NZ511963A - Oxazolidinone antibacterial agents having a thiocarbonyl functionality - Google Patents

Oxazolidinone antibacterial agents having a thiocarbonyl functionality

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Publication number
NZ511963A
NZ511963A NZ511963A NZ51196398A NZ511963A NZ 511963 A NZ511963 A NZ 511963A NZ 511963 A NZ511963 A NZ 511963A NZ 51196398 A NZ51196398 A NZ 51196398A NZ 511963 A NZ511963 A NZ 511963A
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New Zealand
Prior art keywords
oxo
phenyl
methyl
oxazolidinyl
fluoro
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NZ511963A
Inventor
Salvatore Charles Perricone
Eldon George Nidy
Toni-Jo Poel
Jackson B Hester
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Upjohn Co
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Application filed by Upjohn Co filed Critical Upjohn Co
Priority to NZ511963A priority Critical patent/NZ511963A/en
Priority claimed from PCT/US1998/025308 external-priority patent/WO2000032599A1/en
Publication of NZ511963A publication Critical patent/NZ511963A/en

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Abstract

Described is a compound of the formula (I), where: Z2 is -O2S-, -O-, -N(R107)-, -OS-, or-S-; w is 0, 1, 2, or 3; R23 and R24 are the same or different and can be H or F; and R1 is H; NH2; NHalkyl; N(alkyl)2; a group of formula (II); alkyl; Oalkyl; Salkyl; alkyl substituted with 1-3 F, 1-2 Cl, CN, or -COOalkyl, or cycloalkyl, wherein in each occurrence the alkyl group may be straight or branched; and R107 is R102O-C(R110)(R111)-C(O)-, R103O-C(O)-, R108-C(O)-, R109-SO2-, NC-CH2-, FCHCH2-, or R150R151NSO2-; wherein R102 is H, CH3-, phenyl-CH2-, or CH3C(O); each of R110 and R111 is selected from H or CH3; R103 is alkyl or phenyl; R108 is H, alkyl, aryl(CH2)0-5, CNCH2-, ClCH2-, Cl2HC-, FH2C-, F2HC- , or cycloalkyl; R150 and R151 are the same or different and are selected from H, alkyl, or R150 and R151 taken together with the nitrogen to which each is attached forms a monocyclic heterocyclic ring having from 3 to 6 carbon atoms; and R109 is alkyl, -CH2Cl, -CH2CH=CH2, aryl or -CH2CN.

Description

New Zealand Paient Spedficaiion for Paient Number 511 963 6118.P2 CP 51 1 OXAZOLIDINONE ANTIBACTERIAL AGENTS HAVING A THIOCARBONYL FUNCTIONALITY BACKGROUND OF THE INVENTION The present invention relates to new and useful oxazolidinone compounds and their preparations, and more particularly to oxazolidinone compounds in which the carbonyl functionality of -NH-C(0)-R is converted to a thiocarbonyl functionality, such as a thiourea -NH-C(S)-NH2, an alkyl thiourea -NH-C(S)-NH-(CM alkyl), 10 thioamide -NH-C(S)-(CW alkyl) or -NH-C(S)-H.
Replacement of the oxygen atom with a sulfur atom has unexpectedly improved the antimicrobial properties of the compounds. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including Gram-positive aerobic bacteria such as multiply-resistant 15 staphylococci and streptococci, Gram-negative organisms such as H. influenzae and M. catarrahlis as well as anaerobic organisms such as bacteroides and Clostridia species, and acid-fast organisms such as Mycobacterium tuberculosis and Mycobacterium avium. The compounds are particularly useful because they are effective against the latter organisms which are known to be responsible for 20 infection in persons with AIDS.
SUMMARY OF THE INVENTION The present invention provides a compound of the formula wherein Z2 is -02S-, -O-, -N(R107)-, -OS-, or -S-; w is 0, 1, 2, or 3; R23 and R24 are the same or different and can be H or F; and R1 is H, NH2, NHalkylCrC4; N(alkylC1-C4)2; fe6; ■fWfc. alkylCrC4; OalkylC1-C4; SalkylC1-C4; alkylCrC4 substituted with 1-3F, 1-2C1, CN, or -COOalkylC1-C4, or cycloalkylC3-C6, wherein in each occurence of the alkyl group may be straight or branched; and (followed by page la) -la- (followed by page 2) a) R102O-C(R110)(Rm)-C(O)-, b) R103O-C(O)-, c) R108-C(O)-, d) R109-SO2-, e) NC-CHg-, f) FCHCH2-, or g) R150R151NSO2, wherein R102 is H, CH3-, phenyl-CH2-, or CH3C(0); each of R110 and Rlu is selected from H or CH3; R103 is alkylCj-Cg or phenyl; R108 is H, alkylCj-C^ aryl(CH2)0.5, CNCHjj-, C1CH2-, C12HC-, FH2C-, F2HC-, or cycloalkyIC3-C6; R150 and R151 are the same or different and are selected from H, alkylCj-C4, or R150 and R151 taken together with the nitrogen to which each is attached forms a monocyclic heterocyclic ring having from 3 to 6 carbon atoms; and wherein R109 is alkyl C,-C4; -CH2C1, -CH2CH = CH2, aiyl or-CH2CN.
Described is a compound of the Formula I A S W C—R / N \ H I or pharmaceutical acceptable salts thereof wherein: G is n O 731:5 l.DOC a) b) c) d) e) f) g) h) i) j) A is a) b) c) d) H, NH2, NH-C,.„ alkyl, CM alkyl, -OCM alkyl, -S CM alkyl, CM alkyl substituted with 1-3 F, 1-2 CI, CN or -COOC14 alkyl, C3.6 cycloalkyl, N(Cm alkyl)2 or N(CH2)2.5; a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of S, N, and 0, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom, wherein the 5-membered heteroaromatic moiety can additionally have nzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R48, e) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R55, f) a p-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three R^, g) wherein R, is a) H, b) F, c) CI, d) Br, e) C,.3 alkyl, f) N02, or g) R, and R., taken together are -0-(CH2)h-0-; R3 is a) -S(=0), R.,, b) -S(=0),-N=S(0)jR5R6, c) -SC(=0)R7, d) -C(=0)R8, e) -C(aO)Rs, f) -C(=O)NR10R,„ g) -C(=NRi2)Ra> h) -C(R,)(R11)-OR13, i) -C(R,)(R„)-ORlj1 j) -C(Rg)(R1,)-0C(=0)R13, k) -CfRjMRnJ-OasOjRu, 1) -NR10Rn, m) -N(R10)-C(=O)R7, n) -N(R10)-S(=O)iR7> o) -C(ORM)(ORl5)R8, p) -C(R8)(R16)-NR10RM, or q) C].8 alkyl substituted with one or more =0 other than at alpha position, -S(=0)jR17, -NRl0Rn, C2.s alkenyl, or C.,.5 alkynyl; R4 is a) C,.4 alkyl optionally substituted with one or more halos, OH, CN, NR10Rn, or -C02R13, b) alkenyl, c) -NR16R18, d) -N„ e) -NHC(=0)R„ f) -NRJ0C(=O)R7, g) -N(Rlt);j, h) -NR16RI9, or i) -NR19Rjjo, R5 and Rg at each occurrence a) C,.2 alkyl, or b) Rs and R6 taken together are -(CH2)k-; R, is C] 4 alkyl optionally substituted with one or more halos; Rg is a) H, or b) C,.,, alkyl optionally substituted with one or more halos, or C3.8 cycloalkyl; Rg is C,^ alkyl substituted with one or more a) -S(=0)R17, b) -ORI3, c) -0C(=0)R13, d) -NRI0RM, or e) C,.5 alkenyl optionally substituted with CHO; RI0 and Rn at each occurrence are the same or different and are a) H, b) CM alkyl, or c) C.,.3 cycloalkyl; R|2 is a) -NR10Rn, b) -OR,0; or c) -NHC(=O)R10; Ri3 is a) H, or b) 0^4 alkyl; R14 and R15 at each occurrence are the same or different and are a) CM alkyl, or b) Rm and RI5 taken together are -(CH)r; rj6 is R)7 is R,a is a) H, b) ClJ( alkyl, or c) C3.8 cycloalkyl; a) C^ alkyl, or b) C3.„ cycloalkyl; a) H, b) C,.4 alkyl, c) C2.4 alkenyl, d) C:1.4 cycloalkyl, e) -ORj3 or f) -NRojR^; RI9 is a) CI, b) Br, or c) I; R20 is a physiologically acceptable cation; R2, and R,, at each occurrence are the same or different and are a) H, b) Ci.4 alkyl, or c) -NR,,R._,.j taken together are -(CH2)m-; wherein and R_>4 at each occurrence are the same or different and are a) H, b) F, c) CI, d) C,.2 alkyl, e) CN f) OH, g) alkoxy, h) nitro, or i) amino; Q is a) b) c) W—v\^-x d) N—V^"x I M e) 0 ">Or g) ^ ../N i M h) w. <s N" j) k) or 1) ^(CH2) e 71..- 38 ^(CH2)p m) n) oJ P) q) r) a diazinyl group optionally substituted with X and Y, a triazinyl group optionally substituted with X and Y, a quinolinyl group optionally substituted with X and Y, a quinoxalinyl group optionally substituted with X and Y, a naphthyridinyl group optionally substituted with X and Y, a2 CH2)n z1 n A" s) h,f"x (ch2)„ t) u) i 107 \ N v) Y y N- x w) x) N N- y) i^N z) I /^N I Q and RJ4 taken together are r106 \.
Nf wherein Z1 is a) -CH2-, 35 b) -CH(R104)-CH2-, c) -C(O)-, or d) -CH.,CH2CH,-; wherein Z2 is a) -02S-, b) -0-, c) -N(R107)-, d) -OS-, or e) -S-; wherein Z3 is a) -o2s-, b) -0-, c) -OS-, or d) -S-; wherein A1 is a) H-, or b) CH3; wherein A2 is a) h-, b) ho-, c) ch3-, d) ch3o-, e) R102O-CH2-C(O)-NH- 0 Ri03O-C(O)-NH-, g) (CpCJalkyl-O-CfO)-, h) ho-ch2-, i) ch3o-nh-, j) (C,-C3)alkyl-02C- k) CH3-C(0)-, 1) CH.,-C(0)-CH;i-, xt- o o \ / v° A1 and A" taken together are: a) Biiz o °r b) o= , or R 114 C) ^N: wherein R102 is a) H-, b) CH3-, c) phenyl-CH2-, or d) CH3C(0)-; wherein R103 is a) (Cj-C^alkyl-, or b) phenyl-; wherein R104 is a) H-, or b) HO-; wherein R105 is a) H-, 30 b) (C,-C:,)alkyl-, c) CH2 = CH-CH2-( or d) CH3-0-(CH2)2-; wherein R10G is a) CH;)-C(0)-, 35 b) H-C(O)-, c) CLCH-C(O)-, d) HOCH.j-C(O)-, e) CH.,SO,-, j115 f) C(O)- g) F.,CHC(0)-, h) N N—C(O)- \=J i) H3C-C(0)-0-CH,-C(0)-, 10 j) H-C(0)-0-CHa-C(0)-, k) yrc(o)- 1) HC=C-CH,0-CHo-C(0)-, or m) phenyl-CH2-0-CH.2-C(0)-; wherein R'07 is a) RI0ZO-C(R' 10)(R'11 )-C(0)-, b) RI03O-C(O)-, c) R108-C(O)-, 20 o « QV u H e) h) f) H3C-C(0MCH.,)2-C(0)-, g) R109-SO2-, i) H0-CH,-C(0)-, j) R1I6-(CH2V, 35 k) Rl,n-C(0)-0-CH,-C(0)-. 1) (CH3),N-CH,-C(0)-NH-, m) NC-CH.-, n) F2-CH-CHa-, or o) R150R,5lNSOa wherein R108 is a) H-, b) (CpC^alkyl, c) aryl -(CH,)P, d) C1H2C-, e) ci2hc-, 0 fh2c-, g) F,HC-, h) (C3-C6)cycloalkyl, or i) CNCHjj-. wherein R10s is a) alkylC,-C4, b) -CHjCl c) -CH2CH=CH2, d) aryl, or e) -CH2CN; wherein R110 and R111 are indepenc a) h-, b) CH:,-; or wherein R112 is a) h-, b) CH30-CH.,0-CH,-, o] c) HOCH2-; wherein R113 is a) CH,-, b) hoch2-, c) (CH^LN-phenyl, or d) (CH^N-CH,-; wherein R114 is a) HO-, b) CH..O-, c) H,N-, d) CH;!0-C(0)-0-. e) CH3-C(0)-0-CH2-C(0)-0-, f) phenyl-CH2-0-CH.,-C(0)-0-, g) H0-(CH,)2-0-, h) CH30-CH,-0-(CH,)2-0-, or i) CH30-CH2-0-;wherein R113 is a) CH3-, b) HOCH.,-, c) (CH;i)..N-phenyl, or d) (CHjJaN-CHj-; wherein R115 is a) H-, or b) C1-; wherein R116 is a) HO-15 b) CH30-, or c) F; wherein R150 and R151 are each H or alkyl C,-C4 or R150 and R151 taken together with the nitrogen atom to which each is attached form a monocyclic heterocyclic ring having from 3 to 6 carbon atoms; B is an unsaturated 4-atom linker having one nitrogen and three carbons; M is a) H, b) cj.j, alkyl, c) C3.8 cycloalkyl, d) -(CH2)roOR13, or e) -(CHA-NRjjRa; Z is a) O, b) S, or c) NM; Wis a) CH, b) N, or c) S or O when Z is NM; Y is a) H, X is b) F, c) CI, d) Br, e) Cn alkyl, or f) N02; a) H, b) -CN, c) OR27, d) halo, e) NO,, f) tetrazoyl, g) -SH, h) -S^O)^, i) -S(=0).2-N=S(0)jR5R6, j) -SC(=0)R7, k) -Ct-OJRjB, 1) -C^ONR,^, m) -C(=NR29)R25, n) -C(R25)(RM)-OR13, 0) -C(R25)(RM)-0C(=0)R13, p) -C(R28)(OR13)-(CH._,)h-NR27R2a, q) -NR_,7Ras, r) -NCR^C^OR,, s) -N(R27)-S(=0)iR7, t) -C(ORl4)(ORI5)R28, u) -C(R25)(R16)-NR27R,6, or v) C,.8 alkyl substituted with one or more halos, OH, =0 other than at alpha position, -S(=0)iR17, -NR.,7R,8, C.,.5 alkenyl, C.^ alkynyl, or C3.g cycloalkyl; R4, R5, Rfi, R,, R,.„ Ru, R15i R16, and R17 are the same as defined above; Rn5 is a) H, b) C,.8 alkyl optionally substituted with one or more halos, C3.g cycloalkyl, C[.4 alkyl substituted with one or more of -S(=0)[Rn, -0Rj.j, or 0C(=0)R1:J, NR21R2Ri or c) C2.5 alkenyl optionally substituted with CHO, or C02Rl3; Rue is a) Rag, or b) NR,7N2S; R27 and RJ3 at each occurrence are the same or different and are a) H, b) Cu alkyl, c) C3.8 cycloalkyl, d) -(CH2)mORIt1, e) -(CH2)h-NR21R22, or f) Rgv and R28 taken together are -(CH2)20(CH2)ii-, -(CH^CHtCOR,)-, or -(CHa^NfCH.^CRr); R29 is a) -NR^R^, b) -ORa7> or c) -NHC(=0)R28; wherein R^ is a) H, b) C,.g alkyl optionally substituted with one or more halos, or c) C,.g alkyl optionally substituted with one or more OH, or C,^ alkoxy; wherein E is a) NRq9, b) -S(=0)i, or c) O; R38 is a) H, b) C,.6 alkyl, c) -(CH2)q-aryl, or d) halo; R:)9 is a) H, b) C,.6 alkyl optionally substituted with one or more OH, halo, or -CN, c) -(CH.2)q-aryl, d) -COoR^o, e) -COR4i, f) -C(=0)-(CH.,)(1-C(=0)R4 g) -S(=OVCl.g alkyl, h) -S(=0)2-(CH2)q-aryl, or i) -(C=0)j-Het; R4o is a) H, b) C1G alkyl optionally substituted with one or more OH, halo, or -CN, c) -(CH2)q-aryl, or dJ -(CH2)q-OR42; R41 is a) C1-6 alkyl optionally substituted with one or more OH, halo, or -CN, b) -(CH2)q-aryl, or C) -(CHjiq-OR^; R« is a) H, b) C,.6 alkyl, c) -(CHjj)q-aryl, or d) -C(=0)-C1.6 alkyl; aryl is a) phenyl, b) pyridyl, or c) napthyl; a to c optionally substituted with one or more halo, -CN, OH, SH, Cj.u alkyl, C,_6 alkoxy, or C,.B alkylthio; wherein R4;, is a) H, b) C,.2 alkyl, c) F, or d) OH; R44 is a) H, b) CF3> c) Cj.g 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 5-, 6-, or 7-membered ring of the 35 formula, or (C H ,) 2 'h f) R44 and R45 taken together are -(CH2)k-, when R46 is an electron-withdrawing group; R45 and R46 at each occurrence are the same or different and are a) an electron-withdrawing group, b) H, c) CF3, d) C,.3 alkyl optionally substituted with one halo, e) phenyl, provided at least one of R45 or R46 is an electron-withdrawing group, or f) R45 and R46 taken together are a 5-, 6-, 7-membered ring of the formula U is a) ch2, b) o, c) S, or d) nr47; r47 is a) h, or b) c,.5 alkyl; wherein r48 is a) carboxyl. b) halo, c) -cn, d) mercapto, e) formyl, f) cf.„ g) -no,, c —u o c-c< (C H2)r h) C,.6 alkoxy, i) C,.6 alkoxycarbonyl, j.) C,.6 alkythio, k) C,.6 acyl, 1) -NR49 R50, m) C,.6 alkyl optionally substituted with OH, C15 alkoxy, C,.s acyl, or -NR^gRjQ, n) C2.g alkenylphenyl optionally substituted with one or two R51, o) phenyl optionally substituted with one or two RSI, 10 p) a 5-, or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R51, or q> o (CHa), R49 and Rso at each occurrence are the same or different and are a) H, b) C,.4 alkyl, c) C5.6 cycloalkyl, or d) R49 and Rso taken together with the nitrogen atom is a 5-, 6- membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C,.3 alkyl, or C,.s acyl; R51 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF„ g) -NO.,, h) C|.6 alkoxy, i) C].6 alkoxycarbonyl, j) C,.6 alkythio, k) C,.B acyl, WO 00/32599 PCT/US98/25308 1) C,.6 alkyl optionally substituted with OH, C15 alkoxy, C].3 acyl, or -NR49R50, m) phenyl, n) -C(=0)NR52 R53, o) -NR49R50, p) -N(R52)(-SO,R54), q) -S02-NR5;!R53, or r) -S(=0)SRS4; R52 and RS3 at each occurrence are the same or different and are a) H, b) C,_6 alkyl, or c) phenyl; R54 is a) C,.4 alkyl, or b) phenyl optionally substituted with CM alkyl; wherein R5S is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) cf3, g) -no2, h) Cj.g alkoxy, i) Cj.6 alkoxycarbonyl, j) C^g alkythio k) C,.6 acyl, i) -NR5b R57, m) C,.6 alkyl optionally substituted with OH, C15 alkoxy, C,.s acyl, or -NR56R57, n) C2.„ alkenylphenyl optionally substituted with one or two R58, o) phenyl optionally substituted with one or two R58, p) a 5- or 6-membered (un Saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R58, or q> : R56 and Rs7 at each occurrence are the same or different and are 5 a) H, b) formyl, c) CM alkyl, d) CMacyl, e) phenyl, f) C3.6 cycloalkyl, or g) R56 and R57 taken together with the nitrogen atom is a 5-, 6- membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and 0, and can in turn be optionally substituted with, including on the 15 further nitrogen atom, phenyl, pyrimidyl, C,.3 alkyl, or C,.3 acyl; RMis a) car boxy 1, b) halo, c) -CN, d) mercapto, e) formyl, 0 CF3, g) -no2, h) C,.fi alkoxy, i) C,.6 alkoxycarbonyl, j) Ci.5 alkythio, k) C,.6 acyl, 1) phenyl, m) C,.6 alkyl optionally substituted with OH, azido, C,.., alkoxy, C,.5 acyl, -NR^R^, -SR67) -0-S0.,R6H) or NH-CO-O- n) -C(-0)NR59 Rgo? 35 o) -NR56R57, p) -N(Rm)(-SOoR54), q) -S02-NR59R6U, r) -S^O)^, s) -CHsN-Rg,, or t) -CH(0H)-S03R64; RS4 is the same as defined above; R59 and R,;0 at each occurrence are the same or different and are a) H, b) C,.6 alkyl, c) phenyl, or 10 d) tolyl; Rsi is a) OH, b) benzyloxy, c) -NH-C(=0)-NH2, d) -NH-C(=S)-NH2, or e) -NH-C(=NH)-NR62R63; Rg2 and Rg3 at each occurrence are the same or different and are a) H, or b) CM alkyl optionally substituted with phenyl or pyridyl; Re4 is a) H, or b) a sodium ion; Rs5 and Rkb at each occurrence are the same or different and are a) H, b) formyl, c) CM alkyl, d) CMacyl, e) phenyl, f) C.,_6 cycloalkyl, g) R65 and R66 taken together are a 5-, 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C,.3 alkyl, or C,.;J acyl, h) -P(O)(OR70)(OR71), or 35 i) -SO0-R72; R67 is N —N I C H 3 N -N (C H 3)30 S On: or CN >- ■lI C H ■ C H .
Res is C,.3 alkyl; 15 Rg9 is a) Ci_6 alkoxycarbonyl, or b) carboxyl; Rfo and R^ at each occurrence are the same a) H, or b) C,.3 alkyl; R72 is a) methyl, b) phenyl, or c) tolyl; wherein K is a) O, or b) S; R731 R/4> R7 r„ R76, and Rj, at each occurrence a) H, b) carboxyl, c) halo, d) -CN, e) mercapto, f) formyl, g) CF:1, h) -N02) i) alkoxy, j) Cj.6 alkoxycarbonyl, k) C^g alkythio, 1) C,.6 acyl, m) -NRjS 1^79, n) C16 alkyl optionally substituted with OH, alkoxy, acyl, -NRT8R„, -N(phenyl)(CH2-CH,-OH), -0-CH(CH;,)(0CH.,CH3), or -0-phenyl-[para-NHC(=0)CH:J], o) C2.8 alkenylphenyl optionally substituted with ^51» p) phenyl optionally substituted with R5I, or q) a 5-, or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with RSI; R51 is the same as defined above; R1g and &,9 at each occurrence are the same or different and are a) H, b) C,.4 alkyl, c) phenyl, or d) Ryg and taken together with the nitrogen atom is a 5-, 6- membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, and 0, and can in turn be optionally substituted with, including on the further nitrogen atom, C,.;, alkyl, or C,.3 acyl; wherein T is a) O, b) S, or c) S02; R75, Ryg, and R„ are the same as defined above; Rso is aj H, b) formyl, c) carboxyl, d) C,_g alkoxycarbonyl, e) C,.8 alkyl, f) C2.8 alkenyl, wherein the substituents (e) and (f) can be optionally substituted with OH, halo, C,.6 alkoxy, Ci.6 acyl, Ci_6 alkylthio or C,.6 alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted 5 with carboxyl, halo, -CN, formyl, CF3, -NO,, C,.G alkyl, C,.6 alkoxy, C,.6 acyl, C,.6 alkylthio, or Cj.6 alkoxycarbonyl; h) -NR81Rg2, i) -OR90, j) k) -S02-N(Rg2)(R93), or 1) a radical of the following formulas: RA1 and Rg2 at each occurrence are the same or different and are a) H, b) C3< cycloalkyl, c) phenyl, d) Ci.6 acyl, e) C^g alkyl optionally substituted with OH, C,^ alkoxy which can be substituted with OH, a 5-, or 6-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF3, halo, -N02, CM alkoxy, -NR83RB4, or Vis CO 0 ^—r85 .or Rs6—CH— g) y/ (CH2)( ; a) O, b) CH,, or c) NR87; R83 and R84 at each occurrence are the same or different and are a) H, or 5 b) C,.4 alkyl; RS5 is a) OH, b) CM alkoxy, or c) -NR88 R89; R86 is a) H, or b) C,.7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NH„ -CO,H, or -C(=NH)-NH2; Rr7 is a) H, b) phenyl, or c) alkyl optionally substituted by OH; Rr„ and R89 at each occurrence are the same or different and are a) H, b) Cj.s alkyl c) C3.6 cycloalky, or d) phenyl; Rgo is a) C,.8 alkyl optionally substituted with C,.G alkoxy or C[.6 hydroxy, CM cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -NO;,, CF;I, halo, -CN, OH, C,.5 30 alkyl, C,.5 alkoxy, or C,^ acyl; b) /—\ V N—(CH2)t— c) d) phenyl, or pyridyl; R91 is a) CM6 alkyl, b) C2.16 alkenyl, wherein the substituents (a) and (b) can be optionally substituted with 5 C,.6 alkoxycarbonyl, or a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or d) a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three 10 atoms selected from the group consisting of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF„ -NO.,, C,.G alkyl, C,.6 alkoxy, C,.6 acyl, C, r> alkylthio, or alkoxycarbonyl; R92 and RJt at each occurrence are the same or different and are 15 a) H, b) phenyl, c) C,.6 alkyl, or d) benzyl; Rg4 and R,5 at each occurrence are the same or different and are 20 a) H, b) OH, c) C,.6 alkyl optionally substituted with -NR83 R84, or d) R„4 and R.,5 taken together are =0; R96 is a) an aromatic moiety having 6 to 10 carbon atoms, b) a 5-, or 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) which can in turn be substituted 30 with one or three -NO._„ CF:), halo, -CN, OH, phenyl, C,^ alkyl, C,.5 alkoxy, or C,.5 acyl, c) morpholinyl, d) OH, e) C,.G alkoxy, f) -NR8i1RS4, g) -C(=0)-R„7, or R97 >s a) morpholinyl, b) OH, or c) C|.6 alkoxy; h is 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5; 1 is 2 or 3; m is 4 or 5; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; with the proviso that n and p together are 1, 2, 3, 4, or 5; q is 1, 2, 3, or 4; r is 2, 3, or 4; t is 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 new compounds of the invention can be prepared using known compounds and intermediates of oxzolidinones, isoxazolines and butyolactones as 25 intermediates and synthetic methods known in the art. Thioamides of the invention ; can typically be prepared by the reaction of the corresponding amide with 1 Lawesson's reagent.
Compounds disclosed in the following publications are suitable intermediates for preparation of the compounds of this invention and are hereby incorporated by 30 reference for their disclosure of suitable compounds that can be converted to the subject thiocarbonyl derivatives.
U.S. Patents 5,225,565; 5,182,403; 5,164.510; 5,247,090; 5,231,188; 5,565,571; i 5,547,950; and 5,523,403.
PCT Application and publications PCT/US93/04850, W094/01110; PCT/US94/08904, W095/07271; PCT/US95/02972, VV095/25106; PCT/US95/10992, W096/13502; PCT/US96/05202, W096/35691: PCT/US96/12766; PCT/US96/13726; 1 PCT/US96/14135; PCT/US96/17120; PCT/US96/19149; PCT/US97/01970; PCT/US95/12751, W096/15130: and PCT/US96/00718, W096/23788.
Chemical conversion techniques for converting various intermediates having a CH,NH2 on the oxazolidinone ring to CH..NH-C(S)-CH., is disclosed by Hartke, K., 5 Barrmeyer, S., J. prakt. Chem. 1996, 338, 251-6. Similarly, conversion of CH2NHC(=0)CH:, to CH2NHC(S)NHCH:J is reported by Cava, M.P.; Levinson, M.I., Thionation Reactions of Lawesson's Reagents, Tetrahedron 1985, 41, 5061-87.
For the purpose of the present invention, the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum 10 and maximum number of carbon atoms in the moiety, i.e., the prefix Cw defines the number of carbon atoms present from the integer "i" to the integer "j", inclusive. Thus, C,.4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and isomeric forms thereof.
The terms "C,.2 alkyl", "C,.-, alkyl", "C,.4 alkyl", "C,.5 alkyl", "C,.6 alkyl", "C,.8 15 alkyl", and "C,.16 alkyl" 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 to sixteen carbon atoms respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomeric forms thereof.
The terms "C2.4 alkenyl", "C2.5 alkenyl", "C2.8 alkenyl", "C2.l4 alkenyl" and "C2.,6 alkenyl" refer to at least one double bond alkenyl group having two to four, two to five, two to eight, two to fourteen, or two to sixteen carbon atoms, respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptdienyl, octenyl, octdienyl, octatrienyl, nonenyl, nonedienyl, nonatrienyl, undecenyl, undecdienyl, dodecenyl, tridecenyl, tetradecenyl and their isomeric forms thereof.
The terms "C.J 5 alkynyl", "C.2.8 alkynyl", and "C2.10 alkynyl" refer to at least one triple bond alkynyl group having two to five, two to eight, or two to ten carbon atoms respectively such as, for example, ethynyl, propynyl, butynyl, pentynyl, pentdiynyl, hexynyl, hexdiynyl, heptynyl, heptdiynyl, octynyl, octdiynyl, octatriynyl, nonynyl, nonediynyl, nonatriynyl and their isomeric forms thereof.
The terms "C:J4 cycloalkyl", "C.,.G cycloalkyl", "C5.6 cycloalkyl", and "C:J.8 cycloalkyl" refer to a cycloalkyl having three to four, three to six, five to six, or three to eight carbon atoms respectively such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof.
The terms "C14 alkoxy", "C,.fi alkoxy", and "C,.H alkoxy" refer to an alkyl group having one to four, one to six, or one to eight carbon atoms respectively attached to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof.
The terms "C16 alkylamino", and "C,.8 alkylamino" refer to an alkyl group 5 having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, or octoylamino and their isomeric forms thereof.
The terms "C,^ dialkylamino", and "C^ dialkylamino" refer to two alkyl 10 groups having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, dimethylamino, methylethylamino, diethylamino, dipropylamino, methypropylamino, ethylpropylamino, dibutylamino, dipentylamino, dihexylamino, methylhecylamino, diheptylamino, or dioctoylamino and their isomeric forms thereof.
The terms "CM acyl", "CM acyl", "C,.5 acyl", "C,.6 acyl", "C,.8 acyl", and "C2.g 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.
The terms "CM alkoxycarbonyl", "C,.B alkoxycarbonyl", and "C,.8 alkoxycarbonyl" refer to an ester group having an alkyl group of one to four, one to 20 six, or one to eight carbon atoms.
The term "Cu alkyl phenyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical.
The term "C2.„ alkenyl phenyl" refers to a at least one double bond alkenyl 25 group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical.
The term alkyl pyridyl" 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 "C,.,, hydroxyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a hydroxy group.
The term "C,.B alkylsulfonyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a SO, moiety.
The term "C,.6 alkylthio" refers to an alkyl group having one to six carbon 35 atoms and isomeric forms thereof attached 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 forming such groups as, for example, pyridine, thiophene, furan, pyrazoline, pyrimi-dine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-5 isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1- phthalazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-10 isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2- benzoxazolyl, 2-benzothiazolyl, 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-l-oxide, 1,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, 5-oxo-l,2,4-oxadiazol-3-yl, l,2,4-thiadiazol-3-yl, 15 l,2,4-thiadiazol-5-yl, 3-oxo-l,2,4-thiadiazol-5-yl, l,3,4-thiadiazol-5-yl, 2-oxo-l,3,4- thiadiazol-5-yl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl, l,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl,l-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-l,3,4-thiadiazol-2-yl, 20 thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may be substituted as appropriate.
The term halo refers to fluoro, chloro, bromo, or iodo.
The compounds of the present invention can be converted to their salts, where appropriate, according to conventional methods.
The term "pharmaceutical^ acceptable salts" refers to acid addition salts useful for administering the compounds of this invention and include hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form.
When Q is the structure of £ (CH2>n'-"n/Ra> the dotted line in the heterocyclic ring means that this bond can be either single or double. In the case where the dotted line is a double bond, the R;19 group will not be present. 6118.P2 CP The compounds of Formula I of this invention contain a chiral center at C5 of the isoxazoline ring, and as such there exist two enantiomers or a racemic mixture of both. This invention relates to both the enantiomers, as well as mixtures containing both the isomers. In addition, depending on substituents, additional 5 chiral centers and other isomeric forms may be present in any of A or Rx group, and this invention embraces all possible stereoisomers and geometric forms in these groups.
The compounds of this invention are useful for treatment of microbial infections in humans and other warm blooded animals, under both parenteral and 10 oral administration.
Also described are pharmaceutical compositions which may be prepared by combining the compounds of this invention with a solid or liquid pharmaceutical^ acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form composi-15 tions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance which may 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, 20 starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like.
Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided 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 25 agents, stabilizers and thickening agents.
Preferably, the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component, that is, the compound according to this invention.
The quantity of active component, that is the compound according to this 30 invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound, the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.
In therapeutic use for treating, or combatting, bacterial infections in warm-35 blooded animals, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain OO rpMCTUATPTOPERTY -61' OFFICE OF N.Z I 2 9 JUL 2003 1 RECEIVER a concentration, that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective. Generally, such antibacterially effective amount of dosage of active component will be in the range of about 0.1 to about 100, more preferably about 3.0 to about 50 mg/kg of body 5 weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the bacterial infection being treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the 10 optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., 2-4 four times per day.
When the compounds according to this invention are administered parenterally, i.e., by injection, for example, by intravenous injection or by other 15 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 a suitably buffered isotonic solution, for example, having a 20 pH of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compound of this invention generally will be dissolved in the carrier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 25 1 mg/mL to about 400 mg/mL of solution. The resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned antibacterially effective amount of dosage. 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 admixed in a 30 pharmaceutically acceptable gel or cream vehicle that can be applied to the patient's skin at the area of treatment. Preparation of such creams and gels is well known in the art and can include penetration enhancers.
MIC Test Method The in vitro MICs of test compounds were determined by a standard agar 35 dilution method. A stock drug solution of each analog is prepared in the preferred solvent, usually DMSO:H^O (1:3). Serial 2-fold dilutions of each sample are made WO 00/32599 PCT/US98/25308 using 1.0 ml aliquots of sterile distilled water. To each 1.0 ml aliquot of drug is added 9 ml of molten Mueller Hinton agar medium. The drug-supplemented agar is mixed, poured into 15 x 100 mm petri dishes, and allowed to solidify and dry prior to inoculation.
Vials of each of the test organisms are maintained frozen in the vapor phase of a liquid nitrogen freezer. Test cultures are grown overnight at 35°C on the medium appropriate for the organism. Colonies are harvested with a sterile swab, and cell suspensions are prepared in Trypticase Soy broth (TSB) to equal the turbidity of a 0.5 McFarland standard. A 1:20 dilution of each suspension is made in 10 TSB. The plates containing the drug supplemented agar are inoculated with a 0.001 ml drop of the cell suspension using a Steers replicator, yielding approximately 104 to 105 cells per spot. The plates are incubated overnight at 35°C.
Following incubation the Minimum Inhibitory Concentration (MIC jig/ml), the lowest concentration of drug that inhibits visible growth of the organism, is read and 15 recorded. The data is shown in Tables I and II.
TABLE 1 Structure Oxazolidinone MIC Values (Gram+) SAUR 9213 SEPI 12084 EFAE 9217 SPNE 9912 SPYO 152 H Comparison * yy 8 16 4 8 .5 1 ojy.o E»me|«3 "XVi! 0 X\a0 II 8 4 1 2 .25 .5 •not a compound of tha aubjact invention TABLEU (cont'd) 1 Structure Oxazolidinone MIC Values (Gram+) SAUR 9213 SEPI 12084 EFAE 9217 SPNE 9912 SPYO 152 Comparison * ^ir0^ 2 1 2 .5 1 Exampto 1 1 .25 .5 .13 .13 Example 5 o O ^M—ft ^—N/^0 8 w r 1 .25 .5 <.125 .25 EmmptcO O-O-i? j. v—*^-8 I"*"- H 2 1 2 .5 1 •not a compound of tha aubjact invantion TARI.R 1 (cont'd) CO SAUR: SEPI: EFAE SPNE SPYO S. aureus S. epidermidii E. faecalti S. pneumoniae S. pyogenet Structure — — Oxazolidinone MIC Values (Gram+) SAUR 9213 SEPI 12084 EFAE 9217 SPNE 9912 SPYO 152 9 Comparison * N-N XXi j "CM. .5 .25 1 .13 .25 Example 2 N-N CM, S N | j 8 2 4 2 4 % O e o Ci K> in VO VO •not a compound of tha aubjact invantion n H ■ S V) so OO U) OJ * o TABLE II § Example No.
SAUR 9213 MIC SEPI 30593 MIC EFAE 12712 MIC SPNE 9912 MIC SPYO 152 MIC HINF 30063 MIC MCAT 30610 MIC EFAE 9217 MIC 1 1 0.25 0.5 <0.125 <0.125 8 1 0.5 2 8 4 8 2 4 >16 >16 4 3 4 I 1 0.25 0.5 16 4 2 1 0.5 0.5 <0.125 0.25 4 2 0.5 6 2 2 2 0.5 1 16 8 2 7 0.5 0.25 0.5 <0.125 0.25 4 1 0.5 8 2 1 0.5 <0.125 0.25 4 2 1 9 0.3 0.25 0.25 <0.125 <0.125 2 0.5 0.25 2 1 0.5 <0.125 0.25 2 ' 1 1 11 0.23 0.25 0.23 <0.123 0.25 2 1 0.25 12 1 0.5 0.25 <0.125 <0.125 1 0.5 0.5 »3 1 1 2 0.5 1 >16 8 2 14 1 0.5 1 0.25 0.5 8 1 1 32 16 32 4 8 >64 64 32 16 8 8 16 2 8 >64 32 16 17 2 2 4 1 2 64 16 4 18 2 1 2 <0.5 1 32 4 2 19 32 16 32 16 16 64 32 32 21 4 4 8 2 4 64 16 8 22. 23 0.5 0.5 1 <0.125 0.25 4 2 1 24 1 0.25 0.5 <0.123 0.25 4 2 0.5 0.3 0.25 0.3 <0.125 <0.123 2 2 0.5 26 1 0.5 1 0.23 0.5 16 2 1 TABLE II (cont'd) Example No.
SAUR SEPI EFAE SPNE SPYO HINF MCAT EFAE 9213 MIC 30593 MIC 12712 MIC 9912 MIC 152 MIC 30063 MIC 30610 MIC 9217 MIC 27 0.5 0.5 0.5 <0.125 0.25 4 2 1 28 0.5 0.25 0.5 0.25 0.25 2 1 0.5 29 0.23 0.25 0.25 <0.125 <0.125 2 0.5 0.25 4 1 0.5 <0.125 0.25 8 2 1 31 2 1 1 <0.125 0.25 4 1 1 32 16 2 2 0.25 0.25 8 2 4 33 4 2 I 0.25 0.25 4 2 4 34 2 1 2 0.5 1 >16 4 2 1 0.5 1 0.25 0.5 16 2 1 SAUR 9213: S. aureus SEPI 30593: S. epidermidis EFAE 12712: E. Faecium SPNE 9912: S. pneumoniae SPYO 152: S. pyogenes HINF 30063: Haemophilus influenzae MCAT 30610: Moraxella caiarrhalis EFAE 9217: Enterococcus faecalis As shown in Scheme 1, the intermediates II for the compounds of this invention are also intermediates disclosed in the oxazolidinone patents and published applications hereinabove incorporated by reference. The intermediates IV for this invention are final products (Examples) from the oxazolidinone patents . and published applications hereinabove incorporated by reference.
As shown in Scheme 1, Step 1, and illustrated in Example 5, the isothiocyanates III can be conveniently prepared by allowing the amine intermediates (II) to react with l,r-thiocarbonyIdi-2(lH)-pyridone in solvents such as methylene chloride at 0 to 25°C. The thioureas (la, R' = H, alkyl,.,,) can then be 10 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 an appropriate isothiocyanate (R1 - N = C = S) in solvents such as tetrahydrofuran at 0-50°C. Thioamides (lb, R" = H, alkylM) are 15 prepared by allowing II to react with an appropriate dithioester (R"' S-C(=S)-R", Step 4 as illustrated in Example 4. This 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,M is methyl or ethyl, can be catalyzed by an alkali metal fluoride.
The reaction of II with R'"-S-C(S)-R"' {R"'=CH3, C2H5) to give lb (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 3-48 hr.
When the reaction conditions are tolerated by the substituents on R (see, for example. Examples 1-3) the thioamides (lb, R" - H, alkyl,_,) can also be conveniently 25 prepared (Step 5) by allowing the appropriate amide intermediates (IV) to react with reagents such as 2,4-bis(p-methoxyphenyl)-l,3-dithiadiphosphetane-2,4-disulfide (Lawesson's Reagent) in 1,4-dioxane, benzene, toluene or tetrahydrofuran at 60-110°C; phosphorus decasulfide and sodium carbonate in tetrahydrofuran at 20-50°C [Brillon, D., Synthetic Communications, 20, 3085 (1990)] or phosphorus decasulfide 30 and sodium fluoride in 1,2-dimethoxyethane at 20-50°C fHartke, K., Gerber, H.-D., J. Prakt. Chem., 338, 763 (1996)].
Compounds Ic 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 5-24 hours. 35 The resulting intermediate is treated with an alkylating agent (R"" X where X represents bromo, iodo, alkylsulfonyloxy or arylsulfonyloxy) at 0-30°C to give compounds Ic. In Step 7, compounds Ic are allowed to react with alkali metal alkoxide such as sodium methoxide or potassium ethoxide in the corresponding alkanol as solvent. This reaction is conveniently carried out at the reflux temperature of the alkanol for 1-24 hr.
SCHEME 1 TJT R—NH2 R—N=C=S STEP 1 III S II FT—NH2 R—NH—C—NH-R' (R" = H, alkyl,.4) STEP 2 " 13 II R1—N=C=S la (R' = H, alkyl, J STEP 3 S t\ II R'"—S-C-R" R-NH-C—R" (R" = H, alkyl,.4) STEP 4 lb (R™ = ch3, c2h5 hooc_ch2) o II R—NH—C—R" lb (R" = H. alkyl,,4) IV STEP 5 9 s 11 1) CS2/Et3N || (R,m = C,.4 alkyl, X=Br, I, RNH-C-SR"" 0S02 alkyl, 0S02 aryl) 2)R"" X STEP 6 lc Ic MOR' S II HOR"" RNH-C-OR"" . (M=Li,+Na,+K+) STEP 7 Id In order to more fully illustrate the nature of the invention and the manner of practicing the same, the following experimental examples are presented.
EXAMPLE 1: (S)-N-[[3-(3-Fluoro-4-(4-morpholinyl)phenyl|-2-oxo-5-oxazolidinyl|methyl]thioacetamide (I) s i A stirred mixture of II (PCTAJS94/089Q4, 3.37 g, 10.0 mmol) in dry dioxane (100 mL), under nitrogen was treated with Lawesson's Reagent (4.04g, 10.0 mml), warmed to reflux during 1 h and refluxed for 1.5 h. The reaction was complete by TLC on silica gel with 10% MeOH-CHCl;). It was kept at ambient temperature for 18 h and concentrated in vacuo. Chromatography of the residue on silica gel with 15 mixtures of acetone-methylene chloride containing 10-15% acetone gave the product which was crystallized from acetone-hexane to give 1: mp 157.5-158.5 °C; HRMS theory for C16H20FN3O3S (M+): 353.1209; found: 353.1212. Anal, calcd for CI6H.,0FN3O3S: 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-l,3,4-thiadiazol-2-yl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (2) s 2 According to Example 1, for the preparation of 1, 21 (PCT/US97/01970) was allowed to react with Lawesson's Reagent in refluxing dioxane to give 2: mp 222-223 °C; HRMS theory for C19H,4FNfiO,S, (M+H*): 451.1386; found 451.1381.
EXAMPLE 3: (S)-N-[[3-[3-Fluoro-4-[2',5'-dioxospiro[piperidine-4,4'-imidazolidine]-l-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (3).
STEP A: (S)-N-[[3-[3-Fluoro-4-[2',5'-dioxospiro(piperidine-4.4'-imidazolidinel-l-yl]phenyll-2-oxo-5-oxazolidinyllmethyllacetamide (32). o 31 c,9^y:^b% 32 A stirred suspension of 31 (W095/25106, 0.349 g, 1.00 mmol) in 1:1 EtOH:HaO (5 mL), under nitrogen, was treated with potassium cyanide (0.130 g, 2.00 mmol) and ammonium carbonate (0.701 g, 7.30 mmol), warmed at 55-60 °C for 5 h 15 min and kept at ambient temperature for 17 h 15 min. It was then chromatographed on 15 silica gel with mixtures of MeOH-NH4OH-CHCl3 containing 5-20% MeOH and 0.5% NH4OH to give 0.280 g of 32: HRMS calcd for CigH^FN505: 419.1605 (M+); found 419.1613; Anal, calcd for CI9H2!JFN505 • 1 HaO: 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[piperidine-4,4'-imidazolidine]-1 -yl] phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (3). s MeO-^~V-P^ V-OMa o O W XS'|| \=/ o O " , F »—NHAc H F "-NH-C-CHj 32 C„H22FN50)S 3 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), refluxed for 4 h and concentrated in vacuo. The residue was chromatographed on silica gel with mixtures of MeOH-NH4OH-CHCl;! containing 1-10% MeOH and 0.1-0.5% NH4OH and the resulting product was crystallized from MeOH-CHCl;)-EtOAc to give 0.0491 g of 3: mp 218.5 °C; HR FAB MS theory for C^H^N-AS (M+): 435.1376; found 435.1370. Anal, calcd for C19HL(;!FN504S • 0.5 H,0: C, 51.34; H, 5.21; N, 15.76. Found: C. 51.69; H, 5.00; N,. 15.25.
EXAMPLE 4: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl)thioacetamide (4). o s II HjC-C—SEt O VN—N0 * *—N O KOH/NaF * IS NH-C-CH. 41 CieH2oFN303S 4 A solution of 41 (148 mg, 0.500 mmol) and 0.97 M KOH (0.515 mL) in absolute EtOH (5 mL) was added to a solution of ethyl dithioacetate (57 jiL, 0.50 mmol) and sodium fluoride (20 mg. 0.47 mmol) in absolute EtOH (5 mL) and the mixture was kept at ambient temperature for 3 h 40 min. Additional ethyl dithioacetate (5 jiL) was added after 1 h 55 min and additional 0.97 M KOH (40 mL) and sodium fluoride (6 mg) were 15 added to the mixture after 3h 5 min. The reaction was followed by TLC on silica gel with 10% MeOH-CHCl, and 30% acetone-CH:CK. The major product had an Rf on TLC that was the same as that of 4.
EXAMPLE 5: (S)-N-[[3-[3-FIuoro-4-(4-morpholinyl)phenyI]-2-oxo-5-20 oxazolidinyl]methyl]thiourea (5).
A solution of 51 (PCT/US94/08904, 2.07 g, 7.00 mmol) in CH:C1: was added, dropwise during 30 min. under nitrogen to an ice cold, stirred solution of U'-thiocarbonyldi-30 2(lH)-pyridone (1.95 g, 8.40 mmol) in CH,C1, (70 mL). The mixture was warmed slowly to ambient temperature and kept for 18 h. It was then diluted with CH;C1,, washed with water and aqueous NaCI. dried (Na,S04) and concentrated.
Chromatography of the residue on silica gel with 10% acetonitrile-CH:Cl; gave 1.60 g of the isothiocvanate: HRMS theory for C,,H|6FN,0iS (M*): 337.0896: found STEP A: s ii 51 CisHtgFNjOaS 337.0888.
STEP B: ^ ">=/ W...H ^ >=/ W...H s F »—N=C=S '—NH—C—NHj C,5H19FN403S 5 Anhydrous ammonia was bubbled for 7 min through a stirred solution of the product from Step I (1.00 g. 2.96 mmol) in THF (10 mL) and the mixture was kept at ambient temperature for 3 h 25 min and concentrated in vacuo. Crystallization of the residue from acetone-hexane gave 0.861 g of 5: mp 199-199.5 °C: MS m/z 354 (M+). Anal, calcd for C15HI9FNAS: 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-morphoIinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-N'-methylthiourea (6).
CHjNCS ■ O^N-fV^O W ' W».H ^ W"H S h NH2 r *-NH— C-NHCH3 61 C|«H2IFN403S A stirred solution of methyl isothiocyanate (93 mg, 1.27 mmol) in THF, was treated with 61 (295 mg, 1.00 mmol), kept at ambient temperature for 18 h and conccntrated in vacuo. The residue was recrystallized from EtOAc-hexane to give 246 mg of 6: mp 158-160 °C: MS m/z 368 (M+). Anal, calcd for C^H^FN^S: C, 52.16; H, 5.74; N, 15.21. Found: C. 52.20: H. 5.85; N. 15.17.
EXAMPLE 7 (S)-cis-N-([3-[3-Fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4- yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide Step 1: A mixture of (S)-(-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thiopyran-4- yl)phenyl]-2-oxo-5-oxazolidinyI]methyl]acetamide S-oxide (4.50 g, can be obtained 10 according to the procedures disclosed in International Publication "No. WO 97/09328) and platinum oxide (697 mg) in methanol (164 mL) is shaken on the Parr apparatus under a hydrogen atmosphere at 40 psi for 18 hours. The catalyst is then removed by filtration through Celite, and the filtrate is concentrated under reduced pressure and the residue chromatographed on silica gel (230 - 400 mesh, 350 g), eluting with 15 a gradient of methanol/methylene chloride (3/97 - 7/93). Pooling and concentration of those fractions with an Rf = 0.44 by TLC (methanol/chloroform, 10/90) gives (S)-cis-(-)-N-[[3-[3-Fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide, mp 203 - 204°C.
Step 2: A mixture of the compound prepared in Step 1 (2.50 g) and hydroxylamine hydrochloride (2.36 g) in pyridine (30.6 mL) and ethanol (3.4 mL) is stirred in a screw-cap vial at 100°C for 22 hrs and at ambient temperature for 16 hrs, during which additional hydroxylamine hydrochloride (944 mg) and pyridine (4 mL) is added. The reaction mixture is then concentrated under reduced pressure, 25 diluted with saturated aqueous sodium bicarbonate (100 mL) and saline (50 mL), adjusted to pH 11 with solid sodium carbonate and extracted with methanol/methylene chloride (10/90, 5 x 100 mL). The combined organic phase is concentrated under reduced pressure, and the crude product is chromatographed on silica gel (230 - 400 mesh, 150 g), eluting with a gradient of methanol/methylene 30 chloride (6/94 - 10/90). Pooling and concentration of those fractions with an Rf = 0.14 by TLC (methanol/chloroform, 10/90) gives (S)-cis-3-[3-fluoro-4-(tetrahydro-l-oxido-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 35 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-oxido-2H-thiopyran-4- PCIYUS98/25308 yl)phenylJ-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 ambient temperature for 4 hours and was then diluted with methylene chloride (150 mL) and washed with water (50 mL), aqueous 5 potassium hydrogen sulfate (1M, 50 mL) and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo, and the crude product was triturated with methylene chloride/diethyl ether and filtered to give the title compound, mp 176 - 177°C (dec.).
EXAMPLE 8 (S)-cis-[[3- [3-Fluoro-4-(tetrahydro-1 -oxido-2H-thiopyran-4- yl )phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea Step 1: A solution of l,r-thiocarbonyIdi-2(lH)-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-oxido-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) over 30 minutes. The resulting mixture was stirred at 0°C for 30 minutes and at ambient 25 temperature for 1 hour and was then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (70 - 230 mesh, 20 g), eluting with acetonitrile/methylene chloride (40/60), and those fractions with an Rf = 0.07 by TLC (acetonitrile/methylene chloride, 30/70) were 30 pooled and concentrated to give (S)-cis-3-[3-Fluoro-4-(tetrahydro-l-oxido-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-oxido-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 (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot 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. Recrystallization from 5 methanol/methylene chloride/diethyl ether gave the title compound, mp 206 - 208°C (dec.).
EXAMPLE 9 (S)-trans-N-[f3-[3-Fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4- yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide Step 1: (S)-(-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-ox azolidinyl]methyl]acetamide S-oxide (disclosed in International Publication No. 20 WO 97/09328) may be reduced to the corresponding cis- and trans-sulfoxides by catalytic hydrogenation in the presence of a catalyst and solvent. Alternatively, the sulfide by product of this reduction reaction can be oxidized with an oxidizing agent such NaI04 or meta-chloroperoxybenzoic acid in solvent to provide the cis- and trans-sulfoxides. Alternatively, the sulfide byproduct acn be oxidized selectively to 25 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, mp 211 - 212°C (dec.). A mixture of the trans-sulfoxide, (S)-trans-(-)-N-[[3-[3-fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4-yl)phenyll-2-oxo-5-oxazolidinyl]methyl]acetamide, (0.90 g) and 30 hydroxylamine hydrochloride (0.85 g) in pyridine (11.0 mL) and ethanol (1.2 mL) is stirred in a screw-cap vial at 100"C for 23 hrs and at ambient temperature for 19 hrs, during which additional hydroxylamine hydrochloride (340 mg) and pyridine (1 mL) is added. The reaction mixture is then concentrated under reduced pressure, diluted with saturated aqueous sodium carbonate (50 mL) and saline (50 mL) and 35 extracted with methanol/methylene chloride (10/90, 6 x 100 mL). The combined organic phase is concentrated under reduced pressure, and the crude product is PCT7US98/25308 chromatographed on silica gel (230 - 400 mesh, 45 g), eluting with a gradient of methanol/methylene chloride (7.5/92.5 - 10/90). Pooling and concentration of those fractions with an Rr = 0.14 by TLC (methanol/chloroform, 10/90) gives (S)-trans-3-|3-fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-5 oxazolidinone, 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-oxido-2H-thiopyran-4-10 yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepare 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 ambient temperature for 17 hours and was then diluted with methylene chloride (150 mL), washed with water (2 x 50 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude 15 product was chromatographed on silica gel (230 - 400 mesh, 35 g), eluting with methanol/methylene chloride (3/97), and those fractions with an Rf = 0.56 by TLC (methanol/chloroform, 10/90) were pooled and concentrated and the residue recrystallized from methylene chloride/diethyl ether to give the title compound, mp 193 - 194°C (dec.).
EXAMPLE 10 (S)-trans-[[3-[3-Fluoro-4-(tetrahydro-l-oxido-2H- thiopyran-4-yl )phenyl] -2-oxo-5-oxazolidinyl] methyl] thiourea O,, _ ,1 N NH H 2 Step 1: A solution of l,l'-thiocarbonyldi-2(lH)-pyridone (192 mg, 0.827 mmol) in anhydrous methylene chloride (8.3 mL) at 0°C under a nitrogen atmosphere was treated with a solution of (S)-trans-3-[3-fluoro-4-(tetrahydro-l-oxido-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) over 30 35 minutes. The resulting mixture was stirred at 0°C for 30 minutes and at ambient temperature for 40 minutes and was then diluted with methylene chloride (20 mL), washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (32 - 63 mm, 40 g), eluting with a gradient of acetonitrile/methylene chloride (30/70 -60/40) under 15 psi N2, and those fractions with an Rf= 0.12 by TLC 5 (acetonitrile/methylene chloride, 30/70) were pooled and concentrated to give (S)-trans-3-|3-Fluoro-4-(tetrahydro-l-oxido-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-oxido-2H- thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone (Step 1, 230 mg, 0.624 mmol) in anhydrous tetrahydrofuran (31.2 mL) at 0°C under a nitrogen atmosphere was treated (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot 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 15 was concentrated in vacuo to give the crude product. Trituration with methanol/methylene chloride/diethyl ether gave the title compound, mp 209 - 210°C (dec.).
EXAMPLE 11 (S)-N-[[3-[3-Fluoro-4-(tetrahydro-l,l-dioxido-2H- thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide A Step 1: Starting with (S)-cis-(-)-N-[[3-[3-FIuoro-4-(tetrahydro-l-oxido- 2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide as prepared in Example 7, Step 1, and following the general procedure of Step 2, and making non-critical variations by substituting (S)-(-)-N-[[3-[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenylJ-2-oxo-5-oxazolidinyl]methyl)acetamide S,S-dioxide (disclosed in International Publication No. WO 97/09328) for (S)-cis-(-)-N-[[3-[3-fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl)methyl]acetamide, the product (S)-(-)-3-[3-Fluoro-4-( tetrahydro-1, l-dioxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone is obtained, mp 194°C (dec.).
Step 2: A solution of ethyl dithioacetate (100 mL, 0.876 mmol) and sodium fluoride (37 mg, 0.876 mmol) in ethanol (8.8 mL) under a nitrogen atmosphere was treated with a mixture of (S)-(-)-3-[3-fluoro-4-(tetrahydro-l,l-dioxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Step 1, (300 mg, 0.876 5 mmol) and aqueous potassium hydroxide (1M, 0.88 mL) in ethanol (43.8 mL). The resulting mixture was stirred at ambient temperature for 26 hours, during which additional ethyl dithioacetate (50 mL, 0.438 mmol), sodium fluoride (19 mg, 0.438 mmol), aqueous potassium hydroxide (1M, 0.44 mL) and ethanol (3.0 mL) was added, and was then diluted with methylene chloride (150 mL), washed with water 10 (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/diethyl ether to give the title compound, mp 186 - 187°C (dec.).
EXAMPLE 12 (S)-N-[[3-[3-Fluoro-4-(tetrahydro-l,l-dioxido-2H- thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiourea o2s s , C n nh2 h I h Step 1: A solution of l,l'-thiocarbonyldi-2(lH)-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-l,l-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) over 30 minutes. The 30 resulting mixture was stirred at 0°C for 30 minutes and at ambient temperature for 30 minutes and was then diluted with methylene chloride (40 mL), washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (230 -400 mesh, 45 g), eluting with acetonitrile/methylene chloride (7.5/92.5), and those 35 fractions with an Rr= 0.64 by TLC (acetonitrile/methylene chloride, 20/80) were pooled and concentrated to give (S)-3-[3-fluoro-4-(tetrahydro-l,l-dioxido-2H- PCT/U S98/25308 thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone, mp 158 - 162oc (dec.).
Step 2: A solution of (S)-3-[3-fluoro-4-(tetrahydro-l,l-dioxido-2H- thiopyran-4-yI)phenyll-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 (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot 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 10 was concentrated in vacuo to give the crude product. Recrystallization from methanol/methylene chloride/diethyl ether gave the title compound, mp 196 - 198°C (dec.).
EXAMPLE 13: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-15 oxazolidinyl]methyl]-thioformamide (7).
A stirred mixture of acetic anhydride (0.23 mL, 0.0024 mol) and 95-97% formic acid (0.10 mL, 0.0027 mL) was warmed, under nitrogen at 50-55 °C for 2 h, cooled to 25 ambient temperature and treated, portionwise during 2 min, with 39® (0.45 g, 0.0015 mol). The suspension was kept at ambient temperature for 4 h and the resulting solution was treated with Et20 (1 mL) and kept at ambient temperature for 18 h. The mixture was diluted with additional Et20 (10 mL) and the solid was collected by filtration, washed with Et,0 and dried to give 0.38 g of 69: MS (ES) m/z 324 30 (M+H*), 346 (M+Na+); 'H NMR (300 mHz, CDCl;i) d 3.08 (m, 4H), 3.72 (m, 2H), 3.77 (d,d, IH), 3.89 (m, 4H), 4.04 (t, IH), 4.80 (m, IH), 6.33 (s, IH), 7.05 (m, 2H), 7.45 (d,d, IH), 8.27 (s, IH).
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), warmed to reflux during 30 min and kept at 10 this temperature for 90 min. It was then evaporated under a stream of nitrogen. The residue was chromatographed on silica gel with 1.25% MeOH-CH2Cl2 and the slightly impure product was rechromatographed on silica gel with 25% EtOAc-CHjjClj,. The resulting product was crystallized from EtOAc-methyl tert-butyl ether to give 0.114 g of 7: mp 150-155 °C (dec); IR (DRIFT) 3322, 1752 cm'1; MS(ES) m/z 15 340 (M+H+), 362 (M+Na*); 'HNMR [300 MHz, (CD3)2SO] d 2.94 (m, 4H), 3.72 (m, 4H), 3.77 (d,d, IH), 3.94 (t, 2H), 4.12 (t, IH), 4.93 (m, IH), 7.05 (t, IH), 7.16 (d,d, IH), 7.47 (d,d, IH), 9.33 (d, IH), 10.59 (s, IH). Anal, calcd for C15H18FN303S: C, 53.08; H, 5.35; N, 12.38. Found: C, 53.02; H, 5.44; N, 12.36.
EXAMPLE 14: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiopropion-amide (9). 39 An ice cold, stirred solution of 39 (0.395 g, 0.00134 mol) and triethyl amine (0.186 mL, 0.0027 mol) in CH2C12 (20 mL), under nitrogen was treated, dropwise during 2 30 min, with a solution of propionyl chloride (0.128 mL, 0.00147 mol) in CH2CI2 (3 mL). The mixture was kept in the ice bath for 20 min and at ambient temperature for 1 h. It was then diluted with CH>CI2, washed with saturated NaHCOa, water and brine, dried (MgS04) 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, portionwise during 1 min, with Lawesson's reagent (0.58 g, 0.0014 mol) and refluxed for 2 h; it was then concentrated. The residue was chromatographed on silica gel with 2% MeOH-CHCl3 and the product was 10 crystallized from methyl ferf-butyl ether to give 0.259 g of 9: mp 138-139 °C; MS(ES) m!z 368 (M+H*), 390 (M+Na+); IR (DRIFT) 3284, 3266, 1748, 1744 cm1; [arD +20° (MeOH); IH NMR1300 MHz, (CD3)2SO] d 1.12 (t, 3H), 2.56 (q, 2H), 2.94 (m, 4H), 3.72 (m, 4H), 3.78 (d,d, IH), 3.90 (t, 2H), 4.11 (t, IH), 4.93 (m, IH), 7.05 (t, IH), 7.16 (d,d, IH), 7.47 (d,d, IH), 10.30 (broad s, IH). Anal, calcd for 15 C^H^FNAS: C, 55.57; H, 6.03; N, 11.44. Found: C, 55.68; H, 6.21; N, 11.37.
EXAMPLE 15: (S)-N-[[3-[3-FIuoro-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, dropwise, during 15 min with a solution of chloroacetyl chloride (465 mL, 5.8 mmol) in CHBC12 (30 mL) and kept at ambient temperature for 18 h. It was then washed with saturated NaHC03 and dilute NaCl, dried (Na,S04) and concentrated. The residue was flash 30 chromatographed on silica gel with 20-30% acetone-CH2Cl2 to give 1.49 g of 10® 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 refluxed, under nitrogen for 2 h and concentrated under reduced pressure. The residue was chromatographed on silica gel with 3-10% 10 acetone-CH2Cl2 to give 0.143 g of 11: MS (CI) m/z 388 (M+H+); 'H NMR (300 MHz, CDC1.,) d 3.07 (m, 4H), 3.77 (d,d, IH), 3.88 (m, 4H), 4.04 (m, IH), 4.12 (t, IH), 4.35 (m, IH), 4.61 (s, 2H), 4.98 (m, IH), 6.96 (t, IH), 7.08 (d,d, IH), 7.44 (d,d, IH), 8.69 (s, IH). Anal, calcd for CuH.aClFN.AS: 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-Fluoro-4-(4-morophoIinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl]-a,a,a-trifhiorothioacetamide (13). 1.
An ice cold stirred solution of 39 (0.590 g, 2.0 mmol) and triethylamine (640 mL, 4.6 mmol) in CH2C12 (10 mL) was treated with trifluoroacetic anhydride (325 mL, 2.3 mmol) and kept in the ice bath for 10 min and then at ambient 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), 30 4 d (100 mL / 220 mL) and 6 d (325 mL / 1.0 mL). The reaction was complete 1 h after the last addition; it was mixed with CH2C12, washed with water and dilute NaCl, dried (Na2S04) and concentrated. The solid residue was recrystallized from acetone-heptane to give 0.566 g of 12: mp 161-164 °C (dec); MS(EI) m/z 391 (M*). Anal, calcd for C16H17F4N304: C, 49.11; H, 4.38; N, 10.74. Found: C, 48.99; H, 4.56; 35 N, 10.73.
A stirred mixture of 12 (0.391 g, 1.0 mmol) and Lawesson's reagent (0.422 g, 1.1 mmol) in dioxane (10 mL) was refluxed, under nitrogen for 2 h, cooled slowly to ambient temperature and concentrated in vacuo. The residue was flash 10 chromatographed on silica gel with 5-15% acetone-CHXl, and the product was crystallized from acetone-heptane to give 0.249 g of 13: mp 151-152 °C; MS(EI) mtz 407 (M+), 363, 209, 151, 95; 'H NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.75 (d,d, IH), 3.87 (m, 4H), 3.95 (m, IH), 4.14 (t, IH), 4.32 (m, IH), 5.01 (m, IH), 6.92 (t, IH), 7.05 (d,d, IH), 7.38 (d,d, IH), 9.03 (s, IH). Anal, calcd for C16H17F4N303S: C, 47.17; 15 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)phenyI]-2-oxo-5-oxazoIidinyl]methyl]-a-fluorothioacetamide (15).
A stirred, ice cold solution of 39 (0.590 g, 2.0 mmol) and triethylamine (611 mL, 4.4 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), kept in the ice bath for 10 min and at ambient temperature for 2 h. It was then diluted with CH2C12, washed with water and dilute NaCl, dried (Na,S04) and concentrated. The residue was chromatographed on silica gel with 10-30% acetone-CH2Cl2 to give 0.180 g of 14: MS(ES) m!z 356 (M+H*), 378 (M+Na*).
PCT/U S98/25308 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), warmed at 90-100 °C for 1 h and concentrated in vacuo. The residue was chromatographed on silica gel with 15% acetone-CHXL to give 0.161 g of 15: MS(EI) m/z 371 (M*); 'H NMR (300 MHz, 5 CDC1;!) d 3.05 (m, 4H), 3.78 (d,d, IH), 3.87 (m, 4H), 4.03 (m, IH), 4.11 (t, IH), 4.38 (m, IH), 4.98 (m, IH), 5.07 (s, IH), 5.23 (s, IH), 6.93 (t, IH), 7.08 (dd, IH), 7.42 (d,d, IH), 8.42 (s, IH). Anal, calcd for C16H19F,N30;,S: C, 51.74; H, 5.16; N, 11.31.
Found: C, 51.79; H, 5.31; N, 11.02.
EXAMPLE 18: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-a,a-difluorothioacetamide (17). 1- o o A stirred, ice cold mixture of 39 (0.590 g, 2.0 mmol), difluroacetic acid (190 mL, 2.0 mmol), and 1-hydroxybenzotriazole (0.297 g, 2.2 mmol) in DMF (5 mL) under 20 nitrogen, was treated with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.843 g, 4.4 mmol) and kept at ambient temperature for 18 h. It was diluted with CH.,C1.,, washed with water and dilute NaCl, dried (Na2S04) and concentrated. The solid residue was crystallized form EtOAc-heptane to give 0.617 g of 16: mp 149-150 °C; IH NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.66 (m, 2H), 3.85 (m, 5H), 4.08 (t, IH), 4.80 (m, IH), 5.93 (t, J = 53.9 Hz, IH), 6.92 (t, IH), 7.06 (m, 2H), 7.39 (d,d, IH); MS(EI) m/z 373 (M+). Anal, calcd for C16HihF.,N,04: C, 51.48; H, 4.86; N. 11.26. Found: C, 51.59; H, 4.91; N, 11.29. 2.
O O 16 17 A stirred solution of 16 (0.373 g, 1.00 mmol) in dioxane (10 mL), under nitrogen was treated with Lawesson's reagent (0.404 g, 1.00 mmol), warmed at about 95 °C for 1 h and concentrated in vacuo. Chromatography of the residue on silica gel with 10% acetone-CH2Cl, and cyrstallization of the product from EtOAc-heptane gave 0.276 g of 17: mp 125-127 °C; MS(EI) m/z 389 (Ml, 345, 305. 247, 209, 195, 151, 138, 123, 109, 95; lH NMR (300 MHz, CDC13) d 3.05 (m, 4H), 3.76 (d.d, IH), 3.86 (m, 4H), 4.01 5 (m, IH), 4.12 (t, IH), 4.30 (m, IH), 4.99 (m, IH), 6.20 (t, J = 55.9 Hz, IH), 6.92 (t, IH), 7.06 (d.d, IH), 7.38 (d,d, IH). 8.78 (broad s, IH). Anal, calcd for Cl6H18F3N30.,S: C, 49.35; H, 4.66; N, 10.79. Found: C, 49.37; H, 4.71; N, 10.83.
EXAMPLE 19: (S)-N-l[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-10 oxazolidinyl]methyl]-a-cyanothioacetamide (19). 1. o O N-f\. NXn \ / l_V—N O + N=cCHjCOOH J—f W-H 15 F NH2 39 O EDCHCI /—\ X N—(' V—N l ' >=/ H-h U 11 0 N—(' 7—N O host v_y V=/ \_L. h o nh-c-chjcn 18 An ice cold, stirred mixture of 39 (0.646 g, 2.19 mmol), cyanoacetic acid (0.179 g, 2.1 mmol) and 1-hydroxybenzotriazole (0.351 g, 2.6 mmol) in DMF (5 mL), under 20 nitrogen, was treated with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.997 g, 5.2 mmol) and kept at ambient temperature for 24 h. It was diluted with CH2C12, washed with water and dilute NaCl, dried (Na2S04) and concentrated. The solid residue was crystallized from EtOAc-heptane to give 0.546 g of 18: mp 172-174 "C: IR (DRIFT) 3316, 2256, 1754, 1684 cm1; MS(EI) m/z 362 25 (M*). Anal, calcd for C„Hl9FN404: C, 56.35; H, 5.28; N, 15.46. Found: C, 56.33; H, 5.30; N, 15.36. 2.
« ^ CH,0 ^s'n \=/ OCM, -C-CH|CN 0 ■("H 6 NH—C -i CHjCN A stirred solution of 18 (0.453 mg, 1.25 mmol) in dioxane (10 mL), under nitrogen, 35 was treated with Lawesson's reagent (0.505 g, 1.25 mmol) and warmed at about 100 °C. When the reaction was over (TLC with 30% acetone-CH,Cl2) the mixture was cooled and concentrated in vacuo. Chromatography of the residue on silica gel with 10-20% acetone-CHLCla and crystallization of the product from EtOAc-heptane gave 0.110 g of 19: mp 186-187 °C (dec); MS(ES) m/z 379 (M+H*), 401 (M+Na*); 'H NMR (300 MHz, CDC1.,) d 3.05 (m, 4H), 3.81 (d,d, IH), 3.86 (m, 4H), 3.89 (s, 2H), 4.09 (t, IH), 4.14 (m, 2H), 5.01 (m, IH), 6.92 (t, IH), 7.05 (d,d, IH), 7.34 (d,d, IH), 9.15 (s, IH); IR (DRIFT) 3244, 2260, 1754 cm1. Anal, calcd for C17H19FN40:iS: 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-morpholinyl)phenyl]-2-oxo-5-10 oxazolidinyl]methyl]-a,a-dichlorothioacetamide (21). 1. /—^ /r~\ a (ci2chco)2o ^ x o n-^ 7—n o o n—u vn^o is wS ^nh, 20 ^NH-c-cho, 39 A stirred, ice cold solution of 39 (0.885 g, 3.00 mmol) and triethylamine (975 mL, 7 mmol) in CH2C1., (15 mL), under nitrogen was treated, dropwise with a solution of 20 dichloroacetic anhydride (555 mL, 3.5 mmol) in CH2C12 (5 mL) and kept in the ice bath for 15 min and at ambient temperature for 18 h. It was diluted with CH2C12, washed with water, saturated NaHC03 and dilute NaCl, dried (Na2S04) and concentrated. Chromatography of the residue on silica gel with 10% acetone-CH2Cl2 and crystallization of the product from acetone-heptane gave 0.463 g of 20: mp 197-25 198 °C (dec); MS(ES) m/z 406 (M+H+), 428 (M+Na*); 'H NMR (300 MHz, CDC1,) d 3.05 (m, 4H), 3.75 (m, 3H), 3.86 (m, 4H), 4.07 (t, IH), 4.83 (m, IH), 5.94 (s, IH), 6.92 (t, IH), 7.06 (m, 2H), 7.41 (d,d, IH). 2. o o 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), warmed at about 90°C for 1 35 hour, cooled and concentrated in vacuo. Chromatography of the residue on silica gel first with 30% acetone-heptane and then with 10% acetone-methylene chloride and crystallization of rh product form methylene chloride - heptane gave 0.203g with 21: mp 143-144°cd.; HR17S (EI) calculated for C16H18cla F Nn 03 S(M) 421.0431. Anal, calcd for C16Hl8cl, F N, 0:) 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-morpholinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl]-a-(methoxycarbonyl)thioacetamide (23). 1. ^ a ch3ococh2coci m o N-f y-N^O o N-f VN O V—' y—' \—(-H Et3N N' >=' ^ ^—("• H Et3N N^—t»H O ^nh2 22 ^nh-c-ch2cooch3 A stirred solution of 39 (0.955 g, 3.2 mmol) and triethylamine (650 mL, 4.5 mmol) in 15 CHoCl, (50 mL), under nitrogen, was treated, dropwise during 15-20 min with a solution of methyl malonyl chloride (475 mL, 4.3 mmol) in CH2C12 (10 mL) and kept at ambient temperature for 3 days. It was then washed with water and dilute NaCl, dried and concentrated. The residue was flash chromatographed on silica gel with 15-30% acetone-CH2Cl2 and the product was crystallized form acetone-hexane to give 20 0.873 g of 22: mp 150-151 °C; 'H NMR (300 MHz, CDC13) d 3.03 (m, 4H), 3.34 (s, 2H), 3.67 (s, 3H), 3.69 (m, 2H), 3.76 (d,d, IH), 3.85 (m, 4H), 4.00 (t, IH), 4.78 (m, IH), 6.90 (t, IH), 7.06 (d,d, IH), 7.41 (d,d, IH), 7.57 (t, IH); MS(ES) mlz 396 (M+H+), 418 (M+Na*); HRMS (FAB) calcd for ClgH2:)FN;106 (M+H+) 396.1571, found 396.1579. Anal, calcd for C18H2,FN.,06: C, 54.68; H, 5.61; N, 10.63. Found: C, 25 54.69; H, 5.68; N, 10.58. o C^O-^C^P-Q-och, o 0Cn-O-n(a? ► o^N-fyA W ^ ° V_y ">=/ L_L.H S V-NH-C-CH,COOCR.
II -NH-C-CH?COOCH3 23 ^NH-C-CHjCOOCH, 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 ambient 35 temperature for 4 h 10 min and at 80-90 °C for 1.5 h. The reaction was followed by TLC on silica gel with 10% MeOH-CHCl,. At this time a new, less polar product had begun to form. It was kept at ambient temperature for 18 h and at 80 °C for 2 h; additional Laewsson's reagent (40 mg, 0.099 mmol) was added and warming at 80 °C was continued for 2 h; some starting material still remained. The mixture was concentrated and the residue was chromatographed on silica gel with 15% acetone- CH,C1, to.give 0.348 g of 23: 'H NMR (300 MHz, CDC1,) d 3.05 im, 4H), 3.71 (s, 3H), 3.81 (d,d, IH), 3.86 (m, 4H), 3.88 (s, 2H), 4.07 (t, IH), 4.19 (m, 2H), 4.99 (m, IH), 6.91 (t, IH), 7.07 (d.d, IH), 7.42 (d,d, IH), 9.52 (s, IH); IR (DRIFT) 3269, 1743 cm1; MS(EI) m/z 411 (M+). Anal, calcd for C.^FN-AS: C, 52.54; H, 5.39; N, 10.21. Found: C, 52.58; H, 5.43; N, 10.14. 0 EXAMPLE 22: (S)-N-[[3-[4-[l-[l,2,4]Triazolyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]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 h, kept at ambient temperature for 18 h and concentrated in vacuo. Flash 20 chromatography of the residue on silica gel with 5% MeOH-CHCl3 gave the product which was crystallized from MeOH to give 0.100 g (63.4%) of 25: mp 161-163 °C; 'H NMR [300 MHz, (CD3)2S0] d 2.43 (s, 3H), 3.87 (m, 3H), 4.22 (t, IH), 4.99 (m, IH), 7.51 (d, IH), 7.77 (m, 2H), 8.26 (s, IH), 8.97 (d, IH), 10.35 (broad s, IH); IR (mull) 3259, 3226, 3044, 1752 cm1; MS(ES) m/z 336 (M+H+), 358 (M+Na*). Anal, calcd for C,4H14FN502S: 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-[l-[l,2,4]Triazolyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (25). s 24 o II o Ni-/ N n F nh2 CH3-C-SEt KOH/NaF EtOH/HjO NH-C-CH3 s II 277.27 26 335.36 c14h14fn5o2s 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 absolute EtOH (10 mL), under nitrogen, was treated during 5 min with a solution of 0.97 M KOH (1.03 mL) in EtOH and kept at ambient temperature for 2 h. It was then diluted with CH2CL2 5 (75mL), washed with water, 1M KHS04, water and brine and evaporated. The residue was flash chromatographed on silica gel with 57o MeOH-CHCl, and the product was crystallized from MeOH to give 0.118 g, mp 164-165°C (dec) and 0.026 g, mp 162-163°C (dec) of 25.
EXAMPLE 24: (S)-N-[[3-[l-(Hydroxyacetyl)-5-indolinyI]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (28). 1.
Boc ^"^^NHCbz CH2CI2 ^•"^^NHCbz 2. NaHCO, 52 53 A stirred, ice cold solution of 52 (8.80 g, 0.0240 mol) in CH,C1.> (25 mL) was treated 20 during 20 min with a solution of trifluoroacetic acid (25 mL) in CH2C12 (10 mL). The mixture was kept in the ice bath for 2 h 15 min and concentrated under reduced pressure. A solution of the residue in CH2C12 was washed with saturated NaHCO;J and dilute NaCl, dried (Na,S04) and concentrated. The residue was used in the next reaction without further purification. A sample of this material (53) had: 'H NMR (300 MHz, CDC1,) d 3.00 (t, 2H), 3.54 (t, 2H), 3.85 (broad s, IH), 5.17 (s, 2H), 6.59 (d, IH), 6.66 (broad s, IH), 6.91 (d, IH), 7.23 (s, IH), 7.36 (m, 5H); MS m/z 269 (M+H*). 2.
BzO-CH2-C=Q NHCbz 268.22 ^16^16^2^2 53 BzOCH2COCI NaHC03 (CH3)2C0/H20 N NHCbz 416.48 C25H24N204 54 PCT/U S98/25308 An ice cold, stirred mixture of 53 (crude product from the previous reaction), acetone (200 mL), saturated NaHCO., (200 mL) and water (30 mL) was treated, dropwise during 20 min, with a solution of benzyloxyacetyl chloride (4.70 mL, 0.030 mol) in acetone (55 mL), warmed slowly to ambient temperature and kept for 18 h.
Additional benzyloxytacetyl chloride (1.0 mL) in acetone 35 mL) was added dropwise and the mixture was kept at ambient temperature for an additional 3 h and diluted with EtOAc and water. A solid was collected by filtration and dried to give 4.00 g of crude product. The EtOAc solution was dried (Na2S04) and concentrated to give 5.36 g of additional crude product. Crystallization of the product from EtOAc gave a 10 total of 6.35 g of 54", mp 157-159.5°C. The analytical sample had: mp 158-159.5°C; 'H NMR (300 MHz, CDCl.,) 8 3,16 (t,2H), 4.01(t,2H), 4.21 (s, 2H), 4.69 (s, 2H), 5.19 (s, 2H), 6.67 (s, IH), 6.97 (d, IH), 7.36 (m, 10H), 7.50 (braod s, IH), 8.15 (d, IH); MS(EI) m/z (relative intensity) 416 (M*t 9), 310 (8), 202 (10), 133 (8), 92 (8), 91 (99), 79 (7), 77 (9), 65 (12), 51 (6); IR (mull) 2381, 1722, 1659, 1608, 1558 cm'1. Anal. 15 calcd for C^H^NA: C, 72.10; H, 5.81; N, 6.73. Found: C, 72.05; H, 5.86; N, 6.68. 3.
A. 382.42 \ ^>>H C21H22N2O5 ^ 55 A stirred suspension of 54 (1.16 g, 2.78 mmol) in THF (42 mL) was cooled, under nitrogen, to -78°C and treated, dropwise, during 5 min with 1.6 M n-BuLi in hexane (1.83 mL). It was kept at -78°C for 50 min, treated, dropwise, during 5 min with a solution of (RM-)-glycidyl butyrate (0.500 g, 3.47 mmol) in THF (2 mL), allowed to warm to ambient temperature during 3 h and kpet for 18 h. It was then diluted 30 with EtOAc, washed with saturated NH4C1, water and brine, dried (MgSOJ and concentrated. Chromatography of the residue on silica gel with 3% MeOH-O.2% NH4OH-CHCl;) gave 0.60 g (56%) of 5514: *H NMR [300 MHz, (CD.,),,SO] 5 3.14 (t, 2H), 3.59 (m, 2H), 3.79 (d,d, IH), 4.03 (m, 3H), 4.29 (s, 2H), 4.58 (s, 2H), 4.65 (m, IH), 5.20 (t, IH), 7.31 (m, 6H), 7.55 (s, IH), 8.03 (d, IH); MS(ES) m/z 383 (M+H*), 35 405 (M+Na*). 4.
NO, Bz0-CH2-C=0 \ Bz0-CH2-C=0 tojio toa H 3 \ / H -OH 56 O—Nos 55 An ice cold, stirred mixture of 55 (0.60 g, 1.57 mmol), triethylamine (2.2 mL), and CH,C12 (12 mL), under nitrogen, was treated with 3-nitrobenzenesulfonyl chloride (0.44 g, 1.99 mmol) and kept in the ice bath for 30 min and at ambient temperature 10 for 60 min. It was then diluted with CH2C12, washed with water and brine, dried (Na2S04) and concentrated. Chromatography of the residue on silica gel with 15% CHgCN-CHXljj gave 0.70 g of 56: 'H NMR (300 MHz, CDC1,) d 3.19 (t, J = 8.3 Hz, 2H), 3.88 (d,d, IH), 4.04 (t, J = 8.4 Hz, 2H), 4.14 (t, IH), 4.23 (s, 2H), 4.42 (m, 2H), 4.70 (s, 2H), 4.84 (m, IH), 6.97 (m, IH), 7.34 (m, 5H), 7.58 (s, IH), 7.81 (t, IH), 8.22 15 (m, 2H), 8.53 (m, IH), 8.73 (m, IH); MS(ES) m/z 568 (M+H*), 590 (M+Na+).
. BzO—CHZ—C=0 BzO—CHZ—C=0 9 NH3 O CUlNx0 —► CCAnA 56 ^-ONos 57 NH, A stirred mixture of 56 (crude product from 0.00314 mol of 55), acetonitride (70 mL), isopropanol (70 mL) and 29% ammonium hydroxide (70 mL) was warmed at 40-44 25 °C for 7h and kept at ambient temperature for 18 h. It was concentrated in vacuo to an aqueous residue with was extracted with CH2C12. The extract was washed with water and brine, dried (Na2S04) and concentrated. Chromatography of the residue on silica gel with 8% MeOH-O.5% NH4OH-CHCl3 gave 1.05 g of 57: 'H NMR [300 MHz, (CD3)2SO] d 2.78 (m, 2H), 3.13 (t, 2H), 3.82 (d,d, IH), 4.01 (m, 3H), 4.29 (s, 30 2H), 4.58 (s, 2H), 4.58 (m, IH), 7.31 (m, 6H), 7.54 (broad s, IH), 8.03 (d, IH); MS(ES) m/z 382 (M+H+), 404 (M+Na*). 6.
HO CH2-C=0 BzO-CH2-C=Q /-> HCI A mixture of 57 (0.46 g, 1.21 mmol), MeOH (150 mL), 1 M HC1 (1.2 mL) and 5% palladium-on-carbon catalyst (250 mg) was hydrogenated at an initial pressure of 49 psi for 5 h. Additional 1M HC1 (0.5 mL) and catalyst (100 mg) were added and hydrogenation was continued for 18 h. The catalyst was removed by filtration and 15 the filtrate was concentrated to give 0.34 g of 27: 'H NMR [300 MHz, (CD3)2SO) 8 3.15 (t, 2H), 3.22 (broad s, 2H), 3.84 (d,d, IH), 4.00 (t, 2H), 4.15 (s, 2H), 4.15 (m, IH), 4.92 (m, IH), 7.24 (q, IH), 7.50 (d, IH), 8.03 (d, IH), 8.37 (broad s, 3H); MS(ES) m/z 2.92 (M+H+).
A suspension of 27 (0.10 g, 0.34 mmol) in a mixture of EtOH (15 mL) and 0.97 M KOH (0.7 mL) was added, under nitrogen to a stirred mixture of ethyl dithioacetate (0.0412 g, 0.343 mmol) and sodium fluoride (0.0137 g, 0.326 mmol) in EtOH (5 mL) and the mixture was kept at ambient temperature for 2h 15 min. Additional 0.97 M KOH (0.2 mL), sodium iodide (6 mg) and ethyl dithioacetate (20 mg) were added and the mixture was stirred for 2 h. mixed with CH.CL (150 mL), washed with water, 1M KHS04 and brine, dried (NaL,SO,) and concentrated. The residue was crystallized from acetone to give 0.0404 g of 28: mp 175-176 °C (dec); MS (FAB) m/z 350 (M+H*), 349 (M*), 331, 316, 205, 73; HR MS (FAB) calcd for C16H,0N,O4S (M+H*) 350.1174, found 350.1183: 'H NMR [300 MHz, (CD.,),SO] d 2.42 (s, 3H), 3.14 7. (t, 2H), 3.79 (d,d, IH), 3.89 (t, 2H), 4.00 (t, 2H), 4.12 (m, 3H). 4.83 (t, IH), 4.90 (m, IH), 7.25 (d, IH), 7.50 (s, IH), 8.03 (d, IH), 10.35 (s, IH); IR (DRIFT) 3255, 3223, 3068, 1747, 1639, 1614 cm1.
EXAMPLE 25: (S)-N-[[3-[3-FIuoro-4-[4-(hydroxyacetyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (30).
A mixture of 58 (3.00 g, 7.00 mmol), THF (60 mL), absolute EtOH (100 mL) and 10% palladium-on-carbon catalyst (415 mg) was hydrogenated at an initial pressure of 58 psi for 2 h 50 min. 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 next reaction: 'H NMR (300 MHz, CDC13) d 2.16 (broad s), 3.02 20 (m, 8H), 3.73 (d,d, J = 3.9, 12.6 Hz, IH), 3.96 (m, 3H), 4.72 (m, IH), 6.92 (t, J = 9.2 Hz, IH), 7.11 (m, IH), 7.43 (d,d, J = 2.6, 14.3 Hz, IH); MS(ES) m!z 296 (M+H4). ° o ° '—V /T~\ A PhCH2OCH2COCI || /—^ X HN N-^ Vn O BzOCH,-C-N N—<' >-N O N—I y=/ \—L-'H NaHCOj N\—(r,,,H F OH (CH3)2C0/H20 F C 59 60 A stirred, ice cold mixture of 59 (2.67 g from the previous reaction), acetone (190 mL) and saturated NaHCO;) (70 mL) was treated, dropwise during 2-3 min with a 30 solution of benzyloxyacetyl chloride (1.34 mL, 8.61 mmol) in acetone (25 mL), kept in the ice bath for 1 h and diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic solution was washed with dilute NaCl, dried and concentrated. Chromatography of the residue on silica gel with 30% acetone-CH2Cl, gave 2.64 g of 60. 'H NMR (300 MHz, CDC13) d 2.28 (broad s, IH), 3.00 (m, 4H), 35 3.66 (m, 2H), 3.77 (m, 3H), 3.96 (m, 3H), 4.22 (s, 2H), 4.61 (s, 2H), 4.74 (m, IH), 6.88 (t, J = 9.2 Hz, IH), 7.12 (m, IH), 7.35 (s, 5H), 7.46 (d,d, J = 2.6, 14.2 Hz, IH); IR PCT/U S98/25308 (mull) 3406, 1748, 1647 cm1; HRMS(EI) calcd for Ca,H2BFN,Os (M+) 443.1856, found 443.1842. 3. bzoch^c—nqi-q-a. h + qtsojci h f t ? 2 f n-onos 60 N°> A stirred, ice cold mixture of 60 (2.64 g, 6.00 mmol) and triethylamine (1.14 mL, 8.16 mmol) in CHXl^ (200 mL), under nitrogen, was treated with 3-nitrobenzenesulfonyl chloride (1.78 g, 8.04 mmol), warmed to ambient temperature and kept for 5 h 20 min. Additional 3-nitrobenzenesulfonyl chlroide (180 mg) and triethylamine (0.20 mL) were added and the mixture was kept at ambient 15 temperature for 18 h, diluted with CH2C12 and washed with water and dilute NaCl, dried (Na2S04) and concentrated. Chromatography of the residue on silica gel with 40-60% acetone-hexane gave 3.36 g of 77: 'H NMR (300 MHz, CDC13) d 3.02 (broad s, 4H), 3.66 (broad s, 2H), 3.78 (broad s, 2H), 3.87 (d,d, J = 5.9, 9.1 Hz, IH), 4.09 (t, J = 9.2 Hz, IH), 4.22 (s, 2H), 4.41 (m, 2H), 4.61 (s, 2H), 4.84 (m, IH), 6.88 (t, J = 9.1 20 Hz, IH), 7.02 (m, IH), 7.35 (m, 6H), 7.82 (t, J = 8.0 Hz, IH), 8.23 (m, IH), 8.53 (m, IH), 8.73 (m, IH); MS(ES) m/z 629 (M+H*). 4.
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 warmed at 40-45 °C 30 for 18 h, treated with additional ammonium hydroxide (30 mL), warmed at 40-45 °C for 8 h, treated with additional ammonium hydroxide (25 mL) and warmed at 45 °C for 18 h. It was then mixed with water and extracted with CH2C12. The extract was washed with dilute NaCl, dried (NaJSO.,) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-O.5% NH4OH-CHCla gave 2.44 g of 61: 'H NMR 35 (300 MHz. CDCl,) d 1.50 (broad s), 3.04 (m, 6H), 3.65 (broad s, 2H), 3.81 (m, 3H), 3.99 (t, IH). 4.21 (s, 2H), 4.61 (s, 2H), 4.66 (m. IH), 6.88 (t, IH), 7.12 (m, IH), 7.33 (m, 5H), 7.47 (d,d, IH); MS(ES) m/z 443 (M+H*). . o n /—\ BzOCH2-C-N N- i-/\n o >=/ F *—NH. 61 O Hz. 5% Pd / C EtOH HCI HOCHj— A solution of 61 (1.45 g, 3.3 mmol) and 1.0 N HCI (3.65 mL) in 95% EtOH (150 mL) was treated with 5% palladium-on-carbon catalyst (500 mg) and hydrogenated at an 10 initial pressure of 54 psi for 20 h 15 min. Additional 1.0 N HCI (0.5 mL) and catalyst (100 mg) were added and hydrogenation was continued for 20 h 30 min at an initial pressure of 60 psi. The reaction was compete by TLC; it was neutralized with concentrated NH4OH, filtered and concentrated in vacuo to give 1.18 g of 29: 'H NMR [300 MHz, (CD3)2S01 d 2.94 (broad s, 4H), 3.19 (m, 2H), 3.48 (broad s, 2H), 15 3.60 (broad s, 2H), 3.84 (m, IH), 4.14 (m, 3H), 4.66 (broad s, IH), 4.93 (m, IH), 7.07 (t, IH), 7.16 (d,d, IH), 7.48 (d,d, IH), 8.04 (broad s); IR (mull) 3420, 3099, 3040, 3008, 1755, 1641 cm1; MS(ES) m/z 353 (M+H+). Anal, calcd for CI6H22C1FN404: C, 49.42; H, 5.70; CI, 9.12; N, 14.41. Found: C, 48.16; H, 5.82; CI, 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 0.97M KOH (1.46 mL, 1.42 mmol) and the resulting solution was kept at ambient temperature for 3 h 35 min, diluted with CHC1.„ washed with water and dilute NaCl, dried (Na._,S04) and concentrated. Chromatography of the residue on 30 silica gel with 5% MeOH-O.5% NH4OH-CHCl;, and crystallization of the resulting product from absolute EtOH gave 0.238 mg (44.9%) 30: mp 163-165 °C; 'H NMR (300 MHz, CDCl,) d 2.60 (s, 3H), 3.06 (m, 4H), 3.45 (m, 2H), 3.61 (m, IH), 3.82 (m, 3H), 4.07 (m, 2H), 4.25 (m, 3H), 4.97 (m, IH), 6.91 (t, IH). 7.07 (m, IH), 7.45 (d,d, IH), 7.91 (broad s, IH); MS(FAB) m/z (relative intensity) 411 (M+H*, 100), 410 (M*, 35 66.5), 266 (3.1); IR 3292, 1733, 1653 cm1. Anal, calcd for C18H23FN404S: C, 52.67; H, 5.65; N, 13.65. Found: C, 52.76; H, 5.58; N, 13.64. 6. s 29 EXAMPLE 26: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thio-acetamide (32).
II 9 t V. \ fi~\ A CH3—C-SEt /—\ 11 S N—U 7—N O s N—vf y-N O )=/ Et3N >=/ V—^ „ ,.H § 31 NH, F NH—C—CH3 32 An ice cold, stirred mixture 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 kept at ambient temperature for 24.5 h and concentrated in vacuo. A solution of the residue in CH2C12 was washed with saturated NaHCO;1, water and brine, dried (MgS04) and concentrated. 15 Crystallization of the residue from EtOAc-hexane gave 0.355 g of 32: mp 155-156 °C; MS(ES) m/z 370 (M+H*), 392 (M+Na+); IR (DRIFT) 3206, 3042, 1759, 1738 cm1; 'H NMR (300 MHz, CDC13) d 2.60 (s, 3H), 2.95 (s, 4H), 3.43 (m, 4H), 3.82 (d, d, IH), 4.08 (m, 2H), 4.27 (m, IH), 4.98 (m, IH), 7.06 (m, IH), 7.33 (broad s, IH), 7.51 (d, IH), 8.03 (broad s, IH). Anal, calcd for C16H20FN3O2Sa: C, 52.01; H, 5.46; N, 11.37. 20 Found: C, 51.86; H, 5.43; N, 11.20.
EXAMPLE 27: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thio-acetamide, thiomorpholine S-oxide (34). 1.
O O /—\ /r\ A Nal04 /—s r. ^ S N-V >-N O +■ 0=s N—" V-N I \=/ \ L.A F N- Nalu4 /—\ /r^\ A ► o=s N-f Vn^o "H MeOH / HaO V—/ \=J \ £.--H —OH F V_n F OH F OH 62 63 An ice cold, stirred 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 h and at 4 °C for 3 h. It was then treated with additional sodium metaperiodate (0.1 g), kept at 4°C for 3 h and extracted with CHC1.,. The extract was dried (MgSO.,) and concntrated to give 1.4 g of 63: 'H NMR [300 MHz, (CD3)2SO) d 2.84 (m, 2H), 3.01 (m, 2H), 3.16 (m, 2H), 3.50 (m, 3H), 3.65 (m, IH), 3.77 (d.d, IH), 4.03 (t, IH), 4.66 (m, IH), 5.18 (t, IH), 7.16 (m, 2H), 7.52 (m, IH); MS(ES) mtz 329 (M+H*), 351 (M+Na*).
An ice cold, stirred mixture of 63 (1.27 g, 3.87 mmol) and triethylamine (0.732 mL, 10 5.25 mmol) in CH2C12 (130 mL), under nitrogen, was treated with m- nitrobenzenesulfonyl chloride (1.15 g, 5.19 mmol) and kept at ambient temperature for about 24 h. It was diluted with CH2C12, washed with water and brine, dried (Na2S04) and concentrated to give 78 which was used in the next reaction without purification. o O 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% NH.,) and kept at 40 °C for 2 h, at ambient temperature for 18 h and at 40-45 °C for 4 h; it was concentrated to about 50 mL, diluted with water and extracted with CH-jCL. The extracts were washed with water and brine, dried (MgS04) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-CHCl3 gave 0.58 g of 33: MS(ES) mtz 328 (M+H*), 350 (M+Na+); lH NMR [300 MHz, (CD^SO] 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, IH), 4.01 (t, IH), 4.58 (m, IH), 7.19 (m, 2H), 7.51 (m, IH).
S II o ch3—c—set /—\ a o=s n—(' Vn o - Et,N \—/ \=/ \ (. H S r ^^nh-C-CH3 34 A stirred suspension of 33 (3.7 g, 0.011 mol) and triethylamine (3.5 mL, 0.025 mol) in THF (120 mL) was cooled, in an ice bath, under nitrogen, treated, dropwise during 2 min, with a solution of ethyl dithioacetate (1.47 mL, 0.0128 mol) in THF (2 mL) and kept at ambient temperature for 22 h. The resulting solution was 5 concentrated and the residue crystallized from acetonitrile to give 3.61 g of 34: mp 176-177 °C ; 'H NMR [300 MHz, (CD.,)2SO] d 2.42 (s, 3H), 2.85 (m, 2H), 3.01 (m, 2H), 3.18 (m, 3H), 3.50 (m, 2H), 3.78 (d,d, IH), 3.89 (broad s, 2H), 4.12 (t, IH), 4.92 (m, IH), 7.18 (m, 2H), 7.49 (m, IH), 10.33 (s, IH); IR (DRIFT) 3186, 3102, 1741 cm1; MS(ES) mlz 386 (M+H+), 408 (M+Na*). Anal, calcd for C16H20FN303S2o0.5 H20: C, 10 48.71; H, 5.37; N, 10.65; S, 16.26; HA 2.38. Found: C, 48.75; H, 5.17; N, 10.72; S, 16.07; HA 1-72.
EXAMPLE 28: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyI)phenyl]-2-oxo-5-oxazolidinyl]methyl]thio-acetamide, thiomorpholine S, S-dioxide (36). 1.
O s' Vl-^V-N^O \ t \=J \ /■■■■■ H F OH 0s04 /—^ n-\ X 0,=S N-/' VN^O ' 3=/ ^ NMO " N—t y=J \ L-H (CH3)2C0/H20 f OH 64 A stirred mixture of 62 (0.399 g, 0.00128 mol) in 25% water/acetone (12 mL), under nitrogen was treated with N-methylmorpholine, N-oxide (0.45 g, 0.00384 mol) and 0.1 mL of a 2.5 wt% solution of osmium tetroxide in terf-butanol. It was kept at 25 ambient temperature for 18 h, mixed with saturated NaHSO-, (50 mL) and extracted with CH2C12. The extract was washed with saturated NaHS03 and brine, dried (Na,S04) and concentrated. The residue was mixed with 3.5% MeOH-CRjCl., and filtered; the solid was dissolved in 15% MeOH-CH2Cl2 and concentrated to give 0.29 g of 64. The filtrate was chromatographed on silica gel with 3.5% MeOH-CH2Cl2 to 30 give 0.1 of additional 64: MS(ES) m/z 345 (M+H+), 367 (M+Na+); 'H NMR (300 MHz, (CD;1).,SO] d 3.26 (m, 4H), 3.44 (m, 4H), 3.60 (m, 2H), 3.80 (d,d, IH), 4.05 (t, IH), 4.69 (m, IH), 7.22 (m, 2H), 7.54 (d, IH).
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, 10 portionwise during 5 min, with 3-nitrobenzenesulfonyl chloride (0.335 g, 0.00151 mol). The mixture was kept in the ice bath for 20 min and at ambient temperature for 18 h 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), warmed at 50-55 °C for 6 h and kept at ambient temperature for 48 h. It was 15 concentrated to remove the organic solvents, diluted with water and extracted with CHjCIjj. The extract was washed with water and brine, dried (MgS04) and concentrated. Flash chromatography of the residue on silica gel with 6% MeOH-0.4% NH40H-CHC13 gave 0.29 g of 35: 'H NMR [300 MHz, (CD-^SO] d 1.59 (broad s, 2H), 2.78 (m, 2H), 3.24 (m, 4H), 3.43 (m, 4H), 3.81 (d,d, IH), 4.01 (t, IH), 4.57 (m, 20 IH), 7.18 (m, 2H), 7.52 (m, IH); MS(ES) m/z 344 (M+H*), 366 (M+Na+). 3. s yyA H C"'J"SB . s W >=/ e,3N U2 W >=/ W..-H S f ^-nh2 f n_nh—c-ch3 35 36 A stirred, ice cold suspension of 35 (0.28 g, 0.85 mmol) in a mixture of Et.,N (0.26 mL, 1.9 mmmol) and THF (10 mL) was treated with ethyl dithioacetate (0.11 mL, about 6 drops) and kept in the ice bath for 20 min and then at ambient temperature; the reaction was followed by TLC. After 20 h there was still a suspension and only 30 partial reaction; additional THF (10 mL) and ethyl dithioacetate (3 drops) were added. After an additional 48 h the reaction was still incomplete; the suspension was treated with CH.,C12 (10 mL) and kept for 72 h. At this time almost complete solution and an almost complete conversion to product had been obtained. An additional drop of ethyl dithioacetate was added and the mixture was kept at 35 ambient temperature for 5 d and concentrated in vacuo. The residue was mixed with EtOAc, washed with saturated NaHC03, water and brine, dried (MgS04) and concentrated. Crystallization of the residue from MeOH-EtOAc gave 0.209 g of 36: mp 197-198 °C; 'H NMR [300 MHz, (CD3)2SO] d 2.42 (s, 3H), 3.24 (m, 4H), 3.43 (m, 4H), 3.78 (d,d, IH), 3.88 (m, 2H), 4.12 (t, IH), 4.92 (m, IH), 7.18 (m, 2H), 7.50 (m, IH), 10.37 (broad s, IH); IR (mull) 3300, 3267, 1743 cm1; MS(ES) mtz 424 (M+Na*). 5 Anal, calcd for C16H,0FN.,O4S.,: C, 47.87; H, 5.02; N, 10.47. Found: C, 47.84; H, 5.23; N, 10.28.
EXAMPLE 29: (S)-N-[[3-[3,5-Difluoro-4-[4-(hydroxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazoIidinyI]methyI]thioacetamide (38). 1.
F 0 Boc-N7 Yi-^Vn^O \—t \=J f n^nh2 66 A stirred mixture of 65 (1.8 g, 0.00396 mol), pyridine (30 mL) and absolute EtOH (3 mL), under nitrogen, was treated with hydroxylamine hydrochloride (1.44 g, 0.0207 mol), warmed to the reflux temperature during 2 h, refluxed for 3.5 h, kept at 20 ambient temperature for 18 h and at reflux for 4 h. It was concentrated in vacuo and the residue was mixed with water, adjusted to pH 11 with saturated NaHC03 and extracted with Et.,0. The extracts were washed with brine, dried (Na2S04) and concentrated. Chromatography of the residue on silica gel with 5% MeOH-O.35% NH4OH-CHCl3 gave 0.75 g of recovered 65 and 0.72 g of 66: 'H NMR [300 MHz, 25 (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, IH), 4.00 (t, IH), 4.59 (m, IH), 7.27 (d, 2H); MS(ES) mtz 413 (M+H+), 435 (M+Na*). /—^ )r~\ A n n-/' vn o w y=/ M-.-H NH,OH ■ HCI Boc- -;~~; X —" Py/EtOH NHAc 65 2.
F O F O /—\ Va U. PhCH2OCOCI „ K1A„ Boc-N N-/\nA0 »- Boc-N N-^ VN O W y=T Et3N / THF W ..W Mr" F^ V_Nh2 3 F 6? ^NHCbz 66 An ice cold, stirred mixture of 66 (0.75 g, 0.0018 mol) and triethylamine (0.315 mL, 35 0.00225 mol) in THF (12 mL), under nitrogen, was treated, dropwise with benzyl chloroformate (0.29 mL, 0.0020 mol), kept in the ice bath for 15 min and at ambient temperature for 2 h and concentrated in vacuo. The residue was mixed with CH2C12 and washed with saturated NaHC03, water and brine, dried (Na2S04) and concentrated. This residue was mixed with Et20 and filtered to give 0.939 g of 67: mp 116-118 °C; 'H NMR (300 MHz, CDC13) d 1.48 (s, 9H), 3.08 (m, 4H), 3.53 (m, 5 4H), 3.60 (m, 2H), 3.73 (m, IH), 3.96 (t, IH), 4.76 (m, IH), 5.10 (s, 2H), 5.21 (m, 1H),7.07 (d, 2H), 7.31 (s, 5H); MS(ES) m/z 547 (M+H*), 569 (M+Na*).
Compound 67 (0.805 g, 0.00147 mol) was added with stirring, portionwise during 5 min, under nitrogen, to ice cold trifluoroacetic acid (9 mL). The resulting solution was kept in the ice bath for 1 h and then concentrated under a stream of nitrogen. The residue was mixed with ice and saturated NaHC03 and extracted with CH2C12; the extract was washed with water and brine, dried (Na2S04) and concentrated to give 0.63 g of product. The combined aqueous layer was reextracted with EtOAc; the extracts were washed with water and brine, dried (Na2S04) and concntrated to give additional product. The combined product amounted to 0.68 g of 68 which was used in the next reaction without further purification. 4. o A, V>VNAO iavx*v°a Szoc„!4_,T\J'Vr-o J >=/ \—4-"H NaHCO-i V—' _) ^ NaHCOj J—' M^V NHCbz ,CH3)2C0/H20 F NHCbz 68 69 An ice cold, stirred mixture of 68 (0.68 g, 0.00152 mol), saturated NaHC03 (15.2 mL) and acetone (40 mL), under nitrogen was treated, dropwise during 15 min, with a solution of benzyloxyacetyl chloride (0.29 mL, 0.0019 mol) in acetone (5 mL), kept at ambient temperature for 6 h, diluted with EtOAc and washed with water and brine. The extract was dried (MgS04) and concentrated in vacuo to give 0.72 g of 69: 35 MS(ES) m/z 395 (M+H*), 617 (M+Na*); 'H NMR (300 MHz, CDCln) d 3.12 (m, 4H), 3.59 (m. 4H), 3.74 (m, 3H), 3.96 (t, IH), 4.22 (s, 2H), 4.62 (s, 2H), 4.75 (broad s, IH), .10 (s, 2H), 5.22 (m. IH), 7.08 (d, 2H), 7.33 (m, 10H).
. A mixture of 69 (0.72 g, 0.0012 mol), MeOH and 5% palladium-on-carbon catalyst 10 (0.4 g) was hydrogenated at an initial pressure of 45 psi for 4 h. By TLC (8% MeOH-O.5% NH4OH-CHCla) the starting material had been reduced and two products formed. 1M Hydrochloric acid (1.34 mL) was added and hydrogenation was continued at an initial pressure of 40 psi for 21 h. By TLC only the more polar product remained. The catalyst was removed by filtration and the filtrate was 15 concentrated to give 0.40 g of 37: MS(ES) m/z 371 (M+H*), 393 (M+Na+); 'H NMR [300 MHz, (CD3)2SO] d 3.02 (s, 4H), 3.20 (m, 2H), 3.43 (s, 2H), 3.56 (s, 2H), 3.84 (m, IH), 3.84 (broad s), 4.10 (s, 2H), 4.14 (t, IH), 4.96 (m, IH), 7.26 (d, 2H), 8.41 (broad s, 3H). 6.
O F O II \ JL.
I —C-N N-f VN^O u _ \-/ >=/ \_4--H j? F N_NH—C—CHj 3B A stirred suspension of 37 (0.38 g) in a solution of EtaN (0.31 mL) and THF (10 mL), under nitrogen, was treated with ethyl dithioacetate (0.13 mL, about 7 drops) and kept at ambient temperature for 7 d; the reaction was followed by TLC (8% MeOH-0.5% NH4OH-CHCl.,). Additional ethyl dithioacetate (2 drops) was added after 24 h; 30 after 30 h CH^CL, (10 mL) and ethyl dithioacetate (3 drops) were added; after 48 h additional triethylamine (0.3 mL) was added. The mixture was concentrated in vacuo and the residue was mixed with ice and saturated NaHCO, an extracted with CH.CL,. The extract was washed with water and brine, dried (MgS04) and concentrated. The residue was chromatographed on silica gel with 2.5% MeOH-35 CH,CI, and the product was crystallized from MeOH to give 0.182 g of 38: mp 110-111 °C (dec); MS(ES) m/z 429 (M+H+), 451 (M+Na*); HRMS (FAB) calcd for o II HOCH2—C-N S II CH3—C-SEt ilUN xHCI 37 C18H:aF:!N404S (M+H*) 429.1408, found 429.1415; IR (DRIFT) 1760, 1652, 1639 cm1; [cx24d 8° (MeOH).
EXAMPLE 30: (S)-N-[[3-[4-[l-[l,2,4]Triazolyl]phenyl]-2-oxo-5-5 oxazolidinyl]methyl]thiourea (44).
A solution of 26 (0.190 g, 0.685 mmol) in CH,C1., (20 mL) was added, dropwise during 20 min, under nitrogen, to an ice cold, stirred solution of 1,1 (Z-thiocarbonyldi-15 2(lH)-pyridone (0.193 g, 0.831 mmol) in CH,C12 (7 mL). The mixture was kept in the ice bath for 20 min and at ambient temperature for 2 h, diluted with CH2C12> washed with water and brine, dried (MgS04) and concentrated. Chromatography of the residue on silica gel with 10-15% CH3CN-CH2C12 gave 0.11 g of 79 which was used in the next reaction without further purification: MS(ES) m/z 320 (M+H+), 342 20 (M+Na+).
A stirred, ice cold 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 min. It was then evaporated under a stream of nitrogen to a volume of about 5 mL to give a solid which was collected by filtration and washed with cold THF to give 0.105 g of 44: mp 214-215 °C; 'H NMR [300 MHz, (CDs),SO] d 3.82 (m, 3H), 4.18 (t, IH), 4.89 (broad s, IH), 7.20 (broad s, 2H), 7.50 (d, IH), 7.79 (m, 2H), 7.93 (t, IH), 8.26 (s, IH), 8.97 (s, IH); MS(ES) m/z 337 (M+H*). 359 (M+Na*). Anal, calcd for Cl3HJ3FN602S: 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)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]thiourea (45). 1.
Cvr1 o hochj-c—n' ^n—° s ° , hoch2-c—n/ ^n—v-n^o V-y EtjN/CHjClj W 29 NH2 f >— N=C«S HCI 80 An ice cold, stirred solution of l,ltf-thiocarbonyl-2(lH)-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 during 10 min with a solution of triethylamine (0.111 mL, 0.8 mmol) in CH2C12 (10 mL). It was kept in the ice bath for 30 min, at ambient temperature for 2 h and at < 0 °C for 18 h. It was then 15 diluted with CH2C12, washed with water and brine, dried (MgS04) 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: 'H NMR (300 MHz, CDC13) d 1.60 (broad s), 3.07 (m, 4H), 3.45 (m, 2H), 3.85 (m, 4H), 3.97 (d,d, IH), 4.16 (t, IH), 4.21 (s, 2H), 4.82 (m, IH), 20 6.95 (t, IH), 7.13 (d,d, IH), 7.47 (d,d, IH); MS mtz 395 (M+H+); 417 (M+Na+). 2. o o O O hoch2-c—n' V/\-lA> n"3 ► hochj—C—n' \j—o s W >=/ w >=/ MrH M f ^—n=c=s f nh-c—nh2 80 <5 Excess anhydrous ammonia was bubbled into a stirred, ice cold solution of 80 (crude product from the previous reaction) in THF (25 mL) and the mixture was kept in the 30 ice bath for 90 min and concentrated under a stream of nitrogen. The residue was chromatographed on silica gel with 5% MeOH-O.4% NH40H-CHC13 and the product was crystallized from acetonitrile to give 0.0544 g of 45: mp 209-210 °C; 'H NMR [300 MHz, (CD^SO] d 294 (broad s, 4H), 3.47 (broad s, 2H), 3.60 (broad s, 2H), 3.78 (broad s, 3H), 4.07 (t, IH), 4.10 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 5.5 Hz, IH), 4.81 35 (broad s, IH), 7.05 (t, IH), 7.16 (d,d, IH), 7.15 (broad s, 2H), 7.49 (d,d, IH), 7.91 (t, IH); IR (mull) 3443, 3403, 3321, 3202, 3081, 1753, 1655, 1648 cm1; HRMS (FAB) calcd for C^H.^FN^S (M+H*) 412.1454, found 412.1447. Anal, calcd for CnH,,FN504S: C, 49.63; H, 5.39; N, 17.02. Found: C, 49.63; H, 5.48; N, 16.99.
EXAMPLE 32: (S)-N-[[3-[l-(Hydroxyacetyl)-5-indolinyl]-2-oxo-5-5 oxazolidinyl]methyl]thiourea (46). 1.
An ice cold, stirred solution of l,l0-thiocarbonyldi-2(lH)-pyridone (0.096 g, 0.41 mmol) in CH2C12 (5 mL) was treated with a suspension of 27 (0.10 g, 0.34 mmol) in CH2C12 (15 mL) and then with 0.05 mL (0.36 mmol) of triethylamine. It was kept in the ice bath for 30 min and at ambient temperature for 2 h, diluted with CH2C12, 20 washed with water and brine, dried (MgS04) and concentrated. Chromatography ofthe residue on silica gel with 20-40% CH3CN-CH2C12 gave 0.04 g of 81. 2.
HOCHj-C-0 HOCHj -C -0 q NHj o COa .
Mr H 5 N— N=C=S W-C-WH2 81 46 Excess anhydrous ammonia was bubbled into an ice cold solution of 81 (0.04 g) in THF (30 mL) and the mixture was kept in the ice bath for 80 min and concentrated 30 under a stream of nitrogen. The residue was crystallized from CH3CN to give 0.0151 g of 46: mp 214-215 °C (dec); MS (FAB) m/z 351 (M+H*), 350 (M*), 319, 304, 147; HRMS (FAB) calcd for C,3H19N404S (M+H*) 351.1127, found 351.1130; IR (DRIFT) 3329, 3296, 3196, 1746, 1655, 1626 cm1.
EXAMPLE 33: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5- PCT/U S98/25308 oxazoIidinyl]methyl]thiourea, thiomorpholine S-oxide (47).
A suspension of 33 (0.30 g, 0.92 mmol) in CH2C12 (7 mL) was added, during 20 min, 10 to an ice cold, stirred mixture of 1,1 ?-thiocarbonyldi-2( lH)-pyridone (0.258 g, 1.11 mmol) and CH,C12 (20 mL). The mixture was kept in the ice bath for 20 min and at ambient temperature for 2 h, mixed with CH.,C12 (50 mL), washed with water and brine, dried (MgS04) and concentrated. Chromatography of the product on silica gel with 20-50% CH3CN-CHaCl2 gave 0.27 g of 82 which was used in the next reaction: 15 MS(ES) m/z 370 (M+H+), 392 (M+Na+). 2. o o A stirred, ice cold 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 h and 25 concentrated; crystallization of the residue from MeOH gave 0.175 g of 47; mp 212-213 °C; lH NMR [300 MHz, (CD3)2SO] d 2.83 (m, 2H), 3.01 (m, 2H), 3.17 (m, 2H), 3.50 (t, 2H), 3.78 (broad s, 3H), 4.08 (t, IH), 4.80 (broad s, IH), 7.17 (m, 2H), 7.17 (broad s, 2H), 7.50 (d, IH), 7.90 (t, IH); MS(ES) m/z 409 (M+Na*); IR (mull) 3335, 3284, 3211, 3175, 3097, 1750, 1630 cm1. Anal, calcd for C15H19FN403S2: C, 46.62; H, 30 4.95; N, 14.50. Found: C, 46.50; H, 4.95; N, 14.40.
EXAMPLE 34: (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl-S-methyldithiocarbamate (48).
PCMJS98/25308 An ice cold, stirred mixture 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 h and at 5 ambient temperature for 18 h. (A solution was obtained after the addition of carbon disulfide; a white precipitate began to form soon after the mixture was warmed to ambient temperature.) The thick suspension was treated, dropwise during 2 min, with a solution of methyl iodide (0.137 mL, 0.00220 mol) in EtOH (2 mL) and the mixture was kept at ambient temperature for 1.5 h and concentrated in vacuo. A 10 solution of the residue in EtOAc was washed with saturated NaHC03, water and brine, dried (MgS04) 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: mp 154-155 °C; IR (mull) 3354, 3346, 1726 cm"1. Anal, calcd for CuHaFNaOsSg: 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]methy]-0-methylthiocarbamate (50).
NaOOt _ MeOH 48 NH—C—SCH3 F ^—NH-C —OCH3 50 A stirred mixture of 48 (0.200 g, 0.518 mmol), sodium methoxide (0.003 g, 0.06 25 mmol) and MeOH (5 mL), under nitrogen, was refluxed for 4 h and kept at ambient temperature for 18 h. It was found that the starting material and product had similar mobilities on TLC. the reaction was therefore followed by MS(ES). Starting material was still present. The mixture was refluxed for 3 h, additional sodium methoxide (0.005 g) was added and reflux was continued for 2 h. It was kept at 30 ambient temperature for 18 h, refluxed for 1 h, kept at ambient temperature 1.5 h and concentrated in vacuo. The residue was mixed with ice, the pH was adjusted to 9-10 with 1M KHS04 and saturated NaHC03 and the mixture was extracted with CH2CL. The extract was washed with water and brine, dried (MgSOJ and concentrated. The residue was chromatographed on silica gel with 5% acetone-35 CH2CL and the product was crystallized from EtOAc-hexane to give 0.107 g of 50: mp 128-129 °C; MS(ES) mtz 370 (M+H*), 392 (M+Na*); IR (DRIFT) 3282, 3251, 1753, 1735 cm1; 'H NMR [300 MHz, (CD3)2SO] d 2.94 (m, 4H), 3.47, 374 (m,m, 7H), 3.86, 3.91 (s,s, 3H), 4.10 (m, IH), 4.73, 4.86 (m,m, IH), 7.05 (t, IH), 7.16 (d,d, IH), 7.47 (d,d, IH), 9.41, 9.50 (s,s, IH). Anal, calcd for CI6H20FN3O4S: C, 52.02; H, 5.46; N, 11.38. Found: C, 51.97; H, 5.49; N, 11.35.
When in the procedure of Example 35 an appropriate amount of sodium ethoxide was substituted for sodium methoxide, the compound of Example 36 below in Table A was obtained.
When in the procedure of Example 1 an appropriate amount of (S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]isopropylcarboxamide, (S)-N-[[3-[3-fluoro-4-morpholinyJ]phenyI]-2-oxo-5-oxazolidinyl]methyI]cyclopropylcarboxamide, or (S)-N-[[3-[3,5-difluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide was substituted for (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyljacetamide (Compound 11) and the general procedures of Example 1 was followed, the compounds of Examples 37, 38 and 39 respectively as set forth below in Table A were obtained. The isopropylcarboxamide and the cyclopropylcarboxamide are obtained by following the procedure in Example 5 of U.S. Patent No. 5,688,792 only substituting isobutyric anhydride and cyclopropane carbonyl chloride respectively for acetic anhydride in step 7. The acetamide is obtained as described in U.S. Patent No. 5,688,792 at Example 4.
When in the procedure of Example 5, step B, an excess amount of dimethylamine in THF is substituted for anhydrous ammonia, the compound of Example 40 set forth below in Table A is obtained.
TABLE A R o o ^NJ~yNK v_y s F *—NH—C—R' Example No. Compound R. R' 36 (S)-N-[[3-[3-FIuoro-4-(4-morpholinyl)- R = H, R' = OC2H5 phenyl]-2-oxo-5- oxazolidinyl]methyl]-0-ethylthiocarbamate: mp 120 °C. MS(ES) m/z 384 (M+H+). Anal, calcd for C,7H22FN.i04S: C. 53.25: H. 5.78; N. 10.96.
Found: C. 53.23; H, 5.82; N, 10.92.
Example No. 37 Compound (5)-N-[[3-[3-Fluoro-4-(4-morpholinyl)- R. R' R = H. R' = CH(CH3)2 phenyl ]-2-oxo-5-oxazolidinyI]methyl]-2-methylpropanethioamide: mp 152-153 °C (dec.): Anal, calcd for CisHi-jFNiO.iS: C. 56.67: H. 6.34; N. 11.02. Found: C, 56.58: H. 6.41: N. 10.81 38 (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)- r = h, r' = -<3 phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropane-carbothioamide; mp 155-156 °C; Anal, calcd for CisHiiFNjOjS: C, 56.98; H, 5.84: N. 11.07. Found: C. 56.98; H, 5.85: N, 10.97 39 (S)-N-[[3-[3.5-Difluoro-4-(4-morpholinyl)- R = F. R' = CHi phenyl]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide 40 (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)- R = H. R' = N(CHj)2 phenyl]-2-oxo-5-oxazolidinyl]methyl]-N',N'-dimethylthiourea PREPARATION Z Methyl Dithiopropionate cs2 1) CH3CH2MgBr under nitrogen is treated with a crystal of iodine and about 5% of a solution of bromoethane (30.0 mL. 0.40 mol) in THF (200 mL). When the reaction starts, the remainder of the bromoethane solution is added, dropwise at a rate sufficient to maintain a gentle reflux.
After the addition, stirring is continued for 1 hour: the resulting solution is cooled to -20 °C and treated, during 10 minutes with carbon disulfide (24.0 mL. 0.40 mol). The mixture is warmed to 15 °C. treated with methyl iodide (28.0 mL, 0.45 mol) and kept at 60 °C for 1 hour. It is then cooled in an ice bath, treated with ice and extracted with EbO. The extract is washed with brine, dried (MgS04) and concentrated. Distillation of the residue gives 34.0 g of the titled product, bp 48-52 °C (12 mmHg).
WO 00/32599 PCT/US98/25308 The following methyl dithio compounds were obtained when the appropriate alkyl magnesium bromide wus substituted for ethyl magnesium bromide in the above procedure: TABLE B S II Rs-C—SCH3 Rs = (b) (CH,hCH- (h) o- (o [>_ (i) [3_ (d) CH3CH2CH;>- (j) (c) CH3 (k) ch3ch-ch2— (f) CH3 (1) ch3ch2ch— (g) (CHjXiC-CHj- (rn) o [>-ch2— <0^CH2- CD-™2- When following the general procedure of Example 27, step 4, an appropriate 10 amount of the amine listed below is reacted with the dithio compound listed below the respective compounds. Examples 41 to 61 of Table C are obtained.
When following the general procedure of Example 25, step 6, an appropriate amount of the amine listed below is reacted with the dithio compound listed below, the respective compounds. Examples 62 to 67, of Table C are obtained.
WO 00/32599 PCT/US98/25308 TABLE C Example Compound Amine Dithio Compound No. (from Preparation Z) 41 (5)-N-[[3-[3-FIuoro-4- ^ ^ Z (a) (4-thiomorpholinyl)- H phenyI]-2-oxo-5- F L'Nh2 oxazolidinyljmethyl]-propanethioamide, thiomorpholine S-oxide: mp 196-197°C; Anal, calcd for C^HijFNIOJST. C, 51.11: H, 5.55; N, 10.52; S, 16.05. Found: C, 50.99; H, 5.60; N. 10.55; S. 15.75 42 S)-N-[[3-[3-Fluoro-4-(4- Same as above Z (b) thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]mcthyl]-2-methylpropanethio-amide. thiomorpholine S-oxide; mp 195-196°C; Anal, calcd for Ci8H2.tFN3O.1S2: 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 (S)-N-[[3-[3-Fluoro-4- . Same as above Z (c) (4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothio-amide. thiomorpholine S-oxide; mp 109-110°C: Anal, calcd for C|gH22FN.,0.,S2: 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 Example No. 44 45 Compound (5)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]- butanethioamide. thiomorpholine S-oxide (S)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyI]-3- methylbutanethioamide. thiomorpholine S-oxide Amine Same as above Dithio Compound (from Preparation Z) Z(d) Same as above Z (e) 46 (S)-N-[[3-[3-Fluoro-4- Same as above Z (f) (4-thiomorpholinyl)- phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylbutanethioamide, thiomorpholine S-oxide 47 (SyN-t^-tS-Fluoro^- Same as above Z (g) (4-thiomorpholinyl)- phenyl]-2-oxo-5-oxazolidinyljmethyl]-3,3-dimethylbutanethio-amide, thiomorpholine S-oxide 48 (S)-N-[[3-[3-Fluoro-4- Same as above Z(h) (4-thiomorpholinyl)-phenyI]-2-oxo-5-oxazolidinyljmethyl]-cyclobutanecarbothio-amide, thiomorpholine S-oxide 49 (5)-N-[[3-[3-Fluoro-4- Same as above Z (i) (4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyljmethyl]-1 -cyclopentanecarbothio-amide. thiomorpholine S-oxide Example No. 50 Compound (S)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyl )- phenyl]-2-oxo-5- oxazolidinyljmethyl]- cyclohexanecarbothio- amide. thiomorpholine S-oxide Amine Same as above Dithio Compound (from Preparation Z) Z(j) 51 (S)-N-[[3-[3-Fluoro-4- Same as above Z (k) (4-thiomorpholinyi)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-cyclopropylethanethio-amide. thiomorpholine S-oxide 52 (S)-N-[[3-[3-Fluoro-4- Same as above Z (1) (4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-cyclobutylethanethio-amide, thiomorpholine S-oxide 53 (S)-N-[[3-[3-Fluoro-4- Same as above Z (m) (4-thiomorpholinyI)-phenyl]-2-oxo-5-oxazolidinyllmethyl]-2-cyclopentylethanethio-amide, thiomorpholine S-oxide 54 (5)-N-[[3-[3,5-Difluoro- ^ o Ethyl dithioacetate 4-(4-ihiomorpholinyl)- o=S/ vn-/\-n o phenyI]-2-oxo-5- —' /=^ I oxazolidinyljmethyl]-thioacetamide, thiomorpholine S-oxide -h '-nhj 55 (5)-N-[[3-[3.5-Difluoro- Same as above Z (a) 4-(4-thiomorphoIinyl)-phenyl]-2-oxo-5-oxazolidinyljmethyl]-propanethioamide, thiomorpholine S-oxide Example Compound Amine Na 56 (S)-N-[[3-[3.5-Dif]uoro- Same as above 4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazoIidinyl]methyl]-2-methylpropanethio-amide. thiomorpholine -oxide 57 (5)-N-[[3-[3.5-Difluoro- Same as above 4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyljmethyl]-cyclopropanecarbothio-amide. thiomorpholine -oxide 58 (5)-N-[[3-[4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyljmethyl]-thioacetamide, thiomorpholine S-oxide o=s \l— \ t tH •—NH2 59 (J)-N-[[3-[4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide, thiomorpholine S-oxide Same as above 60 (S)-N-[[3-[4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethio-amide, thiomorpholine S-oxide Same as above 61 (5)-N-[[3-[4-(4- Same as above thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothio-amide. thiomorpholine S-oxide Dithio Compound (from Preparation Z) Z(b) Z(c) Ethyl dithioacetate Z(a) Z(b) Z (c) Example Compound No. 62 (5)-N-[[3-[3,5-Difluoro- 4-(4-hydroxyacetyI)-1 - piperazinyl]phenyI]-2- oxo-5-oxazolidinyI]- methyl]propanethio- amide 63 (SyN-[[3-[3,5-Difluoro- 4-(4-hydroxyacetyl)-l- piperazinyl]phenyl]-2- oxo-5-oxazoIidinyl]- methyl]-2-methyI- propanethioamide 64 (5)-N-[[3-[3.5-Difluoro- 4-(4-hydroxyacetyl)-1 - piperazinyl]phenyl]-2- oxo-5-oxazolidinyl]- methyl]cyclopropane- thioamide 65 (5)-N-[[3-[3-[4- (hydroxyacetyl)-l- piperazinyl]phenyl]-2- oxo-5-oxazoIidinyl]- methyl]propanethio- amide 66 (5)-N-[[3-[3-[4- (hydroxyacetyl)-l- piperazinyl]phenyl]-2- oxo-5-oxazolidinyl]- methyl]-2-methyl- propanethioamide 67 (S)-N-[[3-l3-[4- (hydroxyacetyl)-l- piperazinyl]phenyl]-2- oxo-5-oxazolidinyI]- methyl]cyclopropane- carbothioamide Amine o Fw {? ii /—\ A HOCHj-C-N N—P y—N O F Dithio Compound (from Preparation Z) Z(a) in u L-|--H *—nh.
Same as above Z(b) Same as above Z (c) o HOCHj-C-l/ ^N^O w \=/ I 1—H I—IMH Z(a) Same as above Z(b) Same as above Z(c) When following the procedure of Example 28. step 3. an appropriate amount of the amine listed below is reacted with the dithio compound listed below, the respective compounds. Examples 68 to 78 of Table D are obtained.
TABLED Example No.
Compound Amine Dithio Compound (see Preparation Z) 68 (S)-N-[[3-[3-Fluoro-4- o Z (a) (4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyljmethylj- propanethioamide, thiomorpholine S.S- dioxide ■vp-OVS1 „ F 69 (5)-N-[[3-[3-Fluoro-4- Same as above Z(b) (4-thiomorphoIinyl)- phenyl]-2-oxo-5- oxazoIidinyl]methyl]-2- methylpropanethio- amide, thiomorpholine S,S-dioxidc 70 (S)-N-[[3-[3-Fluoro-4- Same as above Z (c) (4-thiomorpholinyl)- phenyl]-2-oxo-5-oxazolidinyl]methyI]-cyclopropanecarbothio-amide, thiomorpholine S,S-dioxide 71 (S)-N-([3-[3,5-Difluoro- Ethyl dithioacetate a (A 4-(4-thiomorpholinyl )-phenyl ]-2-oxo-5-oxazolidinyl]methyI]-propanethioamide. thiomorpholine S,S-dioxide 4-( 4-thiomorpholiny 1 )- phenyl]-2-oxo-5- oxazolidinyl]- methyljthioacctamide, thiomorpholine S,S- dioxide 72 (S)-N-[[3-[3.5- Difluoro- Same as above Z (a) Example No.
Compound Amine Dithio Compound (see Preparation Z) 73 (S)-N-[[3-[3.5- Difluoro-4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethio-amide. thiomorpholine S,S-dioxide Same as above Z(b) 74 (S)-N-[[3-[3,5- Difluoro-4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyljmethyl]-cy c lopropanecarboth io-amide. thiomorpholine S.S-dioxide Same as above Z(c) 75 (5)-N-[[3-{4-(4-thio- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]lhioacetamide, thiomorpholine S,S-dioxide o 02S ^N-^V-N^O w \=/ I—I H 1—NH, Ethyl dithioacetate 76 (S)-N-[[3-{4-(4-thio- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]-methy 1 Jpropanethio-amide. thiomorpholine S.S-dioxide Same as above Z (a) 77 (SVN-[[3-[4-(4-thio- morpholinyl)phenyl]-2- oxo-5-oxazoIidinyl]- methyl]-2-methyl- propanethioamide, thiomorpholine S.S- dioxide Same as above Z (b) 78 (5)-N-[[3-[4-(4-thio- morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]- methyl]cyclopropane- carbothioamide. thiomorpholine S.S- dioxide Same as above Zfc) When following the procedure of Example 26. an appropriate amount of the amine listed below is reacted with the dithio compound listed below the respective compounds. Examples 79 to 99 of Table E are obtained.
TABLE E Example Compound No. 79 (S)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyI]methyl]- propanethioamide 80 (S)-N-[[3-[3-Fluoro-4- (4-thiomorpholiny 1 )- phenyl]-2-oxo-5- oxazolidinyl]methyI]-2- methylpropanethioamide 81 (5)-N-[[3-[3-Fluoro-4- (4-thiomorphol iny 1 )- phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclopropanecarbothio- amide 82 (5)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]- butanethioamide 83 (5)-N-[[3-[3-Fluoro-4- (4-thiomorpholiny 1 )- phenyl]-2-oxo-5- oxazolidinyl]methyl]-3- methylbutanethioamide 84 (S)-N-[[3-[3-Fluoro-4- (4-thiomorphol inyl )- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylbutanethioamide Amine CN-f>Ni° Dithio Compound (See Preparation Z) Z(a) —nh2 Same as above Z(b) Same as above Z (c) Same as above Z(d) Same as above Z (e) Same as above Z(f) Example Compound Amine No. 85 (S)-N-[[3-[3-Fluoro-4- Same as above (4-thiomorpholinyl)-phenyI]-2-oxo-5-oxazo!idinyl]methy]]-3.3-dimethyIbutanethio-amide 86 (S)-N-[[3-[3-Fluoro-4- Same as above (4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyljmethyl]-cyclobutanecarbothio-amide 87 (S)-N-[[3-[3-Fluoro-4- Same as above (4-thiomorpholinyI)-phenyI]-2-oxo-5-oxazolidinyljmethyl]-cyclopentanecarbothio-amide 88 (5)-N-[[3-[3-Fluoro-4- Same as above (4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyljmethyl]-cyclohexanecarbothio-amide 89 (S)-N-[[3-[3-5 FIuoro-4- Same as above (4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyI]methyl]-2-cyclopropylethanethio-amide 90 (5)-N-[t3-[3-Fluoro-4- Same as above (4-thiomorphoIinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-cyclobutylethanethio-amide Dithio Compound (See Preparation Z) Z(g) Z(h) Z(i) Z(j) Z(k) Example Compound Amine No. 91 (5>N-[[3-[3-Fluoro-4- Same as above (4-thiomorpholinyI)-phenyI]-2-oxo-5-oxazolidinyl]methyl]-2-cyclopentylethanethio-amide 92 (5)-N-[[3-[3,5-Difluoro-4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyljmethyl]-thioacetamide ■—NH2 93 (5)-N-[[3-[3,5-Difluoro- Same as above 4-(4-thiomorpholinyI)- phenyI]-2-oxo-5- oxazolidinyl]methyl]- propaneihioamide 94 (5)-N-[[3-[3,5-Difluoro- Same as above 4-(4-thiomorpholinyl)- phenyI]-2-oxo-5- oxazolidinyl]methyl]-2- methylpropanethioamide 95 (J)-N-t[3-[3.5-Difluoro- Same as above 4-(4-thiomorpholinyl)- phenyl]-2-oxo-5-oxazolidinyljmcthyl]-cyclopropanecarbothio-amide 96 (S)-N-[[3-[4-(4-thio- O morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]- \—f \=J \ L methyljlhioacetamide ■H —NH, 97 (S')-N-[[3-[4-(4-thio- Same as above morpholinyl )phenyl]-2-oxo-5-oxazolidinyl]-methyljpropancthio-amide Dithio Compound (See Preparation Z) Z(m) Ethyl dithioacetate Z (a) Z (b) Z (c) Ethyl dithioacetate Z (a) PCT /US98/25308 Example No.
Compound Amine Dithio Compound (See Preparation Z) 98 (S)-N-[[3-[4-(4-thio- Same as above Z(b) morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]-2-methyl-propanethioamide 99 (5)-N-[[3-[4-(4-thio-morpholinyl)phenyl]-2- Same as above Z (c) oxo-5-oxazolidinyl]- methyl]cyclopropane- carbothioamide The amine utilized in Examples 41 to 53 is prepared as described in Example 27, step 3. The amine utilized in Examples 54 to 57 is prepared by the procedure of Example 27, steps 1 to 3 by substituting the appropriate (S)-N-[[3-[3.5-difluoro-4-(4-thio-5 morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methanol for compound 62 in step 1 of Example The amine utilized in Examples 58 to 61 is prepared by the procedure of Example 27, steps 1 to 3 by substituting the appropriate (S)-N-[[3-[4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methanol for compound 62 in Example 27, step 1. The appropriate 10 oxazolidinyl methanol compound is obtained by following the procedure of Example 1 in U.S. Patent 5.688,792, steps 1 through 3. only substituting 4-fluoronitrobenzene for 3,4-difluoronitrobenzene in step 1 thereof.
The amine utilized in Examples 62 to 64 is prepared as compound 37 in Example 29 from the amide. 65, which is prepared as described in Example 32 of U.S. Patent No. 15 5.700.799. The amine utilized in Examples 65 to 67 is prepared by the general procedure of Example 29 from the following amide, the preparation of which is decribed in Example 3 of U.S. Patent 5.700.799: 27.
O NHAc The amine utilized in Examples 68 to 70 is prepared as described in step 2 of Example 28 above.
The amine utilized in Examples 71 to 74 is prepared as described in Example 28 by substituting (S)-N-[[3-[3.5-difluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-5 oxazolidinyljmethanol for compound 62 in step 1 and following the procedure of steps 1 and 2. The appropriate oxazolidinyl methanol compound is prepared by following the general procedure of Example 4 of U.S. Patent No. 5.688.792, steps 1 through 4, only substituting thiomorpholine for morpholine in step 1 thereof.
The amine utilized in Examples 75 to 78 is prepared as described in Example 28, 10 step 1. above by substituting (S)-N-[3-[4-(4-thiomorpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methanol for compound 62 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 through 3, only substituting 4-fluoronitrobenzene for 3,4-difluoronitrobenzene in step 1 thereof.
The amine utilized in Examples 79 to 91 is prepared as described in Example 1, step 4, of U.S. Patent No. 5,688,792. The amine utilized in Examples 92 to 95 is prepared as described in Example 4 of U.S. Patent No. 5,688,792 only substituting thiomorpholine for morpholine in step 1 thereof. The amine utilized in Examples 96 to 99 is prepared by the procedure of Example 1 of U.S. Patent No. 5,688,792, only substituting 4-fluoronitro-20 benzene for 3.4-difluoronitrobenzene in step I thereof.
EXAMPLE 100 (S)-N-[[3-[3-Fluoro-4-(4-thiomorphoIinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0-methyithiocarbamate. thiomorpholine S-oxide O F II NHC-OCH3 A solution of 201 mg (0.554 mmol) of (S)-N-[[3-[3-fluoro-4-(4-thiomorpholinyI)-25 phenyl]-2-oxo-5-oxazolidinyl]methyI]isothiocyanate, thiomorpholine s-oxide compound 82 from Example 33. step 1. in methanol (10 mL) is refluxed. under nitrogen for 18 hours and cooled. The solid is collected by filtration to give 0.138 g of the titled product, m.p. 208-209°C: Anal, calcd for Cr.H.oFN^S:: 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 thicisocyanate listed below is substituted for compound 82 the products listed below as Examples 101 to 109 are obtained.
TABLE F Isothiocyanate Ra o Rc \l—(f "V-N^O Rb —-H N=C=S Rc Ra Rb Example Compound No.
OS F F 101 (S)-N-[[3-[3,5-Difluoro-4-(4- thiomorpho!inyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthio-carbamate, thiomorpholine S-oxide OS H H 102 (5)-N-[[3-[4-(4-thiomorpholinyl)phenyl]-2- oxo-5-oxazolidinyl]methyl]-0-methykhio-carbamate, thiomorpholine S-oxide O2S H F 103 (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)- phenyI]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate, thiomorpholine S.S-dioxide 02S F F 104 (5)-N-[[3-[3.5-Difluoro-4-{4- thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthio-carbamate, thiomorpholine S.S-dioxide 02S H H 105 (5)-N-[[3-[4-(4-thiomorpholinyl)phenyl]-2- oxo-5-oxazolidinyl]methyI]-0-methylthio-carbamate. thiomorpholine S.S-dioxide S H F 106 (5)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)- phenyl]-2-oxo-5-oxazolidinyi]methyl]-0-methylthiocarbamate S F F 107 (5)-N-[[3-[3,5-Difluoro-4-(4-thiomorph- olinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-mcthylthiocarbamate Rc Ra Rb Example Compound No.
S H H 108 (S)-N-[[3-[4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthio-carbamate o H H 109 (S>N-[[3-[3-Fluoro-4-(4-(hydroxyacetyI)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate II HOCHjCN When in the procedure of Example 100 an appropriate amount of ethanol and isopropyl alcohol were substituted for methanol, the following respective compounds were obtained: EXAMPLE 110: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinvl]methyl]-0-ethylthiocarbamate. thiomorpholine S-oxide. m.p. 198-199°C; Anal, calcd for C|7H22FNi04S2: C, 49.14; H, 5.34; N, 10.11. Found: C. 49.06; H, 5.27; N, 10.10.
EXAMPLE 111: (5)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyI]-2-oxo-5-10 oxazolidinyl]methyl]-0-isopropylthiocarbamate, thiomorpholine S-oxide. m.p. 180-181°C; Anal, calcd for C|8H24FN:,0.,S2: 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 an appropriate amount of (S)-N-[[3-[3-fluoro-4-(4-thiomorpholiny])phenyl]-2-oxo-5-oxazolidinyl]isothiocyanate is substituted for 15 compound 82 and ethanol or isopropyl alcohol is substituted for methanol, the following respective products are obtained: EXAMPLE 112: (5)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-ethylthiocarbamate: EXAMPLE 113: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-20 oxazoIidinyl]methyl]-0-iso-propylthiocarbamate; EXAMPLE 114: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazoiidinyI]methyl]-N-methylthiourea. thiomorpholine S-oxide.
A stirred suspension of 240 mg (0.650 mmol) of compound 82 from Example 33. step 1 in THF (5 mL) at 0 °C is treated with a 2M solution of methylamine in THF (0.42 25 mL, 0.845 mmol) and kept at ambient temperature for 18 hours. The solid is collected by filtration to give 0.221 g of the titled product.
Following the procedure of Example 114, only substituting an appropriate amount of dimethylamine and azetidine for methylamine. the following compounds are obtained: EXAMPLE 115: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-N\N'-dimethylthiourea. thiomorpholine S-oxide; Anal. Calcd for 5 C17H23FN4O3S2. C. 49.26: H. 5.59; N. 13.52. Found C, 49.11; H, 5.57: N. 13.40; mp 180-182°C.
EXAMPLE 116: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-l-azetidinecarbothioamide. thiomorpholine S-oxide; Anal. Calcd for CuH23FN403S2. C. 50.69; H. 5.43; N, 13.14. Found: C, 50.79; H, 5.45; N. 12.82; mp 213-10 214°C.
When in the procedure of Example 114 an appropriate amount of C5")-N"-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl]isothiocyanate is substituted for compound 82. the following compound is obtained: EXAMPLE 117: (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-15 oxazolidinyl]methyl]methyl-N'-methylthiourea.
When in the procedure of Example 117 an appropriate amount of dimethylamine and azetidine are substituted for methylamine, the following respective products are obtained: EXAMPLE 118: (5>N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phcnyl]-2-oxo-5-20 oxazolidinyl]methyl]-N'.N'-dimethylthiourea; EXAMPLE 119: (5)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenvl]-2-oxo-5-oxazolidinyljmethyl]-1 -azetidinecarbothioamide.
When in the procedure of Example 33 an appropriate amount of compound 31 from Example 26 is substituted for compound 33 and the general procedure of steps 1 and 2 of 25 Example 33 are followed, the following compound is obtained.
EXAMPLE 120: (5)-N-[[3-f3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyljmethyljthiourea.
EXAMPLE 121: (5)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-l-piperazinyl]phenyl-2-30 oxo-5-oxazolidinyl]methyl]propancthioamide o II / hoch2cn N O hi N^O v_y )=/ | i..-h F V-M 29 s II NH—C I chz ch, A stirred mixture of 200 mg (0.514 mmol) of 29 methyl dithiopropionate (247 mg, 2.06 mmol), triethylamine (0.58 mL, 4.11 mmol), THF (5.4 mL) and methylene chloride (5.4 mL) is kept, under nitrogen, for 3 days, diluted with water and extracted with methylene chloride. The extracts are dried (MgS04) and concentrated. Chromatography of the residue on silica gel and crystallization of the product from methanol gives 0.132 g of the titled product, m.p. 190-191°C: Anal, calcd for CWH25FN4O4S: 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 only substituting dithio compounds Z (b) to Z (m) from Preparation Z above for methyl dithiopropionate, the following compounds are obtained.
TABLE G II /—\ hochgcn^ h VH s nh—c-r Example No. Compound 122 (5)-N-[[3-[3-Fluoro-4-[4-(hydroxy- acetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropane-thioamide: Anal, calcd for C2OH:7FN404S: 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 R = CH(CH,)2 Example No. Compound 123 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- R = —<] acetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropane-carbothioamide: mp 179-181 °C: Anal. calcd for CmHzjFNjOjS: C, 55.03; H, .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- R = CH2-CH2-CH? acetyl)-1 -piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]butanethioamide 125 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- ch3 acetyl)-l-piperazinyl]phenyl]-2-oxo-5- r = ch2—ch-ch3 oxazolidinyl]methyl]-3-methylbutane- thioamide 126 (5)-N-[[3-[3-Fluoro-4-[4-(hydroxy- ch3 acetyl)-1 -piperazinyl )phenyl]-2-oxo-5- r = ch—ch2-ch3 oxazolidinyl]methyI]-2-methylbutane- thioamide 127 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- R = CH2-C(CH3)3 acetyl)-1 -piperaziny l]phenyl ]-2-oxo-5-oxazolidinyl]methyl]-3,3-dimethyl-butanethioamide 128 (5)-N-[[3-[3-Fluoro-4-[4-(hydroxy- r = acetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazoIidinyl]methyl]cyclobutane-carbothioamide 129 (5)-N-[[3-[3-FIuoro-4-[4-(hydroxy-acetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopentane-carbothioamide 130 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy-acetyI)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclohexane-carbothioamide r, -q "--o 131 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy- r= ch2-<^] acetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-cyclopropyl-ethanethioamide Example No.
Compound 132 (S)-N-[[3-[3-Fluoro-4-[4-(hydroxy-acetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-cyclobutyl-ethanethioamide R= CH2-h()> 133 (5>N-[[3-[3-Fluoro-4-[4-(hydroxy-acety I)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-cyclopentyl-ethanethioamide When in the procedure of Example 100 an appropriate amount of compound 80 from Example 31 is substituted for compound 82, and ethanol or isopropyl alcohol is substituted for methanol, the following respective compounds are obtained: EXAMPLE 134: (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-l-piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-0-ethylthiocarbamate; EXAMPLE 135: (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-/jo-propylthiocarbamate; EXAMPLE 136: (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)- l-piperazinyl]phenyJ]-2-oxo-5-oxazolidinyl]methyl]-N'-methylthiourea.
When in the procedure of Example 114 an appropriate amount of compound 80 from Example 31 is substituted for compound 82. the title compound is obtained.
Following the procedure of Example 114 only substituting an appropriate amount of compound 80 from Example 31 for compund 82 and substituting an appropriate amount of dimethylamine and azetidine for methylamine. the following compounds. Examples 137 and 138, are obtained: EXAMPLE 137: (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]methyl]-N\N'-dimethylthiourea: EXAMPLE 138: (S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyD- l-piperazinyl]phenvl]-2-oxo-5-oxazolidinyl]methyl]-l-azetidinecarbothioamide.
EXAMPLE 139: (5)-N-[[3-[3.5-Difluoro-4-[4-(hydroxyacetyl)-l-piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate.
Part A: Following the procedure of Example 33. step 1, only substituting an appropriate amount of compound 37 from Example 29, step 5. for compound 33. (S)-N- [[3,5-[3-difluoro-4-[4-(hydroxyacetyi)-I-piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]-methyl]isothiocyanate is obtained.
Part B: Upon substitution of an appropriate amount of (5)-N-[[3-[3.5-difluoro-4-[4-(hydroxyacetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methylJsothiocyanate for compound 82 in the general procedure of Example 100, the title compound is obtained.
EXAMPLE 140: (5>N-[[3-[4-[4-(hydroxyacetyl)-I-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methy]]-0-methylthiocarbamate Part A: Following the procedure of Example 33. step 1, only substituting an appropriate amount of (5)-N-[[3-[4-[4-(hydroxyacetyl)-l-piperazinyI]phenyl]-2-oxo-5-oxazoIidinyI]methyl]amine for compound 33, (5)-N-[[3-[4-[4-(hydroxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]isothiocyanate is obtained.
PCMJS98/25308 Part B: Upon substituting an appropriate amount of (5)-N-[[3-[4-[4-(hydroxy-acetyl)- l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]isothiocyanate for compound 82 in the general procedure of Example 100. the title compound is obtained.
EXAMPLE 141: (5)-N-[[3-F]uoro-4-(4-acetyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyI]thioacetamide Step 1 no2 PhCHzOCN/ ^N—N^o C=/~ 2 ^ Cbz-N/ ^N-^~\-N'^0 \—/ y f \ / H g ^ ^^ y—' V_/■»•■ F V.OH 3 F \- 58 -OH ° h ONos 85 An ice cold, stirred 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) is treated with w-nitrobenzenesulfonyl chloride (18.8 g, 84.9 mmol) and kept, under nitrogen, at ambient temperature (24 °C) for 24 hours. Additional /n-nitrobenzenesulfonyl chloride (1.88 g) and triethylamine (1.54 mL) are added and the mixture is kept for one 15 additional day at ambient temperature, washed with water, saturated sodium bicarbonate and brine, dried (NaiSO-O and concentrated to give an oily product, 85. The alcohol, 58 is prepared according to the procedures of Brickner (J. Med. Chem. 1996.39. 673-679), see compound 5a therein.
Step 2 O O /—\ /r~\ JJ NH4OH \ CbzN N-^ 7—N O CbzN N—^ N 0 \—f )=/ \__/ H V—7 >=/ (.."'H F *-ONos F ^-NH2 85 86 A stirred mixture of 85, acetonitrile (1270 mL). isopropanol (1270 mL) and ammonium hydroxide (1270 mL) is kept at ambient temperature for 3 days and concentrated in vacuo. Chromatography of the residue on silica gel with 0.5% NHjOH-1% 25 MeOH-CH;Ch gives 22.4 g of the amine, 86.
Step 3 CbzN/ Yj—N"^0 B0C2° » CbzN/ \y-^~\-N^O F *~NH2 F N-NHBOC 86 87 An ice cold, stirred solution of the amine 86 in THF (650 mL) is treated, during 20 mintues with a solution of di-/er/-butyl dicarbonate (12.0 g, 55.2 mmol) in THF (90 mL). The mixture is kept at ambient temperature for 18 hours and concentrated in vacuo. The residue, dissolved in methylene chloride, is washed with dilute sodium bicarbonate, dried (MgSO.t) and concentrated. Crystallization of the residue from methanol-ethyl acetate gives 20.0 g of the Boc protected amine. Additional product (4.1 g) is obtained by chromatographing the mother liquors on silica gel with 1-2% methanol-methylene chloride. Step 4 O o CbzN -—*■ HN ^O 'fsj {/ fg' v—/ >=/ »h Pd/c '"\_y y=J v_£...
F *—NHBoc F \_ 4 H -NHBoc 87 A solution of the protected amine, 87, (5.00 g, 9.46 mmol) in ethanol (150 mL) is treated with 10% palladium-on-carbon catalyst (1.0 g) and hydrogenated at an initial pressure of 30 psi for 3 hours. The catalyst is removed by filtration through Celite and the filtrate was concentrated to give 3.66 g of compound 88.
Step 5 / ^ J7~\ 11 ACsO || / \ X HN H-V >-N O . *- CHoCN N—V-N O N / y / \ /.,..tH Py y V_A«"H F *—NHBoc F NHBoc 88 gg A stirred solution of compound 88 (1.10 g, 2.79 mmol) in pyridine (10 mL) is treated with acctic anhydride (289 ^L. 3.07 mmol). kept at ambient temperature for 2 hours and concentrated in vacuo. A solution of the residue in methylene chloride is washed with 20 dilute hydrochloric acid, dried (MgSCM and concentrated to give 1.23 g of compound 89: MS m/z 436 (M+).
Step 6 O CH, SO-OVS5 „ CH5§N^NHf>NA0 w J—1 M;-'H d,oxane w >=/ \_/. H F —NHBoc F V.MI 2 HCI 89 P-90 An ice cold, stirred 4N solution of HCI in dioxane (10 mL) is treated with compound 89 (1.10 g, 2.52 mmol). The mixture is kept in the ice bath for 30 minutes and at ambient temperature for 1 hour. It was then mixed with methylene chloride and concentrated. The residue is triturated with methylene chloride to give 1.03 g of the amine hydrochloride.
Step 7 11 CH3CSEt n ^ X s II o II t—^ /7~\ A CH,-CSEt II /—^ /r~\ u CH,CN N-^ V-N O CH,CN A_N^O - v_y >=/ e,3N 3 >=/ \__l...h f *—nh2 F V-nh-c-ch, ■hci P-90 3 A stirred mixture of compound P-90 (250 mg), triethylamine (0.75 mL, 5.36 mmol), 10 ethyl dithioacetate (307 |liL, 2.68 mmol), methylene chloride (7.4 mL) and THF (7.4 mL) is kept at ambient temperature for 1 day, concentrated and chromatographed on silica gel with mixtures of methanol-methylene chloride containing 1-2% methanol. Crystallization of the product from ethyl acetate-heptane gives 0.160 g of the titled product: Anal, calcd for C|8H23FN40jS: C, 54.81: H, 5.88: N, 14.20; S, 8.13. Found: C, 54.92; H, 5.95; N, 14.08: 15 S. 7.94: mp 158°C.
When in the general procedure of Example 141 an appropriate amount of PhCH2OC O F 0 o ° C-N ^N-^~V-N^O or PhCHjOCf/ ^N—^-N^O v_v \=J \l H 2 W \=/ V_/ F V-OH .. is substituted for compound 58 and the procedure of steps 1 through 6 are followed, the respective amine compounds P-91 and P-92 listed below arc obtained: U v w ii y-\ A CH3CN N—(' x>— N^l v_/ >=/ I F .-H NH2 P-91 O o CH3C-N N-V ^V-N^O V_y \=/ I l.-H P-92 NH2 The alcohols above designated 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 (trifluoromeihane) sulfonate and 4-fluoronitrobenzene respectively for 3.4-difluoronitrobenzene in the preparation of 2a therein.
When in the procedure of Example 141 an appropriate amount of x or y is substituted for compound 58 and the procedures of steps 1 through 4 arc followed, the following Boc protected compounds listed below are obtained.
F. O J—eV-N^O /—\ HN N- v \ f y=j 1 F x-b —NHBoc O HN/ ^N—N^O \ / X=J L —H —IMHBoc y-b When in the procedure of Example 141, step 5. an appropriate amount of compound 88, compound x-b or compound y-b is treated with the reagent listed below and the general procedures of step 5 and step 6 are followed, the amines listed below as Preparation P-93 through P-128 are obtained.
The amine compound set forth below as P-129 is obtained by refluxing for 6 days a 15 solution of compound 88 (1.00 g, 2.54 mmol), sulfamide (305 mg. 3.18 mmol) and 1,2-dimethyoxyethane (6 mL). The solid which precipitates is collected by filtration and chromatographed on silica gel with 5% methanol-methylene chloride. Crystallization of the product from methanol-methylene chloride gives 0.551 g of the sulfamoyi derivative, which is used in step 6 of Example 141 to give P-129. When compounds x-b and y-b are substituted for compound 88 and this genera] procedure is followed. Preparations P-130 and P-131 respectively set forth below are obtained.
Following the general procedures of steps 5 and 6 of Example 141 only in step 5 substituting chloroacetonitrile or 2-fluoroethyl bromide respectively for acctic anhydride and using potassium carbonate in acetonitrile, and using either compound 88. compound x-b or compound y-b. the respective amines set forth below as Preparations P-132 to P-137 are obtained.
The amine compound set forth below as Preparation P-138 is obtained by combining compound 88 (1.10 g, 2.75 mmol) set forth in step 5 of Example 141 with N-formylbenzotriazole (493 mg, 3.35 mmol) in THF (30 mL) and the mixture is kept at ambient temperature for 18 hours. The mixture is concentrated and the residue in methylene chloride is washed with IN sodium hydroxide and dilute sodium chloride, dried (MgSOj). concentrated, and chromatographed on silica gel with mixtures of methanol and methylene chloride containing 1-2% methanol to give 1.09 g of the N-formyl derivative which is utilized in the general procedure of step 6 of Example 141 to give Preparation P-138. When in this foregoing procedure compound x-b or compound y-b is substituted for compound 88, Preparations P-139 and and P-140 as set forth below are obtained.
Va ° R-N/ VN—N^O \_/ \=J i R* -h ■—nh2 Reagent methoxyacctvlchloride cyanoacetyl chloride acetoxyacetyl chloride Boc Compound 88 x-b y-b 88 x-b y-b 88 x-b y-b R O II ch3och2c— o II ncch2c- o o II II ch3c-o-ch2c- El' K Preparation No.
H F P-93 F F P-94 H H P-95 H F P-96 F F P-97 H H P-98 H F P-99 F F P-100 H H P-101 Reaeent Boc R Rl' R/ Preparati Compound No. benzyloxyacetyl chloride 88 0 11 H F P-102 x-b PhCH2OCH2c— F F P-103 y-b H H P-104 methyl chloroformate 88 0 H F P-105 x-b II ch3oc— F F P-106 y-b H H P-107 methanesulfonyl chloride 88 ch3so2— H F P-108 x-b F F P-109 y-b H H P-110 ethanesulfonyl chloride 88 H F P-lll x-b ch3ch1s02- F F P-112 y-b H h P-113 chloromethanesulfonyl 88 H F P-114 chloride x-b c1ch2s02- F F P-115 y-b H H P-116 cyanomethanesulfonyl 88 H F P-117 chloride x-b ncch2so2- F F P-118 y-b H H P-119 N-methylsulfamoyl 88 H F P-120 chloride x-b ch1nhs02- F F P-121 y-b H H P-122 N,N-dimethylsulfamoyl 88 h F P-123 chloride x-b (ch.02nso2- F F P-124 y-b h H P-125 ethyl chloroformate 88 0 H F P-126 x-b ch3ch2oc- F F P-127 y-b h H P-128 sulfamide 88 h F P-129 x-b h2ns02- F F P-130 y-b h h P-131 chioroacetonitrile 88 h F P-132 x-b ncch;- F F P-133 y-b H h P-I34 - MO - WO 00/32599 PCT/US98/25308 Reagent Boc R RJJ R_' Preparation Compound No. 2-fluoroethyl bromide 88 H F P-135 x-b FCH2CH2- F F P-136 y-b H H P-137 N-formylbenzotriazole 88 O 11 H F P-I38 x-b II HC— F F P-139 y-b H H P-140 EXAMPLES 142-161: When following the general procedures of Example 141, step 7. an appropriate amount of the amine listed below and the dithio compound from Preparation Z listed below are utilized, the respective products designated as Examples 142 to 400 in Table H are obtained.
TABLE H Example Dithio No. Product Amine Compound 142 (5>N-[[3-[3-Fluoro-4-(4-acetyl-1 -piperazinyOphenyl]- P-90 Z(a) 2-oxo-5-oxazolidinyl]methyl]propanethioamide; mp 161-162°C; Anal, calcd for C19H25FN4O3S: 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 (5>N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyl]- P-90 Z(b) 2-oxo-5-oxazolidinyl]methyl]-2-methylpropane- thioamide 144 (S)-N-[[3-[3-Fluoro-4-(4-acetyM-piperazinyOphenyl]- P-90 Z(c) 2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbo- thioamide; mp 159-160°C; Anal, calcd for C20H25FN4O3S: 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. 145 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyl]- P-90 Z(d) 2-oxo-5-oxazolidinyl]methyl]butanethioamide 146 (S)-N-[[3-[3-Fluoro-4-(4-acetyI-l -piperazinyOphenyl]- P-90 Z(e) 2-oxo-5-oxazolidinyl]methyl]-3-methylbutane- thioamide ■ Hi - Example No. Product 147 (5)-N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyOphenyl] 2-oxo-5-oxazolidinyI]methyl]-2-methylbutane-thioamide 148 (5)-N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyI] 2-oxo-5-oxazolidinyl]methyl]-3,3-dimethylbutane-thioamide 149 (5')-N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyOphenyl]-2-oxo-5-oxazolidinyl]methyl]cyclobutanecarbo-thioamide 150 (5)-N-f[3-[3-Fluoro-4-(4-acetyl-l-piperazinyOphenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopentanccarbo-thioamide 151 (5)-N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyOphenyl] 2-oxo-5-oxazoIidinyl]methyI]cycIohexanecarbo-thioamide 152 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-cyclopropylethane-thioamide 153 (5)-N-[[3-[3-Fluoro-4-(4-acetyl-l-piperaziny])phenyI]-2-oxo-5-oxazolidinyl]methyl]-2-cyclobutylethane-thioamide 154 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-1 -piperazinyOphenyl]-2-oxo-5-oxazolidinyl]methyl]-2-cyclopentylethane-thioamide 155 (S)-N-[[3-[3.5-Difluoro-4-(4-acetyl-1 -piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide 156 (S)-N-[[3-[3.5-Difluoro-4-(4-acetyl-l-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]propane-thioamide 157 (5)-N-[[3-[3.5-Difluoro-4-(4-acetyl-l-piperazinyO-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methyl-propanethioamide Dithio Amine Compound P-90 Z (f) P-90 Z(g) P-90 Z (h) P-90 Z (i) P-90 Z (j) P-90 Z (k) P-90 Z (1) P-90 Z (m) P-91 Ethyl dithioacetate P-91 Z (a) P-91 Z(b) WO 00/32599 Example No. Product 158 (S)-N-[[3-[3.5-Difluoro-4-(4-acetyI-l-piperazinyl)-phenyl]-2-oxo-5-oxazoIidinyl]methyl]cyciopropane-carbothioamide 159 (S)-N-[[3-[4-(4-Acetyl-1 -piperazinyDpheny l]-2-oxo-5 oxazolidinyl]methyI]thioacetamide 160 (S)-N-[[3-[4-(4-Acetyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide 161 (5)-N-[[3-[4-(4-Acetyl-1 -piperazinyl)phenyl]-2-oxo*5-oxazolidinyl]methyl]-2-methylpropanethioamide 162 (5)-N-[[3-[4-(4-Acetyl-1 -piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbothioamide 163 (5)-N-[[3-[3-Fluoro-4-[4-(methoxy acetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-thioacetamide 164 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 165 (SyN-[[3-[3-Fluoro-4-[4-( methoxy acetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 166 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-l-piperazinyl]phenyll-2-oxo-5-oxazolidinyl]mcthyl]-cyclopropanecarbothioamide 167 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]-butanethioamide 168 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-3- methylbutanethioamide 169 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylbutanethioamide Dithio Amine Compound P-91 Z(c) P-92 Ethyl dithioacetate P-92 Z (a) P-92 Z (b) P-92 Z (c) P-93 Ethyl dithioacetate P-93 Z (a) P-93 Z (b) P-93 Z (c) P-93 Z (d) P-93 Z (e) P-93 Z (f) Example No. 170 171 172 173 174 175 176 177 178 179 180 Product Amine (S)-N-[[3-[3-FIuoro-4-[4-(methoxyacetyl)-1 - P-93 piperazinyl]phenylj-2-oxo-5-oxazolidinyl]methyI]-3,3- dimethyibutanethioamide (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-I- P-93 piperazinyl]phenvl]-2-oxo-5-oxazolidinyl]methyI]- cyclobutanecarbothioamide (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopentanecarbothioamide (5)-N-[[3-[3-FIuoro-4-[4-(methoxyacetyl)-l- P-93 piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyciohexanecarbothioamide (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 piperazinyI]phenyI]-2-oxo-5-oxazolidinyl]methyI]-2- cyclopropyiethanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(mcthoxyacetyl)-l- P-93 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- cyclobutylethanethioamide f5)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-l- P-93 piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-2- cyclopentylethanethioamide (5)-N-[[3-[3,5-Difluoro-[4-[4-(methoxyacetyl)-l- P-94 piperazinyl]phenyl]-2-oxo-5-oxazolidinylJmethyl]- thioacetamide (.5)-N-[[3-[3,5-Difluoro-[4-[4-(methoxyacetyl)-1 - P-94 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (5)-N-[[3-[3.5-Difluoro-[4-[4-(methoxyacetyl)-l- P-94 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]mcthyl]-2- methylpropanethioamide (5)-N-[[3-[3.5-Difluoro-[4-[4-(meihoxyacetyl)-l- P-94 piperazinyl]phenylJ-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide Dithio Compound Z(g) Z(h) Z(i) Z(j) Z(k) Z(l) Z(m) Ethyl dithioacetate Z(a) Z (b) Z (c) Example No. Product 181 (S)-N-[[3-[4-[4-(methoxyacetyl)-l-piperazinyl]phenyl] 2-oxo-5-oxazolidinyl]methyl]thioacetamide 182 (5)-N-[[3-[4-[4-(methoxyacetylM-piperazinyl]phenyl] 2-oxo-5-oxazolidinyI]methyl]propanethioamide 183 (S)-N-[[3-[4-[4-(methoxyacetyI)-l-piperazinyl Jphenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropane-thioamide 184 (S)-N-[[3-[4-[4-(methoxyacetyl)- l-piperazinyl]phenyl]-2-0X0-5- oxazolidinyl]methyl]cyclopropanecarbothioamide 185 (S)-N-[[3-[3-Fluoro-4-[4-(cyanoacetyl)-1 -piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide 186 (S)-N-[[3-[3-Fluoro-4-[4-(cyanoacetyI)-l-piperazinyI]-phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethio-amide 187 (5)-N-[[3-[3-Fluoro-4-[4-(cyanoacetyl)-l-piperaziny 1]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methyl-propanethioamide 188 (S)-N-[[3-[3-Fluoro-4-[4-(cyanoacetyI)-l-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropane-carbothioamide 189 (S>N-[[3-[3,5-Difluoro-4-[4-(cyanoacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazoIidinyI]-methy 1 ] thioacetamide 190 (S)-N-[[3-[3.5-Difluoro-4-[4-(cyanoacetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyI]propanethioamide 191 (5)-N-[[3-[3,5-Difluoro-4-[4-(cyanoacetyl)-1 -piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanelhioamide 192 (5)-N-[[3-[3.5-Difluoro-4-[4-(cyanoacetyl)-l-piperazinyl]phcnyl]-2-oxo-5-oxazolidinyl]-methyl]cyclopropanecarbothioamide Dithio Amine Compound P-95 Ethyl dithioacetate P-95 Z (a) P-95 Z (b) P-95 Z(c) P-96 Ethyl dithioacetate P-96 Z (a) P-96 Z (b) P-96 Z (c) P-97 Ethyl dithioacetate P-97 Z (a) P-97 Z (b) P-97 Z (c) Example No. 193 194 195 196 197 198 199 200 201 202 203 204 Product Amine (5)-N-[[3-[4-[4-(Cyanoacetyl)-l-piperazinyl]phenyl]-2- P-98 oxo-5-oxazoIidinyi]methyl]thioacetamide (S)-N-[[3-[4-[4-(CyanoacetyIM-piperazinyl]phenyl]-2- P-98 oxo-5-oxazolidinyl]methyl]propanethioamide (5)-N-[[3-[4-[4-(Cyanoacetyl)-l-piperazinyl]phcnyl]-2- P-98 oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide (S)-N-[[3-[4-[4-(Cyanoacety 1)-1 -piperazinyl]phenyI]-2- P-98 oxo-5-oxazolidinyl]methyl]cycopropanecarbothio- amide (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]methyl]- propanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide (5)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperazinyI]phenyI]-2-oxo-5-oxazolidinyl]methyl]- butanethioamide (5')-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperaziny!]phenyl]-2-oxo-5-oxazolidinyl]mcthyl]-3- methylbuianethioamide (S)-N-[[3-[3-Fluoro-4-[4-(aceioxyacetyI)-l- P-99 piperazinyl]phenyl]-2-oxo-5-oxazoIidiny]]methyi]-2- methylbutanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-3,3- dimethylbutanethioamide Dithio Compound Ethyl dithioacetate Z (a) Z(b) Z(c) Ethyl dithioacetate Z (a) Z(b) Z(c) Z(d) Z(e) Z(f) Z(g) Example No. 205 206 207 208 209 210 211 Product (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- piperazinyi]phenyl]-2-oxo-5-oxazolidinvl]methyl]- cyclobutanecarbothioamide (5)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]mcthyl]- cyclopentanecarbothioamide (S)-N-[[3-[3-FIuoro-4-[4-(acetoxyacctyl)-1 - piperazinyl]phenyl]-2-oxo-5-oxazoIidinyI]methyI]- cyclohexanecarbothioamide (S)-N-[[3- [3-Fluoro-4- [4-( acetoxyacety 1)-1 - piperazinyl]phenyl]-2-oxo-5-oxazoIidinyI]methyl]-2- cyclopropylethanethioamide (5)-N- [ [3- [3-Fluoro-4- [4-( acctoxy acetyl)-1 - piperazinyl]phenyl]-2-oxo-5-oxazo!idinyl]methyl]-2- cyclobutylethanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1 - piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- cyclopentylethanethioamide (S)-N-[[3-[3,5-Difluoro-4-[4-(acetoxyacetyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide Dithio Amine Compound P-99 Z (h) P-99 Z (i) P-99 Z(j) P-99 Z (k) P-99 Z (1) P-99 Z (m) P-100 Ethyl dithioacetate 212 (5)-N-[[3-[3.5-Difluoro-4-[4-(acetoxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 213 (5)-N-[[3-[3,5-Difluoro-4-[4-(acetoxyacetyl)-l-piperazinyl]phcnyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 214 (5)-N-[[3-[3.5-Difluoro-4-[4-(acetoxyacetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 215 (5)-N-[[3-[4-[4-( Acetoxyacety 1)-1 -piperazinyl]phenyl]-2-oxo-5-ox;izolidinyl]methyl]thioacetamide 216 (5)-N-[[3-[4-[4-(Acetoxyacetyn-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinvl]methyl]propaneihioamide P-100 Z (a) P-100 Z (b) P-100 Z (c) P-101 Ethyl dithioacetate P-101 Z (a) Example No. 217 218 Product Amine (S)-N-[[3-[4-[4-(Acetoxyacetyl)-l-piperazinyl]phenyl]- P-101 2-oxo-5-oxazolidinyl]methyI]-2-methyIpropane- thioamide (S)-N-[[3-[4-[4-( Acetoxyacctyl)-1 -piperazinyljphenyl]- P-101 2-oxo-5-oxozolidinyl]methyl]cyclopropanecarbo- thioamide Dithio Compound Z(b) Z(c) 219 (5)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacetyl)-l- P-102 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]methyl]- dithio-thioacetamide acetate 220 (S)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacetyl)-I- P-102 Z(a) piperazinyl Jphenyl]-2-oxo-5-oxazolidinyl]methyI]-propanethioamide 221 (5)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacetyl)-l- P-102 Z(b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]-2-methylpropanethioamide 222 (5)-N-[f3-[3-Fluoro-4-[4-(benzyloxyacetyl)-1 - P-102 Z(c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 223 (5)-N-[[3-[3,5-Difluoro-4-[4-(benzyloxyacetyi)-l- P-103 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-thioacetamide acetate 224 (5)-N-[[3-[3.5-Difluoro-4-[4-(benzyloxyacetyl)-l- P-103 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 225 (5)-N-[[3-[3,5-Difluoro-4-[4-(benzyloxyacetyl)-I- P-103 Z(b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide 226 (5)-N-[[3-[3.5-DifIuoro-4-[4-(benzyloxvacetyl)-I- P-103 Z(c) piperazinyl]phenyl]-2-oxo-5-oxazoIidinyl]methyI]-cyclopropanecarbothioamide 227 (5)-N-[[3-[3-Fluoro-4-f4-(methoxycarbonyl)-l- P-105 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio-o.xazolidinyl]methyl]thioacetamide acetate Example No. Product 228 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyI]-2-oxo-5-oxazoIidinyl]methyl]-propanethioamide 229 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 230 (5)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyD-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 231 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]-butanethioamide 232 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-3-methylbutanethioamide 233 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylbutanethioamide 234 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methy]]-3,3 dimethylbutanethioamide 235 (5)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]methyl]-cyclobutanecarbothioamide 236 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopentanecarbothioamide 237 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-1-piperazinyl]pheny]]-2-oxo-5-oxazolidinyI]methyl]-cyclohexanecarbothioamide 238 (S)-N-[[3-[3-FIuoro-4-[4-(methoxycarbonyI)-l-piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-2-cyc lopropy let hane t hi oamide Dithio Amine Compound P-I05 Z(a) P-I05 Z (b) P-105 Z (c) P-105 Z(d) P-105 Z (e) P-105 Z(D P-105 Z(g) P-105 Z(h) P-105 Z (i) P-105 Z (j) P-105 Z(k) Example No. 239 240 241 242 243 244 245 Product (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyD-1 - piperazinyI]phenyI]-2-oxo-5-oxazolidinyl]methyI]-2- cyciobutylethanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l- piperazinyI]phenyI]-2-oxo-5-oxazoIidinyl]methyl]-2- cyclopentylethanethioamide (5)-N-[[3-[3,5-Difluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazo!idinyl]methyl]-thioacetamide (5)-N-[[3-[3.5-Difluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]-propanethioamide (S)-N-[[3-[3.5-Difluoro-4-[4-(methoxycarbonyl)-1 - piperazinyl]phenyl]-2-oxo-5-oxazoiidinyl]methyI]-2- methylpropanethioamide (S)-N-[[3-[3,5-Difluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]-cyclopropanecarbothioamide (S)-N-[[3-{4-[4-(methoxycarbonyl)-l- piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide Dithio Amine Compound P-105 Z (1) P-105 Z (m) P-106 Ethyl dithioacetate P-106 Z (a) P-106 Z(b) P-106 Z (c) P-107 Ethyl dithioacetate 246 (5)-N-[[3-[4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 247 (5)-N-[[3-[4-[4-( methoxycarbonyl)-1 -piperaziny l]phenyl]-2-oxo-5-oxazoIidinyl]melhyl]-2-methylpropanethioamide 248 (S)-N-[[3-[4-[4-(methoxycarbonyl)-l -piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 249 (5)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazoIidinyl]methyI]-thioacetamide: mp 197-198°C: Anal, calcd for C|7H;,FN404S:: 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.
P-107 Z(a) P-107 Z (b) P-107 Z (c) P-108 Ethyl dithioacetate Example No. Product 250 (S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)-1 - piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide: mp 207-208°C: Anal, calcd for C18H25FN4O4S2: C. 48.63: H, 5.67; N, 12.60; S, 14.42. Found: C. 48.51; H. 5.59; N. 12.52; S, 14.09. 251 (5)-N-[[3-[3-Fluoro-4-[4-( methanesulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide; mp 204-206°C; Anal, calcd for C19H27FN4O4S2: 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-(methanesulfonyI)-1 -piperazinyl]pheny!]-2-oxo-5-oxazoIidinyl]methyl]-cyclopropanecarbothioamide; Anal, calcd for C19H25FN4O4S2: 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. 253 (S)-N-[[3-[3,5-Difluoro-4-[4-(methanesulfonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]methyl]-thioacetamide 254 (5)-N-[[3-[3,5-Difluoro-4-[4-(methanesulfonyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 255 (5)-N-[[3r[3,5-Difluoro-4-[4-(methanesulfonyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 256 (S)-N-[[3-[3.5-Difluoro-4-[4-( methanesulfonyl)-1 -piperazinyI]phenyl]-2-oxo-5-oxazoIidinyl]methyl]-cyclopropanecarbothioamide 257 (S)-N-[[3-[4-[4-( methanesulfonyl)-1-piperazinyl]phcnyl]-2-oxo-5-oxazolidinyl]methyI]-thioacetamide 258 (5)-N-f[3-[4-[4-( methanesulfonyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 259 (5)-N-[[3-[4-[4-(methanesulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]-2-methylpropanethioamide Dithio Amine Compound P-108 Z (a) P-108 Z (b) P-108 Z (c) P-109 Ethyl dithioacetate P-109 Z (a) P-109 Z (b) P-109 Z (c) P-110 Ethyl dithioacetate P-110 Z (a) P-110 Z(b) Example No. 260 261 262 263 264 265 266 267 268 269 270 271 Product Amine (5)-N-[[3-[4-[4-(methanesulfonyl)-l- P-110 piperazinyl]phenyl]-2-oxo-5-oxazo!idinyl]methyl]- cyclopropanecarbothioamide (5)-N-[[3-[3-FIuoro-4-[4-(ethanesulfonyl)-I- P-l 11 piperazinyI]phenyi]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide (S)-N-[[3-[3-Fluoro-4-[4-(ethanesulfonyI)-l- P-l 11 piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (5>N-[[3-[3-Fluoro-4-[4-(ethanesulfonyl)-1 - P-111 piperazinyl]phenyI]-2-oxo-5-oxazoIidinyl]methyl]-2- methylpropanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(ethanesuIfonyl)-l- P-l 11 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide (S)-N-[[3-[3,5-Difluoro-4-[4-(ethanesulfonyl)-l- P-l 12 piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyI]- thioacetamide (S)-N-[[3-[3,5-Difluoro-4-[4-(ethanesulfonyl)-l- P-l 12 piperazinyI]phenyI]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (5)-N-[[3-[3.5-Difluoro-4-[4-(ethanesulfonyl)-l- P-l 12 piperazinylJphenyl]-2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide (5)-N-[[3-[3,5-Difluoro-4-[4-(ethanesulfonyl)-l- P-l 12 piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyI]- cyclopropanecarbothioamide (5)-N-[[3-[4-[4-(cthanesulfonyi)-l-piperazinyl]phenyi]- P-l 13 2-oxo-5-oxazolidinyl]methyl]thioacetamide (S)-N-[[3-[4-[4-(ethanesulfonyl)-I-piperazinyl]phenyl]- P-113 2-oxo-5-oxazolidinyl]methyl]propanethioamide (5)-N-[[3-[4-[4-(ethanesulfonyl)-l-piperazinyl]phenylJ- P-l 13 2-oxo-5-oxazolidinyl]methyl]-2-methylpropane- ihioamide Dithio Compound Z(c) Ethyl dithioacetate Z(a) Z (b) Z (c) Ethyl dithioacetate Z(a) Z(b) Z (c) Ethyl dithioacetate Z(a) Z (b) Example No. 272 Product (S)-N-[[3-[4-[4-(ethanesulfony 1)-1 -piperazinyl]pheny 1]- 2-oxo-5-oxazolidinyl]methyI]cyclopropanecarbothio- amide Dithio Amine Compound P-l 13 Z(c) 273 (S)-N-[[3-[3-Fluoro-4-[4-(chloromethanesulfonyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidiny]]methyI]-thioacetamide P-l 14 Ethyl dithioacetate 274 (S)-N-[[3-[3-Fluoro-4-[4-(chloromethanesulfonyl)-l- P-l 14 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 275 (5)-N-[[3-[3-Fluoro-4-[4-(chloromethanesulfonyl)-l- P-l 14 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 276 (5)-N-[[3-[3-Fluoro-4-[4-(chloromethanesulfonyl)-1 - P-l 14 piperazinyl]phenyl]-2-oxo-5-oxazoIidinyI]methyl]-cyclopropanecarbothioamide 277 (5)-N-[[3-[3,5-Difluoro-4-[4-(chloromethanesulfonyl)- P-l 15 l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-thioacetamide Z(a) Z (b) Z(c) Ethyl dithioacetate 278 (5)-N-[[3-[3,5-Difluoro-4-[4-(chloromethanesuIfonyl)- P-l 15 l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 279 (5')-N-[[3-[3.5-Difluoro-4-[4-(chloromethanesuIfonyl)- P-l 15 l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 280 (5)-N-[[3-[3,5-Difluoro-4-[4-(chloromethancsulfonyl)- P-l 15 l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 281 (S)-N-[[3-[4-[4-(chloromethanesulfonyl)-l- P-l 16 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methylJ-thioacetamide Z (a) Z(b) Z (c) Ethyl dithioacetate 282 (S)-N-[[3-[4-[4-(chloromethancsulfonyl)-l- piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide P-l 16 Z (a) Example No. 283 284 285 286 287 288 289 290 291 292 293 Product (5)-N-[[3-[4-[4-(chIoromethancsulfonyI)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methylJ-2- methylpropanethioamide (S)-N-[[3-[4-[4-(chloromethanesulfonyl)-1 - piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide (£)-N-[[3-[3-Fluoro-4-[4-(cyanomethane-sulfonyl)-1 - piperazinyI]phenyl]-2-oxo-5- oxazolidinyl]methyl]thioacetamide (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethane-sulfonyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethane-sulfonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]methyl]-2-methylpropanethioamide (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethane-sulfonyl)-1 - piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethane-sulfonyl)-1 -piperazinyl]phenyI]-2-oxo-5-oxazolidinyI]methyI]thioacetamide (S)-N-[[3-[3.5-Difluoro-4-[4-(cyanomethane-sulfonyl)- l-piperazinyI]phenyI]-2-oxo-5-oxazolidinyl]- methyl]propanethioamide (5)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethane-sulfonyD-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide (5)-N-[[3-[3.5-Difluoro-4-[4-(cyanomethane-sulfonyl)- l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide (S>N-[[3-[4-[4-(Cyanomethanesulfonyl)-l- piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]thioacetamide Dithio Amine Compound P-l 16 Z (b) P-l 16 Z (c) P-l 17 Ethyl dithioacetate P-l 17 Z (a) P-l 17 Z (b) P-l 17 Z (c) P-l 18 Ethyl dithioacetate P-l 18 Z (a) P-l 18 Z (b) P-l 18 Z (c) P-l 19 Ethyl dithioacetate Example No. 294 295 296 297 298 299 300 301 302 303 304 Product (S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)-l- piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]propanethioamide (£)-N-[[3-[4-[4-(Cy anomethanesul fonyl)-1 - piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]methyi]-2- methylpropanethioamide (S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)-l- piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]cyclopropanecarbothioamide (S)-N-[[3-[3-Fluoro-4-[4-(N-methylsulfamoyl)-l- piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]thioacetamide (S)-N-[[3-[3-Fluoro-4-[4-(N-methylsulfamoyl)-1 - piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (S)-N-[[3-[3-FIuoro-4-[4-(N-methylsulfamoyI)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide (S)-N-[[3-[3-Fluoro-4-[4-(N-methylsulfamoyl)-1 - piperazinyI]phenyI]-2-oxo-5-oxazolidinyi]methyI]- cyclopropanecarbothioamide (S)-N-[[3-[3.5-Difluoro-4-[4-(N-methylsulfamoyl)-l- piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]thioacetamide (5)-N-[[3-[3.5-Difluoro-4-[4-(N-methylsulfamoyl)-l- piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (S)-N-[[3-[3.5-Difluoro-4-[4-(N-methylsulfamoyl)-l-piperazinyI]phenyI]-2-oxo-5-oxazolidinyl]methyl]-2-methyl propanethioamide (S)-N-[[3-[3.5-Difluoro-4-[4-(N-methylsulfamoyl)-1 - piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]meihyl]- cyclopropanecarbothioamide Dithio Amine Compound P-l 19 Z (a) P-l 19 Z (b) P-l 19 Z (c) P-l 20 Ethyl dithioacetate P-l 20 Z (a) P-l 20 Z (b) P-l 20 Z (c) P-121 Ethyl dithioacetate P-121 Z (a) P-121 Z (b) P-121 Z(c) Example Na 305 306 307 308 309 310 311 312 313 314 315 Product (S)-N-[[3-[4-[4-(N-methylsulfamoyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazoiidinyl]methyl]- thioacetamide (S)-N-[[3-[4-[4-(N-methylsulfamoyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]methyl]- propanethioamide (S)-N-[[3-[4-[4-(N-methyIsulfamoyl)-1 - piperaziny 1 Jphenyl ]-2-oxo-5-oxazolidiny ljmethy I ]-2- methylpropanethioamide (S)-N-[[3-[4-[4-(N-methylsulfamoyl)-l- piperazinyI]phenyl]-2-oxo-5-oxazolidinyI]methyl]- cyclopropanecarbothioamide (S)-N-[[3-[3-Fluoro-4-[4-(N.N-dimethylsulfamoyI)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide (S)-N-[[3-[3-Fluoro-4-[4-(N,N-dimethylsulfamoyl)-1 - piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyI]- propanethioamide (5)-N-[[3-[3-FIuoro-4-[4-(N,N-dimethyIsulfamoyl)-1 - piperazinyI]phenyl]-2-oxo-5-oxazolidinyI]methyl]-2- methylpropanethioamide (S)-N-[[3-[3-Fluoro-4-[4-(N.N-dimethylsulfamoyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinylJmethyl]- cyclopropanecarbothioamide (S)-N-[[3-[3.5-Difluoro-4-[4-(N?N-dimethylsulfamoyl)- l-piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide (S)-N-[[3-[3.5-Difluoro-4-[4-(N,N-dimcthylsulfamoyl)- l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (S)-N-[[3-[3,5-Difluoro-4-[4-(N.N-dimethylsulfamoyl)-l-piperazinylJphenyl]-2-oxo-5-oxazolidinyI]methyl]-2-methylpropanethioamide Dithio Amine Compound P-I22 Ethyl dithioacetate P-l 22 Z (a) P-l 22 Z (b) P-l 22 Z (c) P-l 23 Ethyl dithioacetate P-l 23 Z (a) P-l 23 Z (b) P-l 23 Z (c) P-l 24 Ethyl dithioacetate P-l 24 Z (a) P-l 24 Z (b) Example No. 316 317 Product Amine (S)-N-[[3-[3.5-Difluoro-4-[4-(N.N-dimethyIsulfamoyl)- P-124 l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide (5>N-[[3-[4-[4-(N,N-dimethylsulfamoyl)-1- P-125 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide Dithio Compound Z(c) Ethyl dithioacetate 318 (S)-N-[[3-[4-[4-(N.N-dimethylsulfamoyI)-l- P-125 piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 319 (5>N-[[3-[4-[4-(N,N-dimethylsulfamoyl)-l- P-125 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-mcthylpropanethioamide 320 (S)-N-[[3-[4-[4-(N.N-dimethylsulfamoyl)-l- P-125 piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 321 (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-thioacctamide Z (a) Z(b) Z (c) Ethyl dithioacetate 322 (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 Z(a) piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 323 (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 Z(b) piperazinyI]phenyl]-2-oxo-5-oxazolidinyl)methyl]-2-methylpropanethioamide 324 (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-I- P-126 Z(c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 325 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 Z (d) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- butanethioamide 326 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyI)-I- piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]mcthyl]-3-methylbutanethioamide P-126 Zfe) Example No. 327 328 329 330 331 332 333 334 335 336 337 Product Amine (S')-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1 - P-126 piperazinyI]phenyl]-2-oxo-5-oxazoIidinyl]methyl]-2- methylbutanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-3,3- dimethylbutanethioamide (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclobutanecarbothioamide (5)-N-[[3-[3-Fluoro-4-[4-(elhoxycarbonyl)-1- P-126 piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]- cyclopentanecarbothioamide (S)-N-[[3-[3-FIuoro-4-[4-(ethoxycarbonyl)-1- P-126 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclohexanecarbothioamide (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- cyclopropylethanethioamide (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyi)-1 - P-126 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- cyclobutylethanethioamide (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 piperazinyl]phcnyl]-2-oxo-5-oxazolidinyl]methyl]-2- cyclopeniylethanethioamide (S)-N-[[3-[3,5-Difluoro-4-[4-(ethoxycarbonyl)-l- P-127 piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]- thioacetmidc (5)-N-[[3-[3.5-Difluoro-4-t4-(ethoxycarbonyl)-I- P-127 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (5)-N-[[3-[3.5-Difluoro-4-[4-(ethoxycarbonyl)-I- P-127 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide Dithio Compound Z(f) Z(g) Z(h) Z(i) Z(j) Z(k) Z(l) Z(m) Ethyl dithioacetate Z(a) Z(b) Example No. 338 339 Product (5)-N-[[3-[3,5-Difluoro-4-[4-(ethoxycarbonyl)-l- piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide (5")-N-[[3-[4-[4-(ethoxycarbonyl)-l-piperazinyl]-pheny]]-2-oxo-5-oxazolidinyI]methyl]thioacetamide Dithio Amine Compound P-127 Z (c) P-l 28 Ethyl dithioacetate 340 (5)-N-[[3-[4-[4-(ethoxycarbonyl)-l-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 341 (S)-N-[[3-[4-[4-(ethoxycarbonyl)-l-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 342 (5)-N-[[3-[4-[4-(ethoxycarbonyI)-l-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropane-carbothioamide P-128 Z (a) P-l 28 Z (b) P-128 Z (c) 343 (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyI-1 -piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide P-129 Ethyl dithioacetate 344 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1 -piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamide 345 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1 -piperazinyl)-phenylJ-2-oxo-5-oxazolidinyl]melhyl]-2-methylpropanethioamide 346 (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- 1-piperazinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 347 (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-l-piperazinyI)phenyI]-2-oxo-5-oxazolidinyl]methyI]butanethioamide 348 (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1 -piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-methylbutanethioamide P-129 Z (a) P-129 Z (b) P-129 Z (c) P-129 Z (d) P-129 Z (e) Example No. 349 350 351 352 353 354 355 356 357 358 359 Product (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1 - piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- methylbutanethioamide (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-l- piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-3,3- dimethylbutanethioamide (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-l- piperazinyl)phenyI]-2-oxo-5- oxazolidinyl]methyl]cyclobutanecarbothioamide (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-l- piperazinyl)phenyI]-2-oxo-5- oxazolidinyl]methyl]cyclopentanecarbothioamide (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-l- piperazinyl)phenyl]-2-dxo-5- oxazolidinyl]methyl]cyclohcxanecarbothioamide (S)-N-[[3- [3-Fluoro-4-(4-sulfamoyI-1 - piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- cyclopropylethanethioamide (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyI-1 - piperazinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl]-2- cyclobutylethanethioamide (5)-N-tt3-[3-Fluoro-4-(4-sulfamoyl-l- piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- cyclopentylethanethioamide (5)-N-[[3-[3.5-Difluoro-4-(4-sulfamoyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidiny 1 ]methy 1 ]thioacetamide (5)-N-[[3-[3.5-Difluoro-4-(4-sulfamoyl-1 -piperazinyl )phenyl ]-2-oxo-5-oxazolidinyi]methyl]propanethioamide (5)-N-[[3-[3.5-Difluoro-4-(4-sulfamoyl-l- piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide Dithio Amine Compound P-129 Z(f) P-129 Z(g) P-129 Z (h) P-129 Z(i) P-129 ZO) P-129 Z(k) P-129 Z (1) P-129 Z (m) P-l 30 Ethyl dithioacetate P-l 30 Z (a) P-130 Z (b) WO 00/32599 Example No. Product 360 (5)-N-[[3-[3.5-Difluoro-4-(4-sulfamoyl-I-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbothioamide 361 (S)-N-[[3-[4-(4-sulfamoyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide 362 (S)-N-[[3-[4-{4-sulfamoyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide 363 (S)-N-[[3-[4-(4-sulfamoyI-1 -piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 364 (5)-N-[[3-[4-(4-sulfamoyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbothioamide 365 (S)-N-[[3-[3-Fluoro-4-[4-(cy anomethy 1)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]thioacetamide 366 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyI)-1-piperazinyI]phenyl]-2-oxo-5-oxazolidiny 1 ] methyl] propanethioamide 367 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazoIidinyl]methyl]-2-methylpropanethioamide 368 (5)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbothioamide 369 (S)-N-[[3-[3,5-Difluoro-4-[4-( cyanomethyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide 370 (5)-N-[[3-[3,5-Difluoro-4-[4-( cyanomethyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidiny 1 ] methyl Jpropanethioamide 371 (S)-N-[[3-[3,5-Difluoro-4-[4 cyanomethyl)-1-piperazinyl]phenyI]-2-oxo-5-oxazoIidinyl]methyI]-2-methylpropanethioamide Dithio Amine Compound P-l 30 Z (c) P-131 Ethyl dithioacetate P-131 Z (a) P-131 Z(b) P-131 Z (c) P-132 Ethyl dithioacetate P-132 Z (a) P-132 Z (b) P-132 Z (c) P-133 Ethyl dithioacetate P-l33 Z(a) P-l 33 Z (b) WO 00/32599 Example No. Product 372 (5)-N-[[3-[3.5-Difluoro-4-[4-(cyanomethyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 373 (5>N-[[3-[4-[4-(cyanomethyl)-l-piperazinyl]phenyl]-2 oxo-5-oxazolidinyl]methyl]thioacetamide 374 (5)-N-[[3-[4-[4-(cyanomethyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]propanethioamide 375 (5)-N-[[3-[4-[4-(cyanomethyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl)methyl]-2-methylpropanethioamide 376 (S)-N-[[3-[4-[4-( cyanomethyl)-l-piperazinyl]phenylj-2-oxo-5-oxazolidinyI]methyl]cyclopropane-carbothioamide 377 (S)-N-[[3-[3-Fluoro-4-[4-(2-fluoroethyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide 378 (S)-N-[[3-[3-Fluoro-4-[4-(2-fluoroethyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide 379 (5)-N-[[3-[3-Fluoro-4-[4-(2-fluoroethyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazoIidinyI]methyl]-2-methylpropanethioamide 380 (5)-N-[[3-[3-Fluoro-4-[4-(2-nuoroethyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclopropanecarbothioamide 381 (S)-N-[[3-[3,5-Difluoro-4-[4-(2-fluoroethyl)-l-piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-thioacetamide 382 (S)-N-[[3-[3.5-Difluoro-4-[4-(2-fluoroethyi)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]-propanethioamide 383 (S)-N-[[3-[3.5-Difluoro-4-[4-(2-fluoroeihyI)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide Dithio Amine Compound P-l 33 Z(c) P-l 34 Ethyl dithioacetate P-l 34 Z(a) P-l 34 Z (b) P-l 34 Z (c) P-l 35 Ethyl dithioacetate P-l 35 Z(a) P-l35 Z (b) P-135 Z(c) P-136 Ethyl dithioacetate P-l36 Z (a) P-l36 Z (b) Example No. 384 385 386 387 388 389 390 391 392 393 Product (S)-N-[[3-[3.5-Difluoro-4-[4-(2-fluoroethyl)-I- piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide (S)-N-[[3-[4-[4-(2-fluoroethyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (5)-N-[[3-[4-[4-(2-fluoroethyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide (S)-N-[[3-[4-[4-(2-fluoroethyl)-1 -piperazinyl]phenyl]- 2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide (5)-N-[[3-[4-[4-(2-fluoroethyl)-l-piperazinyl]phenyl]- 2-oxo-5-oxazolidinyl]methyl]cyclopropane- carbothioamide (5)-N-[[3-[3-Fluoro-4-(4-formyl-1-piperaziny l)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide; Anal calcd for C17H21FN4O3S: 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.
(S)-N-[[3-[3-Fluoro-4-(4-formyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide; mp 166-167°C; Anal, calcd for CisH2jFN403S: C, 54.81; H. 5.88; N, 14.20; S, 8.13. Found: C. 54.83: H, 6.00; N, 14.12: S, 7.96.
(S)-N-[[3-[3-Fluoro-4-(4-formyl-l -piperazinyl )phenyl]-2-oxo-5-oxazolidinyI]methyI]-2-methylpropane-thioamide: mp 157-158°C: Anal, calcd for C19H25FN4O3S: 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. (5)-N-[[3-[3-Fluoro-4-(4-formyl-1 -piperaziny])phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropane-carbothioamide; mp 178-179°C; Anal, calcd for C19H23FN4O3S: 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.
(SVN-fP-P.S-Difluro^-^-formyl-l-piperazinyl)-phenyl]-2-oxo-5-oxazoIidinyl]methyl]thioacetamide Dithio Amine Compound P-l 36 Z (c) P-137 Ethyl dithioacetate P-137 Z(a) P-137 Z (b) P-137 Z (c) P-l 38 P-l 38 P-138 P-138 P-l 39 Ethyl dithioacetate Z(a) Z (b) Z(c) Ethyl dithioacetate Example No. 394 395 396 397 398 399 400 Product (S)-N-[[3-[3,5-Difluro-4-(4-formyl-l-piperazinyl)- phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide (S)-N-[[3-[3.5-Difluro-4-(4-formyI-l-piperazinyl)- phenyl]-2-oxo-5-oxazoIidinyl]methyI]-2-methyl- propanethioamide (S)-N-[[3-[3,5-DifIuro-4-(4-formyl-l-piperazinyI)- phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclo- propanecarbothioamide (5)-N-[[3-[4-(4-formyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (5)-N-[[3-[4-(4-formyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide (5)-N-[[3-[4-(4-formyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyI]-2-methyIpropanethioamide (5)-N-[[3-[4-(4-formyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropane-carbothioamide Dithio Amine Compound P-l 39 Z (a) P-l 39 Z(b) P-l 39 Z(c) P-140 Ethyl dithioacetate P-140 Z(a) P-140 Z (b) P-140 Z(c) When in the general procedure of Example 31, step 1, an appropriate amount of the amine listed below is substituted for compound 33, the isothiocyanate corresponding to the amines P-90, P-93, P-99, P-105, P-126 and P-129 arc obtained.
When in the general procedure of Example 114 an appropriate amount of the isothiocyanate and the amine listed below are substituted for compound 82 and methylamine. the respective products listed below are obtained.
TABLE I Example No.
Product Isothiocyanate Corresponding to Amine No. Amine 401 (5)-N-[[3-[3-Fluoro-4-(4-acctyl-l- piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-methy 1 ]-N' -methy lthiourea P-90 methylamine Example No.
Product Isothiocyanate Corresponding to Amine No. Amine 402 (5>N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinylJ-methyl]-N',N'-dimethylthiourea 403 (5)-N-[[3-[3-Fluoro-4-(4-acetyl-1 -piperazinyl)phenyl]-2-oxo-5-oxazolidinylJ-methyl]-1 -azetidinecarbothioamide 404 (5)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)-phenyl]-2-oxo-5-oxazolidinyl]methyl]-thiourea P-90 dimethylamine P-90 P-90 azetidine anhydrous ammonia 405 (5)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-l- P-93 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N'-methylthiourea 406 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-l- P-93 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N',N'-dimethylthiourea 407 (5)-N-[[3-[3-FIuoro-4-[4-(methoxyacetyI)-l- P-93 piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]methyI]-l-azetidinecarbothioamide methylamine dimethylamine azetidine 408 (5)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N'-methylthiourea 409 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacety])-l- P-99 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-N',N'-dimethylthiourea 410 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l- P-99 piperazinyl Jphenyl ]-2-oxo-5-oxazolidinyl]- methylj-1 -azetidinecarbothioamide 411 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyI)- P-105 l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]-methyl]-N'-methylthiourea 412 (5)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyI)- P-105 l-piperazinylJphenyl]-2-oxo-5-oxazolidinyl]-methylJ-N'.N'-dimethylthiourea methylamine dimethylamine azetidine methylamine dimethvlamine Example No. 413 414 415 416 417 418 419 Product (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-1 -azetidinecarbothioamide (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]- methyl]-N'-methylthiourea (S)-N-[[3-[3-FIuoro-4-[4-(ethoxycarbonyl)-l- piperazinyl]phenyll-2-oxo-5-oxazolidinyl]- methyl]-N'.N'-dimethylthiourea (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-1 -azetidinecarbothioamide (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1 - piperazinyl)pheny!]-2-oxo-5-oxazolidinyl]- methyI]-N'-methylthiourea (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-l-piperazinyl)phenyI]-2-oxo-5-oxazolidinyl]-methy 1 ]-N'.N'-dimethyIthiourea (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1 -piperazinyl)phenyI]-2-oxo-5-oxazo!idinyl]-methyl]-1 -azetidinecarbothioamide Isothiocyanate Corresponding to Amine No.
P-105 P-126 P-126 P-126 P-129 P-129 P-129 Amine azetidine methylamine dimethylamine azetidine methylamine dimethylamine azetidine When in the general procedure of Example 100 an appropriate amount of the isothiocyanate and alcohol listed below are utilized in the same manner as Compound 82 and methanol are utilized, the respective products listed below are obtained.
Example No. 420 TABLE J Product (5)-N-[[3-[3-Fluoro-4-(4-acetyl-1 -piperazinyl )phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate Isothiocyanatc Corresponding to Amine No.
P-90 Amine methanol Example No. Product 421 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-1 -piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyI]-0-ethylthiocarbamate 422 (5>N-[[3-[3-Fluoro-4-(4-acetyl-1 -piperazinyI)phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-/jo-propylthiocarbamate 423 (S)-N-[[3-[3,5-Difluoro-4-(4-acetyl-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate 424 (5)-N-[[3-[4-(4-Acetyl-1 -piperazinyI)phenyI]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate 425 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate 426 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-ethylthiocarbamate 427 (5)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyI)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-/.v«-propylthiocarbamate 428 (S)-N-[[3-[3.5-Difluoro-[4-[4-(methoxy-acetyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methy!thiocarbamate 429 (5)-N-[[3-[4-[4-(methoxyacctyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate 430 (S)-N-[3-[3-Fluoro-4-[4-(cyanoacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidiny!]-methyl]-0-methylthiocarbamate 431 (S)-N-[[3-[3.5-Difluoro-4-[4-(cyanoacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate Isothiocyanate Corresponding to Amine No. Amine P-90 ethanol P-90 isopropyl alcohol P-91 methanol P-92 methanol P-93 methanol P-93 ethanol P-93 isopropyl alcohol P-94 methylaminel P-95 methylamine P-96 methanol P-97 methanol- Example No. 432 433 434 435 436 437 438 439 440 441 442 Product (S)-N-[[3-[4-[4-(Cyanoacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methy 1 ] -O-methy lthiocarbamate (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-ethylthiocarbamate (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyI)-l-piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]-methyI]-0-i5o-propy lthiocarbamate (S)-N-[[3-[3.5-Difluoro-4-[4-(acetoxyacetyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate (S)-N-[[3-[4-[4-(Acetoxyacetyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- methylj-O-methylthiocarbamate (5)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacetyl)- l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- methyI]-0-methylthiocarbamate (5)-N-[[3-[3.5-Difluoro-4-[4-(benzyloxy- acetyl)-l-piperazinyl]phenyl]-2-oxo-5- oxazolidinyI]methyl]-0-methylthiocarbamate (5)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenylJ-2-oxo-5-oxazo!idinyl]-methy I]- O-methy lthiocarbamate (5)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-ethylthiocarbamate (5)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyI)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-/.v«-propylthiocarbamate Isothiocyanate Corresponding to Amine No.
P-98 P-99 P-99 P-99 P-100 P-101 P-102 P-103 P-105 P-105 P-105 Amine methanol methanol ethanol isopropyl alcohol methanol methanol methanol methanol methanol ethanol isopropyl alcohol Example No. 443 444 445 446 447 448 449 450 451 452 453 Product (S)-N-[[3-[3,5-Difluoro-4-[4-(methoxy- carbonyI)-l-piperazinyI]phenyl]-2-oxo-5- oxazolidinyl]methyl]-0-methylthiocarbamate (S)-N-[[3-[4-[4-(methoxycarbonyl)-l- piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- methyl]-0-methylthiocarbamate (S)-N-[[3-[3-FIuoro-4-[4-(methanesulfonyl)- l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- methyl]-0-methylthiocarbamate (S)-N-[[3-[3.5-Difluoro-4-[4-(methane-sulfony 1)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate (5)-N- [ [3- [4-[4-(methanesulfony 1)-1 - piperazinyl]phenyl]-2-oxo-5-oxazoIidinyI]- methylJ-O-methylthiocarbamate (5)-N - [[3- [3-Fluoro-4- [4-(ethanesuIfony I)-1 - piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- methyl]-0-methylthiocarbamate (S)-N-[[3-[3,5-Difluoro-4-[4-(ethane-sulfonyl)-l-piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]cyclopropane-carbothioamide (5)-N-[[3-[4-[4-(ethanesulfonyl)-l- piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-0-methylthiocarbamate (5)-N-[[3-[3-Fluoro-4-[4-(chloromethane-sulfonyl)-1 -piperazinyl]phenyI]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate (S)-N-[[3-[3,5-Difluoro-4-[4-(chloro-methanesulfonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyI]-0-methyl-thiocarbamate (S)-N-[[3-[4-[4-(chloromethanesulfonyl)-l- piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-0-methylthiocarbamatc Isothiocyanate Corresponding to Amine No.
P-106 P-107 P-108 P-109 P-110 P-l 11 P-l 12 P-l 13 P-l 14 P-l 15 Amine methanol methanol methanol methanol methanol methanol methanol methanol methanol methanol P-l 16 methanol Example No. 454 455 456 457 458 459 460 461 462 463 464 Product (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethane-sulfonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate (5)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethane- sulfonyl)-l-piperazinyl]phenyl]-2-oxo-5- oxazoIidinyl]methyl]-0-methylthiocarbamate (S)-N-[[3-[4-[4-(Cyanomethanesulfony 1)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methy]]-0-methylthiocarbamate (5)-N-[[3-[3-FIuoro-4-[4-(N-methyl- sulfamoyl)-l-piperazinyl]phenyl]-2-oxo-5- oxazo!idinyl]methyI]-0-methylthiocarbamate (S)-N-[[3-[3,5-Difluoro-4-[4-(N-methyl-sulfamoyl)-1 -piperazinyI]phenyI]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate (S)-N-[[3-[4-[4-(N-methylsuIfamoyI)-1 - piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- methyl]-0-methylthiocarbamate (S)-N-[[3-[3-Fluoro-4-[4-(N,N-dimethyl-sulfamoyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methy]]-0-methylthiocarbamate (i')-N-[[3-[3,5-Difluoro-4-[4-(N,N-dimethyl-sulfamoyl)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate (5)-N-[[3-[4-[4-(N,N-dimethylsulfamoyI)-l-piperaziny I ]pheny I ]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- piperazinyI]phenyl]-2-oxo-5-oxazolidinyl]- methyl]-0-methylthiocarbamate (5)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- piperazinyI]phenyI]-2-oxo-5-oxazolidinyl]- methyl]-0-ethylthiocarbamate Isothiocyanate Corresponding to Amine No.
P-l 17 P-l 18 P-l 19 P-l 20 P-121 P-l 22 P-l 23 P-l 24 P-125 P-126 P-126 Amine methanol methanol methanol methanol methanol methanol methanol methanol methanol methanol ethanol Example No.
Product Isothiocyanate Corresponding to Amine No.
Amine 465 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-l- P-126 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-O-/50-propylthiocarbamate 466 (S)-N-[ [3-[3,5-Difluoro-4-[4-(ethoxy- P-127 carbonyl)-1 -piperaziny l]phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate 467 (S>N-[[3-[4-[4-(ethoxycarbonyl)-l- P-128 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate 468 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-l- P-129 piperazinyl)phenyl)-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate, 469 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-l- P-129 piperazinyOphenyl ]-2-0X0-5-oxazolidinyl]methyl]-0-ethylthiocarbamate 470 (5)-N-[[3-[3-Fluoro-4-(4-sulfamoyI-l- P-129 piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-wo-propyIthiocarbamate 471 (5)-N-[[3-[3,5-Difluoro-4-(4-sulfamoyl-l- P-l 30 piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate 472 (5)-N-[[3-[4-(4-sulfamoyl-l-piperazinyl)- P-131 phenyl]-2-oxo-5-oxazolidinyI]methyl]-0-methylthiocarbamate 473 (5)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)-l- P-132 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate 474 (S)-N-[[3-[3.5-Difluoro-4-[4-(cyanomethyl)- P-l 33 l-piperozinyl]phenyl]-2-oxo-5-oxozolidinyl]-methyl]-0-methylthiocarbamate 475 (5)-N-[[3-[4-[4-( cyanomethyl)-1- P-l34 piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate isopropyl alcohol methanol methanol methanol ethanol isopropyl alcohol methanol methanol methanol methanol methanoll Example No. 476 All 478 479 480 481 Product (S)-N-[[3-[3-FIuoro-4-[4-(2-fluoroethyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl J-O-methylthiocarbamate (S)-N-[[3-[3,5-Difluoro-4-[4-(2-fluoroethyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]-0-methylthiocarbamate (5)-N-[[3-[4-[4-(2-fluoroethyI)-1 -piperazinyl]phenyl]-2-oxo-5-oxazolidinyI]-methyl ]-0-methy lthiocarbamate (5)-N-[[3-[3-Fluoro-4-(4-formyl-1 - pipcrazinyl)phenyI]-2-oxo-5-oxazolidinyl]- methylJ-O-methylthiocarbamate (5)-N-[[3-[3,5-Difluro-4-(4-formyl-1 - piperazinyl)phenyI]-2-oxo-5-oxazolidinyl]- methylJ-O-methylthiocarbamate (5>N-[[3-[4-(4-formyl-l-piperazinyl)- phenyl]-2-oxo-5-oxazolidinyl]methyl]-0- methylthiocarbamate Isothiocyanate Corresponding to Amine No.
P-l 35 P-136 P-137 P-138 P-l 39 P-140 Amine methanol methanol methanol methanol methanol methanol EXAMPLE 482. (5SHV-[[3-[3-Fluoro-4-(tetrahydro-1.4-thiazepin-4(5^0- yl)phenyI]-2-oxo-5-oxazolidinyl]methyI]thioacetamide, thiazepine S-oxide o. ns— M^n^ch3 s Step 1. Hexahydro-5-oxo-l,4-thiazepine is prepared according to the procedure described by Gallego U. Org. Chem. 1993. 5S, 3905-3911).
Step 2. Lithium aluminum hydride (5.5 mL of a 1M solution in THF) is added dropwise to a stirred solution of hexahydro-5-oxo-1.4-thiazepine (721.5 mg) in dry THF (21 mL) cooled to 0 °C. The reaction mixture is stirred at 0 °C for 10 min, then at room temperature for 4 h. The reaction mixture is quenched by careful successive addition of water (0.2 mL), 5 N aqueous NaOH (0.2 mL) and water (0.74 mL). The reaction mixture becomes very thick and gel-like. The reaction mixture is diluted with ether (50 mL) and filtered through a pad of celite. The filter cake is washed with ether (100 mL).
The filtrate is concentrated to afford 616.6 mg of 1,4-hexahydrothiazepine which is used immediately in the next step.
Step 3. To a stirred solution of 1,4-hexahydrothiazepine (596.0 mg) and 3.4-difluoronitrobenzene (0.51 mL) in acetonitrile (14 mL) is added diisopropylethylamine (1.0 mL). The yellow solution is heated at reflux for 18 h. then cooled and concentrated.
The residue is diluted with CH,C1, (100 mL) and washed with saturated aqueous NH4C1 (35 mL). The phases are separated and the organics are dried (MgS04), filtered and concentrated. The residue is purified by flash chromatography using 20% EtOAc in hexane as the eluent to afford 830.2 mg of the nitrobenzene. Mp 115-116 °C; Anal. Calcd for CnH|;iFN,0,S: 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 EtOH (260 mL) is added a solution of 2 M aqueous CuS04 (11.9 mL). The mixture is cooled to 0 °C and NaBH4 (4.1 g) is added in portions. The reaction mixture turns very dark and is stirred at 0 °C for 10 min. at room temperature for 30 min. and then heated at reflux for 3 h. The cooled reaction mixture is diluted with EtOAc (500 ml) and washed with water (200 mL). The aqueous mixture is extracted with EtOAc (3 x 200 mL). The combined organics are dried (MgS04), filtered and concentrated to afford the aniline 5 intermediate.
Step 5. The dark residue from Step 4 is dissolved in 2:1 acetone/water (255 mL) and cooled to 0 °C. To this stirred mixture is added solid NaHCO., (5.4 g) followed by benzylchloroformate (7.7 mL). The reaction mixture is stirred at 0 °C for 10 min, then at room temperature for 24 h. The reaction mixture is quenched with 10% aqueous 10 NaHS04 (200 mL) and then poured into EtOAc (300 mL). The phases arc separated and the aqueous phase is extracted with EtOAc (2 x 250 mL). The combined organics are dried (MgSOj, filtered and concentrated. The residue is purified by MPLC using 20% EtOAc in hexane to afford 6.03 g of the benzylcarbamate as a yellow solid, mp 72-74 °C; Anal. Calcd for C^FN^S: C, 63.31; H, 5.87: N, 7.77; S, 8.89. Found: C, 15 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 N, cooled to -78 °C, is added dropwise via syringe a 1.6 M solution of nBuLi in hexane (5.4 mL). The reaction mixture was stirred at -78 °C for 35 min, then R-glycidyl butyrate (1.2 mL) is added. The reaction mixture is stirred at -78 °C for 30 min, 20 then at room temperature overnight during which time a precipitate forms. The reaction mixture is quenched with saturated aqueous NH4C1 (33 mL) and poured into EtOAc (100 mL). The phases are separated. The organic phase is washed with saturated aqueous NaHCO., (50 mL). brine ( 50 mL), dried (MgS04). filtered and concentrated.
The residue is purified by flash chromatography using EtOAc as the eluent to afford 2.5 25 g of a hydroxymethyl oxazolidinone. Mp 100-102 °C. Anal. Calcd for C|JH|9FN.,01S: 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 CH,C1, (35 mL) cooled to 0 °C. is added triethylamine (1.1 mL) followed by methanesulfonyl chloride (0.5 mL). The reaction mixture is stirred at 0 °C for 10 min. then at room 30 temperature for 1 h. The reaction mixture is treated with water (35 mL). The phases are separated and the aqueous phase is extracted with CH,CI., (35 mL). The combined organic phases are dried (MgS04), filtered and concentrated. The residue is purified by flash chromatography using 80% EtOAc in hexane as the eluent to afford 2.1 g of the mesylate. Mp 132-142 °C. Anal. Calcd for C|6H21FN,OsS,: 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 is bubbled into a stirred suspension of the mesylate prepared in Step 7 (941.7 mg) in 1:1 THF/CH-.OH (40 mL) until saturated (approx. 5 min). The reaction mixture is heated in a sealed tube at 100 °C for 72 h. The cooled reaction mixture is concentrated to give the crude amine, which is immediately suspended in CH2C1; (35 mL) and cooled to 0 °C. To this stirred suspension is added 10 triethylamine (0.97 mL, 6.9 mmol) followed by di-/cr/-butyl dicarbonate (759.5 mg, 3.5 mmol). The reaction mixture becomes homogeneous and is stirred at RT for 18 h. The reaction mixture is poured into CHiCN (75 mL) and washed with H:0 (1 x 50 mL). The organic phase is dried (MgSOj), filtered and concentrated. The resulting residue is purified on a Biotage 40 S column using 30-35 % ethyl acetate in CH?OH as the eluent 15 to afford 867.4 mg of the protected amine, mp 74-75 °C. Anal Cald: C, 56.45; H, 6.63; N, 9.88. Found: C, 56.95; H, 6.85; N, 9.55.
Step 9. To a stirred suspension of the protected amine prepared in Step 8 (205.2 mg) in 1:1 CH3OH/H2O (6 mL) cooled to 0°C is added sodium meta periodate (113.5 mg). The resulting suspension is stirred at RT for 18 h. The reaction mixture is filtered 20 and the solid is washed with CHiCL (2 x 20 mL). The filtrate is extracted with H>0 (1 x 10 mL). The phases are separated. The aqueous phase is extracted with CHjCK (1 x 25 mL). The combined organic phases are dried (MgS04), filtered and concentrated. The white solid residue is purified on a Biotage 12 M column using 5% CHjOH in . CHiCl: as the eluent to afford 187.3 mg of the sulfoxide, mp 78-81 °C. 25 Step 10. Dry HCI gas is passed over the surface of a stirred solution of the sulfoxide prepared in Step 9 (179.3 mg) in CH.iOH (2 mL) cooled to 0°C for 1 minute. The reaction mixture is stirred at 0 °C for 10 min. then at room temperature for 15 min, then concentrated. The resulting yellow residue is suspended in THF (5 mL) and CH2CI1 (5 mL) and cooled to 0°C. To this stirred suspension is added triethylamine 30 (0.46 mL) followed by ethyldithioacetate (0.18 mL). The dark reaction mixture is stirred at RT overnight then concentrated. The dark residue is diluted with CH2CI2 (30 mL) and washed with HiO (2x15 mL). The organic phases arc dried (MgS04). filtered and concentrated. The dark residue is purified on a Biotage 12 M column using 59c CHiOH in CH2CI2 as the eluent to afford 71.5 mg of the title compound as a tan solid, mp 85-89 °C.
Following the general procedure outlined in Step 10 of Example 4S2. but substituting the dithiocsicrs listed below, the compounds of Examples 483 to 495 of Table K can be obtained.
TABLE K ExamDle No.
Compound Amine Dithioester (from Preparation Z) 483 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yI))- phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide, thiazepine S-oxide 0. 0 pJUNAO M^nh2 Z (a) 484 S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazcpin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyI]methyl]-2- methylpropanethio- amide. thiazepine S- oxide.
Same as above Z(b) 485 (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl))-phenyl]-2-oxo-5-oxazo!idinyI]methyl]-cyclopropanecarbothio-amide. thiazepine S-oxide.
Same as above Z(c) Example No.
Compound Amine Dithioester (from Preparation Z) 486 (5S)-N-[[3-[3-FJuoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]- butanethioamide, thiazepine S-oxide Same as above Z(d) 487 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-3- methyibutanethioamide. thiazepine S-oxide Same as above Z(e) 488 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylbutanethioamide. thiazepine S-oxide Same as above Z(f) 489 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyljmethyl]- 3.3-dimethylbutanethio- amide, thiazepine S- oxide Same as above Z(g) 490 (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1.4-thiazepin-4C5 H )-y 1) )-phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclobutanccarbothio-amide, thiazepine S-oxide Same as above Z(h) Example Compound Amine Dithioester No. (from Preparation Z) 491 (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl))-phenyl]-2-oxo-5-oxazolidinyljmethyl]-1 -cyclopentanecarbothio-amide. thiazepine S-oxide Same as above Z(i) 492 (5S)-N-[[3-[3-FIuoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl]methyl]-cyclohexanecarbothio-amide, thiazepine S-oxide Same as above Z(j) 493 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl»- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- cyclopropylethanethio- amide. thiazepine S- oxide Same as above Z(k) 494 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyI]methyI]-2- cyclobutylethanethio- amide. thiazepine S- oxide Same as above Z(l) ExamDle No.
Compound Amine Dithioester (from Preparation Z) 495 (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1.4-thiazepin-4(5H)-yl))-phenyl J-2-OXO-5-oxazolidinyl]methyl]-2-cyclopentylethanethio-amide. thiazepine S-oxide Same as above Z (m) Example 496. (5S)-./V-[[3-[3,5-Dif1uoro-4-(tetrahydro-I,4-thiazepin-4(5/7)-yl)phenyI]-2-oxo-5-oxazolidinyl]methyl]thioacetamide, thiazepine S-oxide i Ax S The title compound can be prepared by the procedure of Example 482, by substituting an appropriate quantity of 2.6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate for 3.4-difluoroniirobenzene in Step 1.
Utilizing the amine prepared in 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 ExamDle No.
Compound Amine Dithioester (from Preparation Z) 497 (5S)-N-[[3-[3.5- Di fluoro-4- (tetrahydro- 1,4-thiazepin-4(5H)-yI))- phenyl]-2-oxo-5- oxazolidinyljmethyl]- propanethioamide, thiazepine S-oxide O.
Np I AAA M^mh, Z (a) 498 (5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethio-amide, thiazepine S-oxide Same as above Z(b) 499 (5S)-N-[[3-[3,5-Difluoro-4-( tetrahydro-1,4-thiazepin-4(5H)-yl))-phenyl]-2-oxo-5-oxazolidiny]]methyI]-cyclopropanecarbothio-amide, thiazepine S-oxide Same as above Z(c) Example 500. (5S)-A4[3-[4-(Tetrahydro-l,4-thiazepin-4(5//)-yl)phenyI]-2-oxo-5-oxazolidinyljmethyljthioacetamide, thiazepine S-oxide.
WnA0 M^n^ch3 s The title compound can be prepared by the procedure of Example 482. by substituting an appropriate quantity of 4-fluoronitrobenzene for 3,4-difluoronitro-benzene in Step 1.
Utilizing the amine prepared in Example 500. but substituting the dithioester listed below for ethyl dithioacctate in the final step, the compounds of Examples 501 to 503 of Table M are obtained TABLE M Example No.
Compound Amine Dithioester (from Preparation Z) 501 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyljmethyl]- propanethioamide, thiazepine S-oxide 0.
Z (a) 502 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-yI))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylpropanethio- amide. thiazepine S- oxide Same as above Z(b) 503 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclopropanecarbothio- amide, thiazepine S- oxide Same as above Z(c) Example 504. (5S)-iV-[[3-[3-Fluoro-4-( tetrahydro-1.4-thiazepin-4(5/f)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide, thiazepine S,S-dioxide AAA 'vNyCHj s 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) is added 4-methylmorpholine N-oxide (201.5 5 mg) followed by a solution of osmium tetroxide in 2-methyI-2-propanol (2.5 wt %, 30 jiL). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is treated with saturated sodium bisulfate (8 mL), then poured into CHjCIt (50 mL). The phases are separated. The aqueous phase is extracted with CH;Cli (2 x 25 mL). The combined organic phases are washed with brine (I x 25 mL), dried (MgSQi), 10 filtered and concentrated. The residue is purified on a Biotage 40 S column using 1 % CH3OH in CH2CI1 as the eluent to afford 216.1 mg (0.47 mmol, 83%) of the thiazepine S.S-dioxide as a white solid, mp 144-146 °C.
Step 2. Dry HCI gas is passed over the surface of a stirred solution of the thiazepine S.S-dioxide prepared in Step 1 (108.2 mg) in CHiOH(3 mL) at 0°C for 1 15 minute. The reaction mixture is stirred at 0 °C for 10 min and then at room temperature for 15 min. The reaction is concentrated and the yellow residue is suspended in CH2CI2 (2 mL) and THF (2 mL). This stirred suspension is cooled to 0°C and triethylamine (0.27 mL) is added followed by a solution of ethyldithioacetate (0.11 mL) in THF (0.5 mL) with 0.25 mL rinse. The yellowish-green solution is stirred at (PC for 10 min then 20 at room temperature for 18 h. The reaction mixture is poured into CH2CI2 (20 mL) and washed with H2O (2x10 mL). The organic phase was dried (MgSOj), filtered and concentrated. The residue is purified on a Biotage 12 M column using 2 % CH*OH in CH2CI2 as the eluent to afford 77.3 mg of the title compound as a white solid, mp 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 ExamDie No.
Compound Amine Dithioester (from Preparation Z) 505 (5S)-N-[[3-[3-Fiuoro-4- (4-thiomorpholinyl]- phenyI]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide, thiazepine S.S-dioxide o n « 0=s-^ o FWO M^nh2 Z (a) 506 (5S)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyI]- phenyl]-2-oxo-5- oxazolidinyI]methyI]-2- methylpropanethio- amide, thiazepine S,S- dioxide Same as above Z(b) 507 (5S)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyl]- phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclopropanecarbothio- amide. thiazepine S,S- dioxide Same as above Z (c) Example 508. (5S)-iV-[[3-[3,5-Difluoro-4-(tetrahydro-l,4-thiazepin-4(5//)-y])phenyl]-2-oxo-5-oxazolidinyl]methyI]thioacetamide, thiazepine S,S-dioxide O n ,XXNA0 s The title compound can be prepared by the procedures of Examples 504 and 482. by substituting an appropriate quantity of 2.6-difluoro-4-nitrobenzene (trifluoromethane) sulfonate for 3,4-difluoronitrobenzene in Step 1 of Example 482.
Utilizing the 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 No.
Compound Amine Dithioester (from Preparation Z) 509 (5S)-N-[[3-[3,5- Difluoro-4-(4- thiomorpholinyl]- phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide, thiazepine S,S-dioxide O o « M^nh2 Z (a) 510 (5S)-N-[[3-[3,5- Difluoro-4-(4- thiomorpholinyl]- phenyl]-2-oxo-5- oxazolidinyI]methyl]-2- methylpropanethio- amide. thiazepine S.S- dioxide Same as above Z(b) 511 (5S)-N-[[3-[3,5- Difluoro-4-(4- thiomorpholinyl]- phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclopropanecarbothio- amide. thiazepine S.S- dioxide Same as above Z (c) Example 512. (5S)-Af-[[3-[4-(Tetrahydro-l,4-thiazepin-4(5//)-yl)phenyI]-2-oxo-5-oxazolidinyl]methyl]thioacetamide, thiazepine S,S-dioxide o=s-^ M^N^CH3 s The title compound can be prepared by the procedure of Examples 504 and 482, by substituting an appropriate quantity of 4-fluoronitrobenzene for 3.4-difluoronitro-benzene in Step 1 of Example 482.
Utilizing 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 of Table P are obtained.
TABLE P Example No.
Compound Amine Dithioester (From Preparation Z) 513 (5S)-N-[[3-[4- (tetrahydro-1,4- thiazepin-4(5H)- yl))phenyl]-2-oxo-5- oxazolidinyl]- methyI]propanethio- amide, thiazepine S.S- dioxide CM 1 0 JP o ■ Z (a) 514 (5S)-N-[[3-[4- (tetrahydro-1,4- thiazcpin-4(5H)- yl))phenyI]-2-oxo-5- oxazolidinyl]methy]]-2- methylpropancthio- amide, thiazepine S.S- dioxide Same as above Z(b) Example No.
Compound Amine Dithioester (From Preparation Z) 515 (5S)-N-[[3-[4-(tetrahydro-1.4-thiazepin-4(5H)-yl))phenyl]-2-oxo-5-oxazolidinyl]-methy 1 Jcyclopropane-carbothioamide, thiazepine S.S-dioxide Same as above Z(c) EXAMPLE 516. (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5//> yl)phenyl]-2-oxo-5-oxazolidinyi]methyl]thioacetamide.
P> M^n^ch3 s This compound is prepared according to the procedure of Step 8 in Example 482, but stubstituting an appropriate quantity of ethyl dithioacetate for di-rm-butyl dicarbonate: mp 129-131°C.
Utilizing the amine prepared in Step 8 of Example 482. but substituting an appropriate quantity of the dithioester listed below for di-/m-butyl dicarbonate, the compounds of Examples 517 to 529 of Table Q are obtained.
TABLE O Example No.
Compound Amine Dithioester (From Preparation Z) 517 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyljmethyl]- propaneihioamide 0 fWN^O M^NH2 Z (a) Example No.
Compound Amine Dithioester (From Preparation Z) 518 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylpropanethioamide Same as above Z(b) 519 (5S)-N-[[3-[3-FIuoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl))-phenyl]-2-oxo-5-oxazolidi ny 1 ] methyl ]-cyclopropanecarbothioamide Same as above Z(c) 520 (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4( 5 H)-y I))-phenyl]-2-oxo-5-oxazolidinyljmethyl]-butanethioamide Same as above Z(d) 521 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-3- methylbutanethioamide Same as above Z(e) 522 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylbutanethioamide Same as above Z(f) 523 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenylJ-2-oxo-5- oxazolidinyl]methyl]- 3,3-dimethylbutaneihio- amide Same as above Z(g) Example No.
Compound Amine Dithioester (From Preparation Z) 524 (5S)-N-[[3-[3-FIuoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyljmethyl]- cyclobutanecarbothioami de Same as above Z(h) 525 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazol idiny 1 ] methyl ]- cyclopentanccarbothio- amide Same as above Z(i) 526 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yI ))- phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclohexanecarbothio- amide Same as above Z(j) 527 (5S)-N-[[3-[3-5 Fluoro- 4-(tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyI]-2-oxo-5- oxazolidinyI]methyl]-2- cyclopropylethanethio- amide Same as above Z(k) 528 (5S)-N-[[3-[3-FIuoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- cyclobutylethanethio- amide Same as above Z(l) Example No.
Compound Amine Dithioester (From Preparation Z) 529 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl ]methyI]-2- cyclopentylethanethioam ide Same as above Z(m) EXAMPLE 530. (55)-Ar-[[3-[33-Difluoro-4-(tetrahydro-l,4-thiazepin-4(5fl)-yI)phenyI]-2-oxo-5-oxazoIidinyl]methyl]thioacetamide.
H i XKs* h Ha,®.
S This compound can be prepared according to the procedures of Example 482 and Example 516, but substituting an appropriate quantity of 2,6-difluoro-4-nitrophenyl trifluoromethane sulfonate for 3,4-difluoronitrobenzene in Step 1 of Example 482.
Utilizing the amine prepared in Example 530. but substituting an appropriate quantity of the dithioester listed below for di-fm-butyl dicarbonate. the compounds of Examples 531 to 533 of Table R can be prepared.
TABLE R Example No.
Compound Amine Dithio Compound (from Preparation Z) 531 (5S)-N-[[3-[3.5-Difluoro-4-( tetrahydro-1.4-thiazepin-4(5H)-yl))-phenyl]-2-oxo-5-oxazolidinyl]methyl]-propanethioamidc CM -■0 Z (a) Example No.
Compound Amine Dithio Compound (from Preparation Z) 532 (5S)-N-[[3-[3.5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylpropanethioamide Same as above Z(b) 533 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclopropanecarbothio- amide Same as above Z(c) EXAMPLE 534. (5S)-N-[[3-[4-(Tetrahydro-l,4-thiazepin-4(5/7)-yI)phenyI]-2-oxo-5-oxazolidinyi]methyl]thioacetamide; mp 129-131°C P> M^n^ch3 s This compound can be prepared according to the procedures of Example 482 and Example 516, but substituting an appropriate quantity of 4-fluoronitrobenzcne for 3,4-difluoronitrobenzene in Step 1 of Example 482.
Utilizing the amine prepared in Example 534, but substituting an appropriate quantity of the dithioester listed below for di-/m-butyl dicarbonate. the compounds of Examples 535 to 537 of Table S can be prepared.
TABLE S Example No.
Compound Amine Dithio Compound (from Preparation Z) 535 (5S)-N-[[3-[4- (Tetrahydro-1.4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]- methyl]propanethio- amide V-Vil o Z (a) 536 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazoIidinyl]methyl]-2- methylpropanethioamide Same as above Z(b) 537 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]- methyljcyclopropane- carbothioamide Same as above Z (c) EXAMPLE 538. (55)-/V-[[3-[3-Fluoro-4-(tetrahydro-l,4-thiazepin-4(5flr)-yl)phenvl]-2-oxo-5-oxazoIidinyI]methyl]thiourea, thiazepine S-oxide o pAAnA0 h V~CNyNH2 s 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 reaction of the isothiocyanate prepared in Example 538 with the amines and alcohols listed in Table T. the compounds of Examples 539 to 544 can be prepared.
TABLE T Example Compound Isothiocvanate Amine or No.
Alcohol 539 (5S)-/V-[[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5//)- yl)phenyI]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea. thiazepine S-oxide 0 fW/o Mv,n=c=s CH3NH2 540 (5S)-A/-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5tf)- yl)phenyl]-2-oxo-5- oxazolidinyljmethylj- N* ,N' -dimethylthiourea. thiazepine S-oxide Same as above (CH3)2NH 541 (55)-A^-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5//)- yI)phenyl]-2-oxo-5- oxazolidinyljmethyl]-1- azetidinecarbothioamide, thiazepine S-oxide Same as above Azetidine 542 (5SWV-[[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- methylthiocarbamate. thiazepine S-oxide Same as above CHjOH 543 (5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1.4-thiazepin-4(5/7)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-ethy 1 thiocarbamate. thiazepine S-oxide Same as above CH,CH2OH Example No.
Compound Isothiocyanate Amine or Alcohol 544 (5S)-Aq[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- /sopropylthiocarbamate. thiazepine S-oxide Same as above (CHO2CHOH EXAMPLE 545. (5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-l,4-thiazepin-4(5ff)-yl)phenyl]-2-oxo-5-oxazoIidinyl]methyl]thiourea, thiazepine S-oxide ^s-\ 0 s 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 reaction of the isothiocyanate prepared in Example 545 with the amines and alcohols listed in Table U. the compounds of Examples 546 to 551 can be prepared.
TABLE U Example No.
Compound Isothiocvanate Amine or Alcohol 546 (5SWV-[[3-[3,5- Di fl uoro-4-( tetrahy dro- 1.4-thiazepin-4(5//)- yl)phenyI]-2-oxo-5- oxazolidinylJmethyll-N'- methylthiourea. thiazepine S-oxide O *0 I Oyk 0 CH3NH2 Example No.
Compound Isothiocyanate Amine or Alcohol 547 (5S)-W-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyljmethyl]- N'.N'-dimethylthiourea. thiazepine S-oxide Same as above (CH3)2NH 548 {5S)-N-[[3-[3,5- Di fl uoro-4-( tetrahydro- 1,4-thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyI]-l- azetidinecarbothioamidc. thiazepine S-oxide Same as above Azetidine 549 (5S)-W-[[3-[3,5-Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5//)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate, thiazepine S-oxide Same as above CH3OH 550 (55)-yV-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5^)-y 1 )pheny 1 ]-2-oxo-5-oxazolidinyl]methyI]-0-ethylthiocarbamate, thiazepine S-oxide Same as above CH3CH2OH 551 (5S)-/V-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5/7)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0- /^opropy lthiocarbamate. thiazepine S-oxide Same as above (CH3)2CHOH EXAMPLE 552. (55)-/V-[[3-[4-(Tetrahydro-l,4-thiazepin-4(5//)-yI)phenyl]-2-oxo-5-oxazolidinyl]methyl)thiourea, thiazepine S-oxide WO 00/32S99 o M^n>^nh2 s This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 500 for the amine 33.
By 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 ExamDle No.
Compound Isothiocyanate Amine or Alcohol 553 (5S)-/V-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyI]-N'- methylthiourea, thiazepine S-oxide °o M^n=C=S CH3NH2 554 (5S)-/V-[[3-[4- (Tetrahydro-1,4- thiazcpin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyljmethyl]- N'.N'-dimethylthiourea, thiazepine S-oxide Same as above (CH3)2NH 555 (5S)-A4[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyljmethyl]-1 - azetidinecarbothioamide, thiazepine S-oxide Same as above Azetidine ExamDle No.
Compound Isothiocvanate Amine or Alcohol 556 (5SVN-[[3-[4- (Tetrahydro-1.4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- methylthiocarbamate. thiazepine S-oxide Same as above CHiOH 557 (55)-A4[3-[4-(Tetrahydro-1.4- thiazepin-4(5tf)- yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-ethylthiocarbamate. thiazepine S-oxide Same as above CH3CH2OH 558 (5S)-A/-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5f/)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- /jopropylthiocarbamate, thiazepine S-oxidc Same as above (CH3)2CHOH EXAMPLE 559. (5S)-N-[[3-l3-Fluoro-4-(tetrahydro-l,4-thiazepin-4(5//)-yl)phenyI]-2-o\o-5-oxazoIidinyl]methyl]thiourea, thiazepine S,S-dioxide o n \\ °=s-^S| fXAna0 h S This compound can be prepared by the procedure described in Example 33. but substituting the amine prepared in Example 504 for the amine 33.
By reaction of the isothiocyanate prepared in Example 559 with the amines and alcohols listed in Table W. the compounds of Examples 560 to 565 can be prepared.
PCT/U S98/25308 TABLE W Example No.
Compound Isothiocvanate Amine or Alcohol 560 (55)-/V-[[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5//> yl)phenyl]-2-oxo-5- oxazolidinyl]methy!]-N'- methylthiourea, thiazepine S.S-dioxide to II o II & o O^II^— o CH3NH2 561 (55)-/V-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5f/)-yl)phenyl]-2-oxo-5-oxazolidinyljmethyl]-N \N' -dimethylthiourea, thiazepine S,S-dioxide Same as above (CHj)2NH 562 (5S)-/V-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5//)-yl)phenyl]-2-oxo-5-oxazolidinyljmethyl]-1 -azetidinecarbothioamide, thiazepine S,S-dioxide Same as above Azetidine 563 (55)-/V-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyI]-0- mcthylthiocarbamate, thiazepine S,S-dioxide Same as above CH,OH 564 (55)-A^-[[3-[3-Fiuoro-4- (tetrahydro-1.4- thiazepin-4(5//)- yl)phenylJ-2-oxo-5- oxazolidinyl]methyl]-0- ethylthiocarbamate. thiazepine S.S-dioxide Same as above CH*CH:OH Example No.
Compound Isothiocvanate Amine or Alcohol 565 (5S)-/V-[[3-[3-Fluoro-4-(tetrahydro-1.4-thiazepin-4(5//)-yI)phenyI]-2-oxo-5-oxazoIidinyl]methyl]-0-/jopropy lthiocarbamate. thiazepine S.S-dioxide Same as above (CH3)2CHOH EXAMPLE 566. (5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5//)-yl)phenyI]-2-oxo-5-oxazolidinyl]methyI]thiourea, thiazepine S,S-dioxide o n « Aa s This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 508 for the amine 33.
By 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 Example No.
Compound Isothiocvanate Amine or Alcohol 567 (55)-/V-[[3-[3.5- Difluoro-4-(tctrahydro- 1,4-thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyI]-N'- methylthiourea. thiazepine S.S-dioxide "hi ,l-^n=C=S CH3NH2 Example No.
Compound Isothiocvanate Amine or Alcohol 568 (55>N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5//)-yl)phenyl]-2-oxo-5-oxazolidinyljmethyl]-N' ,N' -dimethylthiourea, thiazepine S.S-dioxide Same as above (CH3)2NH 569 (55>A4[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyI]-l- azetidinecarbothioamide. thiazepine S.S-dioxide Same as above Azetidine 570 (5S)-N-[[3-l3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5tf)- yl)phenyI]-2-oxo-5- oxazolidinyl]methyl]-0- methylthiocarbamate, thiazepine S.S-dioxide Same as above CHjOH 571 (5S)-N-[[3-[3,5-Difluoro-4-( tetrahydro-1,4-thiazepin-4(5//)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-0-ethylthiocarbamate. thiazepine S.S-dioxide Same as above CH3CH2OH 572 (55)-/V-[[3-[3,5-Difluoro-4-( tetrahydro-1,4-thiazepin-4(5//)-y])phenyl]-2-oxo-5-oxazolidinyIJmethyl]-0-/jopropy 1 thiocarbamate. thiazepine S.S-dioxide Same as above (CHOICHOH EXAMPLE 573. (5S)-N-[[3-[4-(Tetrahydro-l,4-thiazepin-4(5/f)-yl)phenyl]-2-oxo-5-oxazolidiny]]methyl]thiourea, thiazepine S,S-dioxide O n W o=o NH2 S This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 512 for the amine 33.
By 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 Y Example No.
Compound Isothiocvanate Amine or Alcohol 574 (5S)-A4[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea, thiazepine S.S-dioxide & 0 z ii o II CO ch,nh2 575 (5S)-W-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5/7)- yl)phenyl]-2-oxo-5- oxazolidinyljmethyl]- N \N' -dimethylthiourea, thiazepine S.S-dioxide Same as above (ch,)2nh 576 (5J)-tf-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-1 - azetidinecarbothioamide, thiazepine S.S-dioxide Same as above Azetidine Example No.
Compound Isothiocvanate Amine or Alcohol 577 (55)-A/-[[3-[4- (Tetrahydro-1.4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- methylthiocarbamate. thiazepine S.S-dioxide Same as above ch3oh 578 (5S)-Aq[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- ethylthiocarbamate, thiazepine S.S-dioxide Same as above ch,ch2oh 579 (5S)-/V-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- wopropyl thiocarbamate. thiazepine S.S-dioxide Same as above (ch,)2choh EXAMPLE 580. (55)-Ar-[[3-f3-Fluoro-4-(tetrahydro-l,4-thiazepin-4(5/D-y|)phenyl]-2-oxo-5-oxazolidinyi]methyI]thiourea fW/0 h M^n^nh2 s This compound can be prepared by the procedure described in Example 33. but substituting the amine prepared in Step 8 of Example 482 for the amine 33.
By 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 Isothiocvanate Amine or No.
Alcohol 581 (5S)-yV-[[3-[3-FIuoro-4- (tetrahydro-1.4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazoIidinyl]methyI]-N'- methylthiourea fXAnA0 M^n=C=S CH.,NH2 582 (55)-yV-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5//)- yI)phenyI]-2-oxo-5- oxazolidinyljmcthyl]- N',N'-dimethylthiourea Same as above (CH,)2NH 583 (5S)-iV-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5//)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-1 -azetidinecarbothioamide Same as above Azetidine 584 (55)-Ar-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- methylthiocarbamale Same as above CH,OH 585 (5S)-N- [ [3 - [3 -F1 uoro-4- (tetrahydro-1,4- thiazepin-4(5//)- yI)phenyI]-2-oxo-5- oxazolidinyl]methyl]-0- ethylthiocarbamate Same as above CH,CH2OH 586 (55)-/V-[[3-[3-Fluoro-4- (tetrahydro-1.4- thiazepin-4(5//)- yl)phcnylJ-2-oxo-5- oxazoIidinyl]methyl]-0- (.vopropylthiocarbamate Same as above (CHO2CHOH EXAMPLE 587. (5S)-Ar-[[3-[3,5-DifIuoro-4-(tetrahydro-1.4-thiazepin-4(5H)-yI)phenyl]-2-oxo-5-oxazoIidinyI]methyI]thiourea O i AaA h h^n nha s This compound can be prepared by the procedure described in Example 33, but substituting the amine prepared in Example 530 for the amine 33.
By 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 Compound Isothiocvanate Amine or No.
Alcohol 588 (5S)-/V-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5.W)-y 1 )pheny I ] -2-oxo-5-oxazolidinyl]methyl]-N'-methylthiourea P I V—^,n=C=S ch3nh2 589 (5S)-N-[[3-[3,5-Di fluoro-4-( tetrahydro-1,4-thiazepin-4(5/7)-yI)phenyl]-2-oxo-5-oxazolidinyljmethyl]-N' ,N' -di methy lthiourea Same as above (CH3)2NH 590 (5S)-/V-[[3-[3,5-Difluoro-4-( tetrahydro-1,4-thiazepin-4(5//)-yl)phenyl]-2-oxo-5-oxazolidinyljmethyl]-1 -azetidinecarbothioamide Same as above Azetidine Example No.
Compound Isothiocvanate Amine or Alcohol 591 (55>A/-[[3-[3.5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5//)-y 1 )phenyl ]-2-oxo-5-oxazolidinyl]methyl]-0-methylthiocarbamate Same as above CHjOH 592 (55>yV-[[3-[3,5-Difluoro-4-( tetrahydro-1,4-thiazepin-4(5^)-yl)phenyl]-2-oxo-5-oxazoIidinyl]methyl]-0-ethylthiocarbamate Same as above CH,CH2OH 593 (5S)-A4[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- z'sopropylthiocarbamate Same as above (CH3)2CHOH EXAMPLE 594. (5S)-A?-[[3-[4-(Tetrahydro-l,4-thiazepin-4(5//)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiourea n m^n nha s This compound can be prepared by the procedure described in Example 33. but substituting the amine prepared in Example 534 for the amine 33.
By 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.

Claims (11)

WO 00/32599 TABLE BB PCT/US98/25308 Example Compound Isothiocvanate Amine or No. Alcohol 595 (5S)-A/-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyI]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea CO tl o w °<J 0 o CH3NH1 596 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyI]-2-oxo-5- oxazolidinyljmethyl]- N'.N'-dimethylthiourea Same as above (CH3)2NH 597 (5S)-/V-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-l- azetidinecarbothioamide Same as above Azetidine 598 (5S)-/V-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyI]methyl]-0- methylthiocarbamate Same as above CH3OH 599 (55)-/V-[[3-[4- (Tetrahydro-1.4- thiazcpin-4(5//)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-0- cthylthi ocarbamate Same as above \ CH3CH2OH 600 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5//)- yl)phenyI]-2-oxo-5- oxazolidinyl]methyl]-0- /jopropylthiocarbamate Same as above (CH.,)2CHOH - 175- 6118.P2 CP : WHAT IS CLAIMED:
1. A compound of the formula R" o Z2 \l- ^"V-N^o R24 I NHC-R1 wherein Z2 is -02S-, -0-, -N(R107)-, -OS-, or -S-; w is 0, 1, 2, or 3; 10 R23 and R24 are the same or different and can be H or F; and R1 is H, NH* NHalkylC1-C4; N(alkylC1-C4)2; alkylCj-Q^; OalkylC^C^ SalkylC1-C4; alkylC1-C4 substituted with 1-3F, 1-2C1, 15 CN, or -COOalkylC1-C4, or cycloalkylC3-C6, wherein in each occurence of the alkyl group may be straight or branched; and R107 is a) R102O-C(RU0)(Rin)-C(O)-, b) R103O-C(O)-„ 20 c) R108-C(O)-, d) R109-SO2-, e) NC-CHj-, f) FCHCH2-, or g) R150R151NSO2.. 25 wherein R102 is H, CH3-, phenyl-CH2-, or CH3C(0); each of R110 and RU1 is selected from H or CH3; R103 is alkylC^Cg or phenyl; R108 is H, alkylC1-C4> aryl(CH2)0.5, CNCH2-, C1CH2-, C12HC-, FH2C-, F2HC-, or cycloalkylC3-C6; R150 and R151 are the same or different and are selected from H, alkylC1-C4, or R150 and R151 taken together with the nitrogen to which each is attached forms a monocyclic heterocyclic ring 30 having from 3 to 6 carbon atoms; and wherein R109 is alkyl C,-C4, -CH2C1, -CH2CH = CH2, aryl or-CH2CN.
2. A compound of claim 1 wherein Z2 is -02S-.
3. A compound of claim 2 which is (5S)-iV-[[3-[3-Fluoro-4-(tetrahydro-l,4-35 thiazepin-4(5ff)-yl)phenyl] -2-oxo-5-oxazolidinyl] methyl] thioacetamide, thiazepine S,S-dioxide. -176- intellectual property office of l\i.z 29 JUL 2003 RECEIVED WO 00/32599 PCT/US98/25308
4. A compound of claim 1 wherein Z2 is -OS-.
5. A compound of claim 4 which is (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]- 5 propanethioamide, thiomorpholine S-oxide; (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide, thiomorpholine S-oxide; (S)-N- [ [3- [3-Fluoro-4-(4-thiomorpholinyI Jphenyl] -2-oxo-5-oxazolidinyl]methyl] -cyclopropanecarbothio-amide, thiomorpholine S-oxide; 10 (S)-N-[[3-[3-Fluoro-4-(4-thiomorphoIinyl)phenyl]-2-oxo-5-oxazolidinyl]methylJ- O-methylthiocarbamate, thiomorpholine S-oxide; (S)-N-H3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]- 0-ethyl thiocarbamate, thiomorpholine S-oxide; (S)-N- [ [3- [3-Fluoro-4-( 4-thiomorpholinyl )phenyl] -2-oxo-5-oxazolidinyl] methyl] -15 O-isopropylthiocarbamate, thiomorpholine S-oxide; (5 S)-N- [ [3- [3-Fluoro-4-( tetrahydro-1,4-thiazepin-4( 5H)-yl)phenyl] -2-oxo-5-oxazolidinyl]methyl]thioacetamide, thiazepine S-oxide; (S)-N- [ [3- [3-Fluoro-4-(4-thiomorpholinyl )phenyl]-2-oxo-5-oxazolidinyl] methyl] -N'.N'-dimethylthiourea, thiomorpholine S-oxide; or 20 (S)-JV-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]- 1-azetidinecarbothioamide, thiomorpholine S-oxide.
6. A compound of claim 1 wherein Z2 is O. 25
7. A compound of claim 6 which is (S)-N- [ [3- [3-Fluoro-4-(4-morpholinyl)phenyl] -2-0X0-5- oxazolidinyl] methyl] -O-ethylthiocarbamate; (S)-N-[[3- l3-Fluoro-4-(4-morpholinyl)phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide; 30 (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropane-carbothioamide
8. A compound of claim 1 wherein Z2 is -S-. 35
9. A compound of claim 8 which is (5S)-AMI3-[4-(tetrahydro-l,4-thiazepine-4( 5H)-yl)phenyl] -2-oxo-5-oxazolidinyl] methyl] -thioacetamide. -177- WO 00/32599 PCT/US98/25308
10. A compound of claim 1 wherein Z" is -N(R107)-.
11. A compound of claim 10 which is 5 (S)-N- [ [3- [3-Fluoro-4- [4-(hydroxyacetyD- l-piperazinyl]phenyl-2-oxo-5- oxazolidinyl] methyl] propanethiomide; (S)-N- [ [3- [3-Fluoro-4- [4-(hydroxyacetyl)-1 -piperazinyl] phenyl] -2-oxo-5-oxazolidinyl] methyl] -2-methylpropanethioamide; (S)-N- [ [3- [3-Fluoro-4- [4-(hydroxyacetyD- 1-piperazinyl] phenyl] -2-oxo-5-10 oxazolidinyl] methyl] cyclopropanecarbothioamide; (S)-N-[[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide; (S)-N-[ [3- [3-Fluoro-4-(4-acetyl- l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] propanethioamide; 15 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyl]-2-oxo-5- oxazolidinyl] methyl] cyclopropanecarbothioamide; (S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)-l-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide; (S)-N-[ [3- [3-Fluoro-4- [4-(methanesulfonyl>- 1-piperazinyl] phenyl] -2-oxo-5-20 oxazolidinyl]methyl]cyclopropanecarbothioamide; (S)-N- [ [3-[3-Fluoro-4-(4-formyl- l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] thioacetamide; (S)-N- [ [3-[3-Fluoro-4-(4-formyl-l-piperazinyl)phenyl] -2-0X0-5-oxazolidinyl]methyl]propanethioamide; 25 (S)-N-[[3-[3-Fluoro-4-(4-formyl-l-piperazinyl)phenyl]-2-oxo-5- oxazolidinyl] methyl]-2-methylpropanethioamide; (S)-N-[[3-[3-Fluoro-4-(4-formyl-l-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbothioamide; or (S)-N-[[3-Fluoro-4-(4-acetyl-l-piperazinyl)phenyl]-2-oxo-5-30 oxazolidinyl] methyl] thioacetamide. -178-
NZ511963A 1998-11-27 1998-11-27 Oxazolidinone antibacterial agents having a thiocarbonyl functionality NZ511963A (en)

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