MXPA01005287A - Oxazolidinone antibacterial agents having a thiocarbonyl functionality - Google Patents

Oxazolidinone antibacterial agents having a thiocarbonyl functionality

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Publication number
MXPA01005287A
MXPA01005287A MXPA/A/2001/005287A MXPA01005287A MXPA01005287A MX PA01005287 A MXPA01005287 A MX PA01005287A MX PA01005287 A MXPA01005287 A MX PA01005287A MX PA01005287 A MXPA01005287 A MX PA01005287A
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MX
Mexico
Prior art keywords
oxo
phenyl
methyl
oxazolidinyl
fluoro
Prior art date
Application number
MXPA/A/2001/005287A
Other languages
Spanish (es)
Inventor
Jackson B Hester Jr
Tonijo Poel
Eldon George Nidy
Salvatore Charles Perricone
Original Assignee
Jackson B Hester Jr
Eldon George Nidy
Salvatore Charles Perricone
Pharmacia & Upjohn Company
Tonijo Poel
Filing date
Publication date
Application filed by Jackson B Hester Jr, Eldon George Nidy, Salvatore Charles Perricone, Pharmacia & Upjohn Company, Tonijo Poel filed Critical Jackson B Hester Jr
Publication of MXPA01005287A publication Critical patent/MXPA01005287A/en

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Abstract

The present invention provides compounds of formula (1) or pharmaceutical acceptable salts thereof wherein, A, G and R1 are as defined in the claims which are antibacterial agents.

Description

ANTIBACTERIAL AGENTS OF OXAZOLIDINONE THAT HAVE FUNCTIONAL GROUP TIOCARBONILO BACKGROUND OF THE INVENTION The present invention relates to novel oxazolidinone compounds and also useful with their preparations, and more particularly with oxazolidinone compounds in which the carbonyl functional group of -NH-C (O) -R is converted to a group functional thiocarbonyl, such as a thiourea -NH-C (S) -NH2, an alkyl thiourea -NH-C (S) -NH- (Ci_4 alkyl), thioamide -NH-C (S) - (at C: _d or -NH-C (S) -H The replacement of the oxygen atom with ur * sulfur atom has unexpectedly improved the antimicrobial properties of the compounds.The compounds are useful antimicrobial agents, effective against several of the human and veterinary pathogens, including Gram-positive aerobic bacteria such as staphylococci and multiple-resistance streptococci, Gram-negative organisms such as H. in fl uen za s and M. ca tar ra hlis as well as anaerobic organisms such as bacterial species ides clostridia and acid-fast organisms such as Mycoba c t e r i um tuberculosis and Mycobacterium avium. The compounds are particularly useful because they are effective against the last organisms known to be responsible for infections in people with AIDS.
BRIEF DESCRIPTION OF THE INVENTION In one aspect, the disclosed invention is a compound of Formula I or the pharmaceutically acceptable salts thereof wherein: G is Ri is a) H, b) NH 2 c) NH-C 1 -4 alkyl, d) C 4 alkyl, e) -O C 1-4 alkyl, f) -S-C 1-4 alkyl, g) C 1-4 alkyl substituted with 1-3 F, 1-2 Cl, CN or -COOalkyl of C? _4, h ) C3-6 cycloalkyl, i) N (C? _4 alkyl) 2 or j) N (CH2) 2.5; A is d) a 5-member heteroaromatic entity having from one to three atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic entity is attached via a carbon atom, wherein the 5-membered heteroaromatic entity may additionally have a fused benzene or naphthyl ring, 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 linked by a carbon atom, wherein the 6-membered heteroaromatic entity may additionally have a fused benzene and naphthyl ring, wherein the heteroaromatic entity is optionally substituted with one to three R55, f) a ß -carbolin-3-yl, or indolicind or linked by the 6-membered ring, optionally substituted with one to three R55, wherein R 2 is a H, b F, c Cl, d Br, and C 1-3 alkyl, f N 0 2, or g R 2 and R 3 taken together are -0- (CH 2; h-0-; R, is b -S (-0) 2-N = S (0) jRsRe, c -SC (-0) P, d C (= 0) R8, e C (= 0) R9, f -C (= 0) NR oFi !, g -C (= NR? 2) R8, h -C (R8) (R? - 0R13, i -C (R9) (R?) - 0R? 3, j -C (R8) ( Rn) -OC (= 0) R? 3, k -C (R9) (Rn) -OC (= 0) R13, 1 -NR10R11, m -N (R? O) -C (= 0) R7, n -N (R10) -S { = 0) 1R7 'or -C (OR14) (OR? 5) R8, -C (R8) (R) -NR10R11, or q) alkyl of C? _8 with one or more = 0 other than in the alpha position, -SJ = 0) 1R? 7, -NRioRn, C2-s alkenyl, or C2-s alkynyl; R 4 is a) C 1 alkyl- optionally substituted with one or more haloes, OH, CN, NR 10 R n, or ~ C 0 2 R 3, b) C 2 -4 alkenyl, c) -NRieRiß, d) -N 3, e) -NHQ ( = 0) R7, f) -NR20C (= O) 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 ~; R7 is C4-4 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; R 9 is C 4 alkyl substituted with one or more a) -S (= 0) R 7, b) -0R13, c) -0C (= 0) Ri3, d) -NRxoRxx, or e) -1-5 alkenyl 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; Ri2 is a) -NR10R11, b) -ORio? or c) -NHC (= 0) Rio; -13 a) K, or b) alkyl of C? _4; R? and Ris in each case are the same or different and are a) alkyl of C? _, or b) R? 4 and R? 5 taken together are - (CH) i-; R 16 is a) H, b) C 4 alkyl, or c) C 3-8 cycloalkyl; R? is a) alkyl of C? _4, or c) C3_8 cycloalkyl; a) H, b) C alquilo - alkyl, c) C 2-4 alkenyl ,; d) C3_4 cycloalkyl, e) -OR13 or f) -NR21R22; R 29 is a) Cl, b) Br, or c) - I; R20 is a physiologically acceptable cation; R21 and R2? in each case they are the same or different and are a) H, b) C 1-4 alkyl, or c) -NR 21 R 22 taken together are - (CH 2) p? _; wherein R23 and R24 in each case are the same or different and are a) H, b) F, c) Cl, d) alkyl of C? _2, e) CN f) OH, g) C 2 -2 alkoxy, h) nitro, or i) amino; What is it g)) ^ X i) m) a dianyl group optionally substituted with X and Y, n) a triacynyl group optionally substituted with X and Y, o) a quinolinyl group optionally substituted with X and Y, p) a quinoxalinyl group optionally substituted with X and Y, q) a naphthyridinyl group optionally substituted with X and Y, SJ or) v) bb) or, T Q and R24 taken together are wherein Zi is a) -CH2-, b) CH (R104) -CH2-, c) -C (0) -, or d) -CH2CH2CH2-; wherein Z2 is a) -02S-, b) -o-, c) -N (R107) d) -OS-, or e) -S-; wherein Z3 is a) -o2s-, b) -o-, c) -OS-, or d) -S-; where i is a) H-, or b) CH2; where A 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 (O) -CH2-, 1) CH3 -C (O) -CH2-, m) r O O O / n) tf Together they are a) > 112 o - b) 0 = o R114 \ c) N: wherein R 102 is a) H-, b) CH 3 -, c) phenyl-CH 2 -, or d) CH 3 C (0) -; V wherein R103 is a) (C? -C3) alkyl-, 0 b) phenyl- wherein R104 is a) H-, 0 b) H0-; wherein R 105 is a) H-, b) (C1-C3) alkyl-, c) -CH2 = CH-CH2-, or d) CH3-0- (CH2) 2-; wherein R106 is a) CH3-C (0) -, b) H-C (O) -, c) C12CH-C (0) -, d) CH3S02-, e) CH3S02- -, 115 C (O) -f) li g) F2CHC (0) -, ) N ^ N-CÍO) - \ = J H3C-C (O) -O-CH2-C (O) -, j) H-C (O) -0-CH2-C (O) -, 1) CH = C-CH20-CH2-C (O) -, O m) phenyl-CH2-0-CH2-C (O) -; R107 is a) R102O-C (R)? O) (R111) -C (O) -, b) R103O-C (O) -, c) R108-C (O) -, f) H3C-C (0) - (CH2) 2-C (0) -, g) R109-SO2-, i) HO-CH2-C (o; j) R 116 (CH2) 2-, k) R113-C (0) -0-CH2-C (0) -, 1) (CH3) 2N-CH2-C (q) -NH-, m) NC-CH2-, n) F2-CH-CH2-, or o) R150R151Ng? 2 wherein R 108 is a) H-, b) (C1-C4) alkyl, c) aryl- (CH2) p, d) C1H2C-, e) C12HC-, f) FH2C-, g) F2HC-, h ) (C3-C6) cycloalkyl, oi) CHCH2-, wherein R109 is a) C1-C4 alkyl, b) -CH2C1 c) -CH2CH = CH2, d) aryl, or e) -CH2CN; wherein R110 and R111 are independently a) H-, b) CH 3-; or wherein R312 is a) H-, b) CH3O-CH2O-CH2-, or c) HOCH2-; wherein R113 is a) CH3-V b) HOCH2-, c) (CH3) 2N-f-enyl, or d) (CH3) 2N-CH2-; where R114 is a) HO-, b) CH3O-, c) H2N-, d) CH3O-C (O) -0-, e) CH3-C (O) -0-CH2-C (0) -0 -, f) phenyl-CH2-0-CH2-C (0) -O-, g) HO- (CH2) 2-0-, h) CH30-CH2-0- (CH2) 2-O-, oi) CH30-CH2-0-; wherein R113 is a) CH3-, b) H0CH2-, c) (CH3) 2N-phenyl, or d) (CH3) 2-CH2-; wherein R 115 is a) H-, or b) C1-; wherein R116 is a) H0- b) CH30-, or c) F; wherein R, 150 Y, 151 are each H alkyl C? ~ C R 150 and R taken together with the nitrogen atoms to which each is attached form a monocyclic heterocyclic ring having from 3 to 6 carbon atoms; 3 is an unsaturated 4-atom binder having one nitrogen atom and three carbon atoms; M is a) H, b) C? _8 alkyl, c) C3_8 cycloalkyl, d) - (CH2) mOR? 3, or e) - (CH2) h-NR2? R22; Z is a) O, b) S, or c) NM; W is a) CH, b) N, or c) S or O when Z is NM; Y is a) H, b) F, c) Cl, d) Br, e) alkyl of C? _3, or f) N02; a) H, b) -CN, c) OR27, d) halo, e) N02, f) tetrazoyl, g) -SH, h) -S (= 0) iR4, i) -S (= 0) 2- N = S (0) *) R5R6, j) -SC (= 0) R7, k) -C (= 0) R25, 1) -C (= 0) NR27R28, m) -C (= NR29) R25, n) -C (R25) (Ras) -0Ri3, o) -C (R25) (R28) -OC (= 0) Ri3, P) -C (R28) (0R13) ) - (CÍI2) hNR27R28, q) -NR27R28, r) -N (R27) C (= 0) R7, s) -N (R27) -S (= 0) iR7, t) -C (OR14) (OR15) ) 28, u) -C (R25) (R) -NR27R26, ov) C? _8 alkyl substituted with one or more haloes, OH, = 0 other than ios from the alpha position, -S (= 0) i R17 , -NR2 R28, C2-5 alkenyl, C2-5 alkynyl, or C3-8 cycloalkyl; R4, R5, Re, R7, 13 R14.- R15, Ie and Riv are the same as defined above; R25 is a) H, b) C? _8 alkyl optionally substituted with one or more haloes, C3_8 cycloalkyl, C? _4 alkyl substituted with one or more of -S (= 0) iR? 7, -OR13, or 0C (= 0) Ri3, NR27R28, or c) C2-5 alkenyl optionally substituted with CHO, or C02R? 3; R2e is a) R28, or b) NR27N28; R2 and R28 in each case are the same or different and are a) H, b) C? _8 alkyl, c) C3_8 cycloalkyl, d) - (CH2) m0Ri3, e) - (CH2) b-NR2? R22, of) R27 and R28 taken together are - (CH2) 2? (CH2) 2-, - (CH2) hCH (COR7) -, or - (CH2) 2N (CH2) 2 (R7); R29 is' a) NR2-7R28; b) -OR27 or c) -NHC (= 0) R28; wherein P30 is a) H, b) C? _8 alkyl optionally substituted with one or more haloes, or c) C? -8 alkyl optionally substituted with one or more OH, or C? _6 alkoxy; wherein E is a) NR39, b) -S (= 0) 1, or c) O; 38 is a) H, b) alkyl of C? _6, c) - (CH2) q-aryl, or d) halo; R39 is a) H, b) Ci-e alkyl optionally substituted with one or more OH, halo, or -CN, c) - (CH2) q-aryl, d) -CO2R40, e) -COR '". , f) -C (= 0) - (CH2) qC (= O) R40, g) -S (= 0) or -alkyl of C? _6, h) -S (= 0) 2- (CH2) q -aril, oi) - (C = 0) j-Het; R 40 is a) H, b) C 1-6 alkyl optionally substituted with one or more halo ^ .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) alkyl of C? _6, c) - (CH2) q-aryl, or d) - (C = 0) -alkyl of C? _6; aryl is - a) phenyl, b) pyridyl, or c) naphthyl; 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) alkyl of C? _2, c) F. or d) OH; R44 is a) H, b) CF3, c) C1-3 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, g) R44 and R45 taken together are - (CH2) k-, when R46 is an electron extraction group; R45 and R46 in each case are the same or different and are a) an electron extraction group, b) H, c) CF3, d) C1- .3 alkyl optionally substituted with one halo, e) phenyl, with the proviso of which at least one of R45 or R4s is an electron extraction group, of) R45 46 taken together is a ring of 5, 6, 7 members of the formula U is a) CH2, b) O, c) S, or d) NR47; R47 is a) H, or b) C? _5 alkyl; wherein R 8 is a) carboxyl, b) 'halo, c) -CN, d) mercapto, e) formyl, f) CF,? g) -NO2, h) C6-6 alkoxy, i) C6-6 alkoxycarbonyl, j) C6-6 alkyl, k) C6-6 aci, or C6-6), N) C50 alkyl, m) C6 alkyl; _6 optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or -NR49R50, n) C2-s alkenylphenyl optionally substituted with one or two R51, or) phenyl optionally substituted with one or two R51, p) a heterocyclic entity of 5, or 6 (in) saturated members having from one to three atoms selected from the group consisting of S, N, and 0, optionally substituted with one or two R51, or R49 and R50 in each case are the same or different and are a) H, b) C 1-4 alkyl, c) C 5-6 cycloalkyl, or d) R49, and R 50 taken together with the nitrogen atoms are a saturated heterocyclic entity from ,6 members which optionally has a heteroatom selected from the group consisting of S, N, and 0, and may in turn be substituted with C 1 -3 alkyl, or C 1 -C 3 aci, including on the additional nitrogen the same; a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) -N02, h) C1-6 alkoxy, i) C6-6 alkoxycarbonyl, j) Ci-e alkyl, k) C6-6 acyl, 1) Ci-e alkyl optionally substituted with OH, C? _5 alkoxy, C? _5 acyl, or -NR49R50, m) phenyl, n) -C (= 0) NR52R53, o) -NR49R50, p) -N (R52) (-S02R54), q) -S02-NR52R53, or) -S (? O)! R5; R52 and R53 in each case are the same or different and are a) H, b) C? _6 alkyl, or c) phenyl; R54 is a) C 1 - alkyl, or b) phenyl optionally substituted with C 1 - alkyl; wherein R55 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) -NO2, h) C6-6 alkoxy, i) C6-6 alkoxycarbonyl, j) C6-6 alkylthio, k) C6-6 acyl, 1) -NR56 R57, m) C1-6alkyl 6 optionally substituted with OH, C1-5 alkoxy, C? -5 acyl, or -NR56R5, n) C2_8 alkenylphenyl optionally substituted with one or two R58, or) phenyl optionally substituted with one or two R58, p) a 5 (or 6 membered) heterocyclic (in) saturated entity having from one to three atoms selected from the group consisting of S, N, and 0, optionally substituted with one or two R58, or R56 and R57 in 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, og) 56 and R57 taken together with the nitrogen atom is a saturated, 5-6 membered heterocyclic entity optionally having an additional heteroatom selected from the group consisting of S, N, and O, and its it may optionally be substituted with C1-3 alkyl, or C3-3 acyl, including on the additional nitrogen atom the same; R58 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) form, f) CF3, g) -NO2, h) C6-6 alkoxy, i) C6-6 alkoxycarbonyl, j) C6_6 alkyl, k) C6_6 acyl, 1) phenyl, m) C6_6 alkyl optionally substituted with OH, azido, C5_5 alkoxy, C1-5 acyl, -NR6sR66, -SR67, -0-S02R68, or n) -C (= 0) NR59 Reo, o) -NR56R57, P) -N (R59) (-S02R54), q) -SO2-NR59R60, r) -S (= 0) iR54, s) -CH = N-R6 ?, ot) -CH (0H) -S03R64; R54 is the same as defined above; «. R59 and Reo in each case are the same or different and are a) H, b) C6_6 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) -NR62Re3; β2 and Rβ3 in each case are the same or different and are a) H, or b) C? _4 alkyl optionally substituted on phenyl or pyridyl; Re is a) H, or b) a sodium ion; Res and Ree in each case are the same or different and are a) H, b) formyl, c) C 1 -4 alkyl, d) Cl 4 acyl, e) phenyl, f) C 3 6 cycloalkyl, g) Res and Ree taken together is a saturated 5-6 membered heterocyclic entity having from one to three atoms selected from the group consisting of 3, N, and O, optionally substituted with C? _3 alkyl, C? -3 acyl, including on the nitrogen atom thereof, h) -P (O) (OR70) (OR71), or I) -S02-R72; N -N N -N (CH3) 3C CH3 R68 is C? _3 alkyl; R69 is a) C6-6 alkoxycarbonyl, or b) carboxyl; R7o and R71 in each case are the same or different and are a) H, or b = C1-3 alkyl, R72 is a) methyl, b) phenyl, or c) tolyl; where K is a) O, or b) S; R73, R7; R7, R75 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- 6 alkoxy, j) C6-6 alkoxycarbonyl, k) C6-6, C1) C6-alkyl acyl, m) -NR78 R79, 'n) C6-6 alkyl optionally substituted with OH, C5-5 alkoxy acyl of C? _5-NR78R79, - (phenyl) (CHa ^ CHz-OH), -O-CH (CH3) (OCH2CH3), or -0-phenyl- [para-NHC (= 0) CH3], or ) C2-8 alkenylphenyl optionally substituted with R51, p) phenyl optionally substituted with R51, or q) a 5 (or 6 membered) heterocyclic (in) saturated 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 above; R78 and R79 in each case are the same or different and are a) H, b) C 1 alkyl, c) phenyl, or d) R 8 and R 9 taken together with the nitrogen atom is a saturated heterocyclic entity 5, 6 members optionally having an additional heteroatom selected from the group consisting of S, N, and O, and in turn may be optionally substituted with C? _3 alkyl, or C? _3 acyl; including on the additional nitrogen atom the same; where T is a) O, b) S, or c) S02; R75? R76, - and 77 are the same as defined above; Rso is a) H, b) formyl, c) carboxyl, d) C6-6 alkoxycarbonyl, e) C8-8 alkyl, f) C2-8 alkenyl.- where the substituents (e) and ( f) can optionally be substituted with OH, halo, C? _6 alkoxy, C? _6 acyl, Ci_? alkylthio or Ci_e alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic entity having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF3, -N02, alkyl of C? -6, C? -6 alkoxy, C? _6 acyl, C? _6 alkylthio, or Ci_? Alkoxycarbonyl; h) -NR8? R82, i) -OR90, j) -S (= 0) i-R9 ?, k) -S02-N (R92) (R93), or 1) a radical of the following formulas: Rsi and R <2> in each case are the same or different and are a) H, b) C3_6 cycloalkyl, c) phenyl, d) C? 6 acyl, e) C? _8 alkyl optionally substituted with OH, C? _6 alkoxy which can be substituted with OH, a 5 or 6 member 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, C4-4 alkoxy, -NR83R84, or < • ° -r ^ o - ^^ g) ^ M-W- V is a) O, b) CH2, or R 3 and R 4 in each case are the same or different and are a) H, or b) C 4 alkyl; 85 is a) OH, b) C4-4 alkoxy, or c) -NR88 d9 ae is a) H, or b) optionally substituted C-alkyl with indolyl, OH, mercaptyl, -imidazolyl, methylthio, amino, phenyl optionally substituted with OH, C (= 0) -NH2 / -C02H, or -C (= NH) -NH2; Rs7 is a) H, b) phenyl, or c) optionally substituted C 1-6 alkyl. by OH; Rss and R89 in each case are the same or different and are a) H, b) C 1-5 alkyl c) C 3-6 cycloalkyl, or d) phenyl; R90 is a) C?-8 alkyl optionally substituted with C? _6 hydroxy C alco alco alkoxy, C3_ ciclo cycloalkyl, a 6-membered benzo-fused aromatic heterocyclic entity having from one to three nitrogen atoms, which in turn it may be substituted with one to two -NO2, CF3, halo, -CN, OH, C1-5 alkyl, C-? -5 alkoxy, or Ci-* - acyl; b) / - \ V N CH2) - c) phenyl, or d) pyridyl; R9? is a) alkyl of C? -? 6, b) alkenyl of C? _16, wherein the substituents (a) and (b) can be optionally substituted with alkoxycarbonyl of C? -6, or a 5, 6, 7 membered aromatic heterocyclic entity having from one to three atoms selected from the group consisting of S, N «and 0, c) an aromatic entity having from 6 to 10 carbon atoms carbon, 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 0, wherein the substituents (c) and (d) can be substituted- , optionally with carboxyl, halo, -CN, formyl, CF3, -NO2, C? _6 alkyl, alkoxy Ci-e, acyl of Ci-e, alkylthio of C1-6, or alkoxycarbomyl of Ci-e; R & 2 and R93 in each case are the same or different and are a) H, b) phenyl, c) C 1-6 alkyl, or d) benzyl; R94 and R95 in each case are the same or different and are a) H, b) OH, c) C 1-6 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) an optionally benzo-fused aromatic heterocyclic entity of 5, or 6 members having from one to three atoms selected from the group consisting of S, N, and O , wherein the substituents (a) and (b) which in turn can be substituted with one or three -N02, CF3, halo, -CN, OH, phenyl, C1-5 alkyl, C5-5 alkoxy, or C1-5 acyl, c) morpholinyl, d) OH, e) C alcoe alkoxy, f) -NR83R84, g) -C (= 0) -Ry7, or R9 is a) morpholinyl, b) OH, or c) Ci-β 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 0, 1, 2, '3, 4, 5, or 6; u is 1 or 2; w is 0, 1, 2, or 3. «. DETAILED DESCRIPTION OF THE INVENTION The novel compounds of the invention can be prepared using known compounds and intermediates of oxazolidones, isoxazolines and butyrolactones as intermediates and synthetic methods known in the art. The thioamides of the invention can typically be prepared by the reaction of the corresponding amide with Lawesson's reagent. The compounds set forth in the following publications are suitable intermediates for the preparation of the compounds of this invention and are incorporated herein by reference for the disclosure of their suitable compounds that can be converted to the exposed thiocarbonyl derivatives.
U.S. Patent Nos. 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, WO 94 / O 1110; PCT / US94 / 08904, WO 95/07271; PCT / ÜS95 / 02972, WO 95/25106; PCT / US95 / 10992, WO96 / 13502; PCT / US96 / 05202, W096 / 35691; PCT / US96 / 12766; PCT / US96 / 13726; PCT / US96 / 14135; PCT / US96 / 17120; PCT / US96 / 19149; PCT / ÜS97 / 01970; PCT / US95 / 12751, W096 / 1513C; Y PCT / US96 / 00718, W096 / 23788. The chemical conversion techniques to convert various intermediates that have a CH2NH; on the oxazolidinone ring for CH2NH-C (S) -CH3 are disclosed by Hartke, K, Earrmeyer, S., J. prakt. Chem. 1996, 338, 251-6. Similarly, the conversion of CH2NHC (= 0) CH3 to CH2NHC (S) NHCH3 is disclosed by Cava, M.P .; Levinson, M.I .. Tionation Reactions of Lawesson's Reasents, Tetrahedron 1985, 41, 5061-87. For the purposes of the present invention, the carbon content of various hydrocarbon-containing entities is indicated by a prefix designating the minimum and maximum number of carbon atoms in the entity, ie, the prefix Ci-j defines the number of carbon atoms present from the integer "i" to the whole number "J", inclusive. Thus, C 1-4 alkyl refers to alkyl of 1 to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and the isomeric forms thereof. The terms "C" -2'd alkyl "C" _3"alkyl," C "_4 alkyl", "C_5 alkyl", "C_6 alkyl", "C_8 alkyl", "and" alkyl of C? -? 6"refer to an alkyl group having one to two, one to three, one to four, one to five, one to six, one to eight, or one of sixteen carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, eptyl, octyl, nonyl, decyl,? ndecyl, dodecyl, tridecyl, tetradecyl and the isomeric forms of the The terms "C2-4 alkenyl", "C2-5 alkenyl", "C2-8 alkenyl", "C2-14 alkenyl" and "C2-6 alkenyl" refer to at least one group double bond alkenyl having from two to four, from two to five, from two to eight, from two to fourteen, or two to sixteen carbon atoms, respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentadienyl , hexenyl, hexadienyl, heptenyl, heptadienyl, octenyl, octadienyl, octatrienyl, nonenyl, nonadienyl, nonat rienyl, undecenyl, undecadienyl, dodecenyl, tridecenyl, tetradecenyl and the isomeric forms thereof. The terms "C2-s alkynyl", "C2-81 alkynyl" and "C2-10 alkynyl" refer to at least one triple bond 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, pentadiinyl, hexinyl, hexadiynyl, heptinyl, heptadiinyl, octynyl, octadiinyl, octatriinyl, noninyl, nonadiinyl, nonatynyl and the isomeric forms of The terms "C3-4 cycloalkyl", "C3_6 cycloalkyl", "C5_6 cycloalkyl", and "C3- * 8 cycloalkyl" refer to a cycloalkyl having from three to four, three to six, from five to six, or from three to eight carbon atoms respectively such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the isomeric forms thereof. 4"," C alco _ alkoxy ", and" C?-8 alkoxy "refer to an alkyl group having from one to four or, from one to six, or from one to eight carbon atoms respectively bonded to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and the isomeric forms thereof. The terms "alkylamino of Ci- ', and" alkylamino of C? -8"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, or ^ example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexyla ino, heptylamino, or octoylamino and the isomeric forms thereof The terms "dialkamino of CI_O" and "dialkylamino of C? -8" refer to two alkyl groups having from 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, et ilpropylamino, dibutylamino, dipentylamino, dihexylamino, methylacylamino, diheptylamino, or dioctoylamino and the isomeric forms thereof The terms "acyl of C? _3", "acyl of C? _4", "acyl of C? _5", "acyl of C? -6" , "Acilo de C? _8", and "C2-8 acyl" refer to a carbonyl group having an alkyl group of one to three, one to four, one to five, one to six, one to eight, or two to eight carbon atoms. carbon. The terms "alkoxycarbonyl of C? _4", "Ci-e 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 from one to eight carbon atoms and the isomeric forms thereof which is substituted with at least one phenyl radical. The term "C 8 alkylphenyl" refers to at least one double bond alkenyl group having from one to eight carbon atoms and the isomeric forms thereof which is substituted with at least one phenyl radical. The term "C8-alkylpyridyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof 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. carbon and the isomeric forms thereof bound to a hydroxy group. The term "C?-8 alkylsulfonyl" refers to an alkyl group having from one to eight carbon atoms and the isomeric forms thereof bonded to an S02 entity. The term "alkylthio of C? _6" refers to an alkyl group having from one to six carbon atoms and the isomeric forms thereof linked to a sulfur atom. The term "Het" refers to 5- to 10-membered saturated, unsaturated or aromatic heterocyclic rings containing one or more oxygen, nitrogen and sulfur atoms forming these groups, such as, for example, pyridine, thiophene, furan, pyrazoine, pyrimidine. , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, -isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4 -oxo-2-oxazolyl, 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-benzothiazolinyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl , benzoisothiazole, benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3, -oxathiazole -1-oxide, 1, 2, 4-oxadiazoI-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-l, 2,4-oxadiazol-3-yl, 1,2,4 -thiadiazol-3-yl, l, 2,4-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, l, 2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1, 2, 3, 4 -tet razol-5 -yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1, 2, 3-triazol-l-yl, 1,2,4-triazol-1-yl, 1-tet razolyl, 1-indolyl, 1- indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4-isot iazolyl and 5-isothiazolyl, 1, 3, 4, -oxadiazol, 4 -oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione, 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, where appropriate, according to conventional methods. The term "pharmaceutically acceptable salts" refers to acid addition salts, to administer the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, acid citric, 2-hydroxyethyl sulfonate, fumarate and similar io. 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 I of this invention contain a C5 chiral center of the isoxazoline ring, and as such there are two enantiomers or a racemic mixture of both. This invention relates to both enantiomers, as well as to mixtures containing the two isomers. In addition, depending on the substituents, additional chiral centers and other isomeric forms may be present in either A or Ri group, 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, with 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. The compositions in solid form include powders, tablets, dispersible granules, capsules, cachets 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, tablet disintegrating agent and encapsulating agent. Inert solid carriers include: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, 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 water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavoring agents, flavoring and thickening agents, can be provided. Preferably, the pharmaceutical composition employing conventional techniques in unit dosage form containing effective or suitable amounts of the active component, i.e., the compound according to this invention, is provided. The amount of the active component, which is the compound according to this invention, in the pharmaceutical composition and the unit dosage form thereof can be varied or adjusted widely depending on the particular application, the potency of the particular compound and the desired concentration. In general, the amount of Active component will vary between 0.5% and 90% by weight of the composition. In therapeutic use for treating or combating bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and / or topically 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 treated will be antibacterially effective. In general, this amount of antibacterially effective dose of the active component will be in the range of between about 0.1 and 100, more preferably between about 3.0 and 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 being treated and the particular compound to be used. Also, it should be understood that the initial dose administered may be increased beyond the upper level in order to quickly reach the desired blood level or the initial dose may be smaller than optimal and the daily dose may be progressively increased during the course of the treatment depending on the particular situation. If desired, the daily dose can also be divided into 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 base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water for injection and a buffer to provide an isotonic solution suitably buffered, for example, having a pH of between about 3.5 and 6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L (+) -lysine and L (+) -arginine to name a few of the representative 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 between approximately 1 mg / mL and 400 mg / mL of solution. The resulting liquid pharmaceutical composition will be administered to obtain the antibacterially effective dose amount mentioned above. The compounds according to this invention are advantageously administered orally in solid and liquid dosage forms. As a topical treatment, an effective amount of Formula I is mixed in a pharmaceutically acceptable gel or cream vehicle that can be applied to the skin of the patient in the treatment area. The preparation of these creams and gels is well known in the art and may include penetration enhancers.
MIC test method The MIC in vi tro 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 DMS0: H20 (1: 3). Double-serial dilutions of each sample were made using aliquots of 1.0 ml of sterile distilled water. To each aliquot of 1.0 ml of drug, 9 ml of Mueller Hinton agar medium is added. The agar supplemented with drug is mix, empty in 15 x 100 mm petri dishes, and let it solidify and dry before inoculation. The vials of each of these test organisms were kept frozen in the vapor phase of a liquid nitrogen freezer. The test cultures grew overnight at 35 ° C in the medium suitable for the organism. Colonies were collected with a sterile swab and cell suspensions were prepared in Trypticase soy broth (TSB) t. to balance the turbidity of a McFarland standard of 0.5. A solution of 1:20 of each suspension is made in TSB. The plates containing the drug-supplemented agar were inoculated with a 0.001 ml drop of the cell suspension using a Steers replicator, providing approximately 104 to 105 cells per spot. Plates were incubated overnight at 35 ° C. After incubation of the Minimum Inhibitory Concentration (MIC μg / ml), the lowest concentration of the drug that inhibits the visible growth of the organism was read and recorded. The data is shown in Tables I and II.
Table 1 • is not a compound of the invention disclosed Table 1 (continued) * is not a compound of the invention disclosed Table 1 (continued) SAUR: S. auris SEPI: S. epidermidis EFAE: E. faecalia SPNE: S. pneumoniae SPYO: S. pyogenes "is not a compound of the invention disclosed Table II (continued) or Key: SAUR 9213: S. aureus SEPI 30593: S. epidermidis EFAE 12712: E. Faecium SPNE 9912: S. pneumoniae SPYO 152: S. pyogenes HINF 30063: Haemophilus influenwe MCAT 30610: Moraxella catarrhalis EFAE 9217: Enterococcus faecalis 51 As shown in Scheme 1, intermediates II for the compounds of this invention are also the exposed intermediaries. the published patents and applications of 'oxazolidinone referred to above. Intermediates IV for this invention are final products (Examples) from the patents and published applications of oxazolidinone incorporated herein 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'-thiocarbonyl-2 (IB) - pyridone in solvents such as methylene chloride at 0-25 ° C. The thioureas (la, R, - * - = H, alkyl? -4) can then be prepared as shown in Step 2 by the reaction of III with ammonia or the appropriate primary amines in solvents such as 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 a suitable isothiocyanate (R'-N = C = S) in solvents such as tetrahydrofuran at 0-50. ° C. They prepared thioamides (Ib, R "= H, alkyl 4) by allowing II to react with a suitable dithioester (R" 'SC (= S) -R ", Step 4 as illustrated in Example 4. This reaction is carried The reaction is carried out in aqueous-alcoholic solvents at 0-50 ° C in the presence of an equivalent of an alkali metal hydroxide.This reaction, especially when R "'is methyl or ethyl, can be catalyzed by an alkali metal fluoride. 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 triethylamine in solvents such as THF, dioxane or methylene chloride at 10-50 ° C. for 3 to 48 hours.When the reaction conditions are tolerated by the substituents on R (see, Examples 1 to 3) the thioamides (Ib, R "-H, alkyl-4) can also be conveniently prepared (Step 5) by allowing the appropriate amide intermediates (IV) to react with reagents such as 2,4-bis (p-methoxy phenyl) -1,3-dithiadiphosphetane-2,4-disulfide (Lawesson's Reagent) at 1, 4-dioxane, benzene, toluene or tetrahydrofuran at 60-110 ° C; phosphorus decasulfide and sodium carbonate in tetrahydrofuran a -50 ° C [Brillon, D., Sinthetic Communications, 20, 3085 (1990)] or phosphorus decasulfide and sodium fluoride in 1,2-dimethoxyethane at 20-50 ° 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 triethylamine in solvent mixtures containing water and methanol, ethanol or isopropanol at 10-50 ° C for 5 a 24 you cry The resulting intermediate is treated with an alkylating agent (R "" X where X represents bromine, iodine, alkyl sulfoniium, or arylsulfonyloxy) at 0-30 ° C to provide the le compounds. In Step 7, the compounds are allowed to react with alkali metal alkoxide such as sodium methoxide or potassium ethoxide in the corresponding alkanol as the solvent. This reaction is conveniently carried out at the reflux temperature of the alkanol for 1 to 24 hours.
SCHEME 1 S II R '• NH, R- -NH-C-NH-R' (R '= H, alkyl 1-4) STEP 2 R'-N = C- = S (R * = H, alkyl ,. 4) STEP 3 SSI! R-- -c p- -R "R- H-C R 1 (R" = H, alkyl-.?) STEP 4 Ib (R- »CH3, C2H5, HOOC_CH2) OR II R- NH- -C- -R "¡b (R" = H, alkyl, .4) IV STEP 5 S II 1) CS2 / Et3N II (R "" = C -, .4 alkyl, X = Br, I RNH-C-SR "alkyl OSOs, OSO-, aryl) 2) R" "X STEP I S MOR" "•» 11 HOR '"' RNH-C-OR '" (M = Li, + Na, + K +) STEP 7 Id In order to illustrate more fully the nature of the invention and the way of practicing it , the following experimental examples are presented.
EXAMPLE 1: (S) -N- [[3- [3- Fluoro-4- (4-morpholin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl) -thioacetamide (1) Ct 6H2oFN3? 3S A stirred mixture of II (PCT / US94 / 08904, 3. 37 g, 10.0 mmol) in dry dioxane (100 mL), under nitrogen and treated with Lawesson's Reagent (4.04 g, . 0 mmI), heated to reflux for 1 hour and refluxed for 1.5 hours. The reaction was terminated by TLC on silica gel with 10% MeOH-CHCl3. It is kept at room temperature during 18 hours is concentrated in va cuo. Chromatography of the residue on silica gel with acetone-methylene chloride mixtures containing 10-15% acetone gave the product which was crystallized from acetone-hexane to give 1: p.p. 157.5-158.5 ° C; HRMS theory for Ci6H2oFN303S (M +): 353.1209; found: 353.1212. Analysis calculated for C? 6H2oF 3? 3S: 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, 4-thiadiazol-2-yl) -1-piperazinyl] phenyl] -2 - oxo-5-oxazolidinyl] methyl) thioacetamide (2) 21 c, 9? -y: 'fts > 2 According to Example 1, for the preparation of 1, 21 (PCT / US97 / 01970) it was allowed to react with Lawesson's Reagent dioxane under reflux to provide 2: p.f. 222-223 ° C; HRMS theory for C? 9H2 FN602S2 (M + H +): 451.1386; found 451.1381.
EXAMPLE 3 (S) -N - [[3- [3- Fluoro-4- [2 », 5, -dioxospi ro- [piperidin-4,4'-imidazolidine] -1- yl] phenyl] -2-oxo -5-oxazolidinyl] methyl] thioacetamide (3) STEP A: (S) -N- [[3- [3-Fluoro-4- [21,5'-dioxospiro- [piperidin-4,4'-imidazolidine] -1-yl] phenyl] -2-oxo- 5-oxazolidinyl) met il] acetamide (32) • A stirred suspension of 31 (WO95 / 25106, 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 15 minutes and maintained at room temperature for 17 hours 15 minutes. Then 'was' subjected to chromatography on silica gel with mixtures of MeOK-NH 0H-CHC13 containing 5-20% MeOH and 0.5% NH4OH to provide 0.280 9 of 32: HRMS calculated for C19K2;? FNs? 5 : 419.1605 (Mt) found 419.1613; Analysis calculated for Ci9H22FN505 • 1 H20: C, 52.17; H, 5.53; N, 16.01. Found: C, 52.44; H, 5.30; N, 16.11.
STEP B: (S) -N- [[3- [3-Fluoro-4- [2 », 5 '-dioxospiro- [piperidin-4,4'-imidazolidine] -1-yl] phenyl] -2-oxo -5-oxazolidinyl] methyl] thioacetamide (3) MeO -OJfrO- OMe 33 C, 9H2¡, FN50..S3 A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 mL), under nitrogen was treated with Lawesson's Reagent (0.202 g, 0.500 mmol), brought to reflux for 4 hours and concentrated in va cuo. The residue was chromatographed on silica gel with MeOH-NH 4 OH-CHCl 3 mixtures containing 1-10% MeOH and 0.1-0.5% NH 4 OH and the resulting product was crystallized from p.artir of MeOH-CHCl 3 ~ EtOAc to provide 0.0491 g of 3: pf 218.5 ° C; HR FAB MS theory for C? 9H22FN504S (M +): 435.1376; 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-morpholini-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl) -thioacetamide (4) 4 A solution of 41 (148 mg, 0.500 mmol) and 0.97 M KOH (0.515 mL) in pure EtOH (5 mL) was added to a solution of ethyl dithioacetate (57 μL, 0.50 mmol) and sodium fluoride (20 mg, 0.47 mmole) in pure EtOH (5 mL) and the mixture was maintained at room temperature for 3 hours 40 minutes. Additional ethyl dithioacetate (5 μL) was added after 1 hour 55 minutes and additional 0.97 M KOH (40 L) and sodium fluoride (6 mg) were added to the mixture after 3 shovels 5 minutes. The reaction was followed by TLC on silica gel with 10% MeOH-CHCl3 and 30% acetone-CH2Cl2 • The main product was an Rf on TLC that was equal to that of 4.
EXAMPLE 5 (S) -N- [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea (5) STEP A: A solution of 51 (PCT / US 94/08904, 2.07 g, 7.00 mmol) in CH2Cl2 was added dropwise during minutes, under nitrogen to a stirred solution, cooled with ice of 1, 1'-thiocarbonyldi-2 (1H) -pyridone (1.95 g, 8.40 mmol) in CH2C12 (70 L). The mixture was slowly heated to room temperature and maintained for 18 hours. It was then diluted with CH2Cl2, washed with water and aqueous NaCl, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 10% acetonitrile-CH2Cl2 yielded 1.60 g of the isothiocyanate: HRMS theory for C15H? 6FN303S (M +): 337.0896; found 337.0888.
STEP B C1sH1ßFN40aS S Anhydrous ammonia was bubbled in for 7 minutes through a stirred solution of the product of Step I (1.00 g 2.96 mmole) in THF (10 mL) and the mixture was kept at room temperature for 3 hours 25 minutes and concentrated in vacuo. go cuo. Crystallization of the residue from acetone-hexane gave 0.861 g of 5: p.f. 199-199.5 ° C; MS m / z 354 (M +). Anal, calculated for C15H19FN403S: 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-morpholin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -N'-methylthiourea (6) A stirred solution of methyl isothiocyanate (93 mg, 1.27 mmol) in THF was treated with 61 (295 mg, 1.00 mmol), maintained at room temperature for 18 hours and concentrated in vacuo. The residue was recrystallized from EtOAc-hexane to provide 246 mg of 6: p.p. 158-160 ° C; MS m / 'z 368 (M +). Analysis calculated for C? 6H21FN 03S: 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 - (tet rahydro-1-oxide-2H-thiopyran-4-yl) phenyl] -2-OXO-5-oxazolidinyl] methyl ] etantioamide Step 1: A mixture of (S) - (-) - N - [[3- [3-fluoro-4- (3,6-dihydro-2H-thiopyran-4-yl) phenyl] -2 S-oxide -oxo-5-oxazolidinyl) methyl] acetamide (4.50 can be obtained according to the procedures set forth in International Publication No. I WO97 / 09328) and platinum oxide (697 mg) in methanol (164 mL) was stirred vigorously in The Parr apparatus under a hydrogen atmosphere at 40 psi duarte 18 hours. The catalyst was then removed by filtration through Celite, and the filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel (230-400 mesh, 350 g), eluting with a methanol / chloride gradient. methylene (3 / 97-7 / 93). Collection and concentration of these fractions with a Rf = 0.44 by TLC (methanol / chloroform, 10/90) provides (S) -cis- (-) -N- [[3- [3-Fluoro-4- (tetrahydro- l-oxide-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazole idinyl] met il] acet amide pf 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) was stirred in a vial with screw cap at 100 ° C durnate 22 hours at room temperature for 16 hours, during which additional hydroxylamine hydrochloride (944 mg) and pyridine (4 mL) were added. The reaction mixture was then concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate (100 mL) and saline (50 mL), adjusted to pH 11 with solid sodium carbonate and extracted with methanol / sodium chloride. methylene (10/90, 5 x 100 L). The combined organic phase was concentrated under reduced pressure and the crude product was chromatographed on silica gel (230-400 mesh, 150 g), eluting with a methanol / methylene chloride gradient (6 / 94-10 / 90). . 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-aminomethyl-2-oxazolidinone, 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 acid sulfate (1M, 50 L) 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 / diethylether 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-oxazolidinyl] methyl] thiourea Step 1: A solution of 1, 1'-thiocarbonyldi-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-oxide-2H-thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, as prepared in ". Example 7, Step 2, (275 mg, 0.843 mmol) in anhydrous methylene chloride (34 mL) 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 L) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was subjected to chromatography on silica gel (70-230 mesh, 20 g), eluting with acetonitrile / methylene chloride (40/60) and these fractions with an Rf = 0.07 by TLC (acetonitrile / methylene chloride, 30/70) were collected and concentrated to provide (S) -cis-3- [3-Fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -5-isothiocyanatomethyl-2- oxazolidinone, mp 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 (Step 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 kettle 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 to give the crude product. Recrystallization from methanol / methylene chloride / diethylether afforded the title compound, m.p. 206-208 ° C (dec.).
EXAMPLE 9 (S) -trans-N- [[3- [3-Fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl) -2-oxo-5-oxazolidinyl] methyl] ethanedioamide 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 (disclosed 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 tr.ans-sulfoxides. Alternatively, sulfide by-product can be oxidized selectively to the trans isomer using t-butyl hydroperoxide and a catalyst such as Ti (OiPr) 4 and D-diisopropyl tartrate in a suitable solvent. 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-1-oxide-2H-thiopyran-4-yl) phenyl) -2- oxo-5-oxazolidinyl] methyl) acetamide (0.90 g) and hydroxylamine hydrochloride (0.85 g) in pyridine (11.0 mL) and ethanol (1.2 mL) was stirred in a vial with a screw cap at 100 ° C for 23 hours and room temperature for 19 hours, during which additional hydroxylamine hydrochloride (340 mg) and pyridine (1 mL) were added. The reaction mixture was 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 x 100 mL). The combined organic phase was concentrated under reduced pressure and the crude product was chromatographed 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) provides (S) -trans-3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran- 4-yl) fenii] - 5 -ami nomethyl -2 -oxa zol idi nona, 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-oxazolidinone, as prepared in Step 1, (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 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 crude product was subjected to chromatography on silica gel (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) were collected and concentrated and the residue was recrystallized from methylene chloride / diethylether to provide the title compound, m.p. 193-194 ° C (dec.).
EXAMPLE 10 (S) -trans- [[3- [3-F1-uoro-4- (tetrahydro-1-oxide-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl) thiourea Step 1: A solution of 1,1 '-thiocarbonyldi-2 (1H) -pyridone (192 mg, 0.827 mmol) in chloride Anhydrous methylene (8.3 mL) at 0 ° C under a nitrogen atmosphere was treated with a solution of (S) -trans-3- [3-fluoro-4- (tetrahydro-1-oxide-2H-thiopyran-4-yl) ) phenyl] -5-aminomethyl-2-oxazolidinone, 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 of 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-Fluor'o-4- (tetrahydro-l-oxide-2H-thiopyran- 4-yl) phenyl] -5-isothiocyanatomethyl-2-oxazolidinone, mp 165-167 ° C.
Step 2: A solution of (S) -trans-3- [3-fluoro-4- (tetrahydro-l-oxide-2H-thiopyran-4-yl) phenyl] -5-isot-iocianatomet-il-2-oxazole idinone ( Step 1, 230 mg, 0. 624 mmoles) 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 kettle 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 give the crude product. trituration with methanol / methylene chloride / diethylether afforded the title compound, m.p. 209-210 ° C (dec.).
EXAMPLE 11 (S) -N- [[3- [3-Fluoro-4- (tetrahydro-1, 1-dioxide-2H-t-pyroran-4-yl) phenyl) -2-oxo-5-oxazolidinyl] methyl] etaniotio ida Step 1: Starting with (S) -cis- (-) -N- [[3- [3-Fluoro-4- (t and rahydro-l-oxide-2H-t iopyran-4-yl) phenyl) -2 -oxo-5-oxazolidinyl] met il] acetamide as prepared in Example 7, Step 1, and following the procedure of Step 2, and making non-critical variations when replacing S, S-dioxide (S) - (-) - N - [[3- [3-fluoro-4- (tetrahydro-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide (disclosed in International Publication No. WO 97/09328) for (S) -cis - (-) - N - [[3- [3-fluoro-4- ( tetrahydro-1-oxide-2H-thiopyran-4-yl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -acetamide, - the product (S) - (-) - 3 - [3-Fluoro- 4- (tetrahydro-1, l-dioxide-2H-thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, mp 194 ° C (dec.).
Step 2: A solution of ethyl dithioacetate (100 mL, 0.876 mmole) and sodium fluoride (37 mg, 0.876 mmole) in ethanol (8.8 mL) under a nitrogen atmosphere was treated with a mixture of (S) - (- ) -3- [3-fluoro-4- (tetrahydro-1, l-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) were added and ethanol (3.0 mL), and then diluted with chloride of methylene (150 mL), washed with water (50 mL), aqueous potassium hydrogen sulfate (1M, 50 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. 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-diox do-2H-thiopyran-4-yl) pheayl] -2-oxo-5-oxazolidinyl] methyl] thiourea Step 1: A solution of 1,1 '-thiocarbonyldi-2 (1H) -pyridone (304 mg, 1.31 mmol) in anhydrous methylene chloride (13 mL) at 0 ° C under a nitrogen atmosphere was treated with a solution of (S) - (-) - 3 - [3-fluoro-4- (tetrahydro-1,1-dioxido-2H-thiopyran-4-yl) phenyl] -5-aminomethyl-2-oxazolidinone, as 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-l, l-dioxido-2H-thiopyran-4-yl) phenyl] -5-isothiocyanatomethyl. -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-isothiocyanatomethyl-2-oxazolidinone (Step 1, 380 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 kettle 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 va cuo to provide the raw product. 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-mor-folin-1) 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 L) was heated, under nitrogen at 50-55 ° C for 2 hours, cooled to room temperature and tried, in portions for 2 minutes, with 398 (0.45 g, 0.0015 mol). The suspension was kept at room temperature for 4 hours and the resulting solution was treated with Et20 (1 mL) and kept at room temperature for 18 hours. The mixture was diluted with additional Et20 (10 mL) 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 +); NMR XH (300 mHz, CDC13) d 3.08 (m, 4H), 3.72 (m, 2H), 3.77 (d, d, ÍH), 3.89 (m, 4H), 4.C4 (t, ÍH), 4.80 (m, 1H), 6.33 (s, ÍH), 7.05 (m, 2H), 7. 45 (d, d, ÍH), 8.27 (s, ÍH).
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 chromatographed on silica gel 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 EtOAc-methyl tert-butyl ether to give 0.114 g of 7: p.f. 150-155 ° C (dec); IR (VARIATION) 3322, 1752 cm "1; MS (ES) m / z 340 (M + H +), 362 (M + Na +); NMR XH [300 MHz, (CD3) 2SO] d 2.94 (m, 4H) , 3.72 (m, 4H), 3.77 (d, d, ÍH), 3.94 (t, 2H), 4.12 (t, ÍH), 4.93 (m, ÍH), 7.05 (t, ÍH), 7.16 (d, d , ÍH), 7.47 (d, d, ÍH), 9.33 (d, ÍH), 10.59 (s, 1H). Analysis calculated for C? 5H? 8FN303S: 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-morpholini-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -thiopropionamide (9) 39 A stirred solution, cooled with ice of 39 (0.395 g, 0.00134 mol) and triethylamine (0.186 mL, 0.0027 mol) in CH2C12 (20 mL), under nitrogen was treated, dropwise over 2 minutes, with a solution of propionyl (0.128 mL, 0.00147 mol) in CH2Cl2 (3 ?? L). The mixture was kept in the ice bath for 20 minutes and at room temperature for 1 hour. It was then diluted with cp2Cl2, washed with saturated NaHCO3, water and brine, dried (MgSO4) and concentrated. The residue (8) 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.; This one then concentrated. The residue was chromatographed on silica gel with 2% MeOH-CHCl3 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 (VARIATION) 3284, 3266, 1748, 1744 cm "1; [a] 2 D ^ 20 ° (MeOH); NMR 1H [300 MHz, (CD3) 2SO] d 1.12 (t, 3H), 2.56 (q, 2H), 2.94 (m, 4H), 3.72 (m, 4H), 3.78 (d, d, ÍH), 3.90 (t, 2H), 4.11 (t, 1H), 4.93 (m, ÍH), 7.05 (t , HH), 7.16 (d, d, 1H), 7.47 (d, d, HH), 10.30 (s broad, 1H) Analysis calculated for C 7 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-oxazolidinyl] methyl] -2- chlorothioacetamide (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, drop by drop, for 15 minutes with a solution of chloroacetyl chloride (465 mL, 5.8 mmol) in CH2C12 (30 mL) and kept at room temperature for 18 hours. It was then washed with saturated NaHCO 3 and dilute NaCl, dried (Na 2 SO 4) and concentrated. The residue was subjected to flash chromatography on silica gel with 20-30% acetone-CH2Cl2 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 mmol) and Lawesson's Reagent (0.420 mg, 1.04 mmol) in dioxane (10 mL) was brought to reflux, under nitrogen for 2 hours and concentrated under reduced pressure. The residue was chromatographed on silica gel with 3-10% acetone-CH2Cl2 to give 0.143 9 of 11: MS (Cl) m / z 388 (M + H +); NMR XH (300 MHz, CDC13) d 3.07 (m, 4H), 3.77 (d, d, HH), 3.88 (m, 4H), 4.04 (m, HH), 4.12 (t, 1H), 4.35 (m, ÍH), 4.61 (s, 2H), 4.98 (m, 1H), 6.96 (t, 1H), 7.08 (d, d, ÍH), 7.44 (d, d, ÍH), 8.69 (s, ÍH). Analysis calculated for C l6H? 9ClFN303S: C, 49-55; H, 4.94; N, 10.83. Found: C, 49.38; H, 5.20; N, 10.27.
EXAMPLE 16: (S) -N- [[3- [3-Furo-4- (4-morpholin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a, a, a-trifluorothioacetamide (13) ) A stirred and ice cooled solution of 39 (0.590 g, 2.0 mmol) and triethylamine (640 mL, 4.6 mmol) in CH2Cl2 (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 followed by TLC on silica gel with 30% acetone-CH2Cl2. Additional trifluoroacetic 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 finished in 1 hour after the last addition; it was mixed with CH2C12, washed with water and dilute aCl, dried (Na2304) 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? 6H? 7F4N30: C, 49.11; H, 4.38; N, 10.74. Found: C, 48.99; H, 4.56; N, 10.73.
O r ~ \ oipfíf * STí || sO8 * N- VlAj Y - .. H OO ^ iNH-C-CFg ^ M + C-CF3 12 13 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 go cuo. The residue was subjected to flash chromatography on silica gel with 5-15% acetone-CH2Cl2 and the product was crystallized from acetone-heptane to provide 0.249 g of 13: p.f. 151-152 ° C; MS (EI) m / z 407 (M +), 3.63, 209, 151, 95; NMR 1H (300 MHz, CDC13) d 3.05 (m, 4H), 3.75 (d, d, ÍH), 3.87 (m, 4H), 3.95 (m, 1H), 4.14 (t, ÍH), 4.32 (rn, ÍH), 5.01 (m, ÍH), 6.92 (t, ÍH), 7.05 (d, d, 1H), 7.38 (d, d, ÍH), 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-fluorothioacetamide (15) A stirred and cooled ice solution of 39 (0.590 g, 2.0 mmol) and triethylamine (611 mL, 4.4 25 mmol) in CH2C12 (10 mL), under nitrogen, was treated, dropwise, 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 chromatography on "silica gel with 10-30% acetone-CH2C12 to provide 0.180 g of 14: MS (ES) m / z 356 (M + H +), 378 (M + Nad • 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 chromatographed on silica gel with 15% acetone-CH2Cl2 to give 0.161 g of 15: MS (EI) m / z 371 (M +); NMR 1H (300 MHz, CDC13) d 3.05 (m, 4H), 3.78 (d, d, ÍH), 3.87 (m, 4H), 4.03 (m, ÍH), 4.11 (t, ÍH), 4.38 (m, ÍH), 4.98 (m, ÍH), 5.07 (s, ÍH), 5.23 (s, ÍH), 6.93 (t, ÍH), 7.08 (dd, ÍH) ), 7.42 (d, d, ÍH), 8.42 (s, 1H). Analysis calculated for Ci6H19F2N3? 3S: 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-morpholin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a, a-difluorothioacetamide (17) A stirred and ice-cooled mixture of 39 (0.590 g, 2.0 mmol), diflucroacet Leo acid (190 L, 2.0 mmol), and 1-hydroxybenzotriazole (0.297 g, 2.2 mmol) in DMF (5 mL) under nitrogen was treated. with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.843 g, 4.4 mmol) and maintained at room temperature for 18 hours. It was diluted with CH2CH2, 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; NMR 1H (300 MHz, CDC13) d 3.05 (m, 4H), 3.66 (m, 2H), 3.85 (m, 5H), 4.08 (t, ÍH), 4.80 (m, 1H), 5.93 (t, J = 53.9 Hz, ÍH), 6.92 (t, ÍH), 7.06 (m, 2H), 7.39 (d, d, ÍH); MS (EI) m / z 373 (M +). Analysis calculated for Ci6H? 8F3N304: C, 51.48; H, 4.86; N, 11.26. Found: C, 51.59; H, 4.91; N, 11.29. 2.
A stirred solution of 16 (0.373 g, 1.00 mmol) in dioxane (10 L), 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% acetone-CH2Cl2 and crystallization of the product from EtOAc-heptane gave 0.276 9 out of 17: p.f. 125-127 ° C; MS (EI) m / z 389 (M +), 345, 305, 247, 209, 195, 151, 138, 123, 109, 95; NMR XH (300 MHz, CDC13) d 3.05 (, 4H), 3.76 (d, d, ÍH), 3.86 (m, 4H), 4.01 (m, ÍH), 4.12 (t, ÍH), 4.30 (m, ÍH) ), 4.99 (m, ÍH), 6.20 (t, J = 55.9 Hz, 1H), 6.92 (t, ÍH), 7.06 (d, d, ÍH), 7.38 (d, d, ÍH), 8.78 (s broad) , 1 HOUR) . Analysis calculated for Ci6H? ßF3N303S: 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-morpholin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a- cyanothioaceta ida (19) 1.
A stirred and cooled mixture of ice of 39 (0.C46 g, 2.19 mmole), cyanoacetic acid (0.179 g, 2. 1 mmol) and 1-hydroxybenzotriazole (0.351 g, 2.6 mmol) in DMF (5 ml.), Under nitrogen, was treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 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 (Na2SO) and concentrated. The solid residue was crystallized from EtOAc-heptane to give 0.546 g of 18: p.f. 172-174 ° C: IR (VARIATION) 3316, 2256, 1754, 1684 cm "1; MS (EI) m / z 362 (M +). Analysis calculated for C? H? 9FN404: C, 56. 35; H, 5.28; N, 15.46. Found: C, 56.33; H, 5.30; N, 15.36. 2.
A stirred solution of 18 (0.453 mg, 1.25 mmol) in dioxane (10 mL), under nitrogen, was treated with Reagent from .Lawesson (0.505 g, 1.25 mmol) and heated to about 100 ° C. When the reaction was complete (TLC with 30% acetone-CH2CH1) the mixture was cooled and concentrated in vacuo. Chromatography of the residue on silica gel with 10-20% acetone-CH2Cl2 and crystallization of the product from EtOAc-heptane gave 0.110 g of 19: p.f. 186-187 ° C (dec); MS (ES) m / z 379 (M + H +), 401 (M + Na +); NMR XH (300 MHz, CDC13) d 3.05 (m, 4H), 3.81 (d, d, ÍH), 3.86 (m, 4H), 3.89 (s, 2H), 4.09 (t, ÍH), 4.14 (m, 2H), 5.01 (m, 1H), 6.92 * (t, ÍH), 7.05 (d, d, 1H), 7.34 (d, d, ÍH), 9.15 (s, ÍH); IR (VARIATION) 3244, 2260, 1754 cm "1. Analysis calculated for C? H? 9FN403S: C, 53.96; H, 5.06; N, 14.81. Found: C, 53.88; H, 5.39; N, 14.61.
EXAMPLE 20: (S) -N- [[3- [3-Fluoro-4- (4-morpholin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -a, a-dichlorothioacetamide (21) A stirred and cooled ice solution of 39 (0.885 g, 3.Q0 mmol) and triethylamine (975 mL, 7 mmol) in CH2C12 (15 mL), under nitrogen was treated, dropwise with a dichloroacetic anhydride solution (555 g). 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 on silica gel with 10% -of acetone-CH2Cl2 and crystallization of the product from acetone-heptane gave 0.463 g of 20: mp 197-198 ° C (dec); MS (ES) m / z 406 (M + H +), 428 (M + Na +); NMR XH (300 MHz, CDC13) d 3.05 (m, 4H), 3.75 (m, 3H), 3.86 (m, 4H), 4.07 (t, 1H) ), 4.83 (m, ÍH), 5.94 (s, ÍH), 6.92 (t, ÍH), 7.06 (m, 2H), 7.41 (d, d, ÍH).
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 He concentrated in va c uo. Chromatography of the residue on silica gel first with 30% acetone-heptane and then with 10% acetone-methylene chloride and crystallization of the product from methylene-heptane chloride gave 0.203 g with 21: p.f. 143-144 ° cd .; HR17S (El) calculated for C? 6Hl8Cl2 F N3 03 S (M) 421.0431. Analysis calculated for C 16 H 18 C 12 F N 3 03 S, 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-morpholnyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] - - (methoxycarbonyl) thioacetamide (23) A stirred solution of 39 (0.955 g, 3.2 mmol) and triethylamine (650 mL, 4.5 mmol) in CH2C12 (50 mL), under nitrogen, was treated dropwise for 15-20 minutes with a solution of malonyl methyl 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 flash chromatography on silica gel with 15-30% acetone-CH2Cl2l and the product was crystallized from acetone-hexane to provide 0.873 g of 22: p.f. 150-151 ° C; NMR x \? (300 MHz, CDC13) d 3.03 (m, 4H), 3.34 (s, 2H), 3.67 (s, 3H), 3.69 (m, 2H), 3.76 (d, d, ÍH), 3.85 (, 4H), 4.00 (t, 1H), 4.78 (m, ÍH), 6.90 (t, 1H), 7.06 (d, d, 1H), 7.41 (d, d, 1H), 7.57 (t, ÍH); MS (ES) m / z 396 (M + H +), 418 (M + Na +); HRMS (FAB) calculated for C? 8H23FN306 (M + H +) 396.1571, found 396.1579. Analysis calculated for C? 8H22FN306: C, 54.68; H, 5.61; N, 10.63. Found: C, 54.69; H, 5.68; N, 10.58. 2. 3 - . 23 - * -HN NHH-- 8GC .--. CH2COOCH3 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 kept at room temperature for 4 hours 10 minutes and at 80-90 ° C for 1.5 hours. The reaction was followed by TLC on silica gel with 10% MeOH-CHCl3. At this time, a new polar product had begun to form. It was kept at room temperature for 18 hours and at 80 ° C for 2 hours ^; additional Lawesson reagent (40 mg, 0.099 mmol) was added and heating at 80 ° C continued for 2 hours; There still remained some of the starting material. The mixture was concentrated and the residue was chromatographed on silica gel with 15% acetone-CH2Cl2 to give 0.348 g of 23: NMR 1H (300 MHz, CDC13) d 3.05 (m, 4H), 3.71 (s, 3H ), 3.81 (d, d, ÍH), 3.86 (m, 4H), 3.88 (s, 2H), 4.07 (t, ÍH), 4.19 (m, 2H), 4.99 (m, 1H), 6.91 (t, 1H), 7.07 (d, d, ÍH), 7.42 (d, d, ÍH), 9.52 (s, ÍH); IR (VARIATION) 3269.1743 cm "1; MS (EI) m / z 411 (M +). ' Analysis calculated for C18H22FN305S: 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] f-enyl] • 2-oxo-5-oxazolidinyl] methyl] thioacetamide (25) A stirred mixture of 24 (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 for 18 hours and concentrated in vacuo. Flash chromatography of the residue on silica gel with 5% MeOH-CHCl3 gave the product that was crystallized from MeOH to provide 0.100 g (63.4%) of 25: p.f. 161-163 ° C; NMR XH [300 MHz, (CD3) 2SO] d 2.43 (s, 3H), 3.87 (m, 3H), 4.22 (t, ÍH), 4.99 (m, 1H), 7.51 (d, ÍH), 7.77 (m , 2H), 8.26 (s, ÍH), 8.97 (d, ÍH), 10.35 (s broad, 1H); IR (heating) 3259, 3226, 3044, 1752 cm "1; MS (ES) m / z 336 (M + H +), 358 (M + Na +). Analysis calculated for C 14 H 4 FN 502 S: C, 50.14; H, 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] Triazole] 1] - 2-oxo-5-oxazolidinyl] methyl] thioacetamide (25) A stirred mixture of 26 (0.26 g, 0.938 mmol), ethyl dithioacetate (0.12 g, 0.998 mmol), sodium fluoride (0.040 g, 0.953 mmol) and pure EtOH (10 mL), under nitrogen, was treated for 5 minutes with a 0.97 M KOH solution (1.03 L) in EtOH and kept at room temperature for 2 hours. It was then diluted with CH2Cl2 (75mL), washed with water, 1M KHS0, water and brine and evaporated. The residue was subjected to flash chromatography on silica gel 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-oxazolidinii; - methyl] thioacetamide (28) A stirred and ice-cooled solution of 52 (8.80 g, 0.0240 mol) in CH2C12 (25 L) 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 CH 2 Cl 2 was washed with saturated NaHCO 3 and dilute NaC, dried (Na 2 SO 4) and concentrated. The residue was used in the next reaction without further purification. A sample of this material (53) had: NMR XH (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, ÍH), 6.91 (d, 1H), 7.23 (s, ÍH), 7.36 (m, 5H); MS m / z 269 (M + H +).
BzO-CH2-C = 0 NHCbz 268. 22 416.48 C25H24N204 C16H16N2O2 53 54 A stirred and ice-cooled mixture of 53 (crude product from the previous reaction), acetone (200 mL), saturated NaHCO 3 (200 mL) and water (30 mL) was treated, dropwise for 20 minutes, with a solution of benzyloxycetyl chloride (4.70 mL, 0.030 mol) in acetone (55 mL), warmed slowly to room temperature and maintained for 18 hours. Additional benzyloxy-acetyl-thiyl chloride (1.0 mL) 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 the crude product. The EtOAc solution was dried (a2SO4) and concentrated to provide 5.36 g of the additional crude product. Crystallization of the product from EtOAc gave a total of 6.35 g of 5414, m.p. 157-159.5 ° C. The analytical sample had: p.f. 158-159.5 ° C; NMR lH (300 MHz, CDC13) d 3.16 (t, 2H), 4.01 (t, 2H), 4.21 (s, 2H), 4.69 (s, 2H), 5.19 (s, 2H), 6.67 (s, ÍH), 6.97 (d, ÍH), 7.36 (m, 10H), 7.50 (s broad, ÍH), 8.15 (d, ÍH); 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 cm Analysis calculated for C2sH2 N20: C, 72.10 H, . 81; N, 6.73 Found C, 72.05; H, 5.86; N, 6.68.
BzO- A stirred suspension of 54 (1.16 g, 2.78 mmol) in THF (42 mL) was cooled under nitrogen, at -78 ° C and treated, dropwise, for 5 minutes with 1.6 M n-BuLi in hexane (1.83 mL). ). It was kept at -78 ° C for 50 minutes, treated, dropwise, for 5 minutes with a solution of (R) - (-) - glycidyl butyrate (0.500 g, 3.47 mmol) in THF (2 mL), it was allowed to warm to room temperature during 3 hours and it was maintained for 18 hours. It was then diluted with EtOAc, washed with saturated NH4C1, water and brine, dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with 3% MeOH-0.2% NH OH-CHC13 afforded 0.60 g (56%) of 5514: NMR XH [300 MHz, (CD3) 2 SO] d 3.14 (t, 2H), 3.59 (m, 2H), 3.79 (d, d, ÍH), 4.03 (m, 3H), 4.29 (s, 2H), 4.58 (s, 2H), 4.65 (m, ÍH), 5.20 (t, 1H) , 7.31 (m, 6H), 7.55 (s, 1H), 8.03 (d, ÍH); MS (ES) m / z 383 (M + H +), 405 (M + Na +). 4.
A stirred and cooled mixture with ice of 55 (0.60 g, 1.57 mmol), triethylamine (2.2 mL), and CH2Cl2 (12 mL), under nitrogen, was treated with 3-nitrobenzenesulfonyl chloride (0.44 g, 1.99 mmol) and kept in the bath with ice for 30 minutes and at room temperature for 60 minutes. It was then diluted with CH2Cl2, washed with water and brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 15% CH3CN-CH2Cl2 gave 0.70 g of 56: NMR H (300 MHz, CDC13) d 3. 19 (t, J = 8.3 Hz, 2H), 3.88 (d, d, ÍH), 4.04 (t, J = 8.4 Hz, 2H), 4.14 (t, ÍH), 4.23 (s, 2H), 4.42 (m , 2H), 4.70 (s, 2H), 4.84 (m, ÍH), 6.97 (m, ÍH), 7.34 (m, 5H), 7.58 (s, ÍH), 7.81 (t, 1H), 8.22 (m, 2H), 8.53 (m, 1H), 8.73 (m, ÍH); MS (ES) m / z 568 (M + H +), 590 (M + Na +).
. A stirred mixture of 56 (crude 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 (Na2SO) and concentrated. Chromatography of the residue on silica gel with 8% MeOH-0.5% NH40H-CHC13 afforded 1.05 g of 57: NMR XH [300 MHz, (CD3) 2 SO] d 2.78 (m, 2H), 3.13 (t, 2H) , 3.82 (d, d, ÍH), 4.01 (m, 3H), 4.29 (s, 2H), 4.58 (s, 2H), 4. 58 (m, ÍH), 7.31 (m, 6H), 7.54 (s broad, ÍH), 8.03 (d, ÍH); MS (ES) m / z 382 (M + H +), 404 (M + Na +).
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. Additional 1M HCl (0.5 mL) and catalyst (100 mg) were added and the hydrogenation continued for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated to provide 0.34 g of 27: NMR XH [300 MHz, (CD3) 2 SO] d 3.15 (t, 2H), 3.22 (broad s, 2H), 3.84 (d, d , ÍH), 4.00 (t, H), 4.15 (s, 2H), 4.15 (m, ÍH), 4.92 (m, ÍH), 7.24 (q, ÍH), 7.50 (d, ÍH), 8.03 (d, ÍH), 8.37 (broad s, 3H); MS (ES) m / z 2.92 (M + H +). 7.
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 v mL) and the mixture was kept at room temperature for 2 hours 15 minutes. 0.97 M KOH (0.2 ml), sodium iodide (6 mg) and additional ethyl dithioacetate (20 mg) were added and the mixture was stirred for 2 hours, mixed with CH2C12 (150 mL), washed with water, KHS04 1M 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? 6H2oN304S (M + H +) 350.1174, found 350.1183; NMR XH [300 MHz, (CD3) 2SO] d 2.42 (s, 3H), 3.14 (t, 2H), 3.79 (d, d, ÍH), 3.89 (t, 2H), 4.00 (t, 2H), 4.12 (m, 3H), 4.83 (t, 1H), 4.90 (m, ÍH), 7.25 (d, ÍH), 7.50 (s, ÍH), 8. 03 (d, 1H), 10.35 (s, ÍH); IR (VARIATION) 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 58 (3.00 g, 7.00 mmol), THF (60 mL), pure 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 concentrated in vacuo to give 2.67 g of 59 which was used without further purification in the following reaction: NMR XH (300 MHz, CDC13) d 2.16 (broad s), 3.02 (m, 8H), 3.73 (d, d, J = 3.9, 12.6 Hz, lHi, 3.96 (m, 3H), 4.72 (m, ÍH), 6.92 (t, J = 9.2 Hz, ÍH), 7.11 (m, 1H) 7.43 (d, d, J = 2.6.14.3 Hz, 1H); MS (ES) m / z 296 (M + H +). 60 59 A stirred and cooled mixture with ice of 59 (2.67 9 of the previous reaction), acetone (190 mL) and saturated NaHCO 3 (70 mL) were treated, dropwise during 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 i. 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-CH 2 Cl 2 gave 2.64 g of 60: NMR XH (300 MHz, CDC13) d 2.28 (broad s, 1H), 3.00 (m, 4H), 3.66 (m, 2H), 3.77 (m, 3H), 3.9.6 (m, 3H), 4.22 (s, 2H), 4. 61 (s, 2H), 4.74 (m, 1H), 6.88 (t, J = 9.2 Hz, ÍH), 7. 12 (m, ÍH), 7.35 (s, 5H), 7.46 (d, d, J = 2.6,14.2 Hz, ÍH); IR (heating) 3406, 1748, 1647 cm "1; HRMS (EI) calculated for C23H26FN3? 5 (M +) 443.1856, found 443.1842.
A stirred and cooled mixture with ice of 60 (2.64 g, 6.00 mmol) and triethylamine (1.14 L, 8.16 mmol) in CH2CL2 (200 mL), under nitrogen, was treated with 3-nit robensenulfonyl chloride (1.78 g, 8.C4 mmol), warmed to room temperature and it was maintained for 5 hours 20 minutes. Additional 3-1. Nitrobenzene chloride] (180 mg) and additional triethylamine (0.20 mL) were added and the mixture was kept at room temperature for 18 hours, diluted with CH2C12 and washed with water and dilute NaCl, dried ( Na204) and concentrated. Chromatography of the residue on silica gel with 40-60% acetone-hexane gave 3.36 g of 77: NMR XH (300 MHz, CDC13) d 3.02 (broad s, 4H), 3.66 (broad s, 2H), 3.78 ( s broad, 2H), 3.87 (d, d, J = 5.9, 9.1 Hz, ÍH), 4.09 (t, J = 9.2 Hz, ÍH), 4.22 (s, 2H), 4.41 (m, 2H), 4.61 ( s, 2H), 4.84 (m, 1H), 6.88 (t, J = 9.1 20 Hz, ÍH), 7.02 (m, ÍH), 7.35 (m, 6H), 7.82 (t, J = 8.0 Hz, ÍH) , 8.23 (m, ÍH), 8.53 (m, l: E: i), 8.73 (m, ÍH); 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 ammonium hydroxide (90 mL) was heated at 40-45 ° C for 18 * hours, treated with additional ammonium hydroxide (30 mL), heated at 40-45 ° C for i.8 hours, treated with additional ammonium hydroxide (25 mL) and heated at 45 ° C for 18 hours. Then it was mixed with water and extracted with CH2C12. The extract was washed with dilute NaCl, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.5% NH40H-CHC13 afforded 2.44 g of 61: NMR XH (300 MHz, CDC13) d 1.50 (broad s), 3.04 (m, 6H), 3.65 ( s broad, 2H), 3.81 (m, 3H), 3.99 (t, ÍH), 4.21 (s, 2H), 4.61 (s, 2H), 4.66 (m, ÍH), 6.88 (t, 1H), 7.12 ( m, ÍH), 7.33 (m, 5H), 7.47 (d, d, ÍH); MS (ES) m / z 443 (M + H +).
. A solution of 61 (1.45 g, 3.3 mmol) and 1.0 N HCl (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. Additional 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 NH OH, filtered and concentrated in va cuo to provide 1.18 g of 29: NMR XH [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, ÍH), 4.14 (, 3H), 4.66 (s, broad, 1H), 4.33 (m, ÍH), 7.07 (t, ÍH), 7.16 (d, d, ÍH), 7.48 (d, d, 1H), 8.04 (s broad); IR (heating) 3420, 3099, 3040, 3008, 1755, 1641 c "1; MS (ES) m / z 353 (M + H) Analysis calculated for C? 6H22ClFN 04: 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 was 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, diluted with CHC13, washed with water and dilute NaCl, dried (Na2SO) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.5% NH40H-CHC13 and crystallization of the resulting product from pure EtOH gave 0.238 mg (44.9%) 30: p.f. 163-16'5 ° C; NMR 1 ñ (300 MHz, CDC13) d 2.60 (s, 3H), 3.06 (m, 4H), 3.45 (m, 2H), 3.61 (m, 1H), 3.82 (m, 3H), 4.07 (m, 2H) ), 4.25 (m, 3H), 4.97 (m, 1H), 6.91 (t, 1H), 7.07 (m, ÍH), 7.45 (d, d, 1H), 7.91 (broad s, ÍH); 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? 8H23F 04S: 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- (4-1 iomorpholini-1) phenyl] -2-OXO-5 -oxa-zolidinyl] -methyl] -thioacetamide (32) A stirred and cooled mixture with ice of 31 (0.38 g, 0.0012 mol) and triethylamine (0.38 mL, 0.0027 mol) in THF (12 mL), under nitrogen, was treated with ethyl dithioacetate (0.16 mL, 0.0014 mol) and then maintained at room temperature for 24.5 hours and he concentrated ih 'va cuo. A solution of the residue in CH2C12 was washed with saturated NaHCO3, water and brine, dried (MgSO4) and concentrated. The crystallization of the residue from EtOAc-hexane provided 0.355 g of 32: p.f. 155- 156 ° C; MS (ES) m / z 370 (M + H1 '), 392 (M + Na +); GO (VARIATION) 3206, 3042, 1759, 1738 cm-1; NMR XH (300 MHz, CDCl 3) d 2.60 (s, 3H), 2.95 (s, 4H), 3.43 (m, 4H), 3.82 (d, d, 1H), 4.08 (m, 2H), 4.27 (m, 1H), 4. 98 (m, 1H), 7.06 (m, ÍH), 7.33 (broad s, 1H), 7.51 (d, ÍH), 8.03 (s broad, ÍH). Analysis calculated for C16H2oFN302S2: C, 52.01; H, 5.46; N, 11.37. Found: C, 51.86; H, 5.43; N, 11.20.
EXAMPLE 27: S-Oxide (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide (S). 1. 63 A stirred and ice-cooled mixture of sodium metaperiodate (1.08 g, 5.05 mmol) and water (12 mL), under nitrogen, was treated with 62 (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 CHC13. The extract was dried (MgSO) and concentrated to provide 1.4 g of 63: NMR 1E [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, ÍH), 4.03 (t, ÍH), 4.66 (m, ÍH), 5.18 (t, 1H), 7.16 (m, 2H), 7.52 (m, 1H); MS (ES) m / z 329 (M + H +), 351 (M + Na +).
A stirred and ice-cooled mixture of 63 (1.27 g, 3.87 mmol) and triethylamine (0.732 mL, 5.25 mmol) in CH2C12 (130 mL), under nitrogen, was treated with m-nitrobenzenesulfonyl chloride (1.15 g, 5.19 mmol) and kept at room temperature for about 24 hours. It was diluted with CH2Cl2, washed with water and brine, dried (Na2SO4) 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 ammonium hydroxide (70 mL, 29.9% NH3) and kept at 40 ° 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 +); NMR 1ti [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, HH), 4.58 (m, 1H), 7.19 (m, 2H), 7.51 (m, HH). 34 33 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, dropwise over 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; NMR 1? [300 MHz, (CD3) 2SO] d 2.42 (s, 3H), 2.85 (m, 2H), 3.01 (, 2H), 3.18 (m, 3H), 3.50 (m, 2H), 3.78 (d, d, ÍH), 3.89 (s broad, 2H), 4.12 (t, 1H), 4.92 (m, ÍH), 7.18 (m, 2H), 7.49 (, 1H), 10.33 (Yes H); IR (VARIATION) 3186, 3102, 1741 c "1; MS (ES) m / z 386 (M + H +), 408 (M + Na +). Analysis calculated for C? 6H20FN3O3S2o0.5 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: Tiomorpholin S, S (S) -N- [[3- [3-fluoro-4- (4-t-omorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide S-dioxide, (36) 1.
A stirred mixture of 62 (0.399 g, 0.00128 mol) in 25% water / acetone (12 mL), under nitrogen was treated with N-methyl-morpholine N-oxide (0.45 g, 0.00384 mol) and 0.1 L of an aqueous solution. 2.5% by weight of osmium tetroxide in 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% Me0H-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 +); NMR XH [300 MHz, (CD3) 2SO] d 3.26 (m, 4H), 3.44 (m, 4H), 3.60 (m, 2H), 3.80 (d, d, ÍH), 4.05 (t, ÍH), 4.69 (m, ÍH), 7.22 (m, 2H), 7.54 (d, ÍH).
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 an ice bath and treated, in portions for 5 minutes, with chloride of 3-nitrobenzenesulfonyl (0.335 g, 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 mL), under nitrogen, was treated with 30% NH4OH (25 mL), heated at 50-55 ° C for 6 hours and maintained at room temperature. 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. Instant chromatography of the residue on silica gel with 6% MeOH- 0.4% NH40H-CHC13 yielded 0.29 g of 35: NMR XH [300 MHz, (CD3) 2SO] d 1.59 (broad s, 2H), 2.78 (m, 2H) , 3.24 (, 4H), 3.43 (m, 4H), 3.81 (d, d, ÍH), 4.01 (t, ÍH), 4.57 (m, 1H), 7.18 (m, 2H), 7.52 (m, ÍH); MS (ES) m / z 344 (M + H +), 366 (M + Na +).
A stirred and cooled ice suspension of 35 (0.2 μg 0.85 mmole) in a mixture of Et3N (0.26 mL, 1.9 mmol) and THF (10 mL) was treated with ethyl dithioacetate (0.11 L, 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 it was still a suspension and only partial reaction; THF (10 mL) and ethyl dithioacetate (3 drops) were added. After a further 48 hours the reaction was still incomplete; the suspension was treated with CH2Cl2 (10 mL) and maintained for 72 hours. At this time an almost complete solution and almost complete conversion to the product was obtained. An additional drop of ethyl dithioacetate was added and the mixture was kept at room temperature for 5 days 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; NMR XH [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, ÍH), 4.92 (m, ÍH), 7.18 (m, 2H), 7.50 (m, ÍH), 10.37 (s broad, ÍH); IR (heating) 3300, 3267, 1743 cm "1; MS (ES) m / z 424 (M + Na +). Analysis calculated for C? 6H2oFN30 S2: C, 47.87; H, 5.02; N, 10.47. 47.84; H, 5.23; N, 1.28.
EXAMPLE 29: (S) -N- [[3- [3, 5-Difluoro-4- [4- (hydroxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazole? Din? L] - methyl] thioacetamide (38) 65 66 A stirred mixture of 65 (1.8 g, 0.00396 mol), pyridine (30 mL) and pure EtOH (3 mL), under nitrogen, was treated with hydroxylamine hydrochloride. (1.44 g, 0.0207 mol), heated at reflux temperature 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 (Na2SO) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-0.35% NH40H-CHC13 afforded 0.75%. g of 65 recovered and 0.72 g of 66: NMR XH [300 MHz, (CD3) 2SO) d 1.40 (s, 9H), 1.72 (broad s, 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. 66 A stirred and cooled mixture with ice of 66 (0.75 g, 0.0018 mol) and triethylamine (0.315 L, 0.00225 mol) in THF (12 mL), under nitrogen, was treated dropwise with benzyl chloroformate (0.29 mL, 0.0020 mol), kept in the bath with ice for 15 minutes and at room temperature for 2 hours and concentrated in va cuo. 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 give 0.939 g of 67: p.f. 116-118 ° C; NMR 1 H (300 MHz, CDC13) d 1.48 (s, 9H), 3-.08 (m, 4H), 3.53 (m, 4H), 3.60 (m, 2H), 3.73 (m, ÍH), 3.96 (t , ÍH), 4.76 (m, HH), 5.10 (s, 2H), 5.21 (m, HH), 7.07 (d, 2H), 7.31 (s, 5H); MS (ES) m / z 547 (M + H +), 569 (M + Na +). 3. 67 68 Comet 67 (0.805 g, 0.00147 mol) was added with stirring, in portions for 5 minutes, under nitrogen, 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 NaHCO3 and extracted with CH2C12; 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 re-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. 4.
A stirred and ice-cooled mixture of 68 (0.68 g, 0.00152 mol), saturated NaHCO 3 (15.2 mL) and acetone (40 L), under nitrogen was treated, dropwise over 15 minutes, with a solution of benzyloxy acetyl 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 (MgSO) and concentrated in vacuo to give 0.72 g of 69: MS (ES) m / z 395 (M + H +), 617 (M + Na +); NMR XH (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). 69 37 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 45 psi for 4 hours. Using TLC (8% MeOH-0.5% NH40H-CHC13) the starting material had to be reduced and two products were formed. 1M hydrochloric acid (1.34 mL) was added and the hydrogenation was continued at an initial pressure of 40 psi for 21 hours. Only the most polar product remained by TLC. The catalyst was removed by filtration and the filtrate was concentrated to give 0.40 b of 37: MS (ES) m / z 371 (M + H +), 393 (M + Na +); NMR XH [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). 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. days; 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 CH2Cl2 (10 mL) and ethyl dithioacetate (3 drops) were added; and after 48 hours additional triethylamine was added (0.3 mL). The mixture was concentrated in vacuo and 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 (MgSO4) and concentrated. The residue was subjected to creomatography on silica gel with 2.5% MeOH-CH 2 Cl 2 and the product was crystallized from MeOH to provide 0.182 g of 38: m.p. 110-111 ° C (desc); MS (ES) m / z 429 (M + H +), 451 (M + Na +); HRMS (FAB) calculated for C? 8H23F2N404S (M + H +) 429.1408, found 429.1415; IR (VARIATION) 1760, 1652, 1639 cm-1; [a2 D 8 ° (MeOH).
EXAMPLE 30: (S) -N- [[34 - [1 - [1, 2, 4] Tria zolyl] pheny1] -2-oxo-5-oxazolidinyl] methyl] thiourea (44) 1. 26 A solution of 26 (0.190 g, 0.685 mmoles) er. CH2CI2 (20 mL) was added, dropwise over 20 minutes, under nitrogen, to a stirred, ice-cooled solution of 1, 1'-thiocarbonyldi-2 (1H) -pyridone (0.193 g, 0.831 mmol) in CH2Cl2 ( 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. 44 79 A stirred and ice-cooled solution of 79 (0.10 g, 0.31 mmol) in THF (15 mL) was treated with excess anhydrous ammonia and kept in the ice bath for 90 minutes. It was then evaporated under a stream of nitrogen at a volume of between 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; NMR 1R [300 MHz, (CD3) 2SO] d 3.82 (m, 3H), 4.18 (t, ÍH), 4.89 (s broad, ÍH), 7.20 (broad s, 2H), 7.50 (d, 1H), 7.79 (m, 2H), 7.93 (t, 1H), 8.26 (s, ÍH), 8.97 (s, ÍH); MS (ES) m / z 337 (M + H +), 359 (M + Na +). Analysis calculated for C 13 H 13 FN 6 2 2 S: 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, 1-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 that was purified by flash chromatography on silica gel with 10-20% acetonitrile-CH2Cl2 had: NMR 1 (300 MHz, CDC13) d 1.60 (broad s), 3.07 (m, 4H), 3.45 (m , 2H), 3.85 (m, 4H), 3.97 (d, d, ÍH), 4.16 (t, ÍH), 4.21 (s, 2H), 4.82 (m, 1H), 6.95 (t, ÍH), 7.13 ( d, d, ÍH), 7.47 (d, d, ÍH); MS m / z 395 (M + H +); 417 (M + Na *). 80 45 Excess anhydrous ammonia was bubbled to a stirred and ice-cooled solution of 80 (crude product 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 water. nitrogen. The residue was chromatographed on silica gel 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; NMR XH [300 'MHz, (CD3) 2SO] 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, ÍH), 7.05 (t, ÍH), 7.16 (d, d, 1H), 7.15 (s broad, 2H), 7.49 (d, d, ÍH), 7.91 (t, ÍH); IR (heating) 3443, 3403, 3321, 3202, 3081, 1753,, 1655, 1648 cm "1; HRMS. (FAB) calculated for C? 7H23FN5OfIS (M + H +) 412.1454, found 412.1447. Analysis calculated for C17H22FN504S: 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] methyl] -thiourea (46) 1.
A stirred solution, cooled with ice from 1, 1-thiocarbonyldi-2 (1H) -pyridone (0.096 g, 0.41 mmol) in CH2Cl2 (5 L) was treated with a suspension of 27 (0.10 g, 0.34 mmol) in CH2C12 ( 15 mL) and then ccn 0.05 mL (0.36 mmol) of triethylamine. It was kept in the ice bath for 30 minutes and at room temperature for 2 hours, diluted with CH2Cl2, washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with 20-40% CH3CN-CH2CI2 gave 0.04 g of 81.
KOCH2 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 nitrogen stream. 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 C15H19N404S (M + H +) 351. 1127, found 3511130; IR (VARIATION) 3329 3296, 3196, 1746, 1655, 1626 cm "-i EXAMPLE 33 Tiomorpholin S-Oxide of (S) -N- [[3- [3-fluoro-4- (4-thiomorfo1inyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea (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 and ice-cooled mixture of 1,1F-thiocarbonyldi-2 (HH) -pyridone (0.258 s, 1.11 mmol) 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 (MgSO) and concentrated. Chromatography of the product on 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 A stirred and ice-cooled 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 v MeOH gave 0.175 g of 47; p.f. 212-213 ° C; NMR ñ [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, ÍH), 4.80 (s broad, ÍH), 7.17 (m, 2H), 7.17 (s broad, 2H), 7.50 (d, ÍH), 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 C? 5H? 9FN403S2: 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-morpholyl) phenyl] -2-oxo-5-oxazolidinyl] methyl-S-methyldithiocarbamate (48) 39 A stirred and cooled mixture with ice of 39 (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 mL, 0.0011 mol) and kept in the ice bath for 2 hours and at room temperature for 18 hours. (A solution was obtained after the addition of carbon disulfide, a white precipitate began to form shortly after the mixture was warmed to room temperature.) The slurry was treated, drop by drop for 2 minutes, with a solution of methyl iodide (0.137 mL, 0.00220 mol) in EtOH (2 mL) and the mixture was kept 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 chromatographed on silica gel with 1.8% MeOH-CH2Cl2 and the product was crystallized from EtOAc to give 0.197 g of 48: p.f. 154-155 ° C; GO (heating) 3354, 3346, 1726 cm "1. calculated for C 16 H 20 FN 3 O 3 S 2: 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 48 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. 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-CH2C12 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 (VARIATION) 3282.3251, 1753, 1735 cm "1; NMR XH [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, HH), 4.73, 4.86 (m, m, HH), 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? 6H2oFN30 S: C, 52.02; H, 5.46; N, 11.38, Found: C, 51.97; H, 5.49; N, 11.35. Example 35 a suitable amount of sodium methoxide was replaced by sodium ethoxide, the compound of the following Example 36 was obtained in Table A. When in the procedure of Example 1 a suitable amount of (S) -N- [[ 3- [3-fluoro-4- (4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] -met -yl] acetamide (Compound 11) by (S) -N- [[3- [3-fluoro- 4-morpholinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] isopropylcarboxamide, (S) -N- [[3- [3-f luoro-4- morpholinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropylcarboxamide or (S) -N- [[3- [3,5-di-fluoro-4-morpholinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] acetamide and the general procedures of Example 1 were followed, the compounds of Examples 37, 38 and 39 respectively were obtained as presented below in Table A ... The isopropylcarboxamide and the cyclopropylcarboxamide were obtained following the procedure of Example 5 of U.S. Patent No. 5,688,792 replacing only acetic anhydride from step 7 with isoburric anhydride and cyclopropane carbonyl chloride respectively. Acetamide was obtained as described in U.S. Patent No. 5,688,792 in Example 4. When in the procedure of Example 5, step B, anhydrous ammonia was replaced by an excess amount of dimethylamine in THF, the compound of Example 40 shown later in Table A.
TABLE A Example No, Compound R, R '36 (S) -N- [[3- [3-Fluoro-4- (4- R = H; -OC3Hr, morpholinyl) Ehenyl] -2-oxo-5-oxazolidinyl] methyl ] -0- ethylthiocarba ato; p.f. 120 ° C, MS (ES) m / z 384 (M + H +). Analysis calculated for C17H22FN3O-S: C, 53.25; H, 5.78; N, 10.96. Found: C, 53.23; H, 5.82; N, 10.92. 37 (S) -N- [[3- [3-Fluoro-4- (4- R = H, R '= CH (CH 3) 2 -morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2 - methylpropantioamide; p.f. 152- 153sC (dec.); Analysis calculated for C19H24FN3? 3S: C, 56.67; H, 6.34; N, 11.02. Found: C, 56.58; H, 6.41; N, 10.81 (S) -N - [[3- [3-Fluoro-4-. { 4- R = morphyl) phenyl] -2-oxc-5-oxazolidinyl] met il] -cyclopropane-carbothioamide; p.f. 155-156 ° C; Analysis calculated for C18H22iTN303S: C, 56.98; H, 5.84; N, 11.07. Found: C., 56.98; II, 5.8; N, 10. 7 39 (S) -N - [[3- [3,5-Di-fluoro-4- (4- R = F, R '- = CH 3 morpholinyl) phenyl] -2-oxo-5-oxazolidinyl ] methyl] thioacetamide 40 (S) -N- [[3- [3- Fluoro -4- (4- R = H, R = N (CH3) 2 morpholinyl) phenyl] -2-oxo-5-oxazolxdinil] m ^ ti 1] -N ', N' - dimethylthiourea PREPARATION Z Methyl Dithiopropionate 1) CH3CH2MgBr S cs, II ~ ^ "CH CH - * C * - SCH3 2) CH3I (a) A stirred mixture of magnesium burrs (12.6 g, 0.520 g atoms) and THF (100 L) under nitrogen was treated with a crystal of iodine and about 5% of a solution of bromoethane (30.0 mL, 0.40 mol) in THF (200 g. mL). When the reaction started, the remaining bromoethane solution was added dropwise at a rate sufficient to maintain a gentle reflux. After the addition, stirring was continued for 1 hour; The resulting solution was cold at -20 ° C and treated, for 10 minutes with carbon disulfide (24.0 mL, 0.40 mol). The mixture was heated to 15 ° C, treated with methyl iodide (28.0 mL, 0.45 mol) and kept at 60 ° C for 1 hour. It was then cooled in a bath with ice, treated with ice and extracted with Et20. The extract was washed with brine, dried (MgSO) and concentrated. Distillation of the residue gave 34.0 g of the title product, bp 48-52 ° C (12 mmHg). The following methyl dithio compounds were obtained when the magnesium bromide was replaced by suitable alkyl magnesium bromide in the above procedure: TABLE B S II Rs-C - SCH3 Rs = (b) (CH3) 2CH- () ^ (c)? > ~ (i) o- (e) CH3 () I 3 | -CH2- CHgCH-CH2- (g) (CH3) 3C-CH2- (ra) 0H2 When the general procedure of Example 27, Step 4 was followed, a suitable amount of the amine listed below was reacted with the dithio compound listed below, the respective compounds were obtained, Examples 41 to 61 of Table C. When followed the general procedure of Example 25, step 6, a suitable amount of the amine listed below was reacted with the dithio compound listed below, were obtained the respective compounds, Examples 62 to 67 of Table C. TABLE C Example Compound Amina Compound No dithio (from preparation Z) 41 Tiomorpholin S-oxide of Z (a (S) -N - [[3- [3-Fluoro-4 (4-thiomorpholinyl) -phenyl] -2- oxo-5-oxazolidinyl] -methyl] -propantioa ida; p.f. 196-197 ° C; Analysis calculated for C? 7H22FN3? 3S2: 1 C, 51.11; H, 5.55; N, 10.52; S, 16.05. Found: C, 50.99; H, 5.60; N, 10.5S; S, 15.75 42 Tiomorfolin S-oxide as (b) (S) -N - [[3- [3-Fluoro-4- (4-anterior thiomorpholinyl) phenyl] -2-oxo-5-oxazoIl-dinyl] -methyl- 2-methy] propant LO-amide; p.f. 195-196 ° C; Analysis calculated for C18H24FN3? 3S2: C, 52.28; H, 5.85; N, 10.16; S, 15.51. Found: C, 52.24; H, 5.97; N, 10.16; S, 15.28 43 Tiomorpholin S-Oxide Equal to Z (c; (S) -N- [[3- [3-Fluoro-4 (4-anterior thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] -methyl] cyclopropancarbonate amide; mp 109-110 ° C; Analysis calculated for C18H22FN3O3S2: C, 52.54; H, 5.39; N, 10.21; S, 15.58, Found: C, 52.48; H, 5.51; N, 10.28; S, 15.29 Compound Example Compound Amina. No ditio (from the preparation Z) 44 Tiomorfolin S-oxide Same as Z (d) (S) -N - ([3- [3-fluoro-4 (4-anterior thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] -methyl] butantioamide 45 Tiomorpholin S-oxide Same as Z (e) (S) -N- [[3- [3- Fluoro-4- (4-anterior thiomorpholinyl) phenyl] -2-oxo-5-oxazole idinyl] -methyl ] -3- methylbutantioamide 46 Tiomorfolin S-oxide Same as Z (f) (S) -N- [[3- [3-Fluoro-4- (4-previous thiomorpholinyl) phenyl] -2-oxo-5- oxazolidinyl] -methyl] -2- methylbutantioamide 47 Tiomorpholin S-oxide of the same as 2 (g) (S) -N - [[3- [3-FUuoro-4 (4-anterior thiomorpholine) phenyl] -2-oxo -5- oxazolidinyl] methyl] -3, 3-dimethylbutantioamide 48 Tiomorphol S-oxide of Igua that 1; z ín; (S) -N - [[3- [3-Fluoro-4 (4-anterior thiomorpholinyl) phenyl) ] - 2-oxo-5-oxazolidinyl] -methyl] cyclobutanecarbothiolamide 49 Tiomorpholin S-oxide Same as Z (i) (S) -N- [[3- [3-Fluoro-4 (4-anterior tio orpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -1- cyclopentancarbothioamide 5 0 Tiomorfolin S-oxide Same as Z (j) (S) -N- [[3- [3-Fluoro-4- (4-anterior thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] - cyclohexancarbothioamide Example Compound Amina Compound No dithio (from preparation Z) 51 Ti omo rf olin S-Oxide Equal to Z (k) "(S) -N- [[3 - [3-Fluoro - - (4-anterior thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopropylethanolamide 52 Tiomorpholin S-oxide Same as Z (l) (S) -N- [[3- [3- Fluoro-4- (4-anterior thiomorpholinyl) phenyl] -2-oxo-5 - oxazolidinyl] methyl] -2- cyclobutyletant ioami da 53 Tiomorpholin ^ S-oxide As Same as Z (m) (S) -N- [[3- [3-Fluoro-4- {., thiomorpholinyl) phenyl] -2- oxo-5-oxazolidinyl] -yl] -2- cyclopentylenedioamide 54 Tiomorpholin S-oxide of Dithioacetate (S) -N- [[3- [3, 5-Fluorine- ethyl 4- (4- t i omorpholinyl) phenyl] -2- oxo-5-oxazolidinyl] methyl] thioace tami da 55 Tiomorfolin S-oxide the same as Z (a) (S) -N - [[3- [3, 5-Di fl uoro-anterior 4- (4-thiomorpholinyl) phenyl] -2- oxo-5-oxazolidinyl] methyl] -propanedioamide 56 Tiomorpholin S-oxide as Same as Z (b) (S) -N- [[3- [3,5-Difluoro- anterior 4- (4 -thiomorpholinyl) - phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanthioamide Example Compound Amina Compound No dithio (from preparation Z) 57 Tiomorfolin S-Oxide Same as Z (c) (S) -N- [[3- [3,5-Difluoro-anterior 4- (-thiomorpholinyl) -phenyl] -2-OXO-5-oxazolidinii] methyl] - cyclopropancarbotiamide 58 Ethyl di ioacetate oxazolidinyl] methyl] -thioacetamide 59 Tiomorpholin S-oxide as Same as Z (a) (S) -N- [[3- [4- (4-anterior thiomorpholin-l) -phenyl] -2-oxo-5-oxazolidinyl] ] methyl] - propantioamide 60 Tiomorfolin S-oxide of Ig to which; ) (S) -N- [[3- [4- (4-anterior thiomorpholinyl) -phenyl] -2-oxo-5- or azolidinxl] methyl] -2- and ilpropan-ioamide 61 Tiomorpholin S-oxide as Z (c) (S) -N- [[3- [4- (4-anterior thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide 62 Z (a) oxazolidinyl] methyl] propan thioamide 63 (S) -N- [[3- [3, 5-Difluoro4- Same as Z (b) (4-hydroxyacetyl) -1- above piperazinyl] phenyl] -2-oxo- 5 -oxazolidinyl] methyl] -2- methyl-propantioamide Example Compound Amina Compound No dithio (from preparation Z) 64 (S) -N - [[3- [3,5-Difluoro- Same as Z (c) 4- (4-hydroxyacetyl) -1- above piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - methyl] cycloprppant ioamide 65 (S) -N - [[3- [3- [4- Z (a; (hydroxyacetyl) -1- piperazinyl] phenyl] -2- oxo- -oxazolidinyl] -methyl] propantioamide 66 (S) -N- [[3- [3- As the Z (b) [4 (hydroxyacetyl) -1- above piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] -2- eti lpropant ioamide (S) -N- [[3- [3- [4- Same as Z (c) (hydroxyacetyl) - I - above piperazinyl] phenyl] -2-oxo- 5- oxazolidinyl] - ethyl] cyclopropanecarbium amide When the procedure of Example 28, step 3, is followed, a suitable amount of the amine listed below is reacted with the dithio-listed compound plus -dial, the respective compounds were obtained, Examples 68 to 78 of Table D.
TABLE D Example Compound Composition Non-dithium Compound (see preparation Z) 68 Tiomorfolin S, Z (a) (S) -N- [[3- [3-Fluoro-4- (4- o2s' _ ~ -A0 thiomorpholinyl) -phenyl] -2-oxo- 5- S-dioxide oxazolidinyl] methyl] - F - NH, propantioamide 69 Tiomorfolin S, S-dioxide Same as Z (b) (S) -N- [[3- [3-Fluoro-4- (4- previous thiomorpholinyl) - phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropantioamide 70 Tiomorpholin S, S-dioxide Equal to Z (c) (S) -N- [[3- [3-Fluoro-4- ( 4- previous thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -diclopropanecarbothioamide 71 Tiomorpholin S, S-Dithioacetate dioxide (S) -N- [[3- [3, 5-Difluoro-4- (4- 0 - - / VN P. of ethyl thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidini 1] - - NH , methyl] thioacetamide 72 Tiomorfolin S, S-dioxide Same as Z (a) (S) -N- [[3- [3, 5-Difluoro-4- (4-anterior thiomorpholinyl) -phenyl] -2- oxo-5-oxazolidinyl] methyl] -propanthenolamide 73 Tiomorfolin S, S-dioxide Equal to Z (b) (S) -N- [[3- [3, 5-Difluoro-4- (4-previous thiomorpholinyl ) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropant.i oamide 74 Tiomorfolin S, S-dioxide Same as Z (c) (S) -N- [[3- [3, 5-Difluoro-4- (4-anterior thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropanecarbothioamide Example Compound Amina Compound Nc dithio (see preparation 75 Tiomorfolin S, dithioacetate S-dioxide (S) -N- [[3- [4- (4-thio- ethyl morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] - methyl] thioacetamide 76 Tiomorpholin S, S-dioxide Equal to 1 to Z (a) (S) -N - [[3- [4- (4-thio-anterior morpholinyl) phenyl] -2-oxo-5-oxazolidinyl ] methyl] propantioa mida 77 Tiomorfolin S, S-dioxide (S) - Same as Z (b) N - [[3- [4- (4-t ^ o-anterior mcrolinyl) phenyl] -2-oxo-5 - oxazolidinyl] -methyl] -2-methyl-propantioamide 78 Tiomorpholin S, S-dioxide IC (S) -N- [[3- [4- (4-thio-anterior morpholinyl) phenyl] -2-oxo-5 oxazolidinyl] -methyl] cyclopropancarbotioamid a When the procedure of Example 26 is followed, a suitable amount of the amine listed below is reacted with the dithio compound listed below, the respective compounds were obtained, Examples 79 to 99 of Table E.
TABLE E Example Compound Amina Compound No dithium (see preparation i 79 (S) -N- [[3- [3-Fluoro-4- (4- Z (a) thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -propanedioamide (80 (S) -N- [[3- [3-Fluoro-4- (4- Same as z (b) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -2- methylpropanthioamide 81 (S) -N - [[3- [3- luoro-4- (4 - Same as Z (c) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -cyclopropancarbothioamide 82 (S ) -N- [[3- [3-Fluoro-4- (4- Same as Z (d) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -butantiuamide (S) -N- [[3- [3-Fluoro-4- (4- Same as Z (e) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -3-methylbutantioamide 84 (S) -N- [ [3- [3-Fluoro-4- (4- Same as Z (f) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -2-methylbutantioamide 85 (S) -N - [[ 3- [3-Fluoro-4- (4- the same as z (g) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -3,3-dimethylbutanetioamide 86 (S) -N- [ [3- [3-Fluoro-4- (4- Same as Z (h) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -cyclobutanecarbotioa i da Example Compound Composition Non-dithium Compound (see Preparation Z) 87 (S) -N - [[3- [3-Fluoro-4- (4- the same as z (i) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -cyclopentanecarbothioamide 88 (S ) -N - [[3- [3-Fluoro-4- (4- Same as z tj: thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -cyclohexancarbothioamide 89 (S) -N- [[3- 3- [3-5-Fluoro-4- (4- Same as Z (k) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -2- cyclopropylethanolamide 90 (S) -Nr [3- [3-Fluoro-4- (4- Same as Z (l) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -2- cyclobutyl] etnionamide 91 (S) -N- [[3- [3-Fluoro-4- (4- the same as Z (m) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -2- cyclopentylenedioamide 92 (S) -N- [ [3- [3,5-Difluoro-4- (4- Dithioacetate thiomorpholinyl) -phenyl] -2-oxo- ethyl 5-oxazolidinyl] methyl] -thioacetamide 93 (S) -N - [[3- [3,5-Difluoro-4- (4- Same as Z (a) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -propanedioamide 94 (S) -N - [[3- [3,5-Difluoro ~ 4- (4- Same as Z (b) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] methyl] -2- methylpropanthioamide 95 (S) -N - [[3- [3,5-Difluoro-4- (4- Same as Z (c) thiomorpholinyl) -phenyl] -2-oxo-anterior 5-oxazolidinyl] ethyl] -cyclopropanecarbothioamide Example Compound Amina Compound No dithium (see preparation 96 (S) -N - [[3- [4- (4-thio-Dithioacetate morpholinyl) phenyl] -2-oxo-5- of ethyl oxazolidinyl] -methyl] thioacetamide 97 (S) -N- [[3- [4- (4-thio- Same as Z (a) morpholinyl) phenyl] -2-oxo-5-anterior oxazolidinyl] -methyl] propantioamide 98 (S) -N - [[3- [4- (4-thio- Same as Z (b) morpholinyl) phenyl] -2-oxo-5-anterior oxazolidinyl] -methyl] -2-methylpropantioamide «. 99 (S) -N - [[3- [4- (4-thio- Same as Z (c) morpholinyl) phenyl] -2-oxo-5-anterior oxazolidinyl] -methyl] cyclopropancarbctioamid a The amine used in Examples 41 to 53 is prepared as described in Example 27, step 3. The amine used in Examples 54 to 57 is prepared by the procedure of Example 27, steps 1 to 3, by substituting compound 62 for (S) -N- [[3- [3, 5-difluoro-4 - (4-thio-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methanol in Step 1 of Example 27. The amine used in Examples 58 to 61 is prepared by the procedure of Example 27, steps 1 to 3 by substituting the appropriate compound 62 with (S) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5- oxazolidinyl] methanol in Example 27, step 1. The suitable oxazolidinyl methanol compound is obtained by following the procedure of Example 1 in U.S. Patent 5,688,792, steps 1 to 3, substituting only 3,4-difluoronitrobenzene for 4-fluoronitrobenzene in Step 1 of it. The amine used in Examples 62 to 64 is prepared as the compound 37 of Example 29 from the amide, 65, and which is prepared as described in Example 32 of U.S. Patent No. 5,700,799. The amine used in Examples 65 to 67 is prepared by the general procedure of Example 29 from the next amide, the preparation thereof being described in Example 3 of U.S. Patent 5,700,799: The amine used in Examples 68 to 70 is prepared as described in Step 2 of Example 28 above. The amine used in Examples 71 to 74 is prepared as described in Example 28 to replace compound 62 by (S) -N- [[3- [3,5-difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-oxazolidinyl] methanol in Step 1 and following the procedure of Steps 1 and 2. The oxazolidinyl methanol compound is prepared following the general procedure of Example 4 of U.S. Patent No. 5,688,792, Steps 1 to 4, substituting only morpholine for thiomorpholine in Step 1"thereof. , used in Examples 75 to 78 is prepared as described in Example 28, Step 1, above by substituting compound 62 for (S) -N- [3- [4- (4-thiomorpholinyl) phenyl] -2- oxo-5-oxazolidinyl] -methanol in Step 1. The appropriate oxazolidinyl methanol is obtained by following the procedure of Example 1 in U.S. Patent No. 5,688,792, steps 1 to 3, substituting only 3,4-difluoronitrobenzene for 4 Fluoronitrobenzene in Step 1 thereof The amine used in Examples 79 to 91 is prepared as described in Example 1, Step 4, of U.S. Patent No. 5,688,792. The amine used in Examples 92 to 95 is prepared as described in Example 4 of U.S. Patent No. 5,688,792 substituting only morpholine by thiomorpholine in Step 1 thereof. The amine used in Examples 96 to 99 is prepared by the procedure of Example 1 of U.S. Patent No. 5,688,792, substituting only 3,4-difluoronitrobenzene for 4-fluoro-nitrobenzene in Step 1 thereof.
EXAMPLE 100 Tiomorpholin S-oxide (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methyl-iocarbamate A solution of 201 mg (0.554 mmole) compound 82 of thiomorpholin S-oxide of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] isothiocyanate, from Example 33, step 1, in methanol (10 mL) is brought to reflux, under nitrogen for 18 hours and cooled. The solid is collected by filtration to provide 0.138 g of the title product. m.p. 208-209 ° C; Analysis calculated for C 16 H 20 FN 3 O 4 S 2: C, 47.87; H, 5.02; N, 10.47. Found: C, 47.81; H, 5.04: N, 10.49.
When in the procedure of Example 100 the thioisocyanate listed below is replaced by compound 82, the products listed below are obtained as Examples 101 to 109.
TABLE F Isothiocyanate Rc Ra Rb Example Compound No. OS 101 Tiomorpholin S-oxide (S) -N- [[5- [3,5-Difluoro-4- (4-thiomorpholinyl) pheny] -2-oxo-5-oxazolidinyl] methyl] - O-methylthiocarbamate 102 Tiomorpholin S-oxide of (3) -N- [[3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methyl-carbamate 02S 103 Tiomorpholin S, S-dioxide (S) -N - [[3- [3-Fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate 02S 104 Tiomorpholin S, S (S) -N - [[3- [3,5-Difluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate S-dioxide 02S 105 Tiomorpholin S, S-dioxide (S) -N - ((3- [4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate 106 (S) -N - [[3- [3-Fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate Rc Ra Rb Compound Example No. 107 [S) -N- [[3- [3,5-Difluoro-4- (4-yomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate 108 (S) -N- [[3- [4- (4-thiomorpholinyl) fe yl] -2-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate 109 (S) -N- [[3- [3- Fluoro-4- (4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2- HOCH2CN oxo-5-oxazolidinyl] methyl] -0-methylthiocarbamate When in the procedure of Example 100 a suitable amount of ethanol and alcohol are replaced by methanol, the following respective compounds are obtained: EXAMPLE 110: Tiomorpholin S-oxide of (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-ethylthiocarbamate. p.f. 198-199 ° C; Analysis calculated for C? 7H22H22FN30 S2: C, 49.14; H, 5.34; N, 10.11. Found: C, 49.06; H, 5.27; N, 10.10.
EXAMPLE 111: Tiomorpholin S-oxide of (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-isopropylthiocarbamate. p.f. 180-181 ° C; Analysis calculated for C18H24FN304S2: C, 50.33; H, 5.63; N, 9.78. Found: C, 50.29; H, 5.69; N, 9.82. When in the procedure of Example 114 a suitable amount of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] isothiocyanate is replaced by the compound 82 and ethanol or isopropyl alcohol is replaced by methanol, the following respective products are obtained: EXAMPLE 112: (S) -N- [[3- [3-Fluoro-4 - (4-thio-orpholinyl) -phenyl] -2-oxo-5-oxazo-idinyl] methyl] -O-ethylthiocarbamate; EXAMPLE 113: (S) -N- [[3- [3-Flucro- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-iso-propylthiocarbamate; EXAMPLE 114: Tiomorpholin S-oxide of (S) -N- [[3- [3- Fluoro-4- (4-t -omorpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -N-methylthiourea. A stirred suspension of 240 mg (0.650 mmol) of compound 82 from Example 33, step 1 in THF (5 mL) at 0 ° C was treated with a solution 2M methylamine in THF (0.42 mL, 0.845 mmol) and maintained at room temperature for 18 hours. He solid was collected by filtration to provide 0.221 g of the title product. Following the procedure of Example 114, substituting only a suitable amount of dimethylamine and azetidine for methylamine, the following compounds were obtained: EXAMPLE 115: Tiomorpholin S-oxide of (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -N ', N' -dimethylthiourea; Analysis calculated for.? C? 7H23FN403S2, C, 49.26; H, 5.59; N, 13.52. Found C, 49.11; H, 5.57; N, 13.40; p.f. 180-132 ° C. EXAMPLE 116: Tiomorpholin S-oxide (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidi il] methyl-1-a zetidincarbot ioamid; Aná 1 i sis calculated for C? 8H23FN403S2, C, 50.69; H, 5.43; N, 13.14. Found: C, 50.79; H, 5.45; N, 12.82; p.f. 213-214 ° C. When in the procedure of Example 114 a suitable amount of (S) -N- [[3- [3-fluoro-4- (4-thiomorpholinyl) phenyl-2-oxo-5-oxazolidinyl] methyl] -isothiocyanate is replaced by Compound 82, the following compound is obtained: EXAMPLE 117: (S) -N- [[3- [3-Fluoro- - (4-thiomorpholin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] methyl- '-methylthiourea. When in the procedure of Example 1, a suitable amount of dimethylamine and azetidine is replaced by methylamine, the following respective compound is obtained: EXAMPLE 118: (S) -N- [[3- [3-Fluoro-4- (4 -thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -N ', N' -dimet ilt iourea; EXAMPLE 119: (S) -N- [[3- [3-Fluoro-4 - (4-thiomorpholinyl) -phenyl-2-oxo-5-oxazolidinyl] methyl] -1-azetidincarborioamide. When in the procedure of Example 33 a suitable amount of compound 31 from Example 26 is replaced by compound 33 and the general procedure of Steps 1 and 2 of the Example 33, the following compound is obtained. EXAMPLE 120: (S) -N- [[3- [3-Fluoro-4- (4-t -omorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -thiourea. EXAMPLE 121: (S) ~ N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl-2-oxo-5-oxazolidinyl] methyl] propant-ioamide A stirred mixture of 200 mg (0.514 mmoles) of 29 methyl dithiopropionate (247 mg, 2.06 mmole), triethylamine (0.58 mL, 4.11 mmole), THF (5.4 mL) and methylene chloride (5.4 mL) was kept under nitrogen for 3 days, diluted with water and extracted with methylene chloride. The extracts were dried (MgSO4) and concentrated. Chromatography of the residue on silica gel and crystallization of the product from methanol gives 0.132 g of the title product. p.f. 190-191 ° C; Analysis calculated for C19H25FN404S: C, 53.76; H, 5.94; N, 13.20; S, 7.55. Found: C, 53.66; H, 5.94; N, 13.20; S, 7.37. Following the procedure of Example 121 substituting only the dithio compounds Z (b) for Z (m) from Preparation Z above by methyl dithiopropionate, the following compounds were obtained.
TABLE G Example No. Compound 122 (S) -N - [[3- [3-Fluoro-4- [4- R = CH (CH 3) 2 (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] -2- methylpropantioamide; Analysis calculated for JOHJ? FNÍOIS: C, 54.78; H, 6.21; N, 12.78; S, 7.31. Found: C, 54.67; H, 6.34 ^ N, 12.41; S, 7.15 123 (S) -N- [[3- [3-Fluoro-4- [4- (hydroxy acetyl) -1-piperazinyl] phenyl] -2-oxo-5-R-oxazolidinyl] methyl] cyclopropancarbothioamido; p.f. 179-181 ° C; Analysis calculated for C ^ H- ^ FN ^ S: C, 55.03; H, 5.77; N, 12.84; S, 7.34. Found: C, 55.15; H, 5.72; N, 12.76; S, 7.09 124 (S) -N- [[3- [3-Fluoro-4- [4- (hydroxy P = CH-CH-. -CH 3 acetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] butantioamide 125 (S) -N - [[3- [3-Fluoro-4- [4- CH 3 (hydroxyacetyl) -1-piperazinyl] phenyl] -2- R = CH 2 -CH-CH 3 oxo-5-oxazolidinyl] methyl] -3- methylbutantioamide 126 (S) -N- [[3- [3-Fluoro-4- [4- CH 3 (hydroxyacetyl) -1-piperazinyl] phenyl] -2- H = CH-CH 2 -CH 3 oxo-5-oxazolidinyl] methyl] -2- methylbutantioamide 127 (S) -N - [[3- [3-Fluoro-4- [4- R = CH2-C (CH3) 3 (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -3, 3-dimethylbutantioamide Example No. Compound 128 (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2- O-oxo-5-oxazolidinyl] methyl] cyclobutanecarbothioamine gives 129 (S) -N - [[3- [3-Fluoro-4- [4- R. -O (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopentancarbothioam (130) ) -N - [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclohexanecarbothioamide and 131 (S) - N- [[3- [3-Fluoro-4- [4- (hydroxy R = CH2-] acetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopropylethanolamide 132 (S ) -N- [[3- [3-Fluoro-4- [4- R = CH2 (hydroxyacetyl) -1-piperazinyl] pheny1] -2- O-oxo-5-oxazolidinyl] methyl] -2- cyclobutyletanoticamide 133 ( S) -N - [[3- [3-Fluoro-4- [4- R = CH 2 - (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopentylethanethioamide When in the procedure of Example 100 a suitable amount of compound 80 of Example 31 is replaced by compound 82, and the ethanol or isopropyl alcohol is replaced by methanol, the following respective compounds are obtained: EXAMPLE 134: (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-ethylthiocarbamate; EXAMPLE 135: (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl]] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O-iso- propylthiocarbamate; EXAMPLE 136: (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - '-methylthiourea. When in the procedure of Example 114 a suitable amount of compound 80 of Example 31 is replaced by compound 82, the title compound is obtained. Following the procedure of Example 114 substituting only a suitable amount of compound 80 of Example 31 for compound 82 and substituting an appropriate amount of dimethylamine and azetidine for methylamine, the following compounds are obtained, Examples 137 and 138: EXAMPLE 137: (S) -N- [[3- [3-Fluoro-4 - [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -N ', N' -dimethylthiourea; EXAMPLE 138: (S) -N- [[3- [3-Fluoro-4 - [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] -1-azetidinecarbothioamide.
EXAMPLE 139: (S) * -N- [[3- [3, 5-Difluoro-4 - [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -O- methylthiocarbamate. Part A: Following the procedure of Example 33, step 1, substituting only an appropriate amount of compound 37 of Example 29, step 5, for compound 33, we obtain (S) -N - [[3,5- [3- difluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] -phenyl] -2-oxo-5-oxazolicinyl] methyl] isothiocyanate. Part B: «. At the time of substitution of an adequate amount of (S) -N- [[3- [3, 5-difluoro-4 - [4 (hydroxyacetyl) -1-pi? Erazinyl] -2-oxo-5- oxazoyidinyl] met il] isocyanate by compound 82 in the general procedure of Example 100, the title compound is obtained. EXAMPLE 140: (S) -N- [[3- [4 - [4- (Hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -0-methylthiocarbamate Part A: Following the procedure of Example 33, step 1, substituting only a suitable amount of (S) -N- [[3- [4 - [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] amine by compound 33, (S) -N- [[3- [4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] isothiocyanate is obtained.
Part B: At the time of substitution of an appropriate amount of (S) -N- [3- [4 - [4 - (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] isothiocyanate by compound 82 in the general procedure of Example 100, the title compound is obtained. EXAMPLE 141: (S) -N- [[3-Fluoro-4- (4-acetyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] -methyl] thioacetamide Step 1 58 85 A stirred, ice-cooled solution of 30.4 g (70.8 mmol) of starting material 58 from Example 25, step 1), and triethylamine (15.4 mL, 110 mmol) in methylene chloride (2570 mL) was treated with sodium chloride. -nitrobenzenesulfonyl (18.8 g, 84.9 mmol) and kept, under nitrogen, at room temperature (24 ° C) for 24 hours. Additional nitrobenzenesulfonyl m-chloride (1.88 g) and triethylamine (1.54 mL) were added and the mixture was maintained for an additional day at room temperature, washed with water, saturated sodium bicarbonate and brine, dried (Na2SO) and concentrated to give an oily product, 85. The alcohol, 58 was prepared. according to the Brickner procedure (J. Med. Chem. 1996, 39, 673-679), see compound 5a of this. Step 2 86 85 A stirred mixture of 85, acetonitrile (1270 mL), isopropanol (1270 L) and ammonium hydroxide (1270 mL) was maintained at room temperature for 3 days and concentrated in vacuo. Chromatography of the residue on silica gel with 0.5% NH OH-1% MeOH-CH 2 Cl 2 yielded 22.4 g of the amine, 86. Step 3 86 87 A stirred, ice-cooled solution of amine 86 in THF (650 mL) was treated, for 20 minutes, with a solution of di-tert-butyl dicarbonate (12.0 g, 55.2 mmol) in THF (90 mL). The mixture was kept at room temperature for 18 hours and concentrated in vacuo. The residue, dissolved in methylene chloride, was washed with dilute sodium bicarbonate, dried (MgSO) and concentrated. Crystallization of the residue from methanol-ethyl acetate gave 20.0 g of the protected Boc amine. The additional product (4.1 g) was obtained by chromatographing the mother liquor on silica gel with 1-2% methanol-methylene chloride. Step 4 87 88 A solution of the protected amine, 87, (5.00 g, 9.46 mmol) in ethanol (150 mL) was treated with 10% palladium on carbon catalyst (1.0 g) and hydrogenated at an initial pressure of 30 psi during 3 hours. The catalyst was removed by filtration through Celite and the filtrate was concentrated to provide 3.66 g of compound 88.
P a s o 5 88 89 A stirred solution of compound 88 (1.10 g, 2.79 mmol) in pyridine (10 mL) was treated with acetic anhydride (289 μL, 3.07 mmol), maintained at room temperature for 2 hours and concentrated in vacuo. A solution of the residue in methylene chloride was washed with dilute hydrochloric acid, dried (MgSO 4) and concentrated to provide 1.23 g of compound 89: MS m / z 436 (M +). Pa s o 6 A 4N solution of HCl in stirred and cooled with ice (10 mL) was treated with compound 89 (1.10 g, 2.52 mmol). The mixture was kept in the ice bath for 30 minutes and at room temperature for 1 hour. It was then mixed with methylene chloride and concentrated. The waste was crushed with methylene chloride to provide 1.03 g of the amine hydrochloride. Step 7 P-90 A stirred mixture of compound P-90 (250 mg), triethylamine (0.75 mL, 5.36 mmol), ethyl dithioacetate (307 μL, 2.68 mmol), methylene chloride (7.4 mL) and THF (7.4 mL) was maintained at room temperature. atmosphere for 1 day, concentrated and chromatographed on silica gel with methanol-methylene chloride mixtures containing 1-2% methanol. Crystallization of the product from ethyl acetate-heptane gave 0.160 g of the title product: Analysis calculated for C18H23FN403S: C, 54.81; H, 5.88; N, 14.20; S, 8.13. Found: C, 54.92; H, 5.95; N, 14.08; S, 7.94; p.f. 158 ° C. , When in the general procedure of Example 141 an appropriate amount of Substituted by compound 58 and the procedure of Steps 1 to 6 is followed, the respective amine compounds P-91 and P-92 listed below are obtained: The alcohols shown above as x and Y are prepared according to the procedures of Brickner (J. Med. Chem., 1996, 39, 673-679), by substituting an appropriate amount of 2,6-difluoro-4-nitrobenzene (trifluoromethane). sulfonate and 4-fluoronitrobenzene respectively by 3,4-dif luoronitrobenzene in the preparation of 2a of the present.
When in the procedure of Example 141 a suitable amount of x or y is replaced by compound 58 and the procedures of Steps 1 to 4 are followed, the following protected Boc compounds listed below are obtained.
When in the procedure of Example 141, step 5, a suitable amount of compound 88, compound xb or compound and b is treated with the reagent listed below and digest the general procedures of step 5 and step 6, the most listed amines are obtained go ahead as Preparation P-93 to P-128. The amine compound shown below as F-129 is obtained by refluxing a solution of compound 88 (1.00 g, 2.54 mmol), sulfamide (305 mg, 3.18 mmol) and 1,2-dimethyoxyethane (6 mL) for 6 days. ). The solid that is precipitated is collected by filtration and subjected to chromatography on silica gel with 5% methanol-methylene chloride. Crystallization of the product from methanol-methylene chloride affords 0.551 g of the sulfamoyl derivative, which is used in Step 6 of Example 141 to provide P-129. When the compounds x-b and y-b are replaced by the compound 88 and this general procedure is followed, the Preparations P-130 and P-131 respectively shown below are obtained. Following the general procedures of the Steps 5 and 6 of Example 141 only in step 5 substituting chloroacetonitrile or 2-fluoroethyl bromide respectively for acetic anhydride and using potassium carbonate in acetonitrile, and using either compound 88, - compound xb or compound yb, obtain the respective amines shown below as Preparations P-132 to P-137. The amine compound shown below as Preparation P-138 is obtained by combining compound 88 (1.10 g, 2.75 mmol) shown in Step 5 of Example 141 with N-formylbenzotriazole (493 mg, 3.35 mmol) in THF (30 mL ) and the mixture was kept at room temperature for 18 hours. The mixture was concentrated and the residue in methylene was washed with IN sodium hydroxide and dilute sodium chloride, dried (MgSO 4), concentrated, and chromatographed on silica gel with methanol and methylene chloride mixtures containing 1-2% methanol to provide 1.09 g of the N-formyl derivative which is used in the general procedure of step 6 of Example 141 to provide Preparation P138. When in this compound of the above procedure x-b or the compound y-b is replaced by the compound 88, the preparations P-139 and P-I40 shown below are obtained.
Reagent Compound R R '' Rd Preparation Boc No. 88 methoxyacetyl chloride or H F P-93 II CH3OCH2C- x-b F F P-94 y-b H H P-95 88 O H F P-96 cyanoacetyl II NCCH2C x-b F F P-97 y-b H H P- 98 88 H F P-99 acetoxyacetyl chloride Reagent Compound R '' JLL Preparation Boc No. x-b F F P-100 O O y-b II II CH3C-0-CH2C-H H P-101 O P-102 benzyloxycetyl chloride PhCH2OCH2C- x-b F F P-103 y-b H H P-104 chloroformate of 88 O H F P-105 methyl II CH3OC- x-b F F P-106 chloride CH3S02-HF P-108 methanesulfonyl XD FF P-109 yb HH P-ilO chloride 88 F P-ethanesulfonyl 111 xb CH3CK2302-P-112 yb HH P-113 chloride F P-chloromethane-114 sulfonyl xb C1CH2S02- FF P-115 yb HH P-116 F chloride P-cyanometan-117 sulfonyl xb NCCH, S02- FF P-118 and b HH P-119 Reagent Compound R 'R' Preparation Boc No. of N-88 chloride P-120 methylsulfamoyl xb CH3NHSO2-FF P-121 and b HH P-122 N, N- 88 HF P-123 dimethylsulphamoyl chloride xb (CH3) 2NS02 FF P -124 yb HH P-125 88 OHF chloroformate P-126 ethyl II CH3CH2OC- xb FF P- -127 and b HH P- -128 sulfamide 88 HF P- -129 xb H.-NSO, FF P- -130 yb HH P- -131 chloroacetonitrile 88 HF P- -132 xb NCCH2- FF P- -133 and b HH P- -134 2-88 HF bromide P- -135 fluoroethyl xb FCH: C12- F- '- F P- -136 yb HH P- -137 N-formylbenzo-triazole or H F P- -138 II HC- x-b F F P- -139 y-b H H P- -140 EXAMPLES 142-161: When the general procedures of Example 141, Step 7 are followed, a suitable amount of the amine listed below and the dithio compound of Preparation Z listed below are used, the products designated as Examples 142 a are obtained. 400 in Table H TABLE H Example Product Amina Compound No. Ditxo 142 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z.a) piperazinyl) phenyl] 2-oxo-5-oxazolidinyl] methyl] propantioamide; p.f. 161- 1.62 ° C; Analysis calculated for C10H2a N4? 3S: C, 55.87; H, 6.17; N, 13.72; S, 7.85. Found: C, 55.79; H, 6.26; N, 13.60; S, 7.71 143 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 z (b) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] ethyl] -2- methylpropanthioamide 144 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (c) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide; p.f. 159-160 ° C; Analysis calculated for C2oH25FN4? 3S: C, 57.13; H, 5.99; N, 13.32; S, 7.62. Found: C, 57.05; H, 6.01; N, 13.15; S, 7.45.
Product Use Amina Compound No. ditic 145 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (d) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] butantioamide 146 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (e) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -3- methylbutantioamide 147 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (f) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] «metxl] -2 -methylbutantioamide 148 (S) -N - [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (g) piperazinyl) phenyl] -oxo-5-oxazo! Idinyl] methyl] -3, 3-dimethylbutantioamide 149 (S) -N - [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (h) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methy] cyclobutanecarbothioamide 150 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (i) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopentanecarbothioamide 151 (S) -N- ([3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (j) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclohexanecarbothioamide 152 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (k) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopropyletanothioamide Example Product Amina Compound No. ditic 153 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (l) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- Cyclobutylethanethioamide 154 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 Z (m) piperazinyl) phenyl] 2-oxo-5-oxazolidinyl] methyl] -2- Cyclopentyletothioamide 155 (S) -N- [[3- [3, 5-Difluoro-4- (4-acetyl-1-P-91-Dithiopiperazinyl) phenyl] -2-oxo-5-acetate and oxazolidinyl] methyl] thioacetamide of ethyl 156 (S) -N- [[3- [3, 5-Difluoro-4- (4-acetyl-1-1- P-91 Z (a) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] propantioamide 157 (S) -N- [[3- 13, 5-Difluoro-4- (4-acetyl-1-P-91 Z (b) piperazinyl) phenylj-2-oxo-5-oxazolidinyl] methyl] -2 -methylpropantioamide 158 (S) -N- [[3- [3, 5-Difluoro-4- (4-acetyl-1-P-91 Z (b) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl ] cyclopropancarbothioamide 159 (S) -N- [[3- [4- (4-acetyl-l-piperazinyl) phenyl] -, -92-Dithio-2-oxo-5-oxazolidinyl] methyl] thioacetamide ethyl acetate 160 (S) -N- [[3- [4- (4-acetyl-l-piperazinyl) phenyl] -p-92 Z (a) 2-oxo-5-oxazolidinyl] methyl] propane-amide 161 (S) -N - [[3- [4- (4-acetyl-l-piperazinyl) phenyl] - P-92 Z (b) 2-oxo-5-oxazolidinyl] methyl] -2- methylpropanthioamide Example Product Amina Compound No. ditic 162 (S) -N- [[3- [4- (4-acetyl-l-piperazinyl) phenyl] -p-92 Z (c) 2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide 163 (S) - N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide of ethyl 164 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propantioamide l 165 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (b.piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-methylpropantioamide 166 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] cyclopropanecarbothioamide 167 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Zid) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] butantioamide 168 ( S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (e) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -3- methylbutantioamide 169 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (f) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylbutantioamide 170 '(S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (g) piperazinyl] phenyl] -2-oxo-5- oxazolidinyl] methyl] -3,3-dimethylbutantioamide Example Product Amina Compound No. dithio 171 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (h) piperazinyl] phenyl] -2-oxo-5-oxazolidyl] methyl] Cyclobutanecarbothioamide 172 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 'Z (i) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] cyclopentancarbothioamide 173 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (j) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] cyclohexancarbothioamide 174 (S) -N- f [3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (k) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] metii ] -2-cyclopropylethanolamide 17 (S) -N- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (l) piperazinyl] phenyl] -2-oxo-5- oxazolidi nil J ethyl] -2-cyclobutyleantioamide 176 (S) -N-- [[3- [3-Fluoro-4- [4- (methoxyacetyl) -1- P-93 Z (m) piperazinyl] phenyl] -2 -oxo-5- oxazolidinyl] methyl] -2-cyclopentylethyantimamido 177 (S) -N- [[3- [3,5-Difluoro- [4- [4- (methoxyacetyl) - P-94 Dithio1-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide to ethyl 17. 8 (S) -N- [[3- [3, 5-Difluoro- [4- [4- (methoxyacetyl) -p-94 Z (a) 1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propantioamide 179 (S) -N- [[3- [3, 5-Difluoro- [4- [4- (methoxyacetyl) -p-94 Z (b) 1-piperazinyl] phenyl] -2-oxo-5 - oxazolidinyl] methyl] -2-methylpropantioamide Example Product Amina Compound No. ditic 180 (S) -N- [[3- [3, 5-Difluoro- [4- [4- (methoxyacetyl) -p-94 Z (c) 1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropancarbothioamide 181 (S) -N - [[3- [4- [4- (methoxyacetyl) -l- P-95 Dithio-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide ethyl 182 (S) -N- [[3- [4- [4- (methoxyacetyl) -l- P-95 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propantioamide and 183 (S ) -N- [[3- [4- [4-. { methoxyacetyl) -l- P-95 Z (b) pj perazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropantioamide '184 (S) -N- [[3- [4- [4- . { methoxyacetyl) -1- P-95 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] cyclopropapcarbothioamide 185 (S) -N- [[3- [3-Fluoro-4- [4- ( ethyl cyanoacetyl) -1- P-96 Dithio-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide 186 (S) -N - [[3- [3-Fluoro-4- [4- (cyanoacetyl) -1- P-96 Z (a) piperazinyl] phenyl] -2-OXO-5-oxazolidinyl] methyl] propantioamide 187 (S) -N- [[3- [3-Fluoro-4- [4- (cyanoacetyl) -1- P-96 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-methyl-propantioamide 188 (S) -N - [[3- [3-Fluoro-4- [4- (cyanoacetyl) -l- P-96 Z (c) piperazinyl] phenyl] -2-oxo-5- oxazolidinyl] methyl] cyclopropanecarbothioamide Example Product Amina Compound No. dithio 189 (S) -N- [[3- [3, 5-Difluoro-4- [4- (cyanoacetyl) -1- P-97 Dithiopiperazinyl] phenyl] -2-oxc-5-acetate oxazolidinyl] methyl] thioacetamide of ethyl 190 (S) -N- [[3- [3, 5-Difluoro-4- [4- (cyanoacetyl) -1- P-97 Z { a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] propantioamide 191 (S) -N- [[3- [3, 5-Difluoro-4- [4- (cyanoacetyl) -1- P-97 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropantioamide 192 (S) -N- [[3- [3,5-Difluoro-4- [4- (cyanoacetyl) - 1- P-97 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide 193 (S) -N- [[3- [4- [4- (Cyanoacetyl) -1- P- 98 Ethyl dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide 194 (S) -N- [[3- [4- [4- (Cyanoacetyl) -1- P-98 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propantioamide 195 (S) -N- [[3- [4- [4- (Cyanoacetyl) -1- P-98 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropane-amide 196 (S) - N- [[3- [4- [4- (Cyanoacetyl) -1- P-98 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cyclopropancarbothioamide 197 (S) -N- [[ Ethyl 3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] -thioacetamide Example Product Amina Compound No. dithio 198 (S) -N- [[3- [3-Fluoro-4- [4- (aceoxy-acetyl) -1- P-99 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - propantioamide 199 (S) -N- [[3- [3-Fluoro-4- [4- (acenoxyacetyl) -1- P-99 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropantioamide 200 (S) -N- [[3- [3-Fluoro-4- [4- (acenoxyacetyl) -p-99 Z (c) lpiperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] cyclopropancarbothioamide i. 201 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Z (d) piperazinyl] phenyl] -2-oxo-5-oxazclidinyl] methyl | -butantioar.ida 202 (S) -N- [[3- [3-Fluoro-4- (4- (acenoxyacetyl) -1- P-99 Z (e) piperazinyl] phenyl] -2-oxo-5-oxazolidinylmethyl ] -3-methylbutanetioamide 203 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Z (f) piperazinyl] phenyl] -2-oxo-5- oxazolidinyl] methyl] -2-methylbutantioamide 204 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Z (g) piperazinyl] phenyl] -2-oxo -5- oxazolidinyl] methyl] -3,3-dimethylbutantioamide 205 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Z (h) piperazinyl] phenyl ] -2-oxo-5-oxazolidinyl] methyl] cyclobutanecarbothioamide 206 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Z (i) piperazinyl] phenyl ] -2-oxo-5- oxazolidinyl] methyl] cyclopentancarbothioamide Example Product Amina Compound No. dithio 207 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Z (j) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] cycle hexanocarbotioamide 208 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P99 Z (k) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-cyclopropylethanethioamide 209 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Z (l) piperazinyl] phenyl] -2-oxo-5- and oxazolidinyl] ethyl] t-2-cyclobutyletanothioamide 210 (S) -N- [[3- [3-Fluoro-4- [4- (acetoxyacetyl) -1- P-99 Z (m) piperazinyl] phen? 1] -2-OJ? -5- oxazolidinyl] methyl] -2-cyclopenhlentanethiomide 211 IS) -N- [[3- [3, b-Di-luoro-4- [4- (acetoxyacetyl) - -100-Dithio-1-piperazinyl] phenyl] -2-oxo-5-acetate-oxazolidinyl] methyl] thioacetamide of ethyl 212 (S) -N- [[3- [3, 5-Difluoro-4- [4- (acetoxyacetyl) -p-100 Z (a) 1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] propantioamide 213 (S) -N- [[3- [3, 5-Difluoro-4- [4-. { acetoxyacetyl) - P-100 Z (b) 1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanthioamide 214 (S) -N- [[3- [3, 5-Difluoro-4- [4- (acetoxyacecil) -p-100 Z (c) 1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -cyclopropancarbothioamide Example Product Amina Compound No. dithio 215 (S) -N- [[3- [4- [4- (Acetoxyacetyl) -1- P-101 Dithiopiperazinyl] phenyl] 2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide ethyl 216 (S) -N- [[3- [4- [4- (Acetoxyacetyl) -1- P-101 Z (a) piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] ethyl] propantioamide 217 (S) - N- [[3- [4- [4- (Acetoxyacetyl) -1- P-101 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanthioamide and 218 (S) - N- [[3- [4- [4- (Acetoxyacetyl) -1- P-101 Zich) piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] methyl) cyclopropancarbothioamide 219 (S) -N- [[3- [ 3-Fluoro-4- [4- (benzyloxyacetyl) -1- P-102 Dithioacea piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -thioacetamide ethyl 220 (S) -N- [[3- [3-Fluoro-4- [4- (benzyloxyacetyl) -1- P-102 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] propantioamide 221 (S) -N- [[3- [3-Fluoro-4- [4- (benzyloxy-acetyl) -1- P-102 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-methyl propantioamide 222 (S) -N- [[3- [3-Fluoro-4- [4- (benzyloxy-acetyl) -1- P-102 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] cyclopropancarbothioamide 223 (S) -N- [[3- [3,5-Difluoro-4- [4- P-103 dithio (benzyloxyacetyl) -1-piperazinyl] phenyl] -2-oxo-acetate 5-oxazolidinyl ] methyl] thioacetamide ethyl Example Product Amina Compound No. dithio 224 (S) -N- [[3- [3,5-Difluoro-4- [4- P-103 Z (a) (benzyloxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] propantioamide 225 (S) -N- [[3- [3,5-Difluoro-4- [4- P- 103 Z (b) (benzyloxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] -2-methylpropantioamide 226 (S) -N- [[3- [3,5-Difluoro-4- [4- P-103 Z (c) (benzyloxyacetyl) -1-piperazinyl] phenyl] -2- oxo-5-oxazolidinyl] methyl] cyclopropancarbothioamide 121 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Dithiopiperazinyl] phenyl] -2-oxo-5- acetate oxazolidinil] meti L] ticacetamida de eti le 228 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] ] -propantioamide 229 (S) -M- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-lOl Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanetioamide 230 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (c) piperazinyl] phenyl] -2-oxo-5 oxazolidinyl] methyl] cyclopropancarbothioamide 231 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (d) piperazinyl] phenyl] -2-oxo-5 oxazolidinyl] ethyl] butantioamide 232 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P- 105 Z (e) piperazinyl] phenyl] -2-oxo-5 - oxazolidinyl] methyl] -3-methylbutantioamide Product Use Amina Compound No. ditio 233 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (f) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl) - 2-methyl butanetioamide 234 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (g) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 3, 3-dimethylbutanetioamide 235 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (h) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - Cyclobutanecarbothioamide and 236 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -i- P-105 Z (i) piperazinyl] phenyl] -2-oxo-5-oxazolidinium] methyl ] -ecyclopentancarcotioarr.ida 237 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 'Z (j) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] ] -ciciohexanocarbotioamide 238 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (k) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2- cyclopropylethanethioamide 239 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (l) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-cyclobutyletanothioamide 240 (S) -N- [[3- [3-Fluoro-4- [4- (methoxycarbonyl) -1- P-105 Z (m) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2- cyclopentylethanethioamide Example Product Amina Compound No. dithio 241 (S) -N - [[3- [3,5-Difluoro-4- [4- P-106 Dithio (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-acetate 5-oxazolidinyl] methyl] thioacetamide of ethyl 242 (S) ~ N - [[3- [3,5-Difluoro-4- [4- P-106 Z (a) (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -propantioamide 243 (S) -N - [[3- [3,5-Difluoro-4- [4- P-106 Z (b) (methoxycarbonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropantioamide 244 (S) -N - [[3- [3,5-Difluoro-4- [4- P-106 Z (c) (methoxycarbonii) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl]? netil] - cyclopropancarbotioamide 245 (S) -N- [[3- [4- [4- (methoxycarbonyl) -1- P-107 Dithioacetyl piperazinyl] phenyl] -2-oxo-5-ato oxazolidinyl] methyl] thioacetamide ethyl 246 (S) -N - [[3- [4- [4- (methoxycarbonyl) -l- P-107"Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propantioamide 247 (S) -N- [[3- [4- [4- (methoxycarbonyl) -l- P-107 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide 248 (S) -N- [[3- [4- [4- (methoxycarbonyl) -1- P-107 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide Example Product Amina Compound No. dithio 249 (S) -N - [[3- [3-Fluoro-4- [4- (methanesulfonyl) -1- P-108 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide; p.f. 197- Ethyl 198 ° C; Analysis calculated for Ci7H23FN4? 4S2: C, 47.43; H, 5.39; N, 13.01; S, 14.89. Found: C, 47.25; H, 5.40; N, 12.82; S, 14.56. 250 (S) -N- [[3- [3-Fluoro-4- [4- (methanesulfonyl) -1- P-108 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - propantioamide; p.f. 20"? - 208 ° C; Analysis calculated for C? 8H25F? 4S2: C, 48.63; II, 5.67; N, 12.60; 3, 14.42, Found: C, 48.51; H, 5.59; N, 12.52; S, 14.09 . 251 (S) -N - [[3- [3-Fluoro-4- [4- (methanesulfonyl) -l- P-108 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-methylpropantioamide; p.f. 204-206 ° C; Analysis calculated for C 10 H 2 FN 4 O 4 S 2: C, 49.76; H, 5.93; N, 12.22; S, 13.98. Found: C, 49.63; H, 5.92; N, 14.14; S, 13.91. 252 (S) -N - [[3- [3-Fluoro-4- [4- (methanesulfonyl) -l- P-108 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - Cyclopropancarbothioamide; Analysis calculated for C19H25FN4OS2: C, 49.98; H, 5.52; N, 12.27; S, 14.04. Found: C, 49.42; H, 5.50; N, 12.08; S, 13.80.
Example Product Amina Compound No. dithio 253 (S) -N- [[3- [3, 5-difluoro-4- [4-methanesulfonyl] -p-109-Dithio-piperazinyl] phenyl] -2-oxo-5-acetate-oxazolidinyl] methyl] thioacetamide-ethyl ester 254 (S) -N- [[3- [3, 5-Difluoro-4- [4-methanesulfonyl] -p-109 Z (a) 1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide 255 (S) -N- [[3- [3, 5-Difluoro-4- [4-methanesulfonyl)-P-109 Z (b) 1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] -2-methoxypropanedioamide and 256 (S) -N- [[3- [3,5-Difluoro-4- [4- (methanesulfonyl) -p-109 Z (c) 1-piperazinyl] phenyl] -2- oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide 257 (S) -N- [T3- [4- [4- (methanesulfonyl) -1- P-110 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl ] ethyl thioacetamide 258 (S) -N- [[3- [4- [4- (methanesulfonyl) -1- P-110 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -proparrtylamide 259 (S) -N - [[3- [4- [4- (methanesulfonyl) -l- P-110 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropantioamide 260 ( S) -N- [[3- [4- [4- (methanesulfonyl) -1- P-110 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide 261 (S) - Ethyl N- [[3- [3-Fluoro-4- [4- (ethansulfonyl) -1- P-l, 3-dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] ethyl] thioacetamide Example Product Amina Compound No. dithio 262 (S) -N- [[3- [3-Fluoro-4- [4- (ethansulfonyl) -1- P-lll Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propantioamide 263 (S) -N- [[3- [3-Fluoro-4- [4- (ethansulfonyl) -1- P-lll Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2-methylpropanetioamide 264 (S) -N- [[3- [3-Fluoro-4- [4- (ethansulfonyl) -1- P-lll Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] -cyclopropancarbothioamide and 265 (S) -N- [[3- [3, 5-Difluoro-4- [4- (ethanesulfonyl) - P-112 Dithio¬ Ethyl 1-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamxda 266 (S) -N- [[3- [3, 5-Difluoro-4- [4- (ethansulfonyl) -p-112 Z (a) l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl ] propanticamide 267 (S) -N- L "[3- [3,5-Difluoro-4- [4- (ethanesulfonyl) - F-112 Z (b) l-piperazinyl] phenyl] -2-oxo-5- oxazolidinyl] methyl] -2-methylpropantioamide 268 (S) -N- [[3- [3, S-Difluoro-4- [4- (ethansulfonyl) -p-112 Z (c) l-piperazinyl] phenyl] -2 -oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide 269 (S) -N- [[3- [4- [4- (ethansulfonyl) -1- P-113 Dithiopiperazinyl] phenyl] 2-oxo-5-acetate oxazolidinyl] methyl] ethyl ioacetamide 270 (S) -N [[3- [4- [4- (ethansulfonyl) -1- P-113 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] propantioamide Example Product Amina Compound No. dithio 271 (S) -N- [[3- [4- [4- (ethansulfonyl) -1- P-113 Z (b) piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] methyl] -2-methylpropanthioamide 272 (S) -N- [[3- [4- [4- (ethansulfonyl) -1- P-113 Z (c) piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] methyl] cyclopropanecarbothioamide 273 (S) -N - [[3- [3-Fluoro-4- [4- P-114 Ditio¬ (Chloromethanesulfonyl) -l-piperazinyl] phenyl] -2- ethyl acetate oxo-5-oxazolidinyl] methyl] thioacetamide and 274 (S) -N- [[3- [3-Fluoro-4- [4- P-114 Z (a) (chloromethanesulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolxdin? l] methyl] -propantioai ida 275 (S) -N- [(3- [3-Fluoro-4- [4- P-114 Z (b) (chlorometansuifonyl) -l-piperazinyl] fenii] -2-oxo-5-oxazole idinyl] me il ] -2- methylpropanthioamide 276 (S) -N- [[3- [3-Fluoro-4- [4- P-114 Z (c) (chloromethanesulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - cyclopropancarbothioamide 277 (S) -N - [[3- [3,5-Difluoro-4- [4- P-115 Ditio¬ ethyl (oxo-5-oxazolidinyl] methyl] thioacetamide 278 (S) -N- [[3- [3, 5-Difluoro-4- [4- P-115 Z (a) (chloromethanesulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -propantioamide Example Product Amina Compound No. dithio 279 (S) -N- [[3- [3, 5-Difluoro-4- [4- P-115 Z (b) (chloro-ethanesulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropantioamide 280 (S) -N- [[3- [3, 5-Difluoro-4- [4- P-115 Z (c) (chloro-ethanesulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - cyclopropancarbothioamide 281 (S) -N- [[3- [4- [4- (chloromethanesulfonyl) -1- P-116 Ditioy piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinylmethyl] thioacetamide ethyl 282 (S) -N- [[3- [4 - [4- (cioror..etansulfcniI) -l- .16 Z (ai piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide 283 (S) -N- [L3- [4- [4- (chloromethanesulfonyl) -1- P-I16 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanthioamide 284 (S) -N- [[3- [4- [4- (chloromethanesulfonyl) -1- P-116 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide 285 (S) -N- [[3- [3-Fluoro-4- [4- (cyanometan-P-117 Dithiosulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide of ethyl 286 (S) -N- [[3- [3-Fluoro-4- [4- (cyanomethane-P-117 Z (a) sulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] propantioamide Example Product Amina Compound No. dithio 287 (S) -N- [[3- [3-Fluoro-4- [4- (cyano ethane-P-117 z (b) sulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanthioamide 288 (S) -N- [[3- [3-Fluoro-4- [4- (cyanomethane-P-117 Z (c) sulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -cyclopropancarbothioamide 289 (S) -N- [[3- [3, 5-Difluoro-4- [4- (cyanomethane-P-118 Dithiosulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] ethyl thioacetamide and 290 (S) -N - [[3- [3,5-Difluoro-4- [4- P-llc Z (a) (cyanomethanesulfonyl) -l- piperazir.il] fanil] -2 - oxo-5-oxazolidinyl] methyl] p? -opaneti or one way 291 (S) -N- [[3- [3,5-Difluoro-4- [4- P-118 Z (b) (cyanomethanesulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2- methylpropanthioamide 292 (S) -N- [[3- [3,5-Difluoro-4- [4- P -l, Z (c) (cyanomethanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] - cyclopropanc < prbotioamide 293 (S) -N- [[3- [4- [4- (Cyanomethanesulfonyl) -1- P-119 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] -thioacetamide ethyl 294 (S) -N- [[3- [4-L4- (Cyanomethanesulfonyl) -l- P-119 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide Example Product Amina Compound No. dithio 295 (S) -N- [[3- [4- [4- (Cyanomotansulfonyl) -1- P-119 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropantioamide • 296 (S) -N- [[3- [4- [4- (Cyanomethanesulfonyl) -1- P-119 Z (c) piperazinyl] phenyl] -2-oxo-l-oxazolidinyl] methyl] -cyclopropancarbothioamide 297 (S ) -N- [[3- [3-Fluoro-4- [4- (N-methylsulfamoyl) - P-120 Dithiol-piperazinyl] phenyl] -2-oxo-5-acetate-oxazoli-dinyl] methyl] thioacetamide of ethyl and 298 (S) -N- [[3- [3-Fluoro-4- [4- (N-methylsulfamoyl) -120 Z (a) l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide 299 (S) -N- [[3- [3-Fluoro-4- [4- (N-methylsulfamoyl) -p-120 Z (b) I-pipe? -azinyl] phenyl] -2-oxo- 5- oxaz.olidip.il] methyl] -2-methylpropanetioamide 300 (S) -N- [[3- [3-Fluoro-4- [4- (N-methylsulfamoyl) - P-120 Z (c) l- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] -cyclopropancarbothioamide 301 (S) -N- [[3- [3, 5-Difluoro-4- [4- (N- P-121 Dithiomethylsulfamoyl) - l-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] m ethyl] thioacetamide ethyl 302 (S) -N - [[3- [3,5-Difluoro-4- [4- (N- P-121 Z (a) methylsulfamoyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] -propantioamide 303 (S) -N- [[3- [3, 5-Difluoro-4- [4- (N- P-121 Z (b) methylsulfamoyl) -l-piperazinyl] phenyl] -2- oxo-5- oxazolidinyl] methyl] -2-methylpropanetioamide Example Product Amina Compound No. dithio 304 (S) -N- [[3- [3, 5-Difluoro-4- [4- (N- P-121 Z (c) methylsulfamoyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] -cyclopropancarbothioamide 305 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -1- P-122 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide of ethyl 306 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -1- P-122 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide and 307 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -1- P-122 (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] -2-methylpropanethioamide 308 (S) -N- [[3- [4- [4- (N-methylsulfamoyl) -l- P-122 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazclidinyl] metill-cyclopropancarbotioamxda 309 ( S) -N- [[3- [3-Fluoro-4- [4- (N, N-P-123 Dithiodimethylsulfonyl) -l-piperazinyl] phenyl] -2-oxo-acetate 5-oxazolidinyl] methyl) thioacetamide of ethyl 310 (S) -N- [[3- [3-Fluoro-4- [4- (N, N- P-123 Z (a) dimethylsulfonyl) -l-piperazinyl] phenyl] -2-oxo- 5- oxazolidinyl] methyl] -propantioamide 311 (S) -N- [[3- [3-Fluoro-4- [4- (N, N- P-123 Z (b) dimethylsulfamoyl) -l-piperazinyl] phenyl] -2 -oxo-5-oxazolidinyl] methyl] -2-methylpropanetioamide 312 (S) -N- [[3- [3-Fluoro-4- [4- (N, N-dimethyl-P-123 Z (c) sulfamoyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide Example Product Amina Compound No. dithio 313 (S) -N- [[3- [3,5-Difluoro-4 ~ [4- (N, N-P-124 Dithiodimethylsulfamoyl) -l-piperazinyl] phenyl] -2-oxo-acetate 5-oxazolidinyl] methyl] thioacetamide of ethyl 314 (S) -N- [[3- [3,5-Difluoro-4- [4- (N, N-P-124 (a) dimethyl-sulfamoyl) -l-piperazinyl] phenyl] -2-oxo- 5-oxazolidinyl] methyl] -propantioamide 315 { S) -N- [[3- [3,5-Difluoro-4- [4- (N, N- P-124 Z (b) dimethylsulfamoyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidine .] methyl] -2-methylpropanetioamide 316 (S) -N- [[3- [3,5-D5-fluoro-4- [4- (N, N- P-124 Z (c) dimethylsulfamoyl) -1-pi? Ezinyl] phenyl] -2-oxo - 5-oxazolidinyl] methyl] - cyclopropancarbothioamide 317 IS) -N - [[3- [4-y4- (N, N-dimethylsulfamoxl) -l- P-125-Dithio-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] -thioacetamide ethyl 318 (S) -N - [[3- [4 '- [4- (N, N-dimethylsulfamoyl) -l- P-125 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide 319 (S) -N- [[3- [4- [4- (N, N-dimethylsulfamoyl) -l- P-125 Z (b) piperazin? 1] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropantioamide 320 (S) -N- [[3- [4- [4- (N, N-dimethylsulfamoyl) -l- P-125 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - cyclopropancarbothioamide Example Product Amina Compound No. dithio 321 (S) -N- [[3- [3-Fluoro-4- [4- (Ethoxycarbonyl) -1- P-126 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide ethyl 322 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - propantioamide 323 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropantioamide and 324 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (c) piperazinyl] phenyl] -2-oxo-5- oxazolidinyl] methyl] -cyclopropancarbothioamide 325 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (d) piperazinyl] phenyl] -2-oxo-5 - oxazo idinyl] metj 1] butantioamide 326 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (e) piperazinyl] phenyl] -2-oxo -5- oxazolidinyl] methyl] -3-methylbutanetioamide 327 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (f) piperazinyl] phenyl] - 2-oxo-5-oxazolidinyl] methyl] -2-methylbutantioami at 328 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (g) piperazinyl ] phenyl] -2-oxo-5-oxazolidinyl] methyl] -3,3-dimethylbutanetioamide 329 (S) -N- [[3 - [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (h) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] ethyl] -cyclobutanecarbothioamide Example Product Amina Compound No. dithio 330 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (i) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - cyclopentancarbotioamide 331 (S) -N- [[3- [3-Fluoro-4- [4-. { ethoxycarbonyl) -1- P-126 Z (j) piperazinyl] phenyl] -2-oxo-5-oxazole? dinyl] methyl] -cyclohexanecarbothioamide 332 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (k) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2- and cyclopropylethanethioamide 333 (S) -N- [[3- [3-Fluoro-4- [4- i ethoxycarbonyl) -1- P-126 Z (l) piperazinyl] phenxl] -2-oxo-5-oxazolidinyl] methyl] - 2-cyclobutyletanothioamide 334 (S) -N- [[3- [3-Fluoro-4- [4- (ethoxycarbonyl) -1- P-126 Z (m) piperazinyl] phenJ 1] -2-oxo-5-oxazolidinyl] methyl] -2- ciclopentiletanotioam da 335 (S) -N- [[3- [3,5-Difluoro-4- [4- (ethoxycarbonyl) - P-127 Dithiol-piperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetmide of ethyl 336 (S) -N- [[3- [3, 5-Difluoro-4- [4- (ethoxycarbonyl) -p-127 Z (a) l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -propantioamide 337 (S) -N- [[3- [3, 5-Difluoro-4- [4- (ethoxycarbonyl) -F-127Z (b) l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -2-methylpropanetioamide Example Product Amina Compound No. dithio 338 (S) -N- [[3- [3, 5-Difluoro-4- [4- (ethoxycarbonyl) -p-127 Z (c) 1- [piperazinyl] feDyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide 339 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1- P-12 ^ Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide ethyl 340 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1- P-128 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide and 341. { S) -N- [[3- [4- [4- (ethoxycarbonyl) -1- P-128 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidin-1] otil] -2-methylp-opantioamide 342 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1- P-128 Z { c) piperazinyl] phenyl] -2-oxo-5-oxazolidiyl] ethyl] -cyclopropancarbothioamide 343 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129-Dithiopiperazinyl)] ethyl phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide 344 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (a) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide 345 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (b) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanthioamide 346 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (c) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] metxl] -cyclopropancarbothioamide Example Product Amina Compound No. dithio 347 (S) -N- [. { 3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (d) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -butanetioamide 348 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (e) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -3- methylbutantioamide 349 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-l- P-129 Z (f) piperazinyl) phenyl] -2-oxo-5- -2-methylbutantioamide 350 (S) -N - [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (g) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] ethyl] -3, 3-dimethylbutane ioamide 351 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (h) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] ethyl] -cyclobutanecarboth 352 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-l- P-129 Z (i) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopentancarbothioamide 353 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (j) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclohexanecarbothioamide 354 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (k) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclopropyletanothioamide Product Use Amina Compound No. ditio 355 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-1-P-129 Z (l) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- cyclobutyletanothioamide 356 (S) -N - [[3- [3-Fluoro-4- (4-sUlf'amoj.ll-P-129 Z (m) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] - 2- cyclopentylethanethioamide 357 (S) -N - [[3- [3,5-Difluoro-4- (4-sulfamoyl-1-P-130 Dithio-piperazinyl) fyenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide of ethyl 358 (S) -N - [[3- [3,5-Difluoro-4- (4-sulfamoyl-1-Pl 30 Z (a) piperazinyl-phenyl] -2-oxo-5-oxazolidinyl] methyl] - propantioamide 359 (S) -N - [[3-y3,5-Difluoro-4- (4-sulfamoyl-1-P-130 Z. {b) pxperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanthioamide 360 (S) -N - [[3- [3,5-Diflutar-4 -. (4-sulfamoyl-1-P-130 Z (c) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] ethyl] -cyclopropancarbothioamide 361 (S) -N- [[3- [4- (4-sulfamoyl-l- P-131-Dithio-piperazinyl) phenyl] -2-oxo-5-acetate-oxazolidinyl] methyl] thioacetamide in ethyl 362 (S) -N- [[3- [4- (4-sulfamoyl-1-P-131 Z (a) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -propanthioamide Example Product Amina Compound No. dithio 363 (S) -N- [[3- [4- (4-sulfamoyl-1-P-131 Z (b) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] ethyl] -2-methylpropantioamide 364 (S ) -N- [[3- [4- (4-sulfamoyl-1-P-131 Z (c) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] ethyl] -cyclopropancarbothioamide 365 (S) -N- [ [3- [3-Fluoro-4- [4- (cyanomethyl) -1- P-132-Dithiopiperazinyl] phenyl] -2-oxo-5-acetate-oxazolidinyl] methyl] thioacetamide of ethyl and 366 (S) -N- [ [3- [3-Fluoro-4- [4- (cyanomethyl) -1- P-132 Z (a) piperazinyl] phenyl] ~ 2-oxo-5-oxazolidinyl] methyl] -propanti amy da 367 (S) -N- [[3- [3-Fluoro-4- [4- (cyanomethyl] -1- P-132 Z (b) piperazinyl] pheny1] -2-oxo-5-oxazolidinyl] ethyl] -2-methylpro? antioamide 368 (S) -N- [[3- [3-Fluoro-4- [4- (cyanomethyl) -1- P-132 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide 369 (S) -N- [[3- [3, 5-Difluoro-4- [4- (cyanomethyl) -1- P-133 Dithiopiperazinyl] feryl] -2-oxo-5-acetate oxazolidinyl] methyl] ethyl thioacetamide. 370 (S) -N- [[3- [3, 5-Difluoro-4- [4- (cyanomethyl) -1- P-133 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -propantioamide 371 (S) -N- [[3- [3,5-Difluoro-4- [4-cyanomethyl] -l- P-133 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] -2-methylpropanthioamide Example Product Amina Compound No. dithio 372 (S) -N- [[3- [3, 5-Difluoro-4- [4- (cyanomethyl) -1- P-133 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -cyclopropancarbothioamide 373 (S) -N- [[3- [4- [4- (Cyanomethyl) -1- P-134 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] thioacetamide ethyl 374 (S) -N- [[3- [4- [4- (Cyanomethyl) -1- P-134 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide 375 (S ) -N - [[3- [4- [4- (Cyanomethyl) -1- P-134 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolxdinyl] methyl] -2-methylpropantioamide 376 (S) -N- [[3- [4- [4- (Cyanomethyl) -1- P-134 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyI] -cyclopropancarbothioamide 377 (S) -N- [[3- [3-Fluoro-4- [4- (2-fluoroethyl) -1- P-135 Dithiopiperazinyl] phenyl] -2-oxo-5-acetate oxazolidinyl] ethyl] thioacetamide ethyl 378 (S) -N- [[3- [3-Fluoro-4- [4- (2-fluoroethyl) -1- P-135 Z (a) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl ] -propantioamide 379 (S) -N- [[3- [3-Fluoro-4- [4- (2-fluoroethyl) -1- P-135 Z (b) piperazinyl] phenyl] -2-oxo-5- oxazolidinyl] methyl] -2-methylpropantioamide 380 (S) -N- [[3- [3-Fluoro-4- [4- (2-fluoroethyl) -1- P-135 Z (c) piperazinyl] phenyl] -2 -oxo-5- oxazolidinyl] methyl] -cyclopropancarbothioamide Example Product Amina Compound No. dithio 381 (S) -N- [[3- [3, 5-Difluoro-4- [4- (2-fluoroethyl) P-136 Dithiole-piperazinyl] phenyl] -2-oxo-5-aceta-tza-oxazolidinyl] ethyl ] ethyl thioacetamide 382 (S) -N- [[3- [3, 5-Difluoro-4- [4- (2-fluoroethyl) -p-136 Z (a) l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl ] methyl] -propantioamide 383 (S) -N- [[3- [3, 5-Difluoro-4- [4- (2-fluoroethyl) P-136 Z (b) l-piperazinyl] phenyl] -2-oxo-5-oxazolidinii] ethyl] -2-methylpropanthioamide 384 (S) -N- [[3- [3,5-Difluoro-4- [4- (2-fluoroethyl) -p-136 Z (c) 1-piperazinyl phenyl] -2-cx? -5-oxazolidinyl ] methyl] -cyclopropancarbothioamide 385 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1- P-137 Dithio-piperazinyl] fenii] -2-oxo-5-oxazolidinyl] acetamide methyl] thioacetamide ethyl 386 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1- P-137 Z (a) piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] methyl] -propantioamide 387 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1- P-137 Z (b) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- me ilpropantioamide 388 (S) -N- [[3- [4- [4- (2-fluoroethyl) -1- P-137 Z (c) piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide Example Product Amina Compound No. dithio 389 (S) -N- [[3- [3-Fluoro-4- (4-formyl-1-P-13E-Dithiopiperazinyl) phenyl] -2-oxo-5-acetate-oxazolidinyl] methyl] thioacetamide; Ethyl analysis calculated for Ci7H2? FN403S: C, 53.67; H, 5.56; N, 14.73; S, 8.43. Found: C, 53.14; H, 5.42; N, 14.25; S, 8.18. 390 (S) -N- [[3- [3-Fluoro-4- (4-formyl-1-P-13] Z (a) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantiomide; p.f. 166- 167 ° C; Analysis calculated for C-.8H23FN4O3S: C 4.81; H, 5.88; N, 14.20; S, 8.13. Found: C, 54.83; H, 6.00; N, 14.12; S, 7.96. 391 (S) ~ N - [[3- [3-Fluoro-4- (4-formyl-1-P-13Í (b) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -2- methylpropanthioamide; p.f. 157-158 ° C: Analysis calculated for C10H25FN4? 3S: C, 55.87, H, 6.17; N, 13.72; S, 7.85. Found: C, 55.67; H, 6.19; N, 13.50; S, 7.70. 392 (S) -N- [[3- [3-Fluoro-4- (4-f ormyl-1-P-13E Z (c) piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide; p.f. 178-179 ° C; Analysis calculated for C19H23FN4? 3S: C, 56.14; H, 5.70; N, 13.78; S, 7.89. Found: C, 56.13; H, 5.64; N, 13.64; S. 7.75.
Example Product Amina Compound No. dithio 393 (S) -N- [[3- [3,5-Difluoro-4- (4-formyl-l- P-139 Dithiopiperazinyl) phenyl] -2-oxo-5-acetate oxazolidinyl] methyl] -thioacetamide ethyl 394 (S) -N- [[3- [3,5-Difluro-4- (4-formyl-1-P-139 Z (a) piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -propantioamide 395 (S) -N- [[3- [3, 5-Difluro-4- (4-formyl-1-P-139 Z (b) piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanthioamide 396 (S) -N- [[3- [3, 5-Difluro-4- (4-formyl-1-P-139 Z (c) piperaziryl) -phenyl] -2-oxc-5-oxazolidinyl] methyl] -ciolopropancarboticamide 397 (S) -N - [[3- [4- (4-formyl-l-piperazinyl) - P-140-Dithiophenyl] -? - oxo-5-oxazolidipyl] methyl] -acetic acid thioacetamide 398: S) -N ~ [[3- [4- (4-formyl-l-piperazinyl) -phenyl] -p-140 Z (a) 2-oxo-5-oxazolidinyl] methyl] -propantioamide 399 (S) -N- [[3- [4-. { 4-formyl-l-piperazinyl) -phenyl] - P-140 Z (b) 2-oxo-5-oxazolidinyl] methyl] -2- methylpropanthioamide 400 (S) -N- [[3- [4- (4-formyl-l-piperazinyl) -phenyl] -p-140 Z (c) 2-oxo-5-oxazolidinyl] -methyl] -cyclopropanecarbothioamide When in the general procedure of Example 31, step 1, a suitable amount of the amine listed below is replaced by compound 33, the corresponding isothiocyanate is obtained for the amines P-90, P-93, P-99, P -105, P-126 and P-129. When in the general procedure of Example 114 a suitable amount of the isothiocyanate and the amine listed below are substituted by the compound 82 and methylamine, the respective products are obtained listed two below.
TABLE I Example Product Isothiocyanate Amine No. corresponding to the amine No. 401 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90-methylamine-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N '- methylthiourea 402 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90-dimethylamine-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N ' , N '-dimethylthiourea 403 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-P-90 azetidine piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl ] -1- azetidinecarbotioamide Example Product Isothiocyanate Amine No. corresponding to the amine No. 404 (S) -N- [[3- [3-Fluoro-4- (4- P-90 ammonia-thiomorpholinyl) -phenyl] -2-oxo-5-anhydro-oxazolidinyl] -methyl] -thiourea 405 (S) - N- [[3- [3-Fluoro-4- [4- P-93 methylamine] (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N'-methylthioarea 406 (S) -N- [[3- [3-Fluoro-4- [4- P-93 dimetilamir.a (methoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl-methyl] -N ', M' - dimethylthiourea 407 (S) -N- [[3- [3-Fluoro-4- [4- P-93 azetidine (methoxyacetyl) -1- piperazinyl] pheny] -2-oxo-5-oxazolidinyl] -methyl] -1- azetidinecarbothioamide 408 (S) -N- [[3- [3-Fluoro-4- [4- P-99 methylamine (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N'-methylthiourea 409 (S) -N- [[3- [3-Fluoro-4- [4- P -99 dimethylamine (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N ',, - dimethylthiourea Example Product Isothiocyanate Amine No. corresponding to the amine No. 410 (S) -N- [L3- [3-Fluoro-4- [4- P-99 azeditine (acetoxyacetyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -1-azetidinecarbothioamide 411 (S) -N - [[3- [3-Fluoro-4- [4- P-105 methylamine] (methoxycarbonyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N '- and methylthiourea 412 ÍS) -N - [[3- [3-Fluoro-4- [4- P-105 d-imethylamine (methoxycarboni 1) - 1-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N ', N'-dimethylthiourea 413 lS) -N- [[3d3-Fluoro-4- [4- P-l05 azetidine (methoxycarbonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -1-aze'tidiricarbothioamide 414 { S) -N - [[3- [3-Fluoro-4- [4- P-126 methylamine] (ethoxycarbonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N '-methylthiourea 415 (S) -N - [[3- [3-Fluoro-4- [4- P-126 dimethylamine] (ethoxycarbonyl) -I-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -N ',' -dimethylthiourea Example Product Isothiocyanate Amine No. corresponding to the amine No. 416 (S) -N- [[3- [3-Fluoro-4- [4- P-126 azetidine (ethoxycarbonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -1 -azetidincarbotioamide 417 (S) -N- [[3- [3-Fluoro-4- (4- P-129 methylamine sulfamoyl-1-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] - '- methylthiourea and 418 (S) -N- [[3- [3-Fluoro-4- (4- P-129 dimethylamir.a sulfamoyl-1-plperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -ethyl] - N ',' - dimethylthiourea 419 (S) - - [[3- [3-Fluoro-4- (4- P-129 azetidine sulf oi l-l-piperazinyl] -f nyl] -2-oxo-5-oxazolidinyl] -methyl] -1- azetidinecarbothioamide When a suitable amount of the isothiocyanate and alcohol listed below is used in the general procedure of Example 100 in the same manner as in Compound 82 and methanol is used, the respective products listed below are obtained.
TABLE J Example Product Isothiocyanate Amine Not corresponding to the amine No. 420 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 methanol piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 421 (S) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90 ethanol piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-ethylthiocarbamate 422 (3) -N- [[3- [3-Fluoro-4- (4-acetyl-1-P-90-alcohol piperazinyl) -phenyl] -2-oxo-5-scprv-pyric-oxazolidinyl] -methyl] -0 -iso- propylthiocarbamate 423 (S) -N- [[3- [3,5-Difluoro-4- (4-acetyl-P-91 methanol 1-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0 - methylthiocarbamate 424 (S) -N - [[3- [4- (4-Acetyl-1-P-92 methanol piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 425 (S) -N - [[3- [3-Fluoro-4- [4- P-93 methanol (methoxyacetyl) -l-piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate Example Product Isothiocyanate Amine Not corresponding to the amine No. 426 (S) -N - [[3- [3-Fluoro-4- [4- P-93 ethanol (methoxyacetyl) -1-piperazinyl phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-ethylthiocarbamate 427 (S) -N- [[3- [3-Fluoro-4- [4- P-93 alcohol (methoxyacetyl) -l-piperazinyl] phenyl] isopropyl 2-oxo-5-oxazolidinyl] -methyl] -O- isopropylthiocarbamate 428 (S) -N- [[3- [3,5-Difluoro- [4- [4- P-94 methylamine (methoxy-acetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] - methyl] -C- ethylthiocarbamate 429 (S) -N- [[3- [4- [4- (methoxyacetyl) -I- P-95 methylamine piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 43Q (S) -N- [3- [3-Fluoro-4- [4- P-96 methanol (cyanoacetyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 431 (S) -N- [[3- [3,5-Difluoro-4- [4- P-97 methanol (cyanoacetyl) -l-piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] -methyl] -0 - methylthiocarbamate Example Product Isothiocyanate Amine Not corresponding to the amine No. 432 (S) -N- [[3- [4- [4- (Cyanoacetyl) -1- P-98 methanol piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 433 (S ) -N - [[3- [3-Fluoro-4- [4- P-99 methanol (acetoxyacetyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 434 (S) -N - [[3- [3-Fluoro-4- [4- P-99 ethanol (acetoxyacetyl) -1-. piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0- ethylthiocarbamate 435 (S) -N- [[3- [3-Fluoro-i- [4- d] alcohol (acetoxyacetyl) -1 - isopropyl or piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-isopropylthiocarbamate 436 (S) -N - [[3- [3,5-Difluoro-4- [4- P-100 methanol (acetoxyacetyl) -1- piperazinyl phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 437 (S) -N- [[3- [4- [4- (Acetoxyacetyl) -1- P -101 methanol piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate Example Product Isothiocyanate Amine Not corresponding to the amine No. 438 (S) -N- [[3- [3-Fluoro-4- [4- P-102 methanol (benzyloxy-acetyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O -methylthiocarbamate 439 (S) -N- [[3- [3, 5-Difluoro-4- [4- P-103 methanol. { ben-2-oxyacetyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate and 440 (S) -N- [[3- [3-Fluoro-4- [4- P- 105 methanol (methoxycarbonyl) -l-piperazinyl] -phenyl] -2-oxo-b-oxazolidinyl] -methyl] -O-methylthiocarbamate 441 (S) -N - [[3- [3-Fluoro-4- [4- P-105 ethanol (methoxycarbonyl) -i-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O -ethylthiocarbamate 442 (S) -N - [[3- [3-Fluoro-4- [4- P-105 alcohol (methoxycarbonyl) -l-piperazinyl] -isopropyl phenyl] -2-oxo-5-oxazolidinyl] -methyl] - O-iso-propylthiocarbamate 443 (S) -N - [[3- [3,5-Difluoro-4- [4- P106 methanol (ethoxycarbonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] O- methylthiocarbamate Example Product Isothiocyanate Amine Not corresponding to the amine No. 444 (S) -N - [[3- [4- [4- (oxycarbnyl) -l- P107 methanol piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 445 (S) -N - [[3- [3-Fluoro-4- [4- P108 methanol] . { methanesulfonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate and 446 (S) -N- [[3- [3, 5-Difluoro-4- [4- P109 methanol (methanesulfonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 447 (S) -N- [[3- [4- T4- (methanesulfonyl) -1- P110 methanol piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 448 (S) -N- [[3- [3-Fluoro-4- [4- Pili methanol (ethanesulfonyl) .- l-piperazinyl] phenyl] 2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 449 (S) -N- [[3- [3,5-Difluoro-4- [4- P112 methanol] (ethanesulfonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -cyclopropanecarbothioamide Example Product Isothiocyanate Amine Not corresponding to the amine No. 450 (S) -N-r [3- [4- [4- (ethanesulfonyl) -1- P113 methanol piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 451 (S) -N- [[3- [3-Fluoro-4- [4- P114 methanol (Chloromethanesulfonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 452 (S) -N- [[3- [3, 5-Difluoro-4- [4- P115 methanol] (chloro-urethanesulfonyl) -1-plperazinyl] phenyl] -2-oxo-5-oxazolidir-yl] -ethyl] -O-methylthiocarbamate 453 (S) -N - [[3- [4- [4- P116 methanol (chloromethylsulfonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 454 (S) -N - [[3- [3-Fluoro-4- [4- P117 methanol (cyanomethanesulfonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 455 (S) -N- [[3- [3, 5-Difluoro-4- [4- P118 methanol] (cyanomethanesulfonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate .twenty Example Product Isothiocyanate Amine Not corresponding to the amine No. 456 (S) -N - [[3- [4- [4- P119 methanol . • (Cyanomethanesulfonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 457 (S) -N - [[3- [3-Fluoro-4- [4- (N- P120 methanol methylsulfamoyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O -methylthiocarbamate 458 (S) -N- [[3- [3, 5-Difluoro-4- [4- (N- P121 methanol methylsulfamoyl) -l-piperazinyl] -phenyl] -2 -oxo-5-oxazclidir.il] - methyl] - O-methylthiocarbamate 459 (S) -N- [[3- [4- [4- (N-methylsulfa oil) - P122 methanol 1-piperazinyl] enyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 460 (S) -N - [[3- [3-Fluoro-4- [4- (N, N- P123 methanol dimethylsulfamoyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] O-methylthiocarbamate 461 (S) -N - [[3- [3,5-Difluoro-4- [4- (N, N- P124 methanol dimethylsulfamoyl) -1- piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl ] -0- methylthiocarbamate Example Product Isothiocyanate Amine Not corresponding to the amine No. 462 (S) -N- [[3- [4- [4- (N, N- P125 methanol dimethylsulfamoyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 463 (S) -N - [[3- [3-Fluoro-4- [4- P126 methanol (ethoxycarbonyl) -l-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate and 464 (S) -N- [[3- [3-Fluoro-4- [4- P126 ethanol (x-oxybanbanyl) -l-piperazinyl] -phenyl] -2 -oxo-5-oxazclidir.-yl] -methyl] - O -ethylthiocarbamate 465 (S) -N- [[3- [3.Fluoro-4- [4- P126 alcohol (ethoxycarbonyl) -l-piperazjnii] - isopropyl phenyl] -2-oxo-5-oxazolidinyl] -methyl] • O- iso-propylthiocarbamate 466 (S) -N. [[3- [3, 5-Difluoro-4- [4- (ethoxy P127 methanol carbonyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 467 (S) -N- [[3- [4- [4- (ethoxycarbonyl) -1- P128 methanol piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0- eti1-thiocarbamate Product Isothiocyanate Amine Not corresponding to the amine No. 468 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-P129 methanol 1-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 469 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-P129 ethanol 1-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-ethylthiocarbamate 470 (S) -N- [[3- [3-Fluoro-4- (4-sulfamoyl-P129 alcohol i-piperazinyl) -phenyl] -2-oxc-5-isopropyl-oxazolidinyl] -methyl] -O-iso- propylthiocarbamate 471 (S) -N- [. { 3- [3,5-Difluoro-4- (4- P130 methanol sulfamoyl-1-piperazinyl) -phenoxy] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 472 (S) -N - [[3- [4- (4-sulfamoyl-l- P131 methanol piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate 473 (S) -N - [[3- [3-Fluoro-4- [4- P132 methanol (cyanomethyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate Example Product Isothiocyanate Amine Not corresponding to the amine No. 474 (S) -N - [[3- [3,5-Difluoro-4- [4- P133 methanol (cyanomethyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 475 (S) -N- [[3- [4- [4- (Cyanomethyl) -1- P134 methanol piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 476 (S) -N - [[3- [3-Fluoro-4- [4-. { 2- P135 methanol fluoroethyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazcidinyl-1-methyl] -0-methylthiocarbamate 477 (S) -N- [[3- [3, 5-Difluoro-4- [4- (2-P136 methanol fluoi oethyl) -l-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0- methylthiocarbamate 478 (S) -N- [[3- [4- [4- (2-fluoroethyl) -l- P137 methanol piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 479 (S) -N- [[3- [3-Fluoro-4- (4-formyl-1-P138 methanol piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate Product Isothiocyanate Amine Not corresponding to the amine No. 48 C (S) -N- [[3- [3,5-Difluoro-4- (4-formyl-P139 methanol 1-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methylthiocarbamate 481 (S) -N - [[3- [4- (4-formyl-1-P140 methanol piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -0-methyl thiocarbamate EXAMPLE 482.Tiazepin S-oxide (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-i, 4-thiazepin-4 (SH) iD-phenyl] -2-oxo-3-oxazolidinyl ] -methyl] -thioacetamide Step 1. Hexahydro-5? Xo-l, 4-thiazepine was prepared according to the procedure described by Gallego (J. Org. Chem. 1993, 58, 3905-3911). Step 2. Lithium-aluminum hybrid (5.5 mL of a 1M solution in THF) was added dropwise to a stirred solution of hexahydro-5-oxo-l, 4-t-iazepine (721.5 mg) in dry THF (21 mL) was cooled to 0 ° C. The reaction mixture was stirred at 0 ° C for 10 minutes, then at room temperature for 4 hours. The reaction mixture was quenched by the careful and successive addition of water (0.2 mL), aqueous 5N NaOH (0.2 mL) and water (0.74 mL). The reaction mixture became very thick and gel-like. The reaction mixture was diluted with. ether (50 mL) and filtered through a pad of celite. The filter cake was washed with ether (100 mL). The filtrate was concentrated to yield 616.6 mg of 1,4-hexahydrothiazepine which was used immediately in the next step. Pass 3. To a stirred solution of 1,4-hexahydrothiazepine (596.0 mg) and 3,4-difluoronitrobenzene (0.51 mL) in acetonitrile (14 mL) was added diisopropylethylamine (1.0 mL). The yellow solution was refluxed for 18 hours, then cooled and concentrated. The residue was diluted with CH2C12 (100 mL) and washed with saturated aqueous NH C1 (35 mL). The phases were separated and the organic phases were dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography using 20% EtOAc in hexane as the eluent to produce 830.2 mg of nitrobenzene. P.f. 115-116 ° C; Analysis calculated for CiiH13FN202S: C, 51.55; H, 5.11; N, 10.93; S, 12.51. Found: C, 51.47; H, 5.12; N, 10.79; S, 12.42. Step 4. To a stirred suspension of the nitrobenzene prepared in Step 3 (5.5 g) in the EtOH (260 mL) was added an aqueous 2M CuSO4 solution (11.9 mL). The mixture was cooled to 0 ° C and NaBH 4 (4.1 g) was added in portions. The reaction mixture became very dark and was stirred at 0 ° C for 10 minutes, at room temperature for 30 minutes, and then heated to reflux for 3 hours. The cooled reaction mixture was diluted with EtOAc (500 mL) and washed with water (200 mL). The aqueous mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried (MgSO), filtered and concentrated to yield the aniline intermediate. Step 5. The dark residue from Step 4 was dissolved in 2: 1 acetone / water (255 mL) and cooled to 0 ° C. Solid NaHCO3 was added to this stirred mixture. (5.4 g) followed by benzyl chloroformate (7.7 mL). The reaction mixture was stirred at 0 ° C for 10 minutes, then at room temperature for 24 hours. hours. The reaction mixture was quenched with 10% aqueous NaHS04 (200 mL) and then emptied into EtOAc (300 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 250 mL). The combined organic layers were dried (MgSO 4), filtered and concentrated. The residue was purified by HPLC mediantge using 20% EtOAc in hexane to yield 6.03 g of the benzyl carbamate as a yellow solid. P.f. 72-74 ° C; Analysis calculated for C? 9H2? FN202S: C, 63.31; H, 5.87; N, 7.77; S, 8.89. Found: C, 63.31; H, 5.97; N, 7.69; S, 8.79. Step 6. To a stirred solution of the carbamate from Step 5 (3.0 g) in dry THF (33 mL) under N2 cooled to -78 ° C, a 1.6 M solution of nBuLi in hexane was added dropwise via syringe (5.4 mL). The reaction mixture was stirred at -78 ° C for minutes, then glycidyl butyrate was added (1.2 mL). The reaction mixture was stirred at -78 ° C for 30 minutes, then at room temperature overnight during which a precipitate formed. The reaction mixture was quenched with saturated aqueous NH C1 (33 mL) and was emptied into EtOAc (100 mL). The phases separated. The organic phase was washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography using EtOAc as the eluent to yield 2.5 g of a hydroxymethyl oxazolidinone. P.f. 100-102 ° C. Analysis calculated for C? 5H19FN203S: C, 55.20; H, 5.87; N, 8.58; S, 9.82. Found: C, 55.09; H, 5.91; N, 8.36; S, 9.57. Step 7. To a stirred solution of the alcohol prepared in Step 6 (1.7 g) in CH2C12 (35 mL) cooled to 0 ° C, triethylamine (1.1 mL) was added followed by methanesulfonyl chloruane (0.5 mL). The reaction mixture was stirred at 0 ° C for 10 minutes, then at room temperature for 1 hour. The reaction mixture was treated with water (35 mL). The phases were separated and the aqueous phase was extracted with CH2C12 (35 mL). The combined organic phases were dried (MgSO 4), filtered and concentrated. The residue was purified by flash chromatography using 80% EtOAc in hexane as the eluent to yield 2.1 g of the mesylate. P.f. 132-142 ° C. Analysis calculated for C 16 H 2iF 2 → 5 S 2: C, 47.51; H, 5.23; N, 6.93; S, 15.85. Found: C, 47.18; H, 5.28; N, 6.84; S, 15.60. Step 8. Ammonia gas was bubbled into a stirred suspension of the mesylate prepared in Step 7 (941.7 mg) in 1: 1 THF / CH 3 OH (40 mL) until saturated (approx 5 min). The reaction mixture was heated in a sealed tube at 100 ° C for 72 hours. The cooled reaction mixture was concentrated to give the crude amine, which was immediately suspended in CH 2 Cl 2 (35 mL) and cooled to 0 ° C. to this stirred suspension was added triethylamine (0.97 mL, 6.9 mmol) followed by di-tert-butyl dicarbonate (759.5 mg, 3.5 mmol). The reaction mixture became homogeneous and was stirred at RT for 18 hours. The reaction mixture was poured into CH 2 Cl 2 (75 mL) and washed with H 2 O (1 x 50 mL). The organic phase was dried (MgSO4), filtered and concentrated. The resulting residue was purified on a .Biotage 40 S column using 30-35% ethyl acetate in CH 3 OH as the eluent to yield 867.4 mg of the protected amine. P.f. 74-75 ° C. Analysis calculated for C, 56.45; H, 6.63; N, 9.88. Found: C, 56.95; H, 6.85; N, 9.55. Step9. To a stirred suspension of the protected amine prepared in Step 8 (205.2 mg) in 1: 1 CH3OH / H20 (6 mL) cooled to 0 ° C was added sodium metaperiodate (113.5 mg). The resulting suspension was stirred at RT for 18 hours. The reaction mixture was filtered and the solid was washed with CH2C12 (2 x 20 L). The filtrate was extracted with H20 (1 x 10 mL). The phases separated. The aqueous phase was extracted with CH2Cl2 (1 x 25 mL). The combined organic phases were dried (MgSO 4), filtered and concentrated. The white solid residue was purified on a Biotage 12M column using 5% CH30H in CH2C12 as the eluent to yield 187.3 mg of the sulfoxide. P.f. 78-81 ° C. Step 10. Dry HCl gas was passed over the surface of a stirred solution of the sulfoxide prepared therein and Step 9 (179.3 mg) in CH3OH (2 mL) cooled to 0 ° C for 1 minute. The reaction mixture was stirred at 0 ° C for 10 minutes, then at room temperature for 15 minutes, then concentrated. The resulting yellow residue is suspended in THF (5 mL) and CH2C12 (5 mL) and cooled to 0 ° C. To this stirred suspension was added triethylamine (0.46 mL) followed by ethyl dithioacetate (0.18 mL). The dark reaction mixture was stirred at RT overnight and then concentrated. The dark residue was diluted with CH2Cl2 (30 mL) and washed with H2O (2 x 15 mL). The organic phases dried (MgSO4), filtered and concentrated. The dark residue was purified on a Biotage 12 M column using 5% CH3OH in CH2Cl2 as the eluent for yield 71.5 mg of the title compound as a tan solid. P.f. 85-89 ° C. Following the general procedure outlined in Step 10 of Example 482, but substituting the dithioester listed below, the compounds of Examples 483 to 495 of Table K can be obtained.
TABLE K Example 496. Thiazepine S-oxide (5S) -N- [[3- [3,5-Di-fluoro-4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) -phenyl] -2-oxo -5-oxazole idinyl] - methyl] -thioacetamide The title compound can be prepared by the procedure of Example 482, by substituting a suitable amount of 2,6,6-di f luoro-4-nitrobenzene sulfonate (trifluoromethane) for 3,4-difluoronitrobenzene in Step 1. Al use the amine prepared in the Example 496, but substituting the dithioester listed below for ethyl dithioacetate in the final step, the compounds of Examples 497 to 499 of Table L are obtained.
TABLE L Example 500. Tiazepin S-oxide (5S) -N- [[3- [4 - (Tetrahydro-l, 4-thiazepin-4 (5H) -yl) -phenyl] -2-oxo-5-oxazolidinyl] - methyl] - thioacetamide The title compound can be prepared by the procedure of Example 482, by replacing a suitable amount of 4-flucronitrobenzene with 3,4-difluoronitrobenzene in Step 1. By using the amine prepared in the Example 500, but substituting the dithioester listed below for ethyl dithioacetate in the final step, the compounds of Examples 501 to 503 of Table M are obtained TABLE Example 504. Tiazepine S, S-dioxide (5S) -N- [[3- [3- Fluoro-4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) -phenyl] -2-oxo- 5-oxazolidinyl] -methyl] -thioacetamide Step 1. To a stirred solution of the thiazepine prepared in Step 8 of Example 482 (243.7 mg) in 25% H20 / acetone (8 mL) was added 4-methylmorpholine N-oxide (201.5 mg) followed by one and osmium tetroxide solution in 2-methyl-2-propanol (2.5% by weight, 30 μL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was treated with saturated sodium bisulfate (8 mL), then was emptied into CH2C12 (50 mL). The phases separated. The aqueous phase was extracted with CH2C12 (2 x 25 mL). The combined organic phases were washed with brine (1 x 25 mL), dried (MgSO 4), filtered and concentrated. The residue was purified on a Biotage 40 S column using 1% CH3OH in CH2C12 as the eluent to yield 216.1 mg (0.47 mmol, 83%) of the thiazepine S, S-dioxide as a white solid. P.f. 144-146 ° C. Step 2. Dry HCl gas was passed over the surface of a stirred solution of thiazepin S, S- dioxide prepared in Step 1 (108.2 mg) in CH3OH (3 mL) at 0 ° C for 1 minute. The reaction mixture was stirred at * 0 ° C for 10 minutes and then at room temperature for 15 minutes. The reaction was concentrated and the yellow residue was suspended in CH2Cl2 (2 mL) and THF (2 mL). This stirred suspension was cooled to 0 ° C and triethylamine (0.27 mL), followed by a solution of ethyl dithioacetate (0.11 mL) in THF (0.5 mL) with 0.25 mL of wash. The yellow-gray solution was stirred at 0 ° C for 10 minutes then at room temperature for 18 hours. The reaction mixture was poured into CH 2 Cl 2 (20 L) and washed with R Q (2 x 10 mL). The organic phase was dried (MgSO 4), filtered and concentrated. The residue was purified on a 12M Biotage column using 2% CH3OH in CH2C12 as the eluent to yield 77.3 mg of the title compound as a white solid. P.f. 88-90 ° C. Following the general procedure outlined in Step 2 of Example 504, but substituting the dithioester listed below for ethyl dithioacetate, the compounds of Examples 505 to 507 of Table N are obtained.
TABLE N Example 508. Tiazepin S, S-dioxide (5S) -N- [[3- [3, 5-Difluoro-4- (tetrahydro-1, -thiazepin-4 (SH) -yl) -fenii] -2-oxo -5-oxazolidinyl] -methyl] -thioacetamide 24 The title compound can be prepared by the procedures of Examples 504 and 482, by substituting a suitable amount of 2,6-difluoro-4-nitrobenzene sulfonate (trifluoromethane) for 3,4-difluorcnitrobenzene in Step 1 of Example 482. By using amine prepared in Example 508, but substituting the dithioester listed below for ethyl dithioacetate in the final step, the compounds of Examples 509 to 511 of Table O are obtained.
TABLE O Example 512. Tiazepin S, S (5S) -N- [[3- [4- (Tetrahydro-1,4-thiazepin-4 (SH) -yl) -pheny]] -2-oxo-5-S-dioxide oxazolidinyl] -methi] - thioacetamide The title compound can be prepared by the procedure of Examples 504 and 482, by replacing an appropriate amount of 4- fluoronitrobenzene by 3, 4-difluoronitrobenzene in Step 1 of Example 482. By using the amine-prepared in Example 512, but substituting the dithioester listed below for ethyl dithioacetate in the final step, the compounds of Examples 513 to 515 are obtained. of Table P.
TABLE P EXAMPLE 516. (5S) -N- [[3- [3-Fluoro-4 - (tetrahydro-1,4, < thiazepin-4 (5H) -yl) -phenyl] -2-oxo-5-oxazole idinyl] -methyl] -thioacetamide.
This compound was prepared according to the procedure of Step 8 in Example 482, but substituting a suitable amount of ethyl dithioacetate for di-tert-butyl dicarbonatc; p.f. 129-131 ° C. When using the amine prepared in Step 8 of Example 482, but substituting a suitable amount of the dithioester listed below with di-tert-butyl dicarbonate, the compounds of Examples 517 to 529 of Table Q are obtained.
TABLE Q EXAMPLE 530. (5S) -N- [[3- [3, 5-Di fluoro-4 - (tet rahydroyl, 4-thiazepin-4 (5H) yl) -phenyl] -2-oxo-5-oxazolidinyl ] -methyl] -thioacetamide This compound can be prepared according to the procedures of Example 482 and Example 516, but substituting a suitable amount of 2,6,6-di-fluoro-4-nitrophenyl sulfonate trifluoromethane by 3,4-difluoronitrobenzene in Step 1 of Example 482. Utilizing the amine prepared in Example 530, but substituting a suitable amount of the dithi-esters listed below for di-tert-butyl dicarbonate, the compounds of Examples 531 to 533 of Table R.
TABLE R EXAMPLE 534. (5S) -N- [[3- [4 - (Tetrahydro-1,4-tiazepin-4 (5H) -yl) -phenyl] -2-oxo-5-oxazolidiyl] -methyl] - toioacetamide; p.f. 129-131 ° C This compound can be prepared according to the procedures of Examples 482 and 516, but substituting a suitable amount of 4-fluoronitrobenzene for 3,4-di-fluoronobenzene in Step 1 of Example 482. By using the amine prepared in the Example 534, but by substituting a suitable amount of the dithioester listed below for di-tert-butyl dicarbonate, the compounds of Examples 535 to 537 of Table S can be prepared.
BOARDS EXAMPLE 538. Tiazepin S-oxide (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-1,4-thiazepin-4 (5H) yl) -phenyl] -2-oxo-5- oxazolidinyl] -methyl] - thiourea This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 482 for the amine 33. By the reaction of the isothiocyanate and prepared in Example 538 with the amines and alcohols listed in Table T, the compounds of Examples 539 to 544 can be prepared.
TABLE : 53 EXAMPLE 545. Tiazepin S-oxide (5S) -N- [[3- [3, 5-difluoro-4- (tetrahydro-1,4-thiazepin-4 (5H) yl) phenyl] -2-oxo-5 -oxazolidinyl] - methyl] -thiourea This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 496 for the amine 33. By the reaction of the isothiocyanate prepared in Example 545 with the amines and alcohols listed in Table U, they can prepare the compounds of Examples 546 to 551.
TABLE U EXAMPLE 552. Tiazepin S-oxide (5S) -N- [[3- [4 • (Tetrahydro-l, 4-thiazepin-4 (5H) -iI) -phenyl] -2-oxo-5-oxazolidinyl] - methyl] - thiourea This compound can be prepared by the procedure described in Example 33, but replacing the amine prepared in Example 500 with the amine 33. By the reaction of the isothiocyanate prepared in Example 552 with the amines and alcohols listed in Table V, the compounds of Examples 553 to 558 can be prepared.
TABLE V EXAMPLE 559. Tiazepin S, S (5S) -N- [[3- [3- Fluoro-4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) -sioxide. phenyl] -2-oxo-5-oxazolidinyl] -methyl] -thiourea This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 504 for the amine 33. And by the reaction of the isothiocyanate prepared in Example 559 with the amines and alcohols listed in the Table, they can prepare the compounds of Examples 560 to 565.
TABLE W EXAMPLE 566. Thiazepin S, S-dioxide DE (5S) -N- [[3- [3, 5-Difluoro-4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) -phenyl] -2 -oxo-5-oxa zol idinyl] - methyl] -thiourea This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 5 for the amine 33. By the reaction of the isothiocyanate prepared in Example 566 with the amines and alcohols listed in Table X, the compounds of Examples 561 to 572 can be prepared.
TABLE X 2 6: EXAMPLE 573. Tiazepin S, S (5S) S-N- [[3- [4 (Tetrahydro-l, 4-thiazepin-4 (5H) -yl) -phenyl] -2-oxo-5-oxazolidinyl] -meti 1] - thiourea This compound can be prepared by the procedure described in Example 33, but replacing the amine prepared in Example 512 with the amine 33. By the reaction of the isothiocyanate prepared in Example 573 with the amines and alcohols listed in Table Y, the compounds of Examples 574 to 579 can be prepared.
TABLE AND EXAMPLE 580. (53) -N- [3 - [3-Fluoro-4 - (t et rahi dro-1, -thiazepin-4 (5H) yl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl ] -thiourea This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Step 8 of Example 482 for amine 33.
By the reaction of the isothiocyanate prepared in Example 580 with the amines and alcohols listed in Table Z, the compounds of Examples 581 to 586 can be prepared.
TABLE Z Example Compound Isothiocyanate Amine or Alcohol No. 581 (5S) -N- [[3- [3-Fluoro-4- CH3NH2 (tetrahydro-1,4-thiazepin-4 (5H) -yl) -phenyl] -2-oxo-5- oxa zol idinyl] -me il] -N '- methylthiourea 582 (5S) -N- [[3- [3-Fluoro-4- Same as (CH3) 2NH (tetrahydro-1,4-thiazepin-4 (5H) -yl) -phenyl] -2-oxo- 5- oxazolidinyl] -methyl] -N1, '-dimethylthiourea 583 (5S) -N- [[3- [3-Fluoro-4- As the azetidine (tetrahydro-1,4-thiazepin-anterior (5H) -il) ) -phenyl] -2-OXO-5- oxazolidinyl] -methyl] -1- azetidinecarbothioamide 584 (5S) -N- [[3- [3-Fluoro-4- Like CH3OH (tetrahydro-1,4-thiazepine - previous 4 (5H) -yl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -O-methylthiocarbamate EXAMPLE 587. (5S) -N- [[3- [3,5-Di-fluoro-4 - (terthydro-1,4-thiazepin-4 (5H) -yl) phenyl] -2-oxo-5- oxazolidinyl] -methyl] -thiourea This compound can be prepared by the procedure described in Example 33, but replacing the amine prepared in Example 530 with amine 33.
By the reaction of the isothiocyanate prepared in Example 587 with the amines and alcohols listed in Table AA, the compounds of Examples 588 to 593 can be prepared.
TABLE AA EXAMPLE 594. (5S) -N- [[3 - [4 - (Tetrahydro-1, 4 -1 ia zepi n-4 (5H) -yl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl ] thiourea This compound can be prepared by the procedure described in Example 33, but replacing the amine prepared in Example 534 with the amine 33.
By the reaction of the isothiocyanate prepared in Example 594 with the amines and alcohols listed in Table BB, the compounds of Examples 595 to 600 can be prepared.
TABLE BB

Claims (11)

  1. CLAIMS A compound of the formula where Z2 is -0? S- -0-, -N (RiU) -OS-, -S-; is 0, 1, 2, 3; R, 23 and R, 24 are the same or different and can be H or F; and R1 is H, NH2, NHalkyl of C? -C4; N (alkyl of C? -C4) 2; ^; C? -C4 alkyl; O-alkyl C1-C4; C 4 -C 4 -alkyl; C? -C4 alkyl substituted with 1-3?, 1-2? Cl, CN, or -COOalkyl of C? -C, or C3-C6 cycloalkyl, wherein in each case the alkyl group may be straight or branched; and R 107 is a) R102O-C (R110) (R111) -C (O) -, b) R1030-C (0) -, c) Ri08_c (0) _ f d) R109-SO2-, e) NC-CH2-, f) FCHCH2 -, or g) R1 50R1 1 N S O2 -; wherein R 102 is H, CH phenyl-CH 2 -, or CH 3 C (0); each R 110 and RJ are selected from H CH, R 1103 is C 1 -C 3 alkyl, or phenyl; R 108 is H, C? -C alkyl, aryl (CH2) 0-5, CNCH2-, C1CH2-, C12HC-, FH2C-, F2HC-, or C3-C6 cycloalkyl; R15C and R151 are the same or different and are selected from H, C? -C4 alkyl, or R150 and R151 taken together with the nitrogen to which each is attached and one forms a monocyclic heterocyclic ring having from 3 to 6 carbon atoms.
  2. 2. The compound according to claim 1, wherein Z2 is -02S-.
  3. 3. The compound according to claim 2, which is thiazepine S, S-dioxide (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) - phenyl] -2-oxo-5-oxazolidinyl] -methyl] -thioacetamide.
  4. 4. The compound according to claim 1, wherein Z2 is -OS-.
  5. A compound according to claim 4 which is thiomorpholin S-oxide of (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2 -oxo-5 -propant-ioamide; S-oxide oxides of (S) -N- [[3- [3-Fluoro- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] methyl] -2-methylpropantioamide; Sthiomorpholin S-ox.idc of (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -cyclopropancarbodio-amide; thiomorpholin S-oxide (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxo-5-oxazolidinyl] methyl] -O-methylthiocarbamate; thiomorpholin S-oxide of (S) -N- [[3- [3-F1-uoro-4 - (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxo-5-oxazolidinyl] methyl] -O-et ii thiocarbamate; thiomorpholin S-oxide of (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazoiidinyl] methyl-0-isopropylthiocarbamate; thiazepin S-oxide (5S) -N- [[3- [3-Fluoro-4- (tetrahydro-1,4-thiazepin-4 (5H) -yl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -thioacetamide; thiomorpholin S-oxide of (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -N N '-dimethylthiourea; or thiomorpholin S-oxide of (S) -N- [[3- [3-Fluoro-4- (4-thiomorpholinyl) -phenyl] -2 -oxo-5-oxa zol idinyl] methyl] -1-a zetidincarbothioamide.
  6. 6. The compound according to claim 1 wherein Z2 is 0.
  7. 7. The compound according to claim 6 which is (S) -N- [3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -2-oxo-5 -oxazolidinyl] methyl] -0-ethyl thiocarbamate; (S) -N- [[3- [3-Fluoro-4- (4-morpholin-1) -phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-met i Ipropant-ioamide; (S) -M- [[3- [3-Fluoro-4- (4-morpholinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -cyclopropancarbothioamide
  8. The compound according to claim 1 wherein Z is -S-.
  9. 9. The compound according to claim 8 which is (5S) -N- [[3- [4 - (tetrahydro-1,4-thiazepin-4 (5H) -yl) -phenyl] -2-oxo-5-oxazolidinyl] - methyl] -thioacetamide.
  10. The compound according to claim 1 wherein Z is -N (R 107-
  11. 11. The compound according to claim 10 which is (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl-2-oxazolidinyl] -2-oxo-5-oxazolidinyl ] -methyl] -propantioamide; (S) -N- [[3- [3-Fluoro-4- [4- (hydroxyacetyl) -1-piperazinyl] -fenii] -2-oxo-5-oxazolidinyl] -methyl] -2-methylpropantioamide; (S) -N- [[3- [3-Fluo o-4- [4- (hydroxyacetyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -cyclopropancarbothioamide; (S) -N - [[3-Fluoro-4- (4-acetyl-l-pi.perazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -thioacetamide; (S) -N - [[3- [3- Fluoro-4- (4-acetyl-1-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -propantiomide; (S) -N - [[3- [3- Fluoro-4- (4-acetyl-l-piperazinyl) -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -cyclopropancarbothioamide; (S) -N- [[3- [3-Fluoro-4- [4- (methanesulfonyl) -1-piperazinyl] -phenyl] -2-oxo-5-oxazolidinyl] -methyl] -2-met-ilpropant-ioamide; (S) -N- [[3- [3- Fluoro-4- [4- (methanesulfonyl) -1-piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] -methyl] -cyclopropancarbothioamide; (S) -N - [[3- [3-Fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazole idinyl] -methyl] thioacetamide; (S) -N- [[3- [3-Fluoro-4- (4-formyl-1-piperazinyl) phenyl] -2-oxo-5-oxazolidinyl] -methyl] -propantioamide; (S) -N- [[3- [3-Fluoro-4- (4-formyl-l-piperazinylphenyl) -2-oxo-5-oxazolidinyl] -methyl] -2-methylpropantioamide; (S) -N- [[3- [3- Fluoro-4- (4-formyl-1-piperazinyl) -phenyl] -2 -oxo-5-oxazolidinyl] methyl] -cyclopropancarbothioamide; or (S) -N- [[3-F1uoro-4- (4-acetyl-l-piperazinyl) -phenyl) -2-oxo-5-oxazolidinyl] methyl] thioacetamide.
MXPA/A/2001/005287A 2001-05-25 Oxazolidinone antibacterial agents having a thiocarbonyl functionality MXPA01005287A (en)

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