added. treated for 5 minutes with a solution of 0.97 M KOH (1.03 mL) in EtOH and kept at room temperature for 2 hours, then diluted with CH2C12 (75mL), washed with water, 1M KHS04, water and brine and evaporated . The residue was subjected to silica gel chromatography with 5% MeOH-CHCl 3 and the product was crystallized from MeOH to provide 0.118 g, m.p. 164-165 ° C (dec) and 0.026 g, m.p. 162-163 ° C (dec) of 25.
EXAMPLE 24: (S) -N- [[3- [1- (Hydroxyacetyl) -5-indolinyl] -2 -oxo-5-oxazolidinyl] methyl] thioacetamide (28). 1.
NHCbz An ice-cooled, stirred solution of 5213'14 (8.80 g, 0.0240 mol) in CH2C12 (25 mL) was treated for 20 minutes with a solution of trifluoroacetic acid (25 mL) in CH2C12 (10 mL). The mixture was kept in the ice bath for 2 hours 15 minutes and concentrated under reduced pressure. A solution of the residue in CH2C12 was washed with saturated NaHCO3 and dilute NaCl, dried (Na2SO4) and concentrated. The residue was used in the following reaction without further purification. A sample of this material (53) had: XH NMR (300 MHz, CDC13) d 3.00 (t, 2H), 3.54 (t, 2H), 3.85 (broad s, 1H), 5.17 (s, 2H), 6.59 ( d, 1H), 6.66 (broad s, 1H), 6.91 (d, 1H), 7.23 (s, 1H), 7.36 (m, 5H); MS m / z 269 (M + H +).
NHCbz A stirred mixture, cooled with ice, of 53 (product not purified from the previous reaction), acetone (200 mL), saturated NaHCO3 (200 mL) and water (30 L) was treated, in drops, for 20 minutes, with a solution of benzyloxy acetyl chloride (4.70 mL). , 0.030 mol) in acetone (55 mL), warmed slowly to room temperature and maintained for 18 hours. Chloride (1.0 L) in acetone (35 mL) was added dropwise and the mixture was kept at room temperature for an additional 3 hours and diluted with EtOAc and water. A solid was collected by filtration and dried to provide 4.00 g of unpurified product. The EtOAc solution was dried (Na2SO4) and concentrated to provide 5.36 of the product without further purification. Crystallization of the product from EtOAC gave a total of 6.35 of 5414, p. f 157-159.5 ° C The analytical sample had: p.f. 158-159.5 ° C; 1H NMR (300 MHz, CDC13) d 3.16 (t, 2H), 4.01 (t, 2H), 4.21 - (s, 2?, 4.69 s, 2H), 5.19 (s, 2H), 6.67 (s, 1H), 6.97 (d, 1H), 7.36 (m, 10H), 7.50 (broad s, 1H), 8.15 (d, 1H); MS (EI) m / z (relative intensity) 416 (M +, 9), 310 (8), 202 (10), 133 (8), 92 (8), 91 (99), 79 _ (7), 77 (9), 65 (12), 51 (6); IR (heating) 2381, 1722, 1659, 1608, 1558 crn "1. Analysis calculated for C25H24N204: C, 72. 10; H, 5.81; N, 6.73. Found: C, 72.05; H, . 8 6; N, 6 6 8.
A stirred suspension of 54 (1.16 g, 2.78 mmol) in THF (42 mL) was cooled, under nitrogen, to -78 ° C and treated, in drops, for 5 minutes with 1.6 M n-BuLi in hexane (1.83 mL). ). It was kept at -78 ° C for 50 minutes, treated, in drops, for 5 minutes with a solution of butyrate of (R) - (-) - glycidyl (0.500 g, 3.47 mmol) in THF (2 mL), left to warm at room temperature for 3 hours and kept for 18 hours. After dilution with EtOAc, it was washed with saturated NH 4 Cl, water and brine, dried (MgSO 4) and concentrated. Chromatography of the residue on silica gel with 3% MeOH-0.2% NH4OH-CHC13 afforded 0.60 g (56%) of 5514: XE NMR [300 MHz, (CD3) SO] d 3.14 (t, 2H), 3.59 (m, 2H), 3.79 (d, d, 1H), 4.03 (m, 3H), 4.29 (s.2H), 4.58 (s, 2H), 4.65 (m, 1H), 5.20 (t, 1H), 7.31 (m, 6H), 7.55 (s, 1H), 8.03 (d, 1H); MS (ES) m / z 383 (M + H +), 405 (M + Na +).
A stirred mixture, cooled with ice, of 55 (0.60 g, 1.57 mmol), triethylamine (2.2 mL), and CH2C12 (12 mL), under nitrogen, was treated with 3-nor t robencenesulfoni chloride (0.44 g, 1.99 mmol) and kept in the ice bath for 30 minutes and at room temperature for 60 minutes. It was then diluted with CH2C12, washed with water and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 15% CH3CN-CH2C12 yielded 0.70 g of 56: XH NMR (300 MHz, CDC13) d 3.19 (t, J = 8.3 Hz, 2H), 3.88 (d, d, 1H) , 4.04 (t, J = 8.4 Hz, 2H), 4.14 (t, 1H), 4.23 (s, 2H), 4.42 (m, 2H), 4.70 (s, 2H), 4.84 (m, 1H), 6.97 ( m, 1H), 7.34 (m, 5H), 7.58 (s, 1H), 7.81 (t, 1H), 8.22 (m, 2H), 8.53 (m, 1H), 8.73 (m, 1H); MS (ES) m / z 568 (M + H +), 590 (Ni + Na +).
A stirred mixture of 56 (unpurified product from 0.00314 mol of 55), acetonitride (70 mL), isopropanol (70 mL) and 29% __ of ammonium hydroxide (70 mL) was heated at 40-44 ° C for 7 hours and kept at room temperature for 18 hours. It was concentrated in vacuo to an aqueous residue which was extracted with CH2C12. The extract was washed with water and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 8% MeOH-0.5% NH40H-CHC13 afforded 1.05 g of 57: XR NMR [300 MHz, (CD3) 2S0] d 2.78 (m, 2H), 3.13 (t, 2H ), 3.82 (d, d, 1H), 4.01 (m, 3H), 4.29 (s, 2H), 4.58 (s, 2H), 4.58 (m, 1H), 7.31 (m, 6H), 7.54 (s broad) , 1H), 8.03 (d, 1H); MS (ES) m / z 382 (M + H +), 404 (M + Na +). 6. 27 A mixture of 57 (0.46 g, 1.21 mmol), MeOH (150 mL), 1 M HCl (1.2 mL) and 5% palladium on carbon catalyst (250 mg) was hydrogenated at an initial pressure of. 49 psi for 5 hours. 1M HCl (0.5 mL) and catalyst (100 mg) were added and the hydrogenation was continued for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated to provide 0.34 g of 27: XB. NMR [300 MHz, (CD3) 2SO] d 3.15 (t, 2H), 3.22 (broad s, 2H), 3.84 (d, d, 1H), 4.00 (t, 2H), 4.15 (s, 2H), 4.15 (m, 1H), 4.92 (m, 1H), 7.24 (c, 1H), 7.50 (d, 1H), 8.03 (d, 1H), 8.37 (broad s, 3H); MS (ES) m / z 2.92 (M + H +).
A suspension of 27 (0.10 g, 0.34 mmol) in a mixture of EtOH (15 mL) and 0.97 M KOH (0.7 mL) was added, under nitrogen to a stirred mixture of ethyl dithioacetate (0.0412 g, 0.343 mmol) and fluoride of sodium (0.0137 g, 0.326 mmol) in EtOH (5 mL) and the mixture was kept at room temperature for 2 hours 15 minutes. 0.97 M KOH was added (0.2 mL), sodium iodide (6 mg) and ethyl dithioacetate (20 mg) and the mixture was stirred for 2 hours, mixed with CH2C12 (150 mL), washed with water, 1M KHS04 and brine, dried (Na2SO4) and concentrated. The residue was crystallized from acetone to provide 0.0404 g of 28: p.f. 175-176 ° C (dec); MS (FAB) m / z 350 (M + H +), 349 (M +), 331, 316, 205, 73; HR MS (FAB) calculated for C? 6H20N3O4S (M + H +) 350.1174, found 350.1183; XH NMR [300 MHz, (CD3) 2) SO] d 2.42 (s, 3H), 3.14 (t, 2H), 3.79 (d, d, 1H), 3.89 (t, 2H), 4.00 (t, 2H) , 4.12 (m, 3H), 4.83 (t, 1H), 4.90 (m, 1H), 7.25 (d, 1H), 7.50 (s, 1H), 8.03 (d, 1H), 10.35 (s, 1H); IR (DRIFT) 3255, 3223, 3068, 1747, 1639, 1614 cm "1.
EXAMPLE 25: (S) -N- [[3- [3-Fluoro-4 - [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2 -oxo-5-oxazolidinyl] -methyl] thioacetamide (30). 58 59 A mixture of 5815 (3.00 g, 7.00 mmol), THF (60 mL), absolute EtOH (100 mL) and 10% palladium on carbon catalyst (415 mg) was hydrogenated at an initial pressure of 58 psi for 2 hours 50 minutes The catalyst was removed by filtration and the filtrate was evaporated to give 2.67 g of 59 which was used without further purification in the following reaction: XH NMR (300 MHz, CDC13) d 2.16 (broad s), 3.02 (m, 8H), 3.73 (d, d, J = 3.9, 12.6 Hz, 1H), 3.96 (m, 3H), 4.72 (m, 1H), 6.92 (t, J = 9.2 Hz, 1H), 7.11 (m, 1H ), 7.43 (d, d, J = 2.6, 14.3 Hz, 1H); MS (ES) m / z 296 (M + H +).
An ice-cooled, stirred mixture of 59 (2.67 g from the previous reaction), acetone (190 mL) and saturated NaHCO 3 (70 mL) was treated, in drops, for 2-3 minutes with a solution of benzyloxycetyl chloride (1.34 mL, 8.61 mmol) in acetone. (25 mL), was kept in the ice bath for 1 hour and diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic solution was washed with diluted NaCl, dried and concentrated. Chromatography of the residue on silica gel with 30% acetone-CH2Cl2 yielded 2.64 g of 60: XH NMR (300 MHz, CDC13) d 2.28 (broad s, 1H), 3.00 (m, 4H), 3.66 (m, 2H ), 3.77 (m, 3H), 3.96 (m, 3H), 4.22 (s, 2H), 4.61 (s, 2H), 4.74 (m, 1H), 6.88 (t, J = 9.2 Hz, 1H), 7.12 (, 1H), 7.35 (s, 5H), 7.46 (d, d, J = 2; 6, 14.2 Hz, 1H); IR (heating) 3406, 1748, 1647 cm "1; HRMS (EI) calculated for C23H26FN305 (M +) 443.1856, found 443.1842.
An ice-cooled, stirred mixture of 60 (2.64 g, 6.00 mmol) and triethylamine (1.14 mL, 8.16 mmol), in CH2C12 (200 mL), under nitrogen, treated with 3-nitrobenzenesulfonyl chloride (1.78 g, 8.04 mmol), warmed to room temperature and kept for 5 hours 20 minutes. 3-nitrobenzenesulfonyl chloride (180 mg) and triethylamine (0.20 mL) were added and the mixture was kept at room temperature for 18 hours, diluted with Cfl2Cl2 and washed with water and dilute NaCl, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 40-60% acetone-hexane gave 3.36 g of 77: XH NMR (300 MHz, CDC13) d 3. 02 (s broad, 4H), 3.66 (broad s, 2H), 3.78 (broad s, 2H), 3.87 (d, d, J = 5.9, 9.1 Hz, 1H), 4.09 (t, J = 9.2 Hz, 1H), 4.22 (s, 2H), 4.41 (m, 2H), 4.61 (s, 2H), 4.84 (m, 1H), 6.88 (t, J = 9.1 Hz, 1H), 7.02 (m, 1H), 7.35 (, 6H), 7.82 (t, J = 8.0 Hz, 1H), 8.23 (m, 1H), 8.53 (m, 1H), 8.73 (m, 1H); MS (ES) m / z 629 (M + H +). 77 61 A solution of 77 (3.36 g, 5.34 mmol) in a mixture of acetonitrile (90 mL), isopropanol (90 mL) and concentrated ammonia hydroxide (90 mL) was heated at 40-45 ° C for 18 hours, treated with additional ammonia hydroxide (30 mL), it was heated at 40-45 ° C for 8 hours, treated with additional ammonia hydroxide (25 mL) and heated at 45 ° C for 18 hours. It was then mixed with water and extracted with CH2C12. The extract was washed with diluted NaCl, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.5% NH 0H-CHC13 yielded 2.44 g of 61: 1 E NMR (300 MHz, CDC13) d 1.50 (broad s), 3.04 (m, 6H), 3.65 (s broad, 2H), 3.81 (m, 3H), 3.99 (t, 1H), 4.21 (s, -2H), 4.61 (s, 2H). 4.66 (m, 1H), 6.88 (t, 1H), 7.12 (m, 1H), 7.33 (m, 5H), 7.47 (d, d, 1H); MS (ES) m / z 443 (M + H +).
. A solution of 61 (1.45 g, 3.3 mmol) and CHl 1. 0 N (3.65 mL) in 95% EtOH (150 mL) was treated with 5% palladium on carbon catalyst (500 mg) and hydrogenated at an initial pressure of 54 psi for 20 hours 15 minutes. 1.0 N HCl (0.5 mL) and catalyst (100 mg) were added and the hydrogenation was continued for 20 hours 30 minutes at an initial pressure of 60 psi. The reaction was completed by TLC; neutralized with concentrated NH4OH, filtered and concentrated in vacuo to provide 1.18 g of 29: 1 H NMR [300 MHz, (CD3) 2 SO] d 2.94 (broad s, 4H), 3.19 (m, 2H), 3.48 (s) broad, 2H), 3.60 - (broad s, 2H), 3.84 (m, 1H), 4.14 (m, 3H), 4.66 (s broad, 1H), - 4.93 (, 1H), 7.07 (t, 1H), 7.16 (d, d, 1H), 7.48 (d, d, 1H), 8.04 (s broad); IR (heating) 3420, 3099, 3040, 3008, 1755, 1641 cm "1; -MS (ES) m / z 353 (M + H"). Analysis calculated for C? 6H22Cl FN404: C, 49.42; H, 5.70; Cl, 9.12; N, 14.41. Found: C, 48.16; H, 5.82; Cl, 10.00; N, 14.28.
A stirred mixture of ethyl dithioacetate (180 mL, 1.56 mmol), sodium fluoride (72 mg, 1.7 mmol), 29 (500 mg, 1.29 mmol) and EtOH (70 mL) under nitrogen, treated with 0.97 M KOH (1.46 mL, 1.42 mmol) and the resulting solution was kept at room temperature for 3 hours 35 minutes, was cured with CCH13, washed with water and dilute NaCl, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.5% NH40H-CHC13 and crystallization of the resulting product from absolute EtOH gave 0.238 mg (44.9%) 30: p.f. 163-165 ° C; 1E NMR (300 MHz, CDC13) d 2.60 (s, 3H), 3.06 (, 4H), 3.45 (m, 2H), 3.61 (m, 1H), 3.82 (, 3H), 4.07 (m, 2H), 4.25 (m, 3H), 4.97 (m, 1H), 6.91 (t, 1H), 7.07 (m, 1H), 7.45 (d, d, 1H), 7.91 (broad s, 1H); MS (FAB) m / z (relative intensity) 411 (M + H +), 100), 410 (M +, 66.5), 266 (3.1); IR 3292, 1733, 1653 cm "1. Analysis calculated for C? 8H23FN40 S: C, 52.67; H, 5.65; N, 13.65, Found: C, 52.76; H, 5.58; N, 13.64.
EXAMPLE 26: (S) -N- [[3- [3-Fluoro-4 - (4-thiomorpholinyl) phenyl] -2 -oxo-5-oxazolidinyl] methyl] thioacetamide (32).
A stirred mixture, cooled with ice of 31 (0.38 g 0.0012 mol) and triethylamine (0.38 mL, 0.0027 mol) in THF (12 mL), under nitrogen, treated with ethyl dithioacetate (0.16 mL, 0.0014 mol) and then maintained at room temperature for 24.5 hours and it was concentrated in vacuo. A solution of the residue in CH2C12 was washed with saturated NaHCO3, water and brine, dried (MgSO4) and concentrated. Crystallization of the residue from EtOAc-hexane gave 0.355 g of 32: p.f. 155-156 ° C; MS (ES) m / z 370 (M + H +), 392 (M + Na +); IR (DRIFT) 3206, 3042, 1759, 1738 cm "1 1R NMR (300 MHz, CDC13) d 2.60 (s, 3H), 2.95 (s, 4H), 3.43 (, 4H), 3.82 (d, d, 1H ), 4.08 (m, 2H), 4.27 (m, 1H), 4.98 (m, 1H), 7.06 (m, 1H), 7.33 (broad s, 1H), 7.51 (d, 1H), 8.03 (s broad, 1H) Analysis calculated for C? 6H2oFN302S2: C, 52.01; H, 5.46; N, 11.37. Found: C, 51.86; H, 5.43; N, 11.20.
EXAMPLE 27: (S) -N- [[3- [3-Fluoro-4 - (-1 iomor folini 1) • phenyl] -2-oxo-5-oxazolidinyl] methyl] thio-acet amide, S-oxide thiomorpholine (34).
A stirred, ice-cooled mixture of sodium metaperiodate (1.08 g, 5.05 mmol) and water (12 mL), under nitrogen, was treated with 6216 (1.5 g, 4.8 mmol) and MeOH (17 mL) and kept at 6 ° C for 18 hours and at 4 ° C for 3 hours. Then it was treated with additional sodium metaperiodate (0.1 g), kept at 4 ° C for 3 hours and extracted with CCH13. The extract was dried (MgSO4) and concentrated to provide 1.4 g of 63: XH NMR [300 MHz, (CD3) 2 SO] d 2.84 (m, 2H), 3.01 (m, 2H), 3.16 (m, 2H ), 3.50 (m, 3H), 3.65 (m, 1H), 3.77 (d, d, 1H), 4.03 (t, 1H), 4.66 (m, 1H), 5.18 (t, 1H), 7.16 (m, 2H), 7.52 (m, 1H); MS (ES) / z 329 (M + H +), 351 (M + Na +).
A stirred mixture, cooled with ice, of 63 (1.2-, g, 3.87 mmol) and triethylamine (0.732 mL, 5.25 mmol) in CH2C12 (130 mL), under nitrogen, was treated with nitrous oxide robenzenesulfonyl (1.15 g, 5.19 mmoles) and kept at room temperature for about 24 hours. It was diluted with CH2C12, washed with water and brine, dried (Na2SO) and concentrated to give 78 which was used in the next reaction without purification. 78 33 A stirred mixture of the product (78) from the previous reaction, acetonitrile (70 mL) and isopropanol (70 mL) was treated with concentrated ammonia hydroxide (70 L, 29.9% NH3) and maintained at 40 ° C. C for 2 hours, at room temperature for 18 hours and at 40-45 ° C for 4 hours; it was concentrated to approximately 50 mL, diluted with water and extracted with CH2C12. The extracts were washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-CHCl3 yielded 0.58 g of 33: MS (ES) m / z 328 (M + H +), 350 (M + Na +); XH NMR [300 MHz, (CD3) 2SO] d 2.81 (m, 4H), 3.01 (m, 2H), 3.16. (m, 2H), 3.30 (broad s), 3.49 (m, 2H), 3.80 (d, d, 1H), 4.01 (t, 1H), 4.58 (m, 1H), 7.19 (m, 2H), 7.51 (m, 1H). 33 34 A stirred suspension of 33 (3.7 g, 0.011 mol) and triethylamine (3.5 mL, 0.025 mol) in THF (120 mL) was cooled, in a bath with ice, under nitrogen, treated, in drops, for 2 minutes, with a solution of ethyl dithioacetate (1.47 mL, 0.0128 mol) in THF (2 mL) and kept at room temperature for 22 hours. The resulting solution was concentrated and the residue was crystallized from acetonitrile to give 3.61 g of 34: p.f. 176-177 ° C; XH NMR [300 MHz, (CD3) 2S0] d 2.42 (s, 3H), 2.85 (m, 2H), 3.01 (m, 2H), 3.18 (, 3H), 3.50 (m, 2H), 3.78 (d, d, 1H), 3.89 (broad s, 2H), 4.12 (t, 1H), 4.92 (m, 1H), 7.18 (m, 2H), 7.49 (m, 1H), 10.33 (s, 1H); IR (DRIFT) 3186. 3102, 1741 cm "1 MS (ES) m / z 386 (M + H +), 408 (M + Na +). Analysis calculated for C,? 6H20FN3O3S2o0.5 H20 H20: C, 48.71; H 5.37, N, 10.65, S, 16.26, H20, 2.38, Found: C, 48.75, H, 5.17, N, 10.72, S, 16.07, H20, 1.72.
EXAMPLE 28: (S) -N- [[3- [3-Fluoro-4 - (4-thiomorpholinyl) phenyl] -2-oxo-5-oxa zol idini 1] methyl] thio -acetamide, S, S-dioxide thiomorpholine (36).
A stirred mixture of 6216 (0.399 g, 0.00128 mol) in 25% water / acetone (12 mL), under nitrogen was treated with N-methylmorpholine, N-oxide (0.45 g, 0.00384 mol) and 0.1 mL of a solution to 2.5% by weight osmium tetroxide tert-butanol. It was kept at room temperature for 18 hours, mixed with saturated NaHS03 (50 mL) and extracted with CH2C12. The extract was washed with saturated NaHS03 and brine, dried (Na2SO4) and concentrated. The residue was mixed with 3.5% MeOH-CH2Cl2 and filtered; the solid was dissolved in 15% MeOH-CH2Cl2 and concentrated to give 0.29 g of 64. The filtrate was subjected to silica gel chromatography with 3.5% MeOH-CH2Cl2 to provide 0.1 of 64 additional: MS (ES) m / z 345 (M + H +), 367 (M + Na +); X H NMR [300 MHz, (CD 3) 2 SO] d 3.26 (m, 4 H), 3.44 (m, 4 H), 3.60 (m, 2 H), 3.80 (d, d, 1 H), 4.05 (t, 1 H), 4.69 (m, 1H), 7.22 (m, 2H), 7.54 (d, 1H).
A stirred mixture of 64 (0.39 g, 0.00113 mol) and triethylamine (0.214 mL, 0.00154 mol) in CH2C12 (37 mL) was cooled, under nitrogen. in a bath with ice and treated, in drops for 5 minutes, with 3-nit robencensul fonilo chloride (0.335 0.00151 mol). The mixture was kept in the ice bath for 20 minutes and at room temperature for 18 hours and concentrated in vacuo. A stirred solution of the residue in 2-propanol (25 mL) and acetonitrile (25 L), under nitrogen, was treated with 30% NH40H (25 mL,), heated at 50-55 ° C for 6 hours and maintained at room temperature for 48 hours. Concentrate to remove organic solvents, dilute with water and extract with CH2C12.
The extract was washed with water and brine, dried (MgSO4) and concentrated. Flash chromatography of the residue on silica gel with 6% MeOH-0.4% NH40H-CHC13 yielded 0.29 g of 35: XH NMR [300 MHz, (CD3) 2SO] d 1.59 (broad s, 2H), 2.78 (m, 2H), 3.24 (m, 4H), 3.43 (m, 4H), 3.81 (d, d, 1H), 4.01 (t, 1H), 4.57 (, 1H), 7.18 (m, 2H), 7.52 (m, 1H); MS (ES) m / z 344 (M + H +), 366 (M + Na +).
A stirred, ice-cooled suspension of 35 (0.28 g, 0.85 mmol) in a mixture of Et3N (0.26 mL, 1.9 mmol) and THF (10. mL) was treated with ethyl dithioacetate (0.11 mL, approximately 6 drops). and kept in the ice bath for 20 minutes and then at room temperature; the reaction was followed by TLC. After 20 hours there was still a suspension and only a partial reaction; THF (10 mL) and ethyl dithioacetate (3 drops) were added. After a further 48 hours the reaction was still incomplete; Luna suspension was treated with CH2C12 (10 L) and maintained for 72 hours. At the same time an almost complete solution and almost complete conversion for the product was obtained. An additional drop of ethyl dithioacetate was added and the mixture was kept at room temperature for 5 d and concentrated in vacuo. The residue was mixed with EtOAc, washed with saturated NaHCO 3, water and brine, dried (MgSO 4) and concentrated. Crystallization of the residue from MeOH-EtOAc gave 0.209 g of 36: p.f. 197-198 ° C; XH NMR [300 MHz, (CD3) 2SO] d 2.42 (s, 3H), 3.24 (m, 4H), 3.43 (m, 4H), 3.78 (d, d, 1H), 3.88 (m, 2H), 4.12 (t, 1H), 4.92 (m, 1H), 7.18 (m , 2H), 7. 50 (m, 1H), 10.37 (broad s, 1H); IR (heating) 3300, 3267, 1743 cm "1; MS (ES) m / z 424 (M + Na +). Analysis calculated for Ci6H20FN3O4S2: C, 47. 87; H, 5. "? 2; N, 10.47 \ Found: C, 47.84; H, . 2. 3; N, 10.28.
EXAMPLE 29: (S) -N- [[3- [3, 5-Dif luoro-4 - [4 - (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (38 ). 1.
A stirred mixture of 65, 17 (1.8 g, 0.00396 mol), pyridine (30 mL) and absolute EtOH (3 mL), under nitrogen, was treated with hydroxylamine hydrochloride (1.44 g, 0.0207 mol), heated to room temperature. reflux for 2 hours, refluxed for 3.5 hours, maintained at room temperature for 18 hours and refluxed for 4 hours. It was concentrated in vacuo and the residue was mixed with water, adjusted to pH 11 with saturated NaHCO3 and extracted with Et20. The extracts were washed with brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.35% NH40H-CHC13 yielded 0.75 g of 65 recovered and 0.72 g of 66 LH NMR [300 MHz, (CD3) 2SO] d 1.40 (s, 9H), 1.72 (s, broad, 2H), 2.78 (m, 2H), 2.97 (m, 4H), 3.40 (m, 4H), 3.80 ( d, d, 1H), 4.00 (t, 1H), 4.59 (m, 1H), 7.27 (d, 2H); MS (ES) m / z 413 (M + H 435 (M + Na +) 2.
A stirred mixture, cooled with ice, of 66 (0.75 g, 0.0018 mol) and triethylamine (0.315 L, 0. 00225 mol) in THF (12 mL), under nitrogen, treated, in drops, with benzyl chloroformate (0.29 mL, 0.0020 mol), kept in the ice bath for 15 minutes and at room temperature for 2 hours and concentrated in vacuo The residue was mixed with CH2C12 and washed with saturated NaHCO3, water and brine, dried (Na2SO4) and concentrated. This residue was mixed with Et20 and filtered to provide 0. 939 g of 67: p.f. 116-118 ° C; XH NMR (300 MHz, CDC13) d 1.48 (s, 9H), 3.08 (m, 4H), 3.53 (m, 4H), 3.60 (m, 2H), 3.73 (m, 1H), 3.96 (t, 1H), 4.76 (m, 1H), 5.10 (s, 2H), 5.21 (m, 1H), 7.07 (d, 2H), 7.31 (s, 5H); MS (ES) m / z 547 (M + H +), 569 (M + Na +). 67 68 Compound 67 (0.805 g, 0.00147 mol) was added with stirring, in portions for 5 minutes, under nitrogen, to ice-cooled trifluoroacetic acid (9 mL). The resulting solution was kept in the ice bath for 1 hour and then concentrated under a stream of nitrogen. The residue was mixed with ice and saturated NaHCO 3 and extracted with CH 2 C 12; The extract was washed with water and brine, dried (Na2SO4) and concentrated to provide 0.63 g of the product. The combined aqueous layer was back extracted with EtOAc; the extracts were washed with water and brine, dried (Na2SO4) and concentrated to provide the additional product. The combined product was 0.68 g of 68 which was used in the next reaction without further purification.
A stirred mixture, cooled with ice, of 68 (0.68 g, 0.00152 mol), saturated NaHCO3 (15.2 mL) and acetone (40 mL), under nitrogen was treated, in drops, for 15 minutes, with a solution of benzyloxycetyl chloride (0.29 mL, 0.0019 mol) in acetone. (5 mL), was maintained at room temperature for 6 hours, diluted with EtOAc and washed with water and brine. The extract was dried (MgSO4) and concentrated in vacuo to give 0.72 g of 69: MS (ES) m / z 395 (M + H +), 617 (M + Na +); XH NMR (300 MHz, CDC13) d 3.12 (m, 4H), 3.59 (m, 4H), 3.74 (m, 3H), 3.96 (t, 1H), 4.22 (s, 2H), 4.62 (s, 2H) , 4.75 (broad s, 1H), 5.10 (s, 2H), 5.22 (m, 1H), 7.08 (d, 2H), 7.33 (m, 10H). 37 69 A mixture of 69 (0.72 g, 0.0012 mol), MeOH and 5% palladium on carbon catalyst (0.4 g) was hydrogenated at an initial pressure of 4.5 psi for 4 hours by TLC (8% MeOH-0.5% NH40H- CCH13) the starting material has been reduced and two products were formed. 1M hydrochloric acid (1.34 mL) was added and hydrogenation was continued at an initial pressure of 40 psi for 21 hours. Only the most polar product remained through TLC. The catalyst was removed by filtration and the filtrate was concentrated to give 0.40 g of 37: MS (ES) m / z 371 (M + H +), 393 (M + Na +); XH NMR [300 MHz, (CD3) 2SO] d 3.02 (s, 4H), 3.20 (m, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 3.84 (m, 1H), 3.84 (s) broad), 4.10 (s, 2H), 4.14 (t, 1H), 4.96 (m, 1H), 7.26 (d, 2H), 8.41 (broad s, 3H). 6. -xHCI 38 37 A stirred suspension of 37 (0.38 g) in a solution of Et3N (0.31 mL) and THF (10 mL), under nitrogen, was treated with ethyl dithioacetate (0.13 mL, approximately 7 drops) and maintained at room temperature for 7 hours. d; the reaction was followed by TLC (8% MeOH-0.5% NH40H-CHC13). Additional ethyl dithioacetate (2 drops) was added after 24 hours; after 30 hours CH2C12 (10 mL) and ethyl dithioacetate (3 drops) were added; After 48 hours additional triethylamine (0.3 mL) was added. The mixture was concentrated in vacuo and the residue was mixed with ice and saturated NaHCO3 and extracted with CH2C12. The extract was washed with water and brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography with 2.5% MeOH-CH2Cl2 and the product was crystallized from MeOH to provide 0.182 g of 38: m.p. 110-111 ° C (dec); MS (ES) m / z 429 (M + H +), 451 (M + Na +); HRMS (FAB) calculated for C? 8H23F2N404S (M + H +) 429.1408, found 429.1415; IR (DRIFT) 1760, 16.52, 1639 cm "1; [a24D 8o (MeOH).
EXAMPLE 30: (S) -N- [[3- [4 - [1- [1, 2,4] Triazolyl] f eni 1] -2-oxo-5-oxazolidinyl] methyl] thiourea (44). 1.
A solution of 26 (0.190 g, 0.685 mmol) in CH2C12 (20 mL) was added, in drops for 20 minutes, under nitrogen, to a stirred solution, cooled with ice of 1. lc-thiocarbonyldi-2 (1H) -pyridone (0.193 g, 0.831 mmol) in CH2C12 (7 mL). The mixture was kept in the ice bath for 20 minutes and at room temperature for 2 hours, diluted with CH2C12, washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with 10-15% CH3CN-CH2C12 yielded 0.11 g of 79 which was used in the next reaction without further purification: MS (ES) m / z 320 (M + H +), 342 (M + Na +). 2. 79 44 A stirred, ice-cooled solution of 79 (0.10 g, 0.31 mmol) in THF (15 niL) was treated with excess anhydrous ammonia and kept in the ice bath for 90 minutes. Then it was evaporated under a stream of nitrogen to a volume of about 5 mL to provide a solid which was collected by filtration and washed with cold THF to give 0.105 g of 44: p.f. 214-215 ° C; XH NMR [300 MHz, (CD3) 2SO] d 3.82 (m, 3H), 4.18 (t, 1H), 4.89 (broad s, 1H), 7.20 (broad s, 2H), 7.50 (d, 1H), 7.79 (m, 2H), 7.93 (t, 1H), 8.26 (s, 1H), 8.97 (s, 1H); MS (ES) m / z 337 (M + H +), 359 (M + Na +). Analysis calculated for C? 3 H13FN602s: C, 46.42; H, 3.90; N, 24.99. Found: C, 46.22; H, 3.98; N, 24.55.
EXAMPLE 31: (S) -N- [[3- [3-Fluoro-4 - [4- (hydroxyacetyl-1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] thiourea (45).
A stirred, ice-cooled solution of 1, l-thiocarbonyl-2 (1H) -dipyridone (0.123 g, 0.530 mmol) in CH2C12 (5 mL), under nitrogen, was treated with a suspension of 29 (0.17 g, 0.4 mmol. ) in CH2C12 (20 mL) and then for 10 minutes with a solution of triethylamine (0.111 mL, 0.8 mmol) in CH2C12 (10 mL). It was kept in the ice bath for 30 minutes at room temperature for 2 hours and at < 0 ° C for 18 hours. It was then diluted with CH2C12, washed with water and brine, dried (MgSO4) and concentrated. The residue (80) was used without further purification in the next reaction. A sample of 80 was purified by flash chromatography on silica gel with 10-20% acetonitrile-CH2Cl2 had: XH NMR (300 MHz, CDC13) d 1.60 (broad s) ', 3.07 (m, 4H), 3.45 (m , 2H), 3.85 (m, 4H), 3.97 (d, d, 1H), 4.16 (t, 1H), 4.21 (s, 2H), 4.82 (m, 1H), 6.95 (t, 1H), 7.13 ( d, d, 1H), 7.47 (d, d, 1H); MS m / z 395 (M + Ht); 417 (M + Na +).
SO 45 Excess anhydrous ammonia was bubbled into a stirred, ice-cold solution of 80 (product not purified from the previous reaction) in THF (25 mL) and the mixture was kept in the ice bath for 90 minutes and concentrated under a stream of nitrogen. The residue was subjected to silica gel chromatography with 5% MeOH-0.4% NH40H-CHC13 and the product was crystallized from acetonitrile to provide 0.0544 g of 45: p.f. 209-210 ° C; XH NMR [300 MHz, (CD3) 2S0] d 294 (broad s, 4H), 3.47 (broad s, 2H), 3.60 (broad s, 2H), 3.78 (broad s, 3H), 4.07 (t, 1H) , 4.10 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 5.5 Hz, 1H), 4.81 (s broad, 1H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.15 (s broad, 2H), 7.49 (d, d, 1H), 7.91 (t, 1H); IR (heating) 3443, 3403, 3321, 3202 3081 1753 1655 1648 cm -i HRMS (FAB) calculated for C17H23FN504S (M + H +) 412.1454, found 412.1447. Analysis calculated for C? 7H22FN504S: C, 49.63; H, 5.39; N, 17.02. Found: C, 49.63; H, 5.48; N, 16.99.
EXAMPLE 32: (S) -N- [[3 - [1 - (Hydroxyacetyl) -5-indolinyl] -2-oxo-5-oxazolidinyl] met il] thiourea (46). 1.
~~ A "stirred solution, cooled with ice from 1, 1-thiocarbonyldi-2 (1H) -pyridone (0.096 g, 0.41 mmol) in CH2C12 (5 mL) was treated with a suspension of 27 (0.10 g, 0.34 mmol) in CH2C12 (15 mL) and then 0.05 mL (0.36 mmole) of triethylamine. It was kept in the ice bath for 30 minutes and at room temperature for 2 hours, diluted with CH2C12, washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue in silica gel with 20-40% CH, CN-CH, C12 gave 0.04 g of 81.
Excess anhydrous ammonia was bubbled into an ice-cooled solution of 81 (0.04 g) in THF (30 mL) and the mixture was kept in the ice bath for 80 minutes and concentrated under a stream of nitrogen. The residue was crystallized from CH3CN to provide 0.0151 g of 46: p.f. 214-215 ° C (dec); MS (FAB) m / z 351 (M + H +), 350 (M +), 319, 304.147; HRMS (FAB) calculated for C? 5H19N 04S (M + H +) 351.1127, found 351.1130; IR (DRIFT) 3329, 3296, 3196, 1746, 1655, 1626 cm "1.
EXAMPLE 33: (S) -N- [[3 - [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea, S-oxide of thiomorpholine (47). 33 82 A suspension of 33 (0.30 g, 0.92 mmol) in CH2C12 (7 mL) was added over 20 minutes to a stirred, ice-cooled mixture of 1,1c-thiocarbonyldi-2 (1H) -pyridone (0.258 g, 1.11 g. mmoles) and CH2C12 (20 mL). The mixture was kept in the ice bath for 20 minutes and at room temperature for 2 hours, mixed with CH2C12 (50 mL), washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the product in silica gel with 20-50% CH3CN-CH2C12 yielded 0.27 g of 82 which was used in the following reaction: MS (ES) m / z 370 (M + H +), 392 (M + Na +) . 2. 82 47 An ice-cooled, stirred solution of 82 (0.27g, 0.73 mmol) in THF (15 mL), under nitrogen, was treated with excess anhydrous ammonia, kept in the ice bath for 1 hour and concentrated; crystallization of the residue from MeOH gave 0.175 g of 47; p.f. 212-213 ° C; X NMR [300 MHz, (CD3) 2SO] d 2.83 (m, 2H), 3.01 (m, 2H), 3.17 (m, 2H), 3.50 (t, 2H), 3.78 (broad s, 3H), 4.08 ( t, 1H), 4.80 (broad s, 1H), 7.17 (m, 2H), 7.17 (broad s, 2H), 7.50 (d, 1H), 7.90 (t, 1H); MS (ES) m / z 409 (M + Na +); IR (heating) 3335, 3284, 3211, 3175, 3097, 1750, 1630 cm "1. Analysis calculated for Ci5H? 9FN4? 3S2: C, 46.62; H, 4.95; N, 14.50 Found: C, 46.50; H, 4.95; N, 14.40.
EXAMPLE 34: (S) -N- [[3 - [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] met il-S-methylditiocarbamate (48). 48 39 A stirred mixture, cooled with ice, of 398 (0.59 g, 0.0020 mol), EtOH (1.5 mL), water (2 drops) and triethylamine (0.613 mL, 0.00440 mol), under nitrogen, was treated with carbon disulfide (0.066 L, 0.0011 mol) and maintained in the bath with ice for 2 hours and at room temperature for 18 hours. (A solution was obtained after the addition of carbon disulfide, a precipitate began to form shortly after the mixture was warmed to room temperature.) The slurry was treated, in drops, for 2 minutes, with an iodide solution. of methyl (0.137 mL, 0.00220 mol) in EtOH (2 mL) and the mixture was maintained at room temperature for 1.5 hours and concentrated in vacuo. A solution of the residue in EtOAc was washed with saturated NaHCO 3, water and brine, dried (MgSO 4) and concentrated. The residue was subjected to silica gel chromatography with MeOH-CH2Cl2 and the product was crystallized from EtOAe to give 0.197 g of 48: p.f. 154-155 ° C. IR (heating) 3354, 3346, 1726 cm "1.
Analysis calculated for C? 6H20FN3O3S2: C, 49.85; H, 5.23; N, 10.90. Found: C, 49.73; H, 5.25- N, 10.82.
EXAMPLE 35: (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl-0-methylthiocarbamate (50). 50 43 A stirred mixture of 48 (0.200 g, 0.518 mmol), sodium methoxide (0.003 g, 0.06 mmol) and MeOH (5 mL), under nitrogen, was brought to reflux for 4 hours and maintained at room temperature for 18 hours. hours. It was found that the starting material and the product had similar mobilities in TLC. Therefore, the reaction was followed by MS (ES). The starting material was still present. The mixture was refluxed for 3 hours, additional sodium methoxide (0.005 g) was added and the reflux was continued for 2 hours. It was kept at room temperature for 18 hours, refluxed for 1 hour, maintained at room temperature 1.5 hours and concentrated in vacuo. The residue was mixed with ice, the pH was adjusted to 9-10 with 1M KHS04 and saturated NaHCO3 and the mixture was extracted with CH2C12. The extract was washed with water and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with 5% acetone-CH2Cl2 and the product was crystallized from EtOAc-hexane to give 0.107 g of 50: p.f. 128-129 ° C; MS (ES) m / z 370 (M + H +), 392 (M + Na *); IR (DRIFT) 3282, 3251, 1753, 1735 cm "1; XH NMR [300 MHz, (CD3) 2SO] d 2.94 (m, 4H), 3.47, 374 (m, m, 7H), 3.86, 3.91 (s) , s, 3H), 4.10 (m, 1H), 4.73, 4.86 (m, m, 1H), 7.05 (t, 1H), 7.16 (d, d, 1H), 7.47 (d, d, 1H), 9.41 9.50 (s, s, 1H) Analysis calculated for C? 6H2oFN304S: C, 52.02; H, 5.46; N, 11.38 Found: C, 51.97; H, 5.49; N, 11.35.

Claims (1)

CLAIMS A compound of Formula I or acceptable pharmaceutical salts thereof characterized in that: G is a) H, b) NH 2, c) NH-C 1 -4 alkyl, d) C 4 alkyl, e) alkyl of -OC 4, f) -S alkyl of C 4, g) alkyl of C? -4 substituted with 1-3 F, 1-2 Cl, CN or alkyl of -COOC? _4, h) C3-6 cycloalkyl, i) N (alkyl of 01-4) 2 j) N ^ CH2) 2-5; A is d) a 5-membered heteroaromatic entity having from one to three atoms selected from the group consisting of S, N, and 0, wherein the 5-membered heteroaromatic entity is linked by a carbon atom, wherein the heteroaromatic entity of 5 members may additionally have a ring fused in benzene or naphthyl, wherein the heteroaromatic entity is optionally substituted with one to three R48, e) a 6-membered heteroaromatic entity having at least one nitrogen atom, wherein the heteroaromatic entity is bound by a carbon atom, wherein the 6-membered heteroaromatic entity may additionally have a ring fused to benzene or naphthyl, wherein the heteroaromatic entity is optionally substituted with one to three R55, f) a β-carbolin-3-yl , or indolizinyl through the 6-membered ring, optionally substituted with one to three R55, wherein R2 e s a) H, b) F, c) Cl, d) Br, e) alkyl of C? _3, f) N02, or g) R2 and R3 taken together are -O- (CH2) -0-; a) -S (= 0)? R, b) -S (= 0) 2-N = S (O) jR5R6, c) -SC (= 0) R7, d) -C (= 0) R8, e) -C (= 0) R9, f) -C (= 0) NR? oRn, g) -C (= NR? 2) R8, h) -C (R8) (Rn) -OR13, i) -C (R9) (R ??) - OR13, • j) -C (R8) (Rn) -OC (= 0) Rx3, k) -C (R9) (Rn) -OC (= 0) Ri3, 1) -NRioRn, m) -N (Rio ) -C (= 0) R7, n) -N (R? O) -S (= 0) 1R7 / o) -C (0R14) (0R15) Rs, p) -C (R8) (R? 6) - RioRn, oq) alkyl of Cl-8 substituted with one or more = 0 other than those of the alpha position, -NR10Rn, alkenyl of C2_5, or alkynyl of C2_5; R is a) C 1 alkyl optionally substituted with one or more haloes, OH, CN, NRioRn, or -C02R? 3, b) C2_ alkenyl, e) -NR16R? S, d) -N3, e) - NHC (= 0) R7, f) -NR20C (= 0) R7, g) -N (R? 9) 2, h) -NR16R? 9, oi) -NR19R20, R5 and Re in each case are the same or different and are a) alkyl of C? -2, or b) R5 and Re taken together are - (CH2) k ~; R is C 1 -4 alkyl optionally substituted with one or more haloes; R8 is a) H, or b) C? -8 alkyl optionally substituted with one or more haloes, or C3_8 cycloalkyl; Rg is C ?4 alkyl substituted by one or more a) -S (= 0) Ri7, b) -0R13, c) -0C (= 0) R3, d) -NR10R11, oe) alkenyl of -1 -5 optionally substituted with CHO; Rio and Rn in each case are the same or different and are a) H, b) Cx_ alkyl, or c) C3_8 cycloalkyl; Ri2 is a) -NRioRn, b) -OR10; or c) -NHC (= 0) Rio, "R? 3 is a) H, or b) alkyl of C? _4; 14 and Ris in each case are the same or different and are a) alkyl of C? _4, or b) R and Ris taken together are - (CH)? -; R 16 is a) H, b) C 4 alkyl, c) C 3 8 cycloalkyl, Ri 7 is C 4 alkyl, or C 3 8 cycloalkyl, Ris is a) H, b) C ?4 alkyl, c) C2_4 alkenyl, d) C3_ cycloalkyl, e) -OR13 of) -NR21R22; '19 is a) Cl, b) Br, oc) I; R20 is a physiologically acceptable cation, R 2 and R 22 in each case are the same or different and are a) H, b) C 1 alkyl, o c) -NR 21 R 22 taken together are - (CH 2) m-; wherein R 23 and R 2 24 in each case are the same and are a) H, b) F, c) Cl, d) alkyl of C? _2, e) CN f) OH, g) alkoxy of C? _2, h) nitro, oi) amino; Q is w- ^ d) * M £ 'N ) j) m _ * 1 ) m) a diazinyl group optionally substituted with X and Y, n) a triazinyl group optionally substituted with X and Y, or) an inyl quinol group optionally substituted with X and Y, p) a quinoxalinyl group optionally substituted with X and Y And, q) a naft iridinyl group optionally substituted with X and Y, s) or V) -p-) O » x) N N- y) And I z) NEITHER \ aa) ^ "N Y Q and R taken together are wherein Z1 is a) -CH2-, b) -CH (R104) -CH2-, c) -C (O) -, or. d) -CH2CH2CH2-; wherein Z2 is a) -02S-, b) -0-, c) -N (R107) -, d) -OS-, or e) -S-; wherein Z3 is a) ~ 02S-, c) -OS-, or d) -S-; wherein A1 is a) H-, or b) CH3; wherein A2 is a) H-, b) HO-, c) CH3-, d) CH30-. e) R102O-CH2-C (O) -NH-f) R103O-C (O) -NH-, g) (C? C2) alkyl-OC (O) -, h) HO-CH2-, i) CH30 -NH-, j) (C1-C3) alkyl-02C-k) CH3-C (0) -, 1) CH3-C (0) -CH2-, madas together are a) R1 »2 1+ - ^ o = o \ c) wherein R102 is a H-, b) CH3-, c) phenyl-CH2-, or d) CH3C (O) -; wherein R103 is a) (C1-C3) alkyl-, or b) phenyl- wherein R104 is a) H-, or b) H0-; wherein R105 is a) H-, b) (C! -C3) alkyl-, c) CH2 = CH-CH2-, or d) CH3-0- (CH2) 2-; where R 106 is a) CH3-C (0) -, b) H-C (O) -, c) C12CH-C (0) -, d) HOCH2-C (0) -, e) CH3S02-, f) C (O) -! - F2CHC (0) -, h) N ^ N-C (O) - i) H3C-C (0) -0-CH2-C (0) -, j) H-C (0) -0-CH2-C (0) -, k) < r0 { O) - 1) CH = C-CH20-CH2-C (0) -, or m) phenyl-CH2-0-CH2-C (0) -; wherein R107 is a) R102O-C (R110) (R111) -C (0) -, b) R103O-C (O) -, c) R108-C (O) -, d) Q < f) H3C-C (0) - (CH2) 2-C (0) -g) R109-S02-, h) < »? HO-CH2-C (O) R 116 (CH2: k) R113-C (0) -0-CH2-C (O) -, 1) (CH3) 2N-CH2-C (O) -NH-, m) NC-CH2-, or n) F2-CH-CH2-; R108 is a) H-, b) (Ci-C4) alkyl, c) aryl- (CH2) p, d) C1H2C-, e) C12HC-, f) FH2C-, g) F2HC-, oh) (C3- C6) cycloalkyl; wherein R109 is a) -CH3, b) -CH2C1 c) -CH2CH-CH2, d) aryl, or e) -CH2CH; wherein R110 and R111 are independently a) H-, b) CH3-; or wherein R112 is a) H-, b) CH30-CH20-CH2-, or c) HOHC2-; wherein R113 is a) CH3-, b) HOCH2-, c) (CH3) 2-phenyl, or d) (CH3) 2N-CH2-; where R114 is aa)) HO-, b) CH30-, c) H2N-, d) CH30-C (0) -0-, e) CH3-C (0) -0-CH2-C (0) - O-, ff)) phenyl-CH2-0-CH2-C (0) -O-, g) HO- (CH2) 2-0-, h) CH30-CH2-0- (CH2) 2-0-, or i) CH30-CH2-0-, wherein R 113 is a) CH3-, b) HOCH2-, c) (CH3) 2N-phenyl, or d) (CH3) 2N-CH2-, wherein R115 is a) H -, or b) C 1 -; wherein R116 is a) H0- b) CH30-, or B is an unsaturated 4-atom binder having one nitrogen and three carbons; M is a) H, b) C? _8 alkyl, c) C3_8 cycloalkyl, d) - (CH2) mOR13, or e) - (CH2) h-NR2? R22; Z is a) 0, b) S, or c) NM; is CH, N, or S or O when Z is NM; Y is H, F, Cl, Br, alkyl of C? _3, or N02; X is a]) H, b: > -CN, c: 1 0R27, d:) halo, e: 1 N02, f:) tetrazoyl, g: 1 -SH, h; 1 -S (= 0) iR4, i:! -S (= 0) 2-N = S (0) jR5R6 j: 1 -SC (= 0) R7,: 1 -C = 0) R25, i:) -C (-0) NR27R28,: 1 -C (= NR29) R25, n) -C (R25) (R28) -OR? 3, o) -C (R25) (R28) -OC (= 0) R13, P) -C (R28) (OR13) - (CH2) h-NR27R28, q) -NR27R28, r) -N (R27) C (= 0) R7, s) -N (R27) -S (= 0) iR7, t) -C (OR14) (0R15 ) R28, u) -C (R25) (R) -NR27R26, ov) C? -8 alkyl substituted with one or more haloes, OH, = 0 other than in the alpha position, -S (= 0) iR? 7 / -NR27R28, C2-5 alkenyl, C2-5 alkynyl, or C3_8 cycloalkyl; R4, R5, e, R7, 13? 4, 15, La, and R17 are the same as defined above; R25 is a) H, b) C8-8 alkyl optionally substituted with one or more haloes, C3_8 cycloalkyl, alkyl substituted with one or more of -S (= 0)? R? 7, -OR13, or 0C (= 0) Ri3, NR27R28, oc) C2-5 'alkenyl optionally substituted with CHO, or C02R13; R26 is a) R28, or b) NR27N28; R27 and 28 in each case are the same or different and are a) H, b) C? -8 alkyl, c) C3_8 cycloalkyl, d) - (CH2) ra0R13, e) - (CH2) h-NR21R22, of ) R27 and R28 taken together are - (CH2) 20 (CH2) 2-, - (CH2) hCH (C0R7) -, or - (CH2) 2N (CH2) 2 (R7); R2g is a) -NR27R28, b) -0R27, or c) -NHC (= 0) R28; wherein R3o is a) H, b) C8 alkyl optionally substituted with one or more haloes, or c) C8-8 alkyl optionally substituted with one or more OH, or Ci-e alkoxy; where E is a) NR39, b) -S (= 0) ?, or c) O; R3s is a) H, b) C1-6 alkyl, c) - (CH2) q-aryl, or d) halo; R3g is a) H, b) C6-6 alkyl optionally substituted with one or more OH, halo, or -CN, c) - (CH2) q-aryl d) -CO2R40, e) -COR41, f) - C (= 0) - (CH2) qC (= O) R40, g) -S (= 0) 2-alkyl of C? -d, h) -S (= 0) 2- (CH2) q-aryl , oi) - (C = 0) j-Het; R 40 is a) H, b) C 1-6 alkyl optionally substituted with one or more OH, halo, or -CN, c) - (CH 2) q-aryl, or d) - (CH 2) q-OR 42; R41 is a) C6_6alkyl optionally substituted with one or more OH, halo, or -CN, b) - (CH2) q-aryl, or c) - (CH2) q-OR42. ; R42 is a) H, b) C6_6 alkyl, c) - (CH2) q-aryl, or d) -C (= 0) -alkyl of C6_6; aryl is a) phenyl, b) pyridyl, or c) naphthyl; from a to c optionally substituted with one or more halo, -CN, OH, SH, C-e alkyl, C? -6 alkoxy or C? _6 alkylthio; wherein R43 is a) H, b) Cl-2 alkyl, c) F, or d) OH; R 4 is a) H, b) CF 3, c) C 1 -C 3 alkyl optionally substituted with one or more halo. d) phenyl optionally substituted with one or more halo, e) R44 and R45 taken together are a ring of 5-, 6-, or 7 members of the formula, f) R44 and R45 taken together are - (CH2) k-, when R46 is an electronic withdrawal group; R 45 and 46 in each case are the same or different and are a) an electronic removal group, b) H, c) CF 3, d) C 1 -C 3 alkyl optionally substituted with a halo, e) phenyl, with the proviso that at least one of R45 or R46 is an electronic withdrawal group, of) R45 and R46 taken together are a ring of 5-, 6-, or members of the formula c c - < cx (CH2) f U U is a) CH2, b) O, c) S, or d) NR47; R47 is a) H, b) C? _5 alkyl; where R48 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) -N02, h) C6 -6 alkoxy, i) C6-6 alkoxycarbonyl, i) alkylthio of C? _6, k) acyl of C? _6, 1) -NR49 R50, m) C-? _6 alkyl optionally substituted with OH, C1-5 alkoxy, C? _5 acyl, or -NR 9R50 , n) C2_8 alkenylphenyl optionally substituted with one or two R51, o) phenyl optionally substituted with one or two R51, p) a saturated or unsaturated 5 or 6 member heterocyclic entity having from one to three atoms selected from the group consisting of S, N, and 0, optionally substituted with one or two R51, or q) (CHaJT / - R49 and R50 in each case are the same or different and are a) H, b) C4_4 alkyl, c) C5_6 cycloalkyl, or d) R49 and R50 taken together with the nitrogen atom is a saturated heterocyclic entity of 5, 6 members optionally having an additional heteroatom selected from the group consisting of S, N, and O, and in turn may optionally be substituted, including at the additional nitrogen atom, C? _3 alkyl, or C? _3 acyl; R51 is _ _ _ _ a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3 g) -N02. h) C6 -6 alkoxy. i) Ci-e alkoxycarbonyl. j) alkylthio of C? _6. k) Acyl of C? -e, 1) C? _6 alkyl optionally substituted with OH, C? _5 alkoxy, C1-5 acyl, or -NR49R50, m) phenyl, n) -C (= 0) NR52 R53, o) -NR49R50, P) -N (R52) (-S02R54). q) -S02-NR52R53. or r) -S (= 0) iR54; R52 and R53 in each case are the same or different and are a) H, b) C 1-6 alkyl. or c) phenyl; R54 is a) C 4 alkyl, or b) phenyl optionally substituted with C 1-4 alkyl; wherein R55 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) -N02. h) C 1-6 alkoxy. i) C6-6 alkoxycarbonyl, j) C6-C6 alkylthio) C ac-β acyl, 1) -NR56 R57, m) C -6 alkyl optionally substituted with OH, C 1-5 alkoxy. C1-5 acyl, or -NR56 57, n) C2_8 alkenyl phenyl optionally substituted with one or two Rs8, o) phenyl optionally substituted with one or two R58, p) an unsaturated heterocyclic 5 or 6 members having one to three carbon atoms selected from the group consisting of S, N, and O, optionally substituted with one to two Rs8, or R50 and 57 in each case are the same different and are a) H, b) formyl, c) C 1 alkyl, d) C 1 4 acyl, e) phenyl, f) C 3-6 cycloalkyl, o) R56 and R5 -7 taken together with the nitrogen atom is a 5-6 membered saturated heterocyclic entity which optionally has an additional heteroatom selected from the group consisting of S, N, and O, and may in turn be optionally substituted with, including on the additional nitrogen atom, phenyl, pyrimidyl, C 1-3 alkyl, or C 1-3 acyl; R58 is a) carboxyl, b) halo, e) -CN, d) mercapto, e) formyl, f) CF3, g) -N02, h) C6-6 alkoxy, i) C5-5 alkoxycarbonyl, ) alkylthio of C? _6, k) acyl of C? _6, 1) phenyl, m) C? -6 alkyl optionally substituted with OH, azido, C? -5 alkoxy, C? _5 acyl, -NR65 66 .SR67, -0-S02R68, or n) -C (= 0) NR59 R60, o) -NR56R57, p) -N (R59) (-S02R54), q) -SO2-NR59R60, r) -S (= 0) iR54, s) -CH = N-R6 ?, ot) -CH (OH) -S03R64; R54 is the same as defined above; R59 and R60 in each case are the same or different and are a) H, b) C6_6 alkyl, c) phenyl, or d) tolyl; R61 is a) OH, b) benzyloxy, c) -NH-C (= 0) -NH2, d) -NH-C (= S) -NH2, or e) -NH-C (= NH) -NR62R63; Re2 and R3 in each case are the same or different and are a) H, or "b) C 1 alkyl optionally substituted with phenyl or pyridyl, Re 4 is a) H, or b) a sodium ion; each case are the same or different and are a) H, b) formyl, c) C ?4 alkyl, d) C ?4 acyl, e) phenyl, f) C3_6 cycloalkyl) R65 and R tom taken together are a portion 5-6 membered saturated heterocyclic having from one to three carbon atoms selected from the group consisting of S, N, and O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C 1-3 alkyl, or acyl of C? -, * h) -P (0) (OR70) (OR71), oi) -S02-R72; N -N N -N V N (CHjljC I CH3 R68 is C3_3alkyl; R69 is a) C6_6 alkoxycarbonyl or b) carboxyl; R70 and R71 in each case are. same or different and are a) H, or b) C? _3 alkyl; R72 is a) methyl, b) phenyl, or c) tolyl; where K is a) O, or b) S; Ri3r Rur Ri 5 r R76 and R77 in each case are the same or different and are a) H, b) carboxy lo, c) halo, d) -CN, e) mercapto, f) formyl, g) CF3 h) -NO2 , i) C6-6 alkoxy. j) C?-6 alkoxycarbonyl, k) C?-6, 1) C 1 -6 alkyl acyl. m) -OR78 R-79, n) C6-6 alkyl optionally substituted with OH, C5-5 alkoxy, C5-5 acyl, -NR78R79, N (phenyl) (CH2-CH2-OH), -0-CH (CH3) (OCH2CH3), or -0-pheni lo- [para-NHC (= 0) CH3], or) C2_8 alkenylphenyl optionally substituted with R51, p) phenyl optionally substituted with R51, or q) a saturated or unsaturated 5 or 6 membered heterocyclic entity having from one to three atoms selected from the group consisting of S, N, and 0, optionally substituted with R51; R51 is the same as defined in the above; R7S and R79 in each case are the same or different and are a) H, b) C? -4 alkyl, c) phenyl, or d) R 8 and R 79 taken together with the nitrogen atom is a saturated heterocyclic entity of 5, 6 members which optionally has an additional heteroatom selected from the group consisting of S, N, and 0, and can in turn be optionally substituted with, including on the additional nitrogen atom, C? _3 alkyl, or C? -3; where T is a) 0, b) S, or c) S02; R75 »- 76? and R77 are the same as defined in the above; R a is a) H, b) formyl, c) carboxyl, d) C 1-6 alkoxycarbonyl, e) C 8 alkyl, f) C 2-8 alkenyl, wherein the substituents (e) and (f) are they can optionally be substituted with OH, halo, C? _6 alkoxy, C? -6 acyl, C? _6 alkylthio or C? _6 alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic entity having from 6 to 10 carbon atoms optionally substituted with carbonyl, halo, -CN, formyl, CF3, -N02, C6-6 alkyl, C6-6 alkoxy, C6-6 acyl, C6-6 alkylthio, or alkoxycarbonyl Ci-e; h) -NR8? R82, i) -OR90. j) S (= 0)? - R9 ?, k) -S02-N (R92) (R93), or 1) a radical of the following formulas: R8? and R82 in each case are the same or different and are a) H, b) C3_6 cycloalkyl, 6 c) phenyl, d) C6_6 acyl, e) C8_8 alkyl optionally substituted with OH, C alkoxy ? 6 which can be substituted with OH, a 6-membered aromatic heterocyclic entity having from one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF3, halo, -N02, alkoxy of C? _, -NR83R84, or < c- «85. O R85- Ch V is a) 0, b) CH2, or c) NR87; R83 and R84 in each case are the same or different and are a) H, or b) C? _ Alkyl; R85 is a) OH, b) C4-4 alkoxy, or c) -NR88 R89; R86 is a) H, or b) C? -7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazolyl, methylthio, amino, phenyl optionally substituted with OH, -C (= 0) -NH2, -C02H, or -C (= NH) -NH2; a) H, b) phenyl, or e) C? -6 alkyl optionally substituted by OH; Rss and ß9 in each case are the same or different and are a) H, b) C5-C5 alkyl) C3_6 cycloalkyl, or d) phenyl; R9o is a) C -8 alkyl optionally substituted with C6-6 alkoxy or C6-6 hydroxy, C3-6 cycloalkyl, a 6-membered aromatic heterocyclic entity optionally fused with benzo having from one to three atoms of nitrogen, which in turn can be substituted with one or two -N02, CF3, halo, -CN, OH, C5 alkyl, C5-5 alkoxy, or Cx5 acyl; b) / - \ V N- (CH.) - c) phenyl, or d) pyridyl; R91 is a) C6-6 alkyl, b) C2-6 alkenyl. wherein the substituents (a) and (b) can be optionally substituted with C5-5 alkoxycarbonyl, or a 5-, 6-7-membered aromatic heterocyclic moiety having from one to three atoms selected from the group consisting of S, N , and O, c) an aromatic entity having from 6 to 10 carbon atoms, or d) a 5, 6, 7-membered aromatic heterocyclic entity having from one to three atoms selected from the group consisting of S, N, and Or, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF3, -N02, C6-6 alkyl. C? _6 alkoxy, C? _6 acyl,? -l-alkylthio, or C? -6-alkoxycarbonyl; R92 and R93_ in each case are the same or different and are a) H, b) phenyl, c) C? _6 alkyl. or d) benzyl; Rg4 and R95 in each case are the same or different and are a) H, b) OH, c) C?-Alkyl optionally substituted with -NR83 R84, or d) R94 and R95 taken together are = 0; R96 is a) an aromatic entity having from 6 to 10 carbon atoms, b) a 5 or 6 member aromatic heterocyclic entity optionally fused with benzo having from one to three atoms selected from the group consisting of S, N, and 0, wherein the substituents (a) and (b) in turn can be substituted with one or three -N02, CF3, halo, -CN, OH, phenyl, C1-5 alkyl, C? -5 alkoxy , or acyl of C? _5, c) morpholinyl, d) OH, e) C? -6 alkoxy, f) -NR83R84, g) -C (= 0) -R97, oh) < : > R c e s a) morpholinyl, b) OH, or c) C6-6 alkoxy; h is 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5; 1 e s 2 or 3; m is 4 or 5; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; with the proviso that n and p together are 1, 2, 3, 4, or 5; q is 1, 2, 3, or 4; r is 2, 3, or 4; t is 0, 1, 2, 3, 4, 5, or 6; u is 1 or 2. 2. A compound according to claim 1, characterized in that it is: a) (S) -N - [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide; b) (S) -N - [[3- [3-Fluoro-4- [4- (5-methyl-l, 3,4-thiadiazol-2-yl) -1-piperazinyl] phenyl] -2-oxo -5-oxazolidinyl] -yl] thioacetamide; c) (S) -N- [[3- [3-Fluoro-4- [2 ', 5' -dioxospiro [piperidin-4,4'-imidazolidin] -1-yl] phenyl] -2-oxo-5 -oxazolidinyl] met il] thioacetamide; d) (S) -N-3- [3-Fluoro-4- (4-morpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl] thioacetamide; e) (S) -N - [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2 -oxo-5-oxa zol idini 1] methyl] thiourea; f) (S) -N - [[3- [3-Fluoro-4- (4'-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] - '-methylthiourea; g) (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl-phenyl] -2 -oxo-5-oxazolidinyl] methyl] thioformamide; h) (S) -N- [[3 -] 3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -thiopropionamide; i) (S) -N - [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] 2-chlorothioacetamide; j) (S) '- N - [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-oxazolidinyl] -methyl] -a, a, α-trifluorothioacetamide; k) (S) -N - [[3- [3-Fluoro-4- (4-morpholinyl) -phehyl] -2 -oxo-5-oxazolidinyl] methyl] -a-fluorotioacetamide;
1) (S) -N - [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a, a-difluorothioacetamide; m) (S) -N - [[3- [3-Fluoro-4- (4-morph 1-ynyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a-cyanothioacetamide; n) (S) -N - [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a, a-dichlorotioacetamide; o) (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a- (methoxycarbonyl) thioacetamide; p) (S) -N - [[3- [4- [l- [1, 2,4] Triazolyl] phenyl] -2 -oxo-5-oxazolidinyl] met il] t -ioacetamide; .q) p) (S) -N- [[3- [4- [1- [1,2,4] Triazolyl] -phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide; r) (S) -N - [[3- [l- (Hydroxyacetyl) -5-indolinyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide; s) (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl-1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] thioacet amide; t) ( S) -N - [[3- [3- Fluoro-4- (-tiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide; u) S-oxide of (S) -N- [[3- [3-Fluoro-4 - (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide, thiomorpholine; v) thiomorpholine S, S-dioxide (S) -N - [[3- [3-Fluoro-4- (4-thiomorphonyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide; w) (S) -N- [[3- [3, 5-Difluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2 -oxo-5-oxazolidinyl] methyl] thioacetamide; x) (S) -N- [[3- [4- [l- [1,2,4] Triazolyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea; y) (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] thiourea; z) (S) -N- [[3- [1- (Hydroxyacetyl) -5-indolinyl] -2-oxo-5-oxazolidinyl] metyl] thiourea; aa) S-oxide (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methylthiourea, thiomorpholine; bb) (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl-S- et i-ldi thiocarbamate; 3. A method for treating microbial infections in patients, characterized in that it comprises administering to a patient in need thereof an effective amount of a compound of Formula I.
MXPA/A/1999/011069A 1997-05-30 1999-11-30 Oxazolidinone antibacterial agents having a thiocarbonyl functionality MXPA99011069A (en)

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US60/048342 1997-05-30

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