U.S. patent application number 09/822666 was filed with the patent office on 2002-02-07 for oxazolidinone antibacterial agents having a thiocarbonyl functionality.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to Hester, Jackson B. JR., Nidy, Eldon George, Perricone, Salvatore Charles, Poel, Toni-Jo.
Application Number | 20020016323 09/822666 |
Document ID | / |
Family ID | 26726032 |
Filed Date | 2002-02-07 |
United States Patent
Application |
20020016323 |
Kind Code |
A1 |
Hester, Jackson B. JR. ; et
al. |
February 7, 2002 |
Oxazolidinone antibacterial agents having a thiocarbonyl
functionality
Abstract
The present invention provides compounds of Formula 1 1 or
pharmaceutical acceptable salts thereof wherein A, G and R.sub.1
are as defined in the claims which are antibacterial agents.
Inventors: |
Hester, Jackson B. JR.;
(Galesburg, MI) ; Nidy, Eldon George; (Kalamazoo,
MI) ; Perricone, Salvatore Charles; (Delton, MI)
; Poel, Toni-Jo; (Wayland, MI) |
Correspondence
Address: |
Lucy X. Yang
Pharmacia & Upjohn Company
Global Intellectual Property
301 Henrietta Street
Kalamazoo
MI
49001
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
26726032 |
Appl. No.: |
09/822666 |
Filed: |
March 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09822666 |
Mar 30, 2001 |
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09200904 |
Nov 27, 1998 |
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6255304 |
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09200904 |
Nov 27, 1998 |
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09080751 |
May 18, 1998 |
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6218413 |
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60048342 |
May 30, 1997 |
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Current U.S.
Class: |
514/227.8 ;
514/236.8; 514/374; 544/132; 544/60; 548/215 |
Current CPC
Class: |
C07D 231/12 20130101;
C07D 413/04 20130101; C07D 413/10 20130101; C07D 471/10 20130101;
C07D 307/33 20130101; C07D 233/56 20130101; C07D 249/08 20130101;
C07D 417/12 20130101; C07D 261/04 20130101; C07D 263/20
20130101 |
Class at
Publication: |
514/227.8 ;
514/236.8; 514/374; 544/60; 544/132; 548/215 |
International
Class: |
A61K 031/541; A61K
031/5377 |
Claims
What is claimed:
1. A compound of the formula I 330or pharmaceutical acceptable
salts thereof wherein: G is 331R.sub.1 is a) H, b) NH.sub.2, c)
NH--C.sub.1-4 alkyl, d) C.sub.1-4 alkyl, e) --OC.sub.1-4 alkyl, f)
--S C.sub.1-4 alkyl, g) C.sub.1-4 alkyl substituted with 1-3 F, 1-2
Cl, CN or --COOC.sub.1-4 alkyl, h) C.sub.3-6 cycloalkyl, i)
N(C.sub.1-4) alkyl).sub.2 or j) N(CH.sub.2).sub.2-5; A is 332d) a
5-membered heteroaromatic moiety having one to three atoms selected
from the group consisting of S, N, and O, wherein the 5-membered
heteroaromatic moiety is bonded via a carbon atom, wherein the
5-membered heteroaromatic moiety can additionally have a fused-on
benzene or naphthyl ring, wherein the heteroaromatic moiety is
optionally substituted with one to three R.sub.48, 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 R.sub.55, f) a
.beta.-carbolin-3-yl, or indolizinyl bonded via the 6-membered
ring, optionally substituted with one to three R.sub.65, 333wherein
R.sub.2 is a) H, b) F, c) Cl, d) Br, e) C.sub.1-3 alkyl, f)
NO.sub.2, or g) R.sub.2 and R.sub.3 taken together are
--O--(CH.sub.2).sub.h--O--; R is a) --S(.dbd.O).sub.i R.sub.4, b)
--S(.dbd.O).sub.2--N.dbd.S(O).sub.jR.sub.5R.sub.6, c)
--SC(.dbd.O)R.sub.7, d) --C(.dbd.O)R.sub.8, e) --C(.dbd.O)R.sub.9,
f) --C(.dbd.O)NR.sub.10R.sub.11, g) --C(.dbd.NR.sub.12)R.sub.8, h)
--C(R.sub.8)(R.sub.11)--OR.sub.13, i)
--C(R.sub.9)(R.sub.11)--OR.sub.13, j)
--C(R.sub.8)(R.sub.11)--OC(.dbd.O)R.sub.13, k)
--C(R.sub.9)(R.sub.11)-- -OC(.dbd.O)R.sub.13, l)
--NR.sub.10R.sub.11, m) --N(R.sub.10)--C(.dbd.O)R.- sub.7, n)
--N(R.sub.10)--S(.dbd.O).sub.iR.sub.7, o)
--C(OR.sub.14)(OR.sub.15)R.sub.8, p)
--C(R.sub.8)(R.sub.16)--NR.sub.10R.s- ub.11, or q) C.sub.1-8 alkyl
substituted with one or more .dbd.O other than at alpha position,
--S(.dbd.O).sub.iR.sub.17, --NR.sub.10R.sub.11, C.sub.2-5 alkenyl,
or C.sub.2-5 alkynyl; R.sub.4 is a) C.sub.1-4 alkyl optionally
substituted with one or more halos, OH, CN, NR.sub.10R.sub.11, or
--CO.sub.2R.sub.13, b) C.sub.2-4 alkenyl, c) --NR.sub.16R.sub.18,
d) --N.sub.3, e) --NHC(.dbd.O)R.sub.7, f)
--NR.sub.20C(.dbd.O)R.sub.7, g) --N(R.sub.19).sub.2, h)
--NR.sub.16R.sub.19, or i) --NR.sub.19R.sub.20, R.sub.5 and R.sub.6
at each occurrence are the same or different and are a) C.sub.1-2
alkyl, or b) R.sub.5 and R.sub.6 taken together are
--(CH.sub.2).sub.k--; R.sub.7 is C.sub.1-4 alkyl optionally
substituted with one or more halos; R.sub.8 is a) H, or b)
C.sub.1-8 alkyl optionally substituted with one or more halos, or
C.sub.3-8 cycloalkyl; R.sub.9 is C.sub.1-4 alkyl substituted with
one or more a) --S(.dbd.O)R.sub.17, b) --OR.sub.13, c)
--OC(.dbd.O)R.sub.13, e) C.sub.1-5 alkenyl optionally substituted
with CHO; R.sub.10 and R.sub.11 at each occurrence are the same or
different and are a) H, b) C.sub.1-4 alkyl, or c) C.sub.3-8
cycloalkyl; R.sub.12 is a) --NR.sub.10R.sub.11, b) --OR.sub.10; or
c) --NHC(.dbd.O)R.sub.10; R.sub.13 is a) H, or b) C.sub.1-4 alkyl;
R.sub.14 and R.sub.15 at each occurrence are the same or different
and are a) C.sub.1-4 alkyl, or b) R.sub.14 and R.sub.15 taken
together are --(CH).sub.l--; R.sub.16 is a) H, b) C.sub.1-4 alkyl,
or c) C.sub.3-8 cycloalkyl; R.sub.17 is a) C.sub.1-4 alkyl, or b)
C.sub.3-8 cycloalkyl; R.sub.18 is a) H, b) C.sub.1-4 alkyl, c)
C.sub.2-4 alkenyl, d) C.sub.3-4 cycloalkyl, e) --OR.sub.13 or f)
--NR.sub.21R.sub.22; R.sub.19 is a) Cl, b) Br, or c) I; R.sub.20 is
a physiologically acceptable cation; R.sub.21 and R.sub.22 at each
occurrence are the same or different and are a) H, b) C.sub.1-4
alkyl, or c) --NR.sub.21R.sub.22 taken together are
--(CH.sub.2).sub.m--; wherein R.sub.23 and R.sub.24 at each
occurrence are the same or different and are a) H, b) F, c) Cl, d)
C.sub.1-2 alkyl, e) CN f) OH, g) C.sub.1-4 alkoxy, h) nitro, or i)
amino; Q is 334m) a diazinyl group optionally substituted with X
and Y, n) a triazinyl group optionally substituted with X and Y, o)
a quinolinyl group optionally substituted with X and Y, p) a
quinoxalinyl group optionally substituted with X and Y, q) a
naphthyridinyl group optionally substituted with X and Y, 335Q and
R.sub.24 taken together are 336wherein Z.sup.1 is a) --CH.sub.2--,
b) --CH(R.sup.104)--CH.sub.2--, c) --C(O)--, or d)
--CH.sub.2CH.sub.2CH.sub.2--; wherein Z.sup.2 is a) --O.sub.2S--,
b) --O--, c) --N(R.sup.107)--, d) --OS--, or e) --S--; wherein
Z.sup.3 is a) --O.sub.2S--, b) --O--, c) --OS--, or d) --S--;
wherein A.sup.1 is a) H--, or b) CH.sub.3; wherein A.sup.2 is a)
H--, b) HO--, c) CH.sub.3--, d) CH.sub.3O--, e)
R.sup.102O--CH.sub.2--C(O)--NH--f) R.sup.103O--C(O)--NH--, g)
(C.sub.1-C.sub.2)alkyl--O--C(O)--, h) HO--CH.sub.2--, i)
CH.sub.3O--NH--, j) (C.sub.1-C.sub.3)alkyl--O.sub.2C--- k)
CH.sub.3--C(O)--, l) CH.sub.3--C(O)--CH.sub.2, 337A.sup.1 and
A.sup.2 taken together are: 338wherein R.sup.102 is a) H--, b)
CH.sub.3--, c) phenyl-CH.sub.2-- or d) CH.sub.3C(O)--; wherein
R.sup.103 is a) (C.sub.1-C.sub.3)alkyl-, or b) phenyl-; wherein
R.sup.104 is a) H--, or b) HO--; wherein R.sup.105 is a) H--, b)
(C.sub.1-C.sub.3)alkyl-, c) CH.sub.2.dbd.CH--CH.sub.2--, or d)
CH.sub.3--O--(CH.sub.2).sub.2--; wherein R.sup.106 is a)
CH.sub.3--C(O)--, b) H--C(O)--, c) Cl.sub.2CH--C(O)--, d)
HOCH.sub.2--C(O)--, e) CH.sub.3SO.sub.2--, 339g) F.sub.2CHC(O)--,
340i) H.sub.3C--C(O)--O--CH.sub.2--C(O)--, j)
H--C(O)--O--CH.sub.2--C(O)--, 341l)
HC.ident.C--CH.sub.2O--CH.sub.2--C(O- )--, or m)
phenyl-CH.sub.2--CH.sub.2--O--CH.sub.2--C(O)--; wherein R.sup.107
is a) R.sup.102O--C(R.sup.110)(R.sup.111)--C(O)--, b)
R.sup.103O--C(O)--, c) R.sup.108--C(O)--, 342f)
H.sub.3C--C(O)--(CH.sub.- 2).sub.2--C(O)--, g)
R.sup.109--SO.sub.2--, 343i) HO--CH.sub.2--C(O)--, j)
R.sup.116--(CH.sub.2).sub.2--, k)
R.sup.113--C(O)--O--CH.sub.2--C(O)--- , l)
(CH.sub.3).sub.2N--CH.sub.2--C(O)--NH--, m) NC--CH.sub.2--, n)
F.sub.2--CH--CH.sub.2--, or o) R.sup.150R.sup.151NSO.sub.2--;
wherein R.sup.108 is a) H--, b) (C.sub.1-C.sub.4)alkyl, c) aryl
--(CH.sub.2).sub.p, d) ClH.sub.2C--, e) Cl.sub.2HC--, f)
FH.sub.2C--, g) F.sub.2HC--, h) (C.sub.3-C.sub.6)cycloalkyl, or i)
CNCH.sub.2--; wherein R.sup.109 is a) (C.sub.1-C.sub.4)alkyl, b)
--CH.sub.2Cl c) --CH.sub.2CH.dbd.CH.sub.2, d) aryl, or e)
--CH.sub.2CN; wherein R.sup.110 and R.sup.111 are independently a)
H--, b) CH.sub.3--; or wherein R.sup.112 is a) H--, b)
CH.sub.3O--CH.sub.2O--CH.sub.2--, or c) HOCH.sub.2--; wherein
R.sup.113 is a) CH.sub.3--, b) HOCH.sub.2--, c)
(CH.sub.3).sub.2N-phenyl, or d) (CH.sub.3).sub.2N--CH.sub.2--;
wherein R.sup.114 is a) HO--, b) CH.sub.3O--, c) H.sub.2N--, d)
CH.sub.3O--C(O)--O--, e) CH.sub.3--C(O)--O--CH.sub.2--C(O)--O--, f)
phenyl-CH.sub.2--O--CH.sub.2--C(O)--O--, g)
HO--(CH.sub.2).sub.2--O--, h)
CH.sub.3O--CH.sub.2--O--(CH.sub.2).sub.2--O--, or i)
CH.sub.3O--CH.sub.2--O--; wherein R.sup.113 is a) CH.sub.3--, b)
HOCH.sub.2--, c) (CH.sub.3).sub.2N-phenyl, or d)
(CH.sub.3).sub.2N--CH.su- b.2--; wherein R.sup.115 is a) H--, or b)
Cl--; wherein R.sup.116 is a) HO--b) CH.sub.3O--, or c) F; wherein
R.sup.150 and R.sup.151 are each H or alkylC.sub.1-C.sub.4 or
R.sup.150 and R.sup.151 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) C.sub.1-8 alkyl, c)
C.sub.3-8 cycloalkyl, d) --(CH.sub.2).sub.mOR.sub.13, or e)
--(CH.sub.2).sub.h--NR.sub.21R.sub.22; Z is a) O, b) S, or c) NM; W
is a) CH, b) N, or c) S or O when Z is NM; Y is a) H, b) F, c) Cl,
d) Br, e) C.sub.1-3 alkyl, or f) NO.sub.2; X is a) H, b) --CN, c)
OR.sub.27, d) halo, e) NO.sub.2, f) tetrazoyl, g) --SH, h)
--S(.dbd.O).sub.i--R.sub.4, i)
--S(.dbd.O).sub.2--N.dbd.S(O).sub.jR.sub.5R.sub.6, j)
--SC(.dbd.O)R.sub.7, k) --C(.dbd.O)R.sub.25, l)
--C(.dbd.O)NR.sub.27R.sub- .28, m) --C(.dbd.NR.sub.29)R.sub.25, n)
--C(R.sub.25)(R.sub.28)--OR.sub.13- , o)
--C(R.sub.25)(R.sub.28)--OC(.dbd.O)R.sub.13, p)
--C(R.sub.28)(OR.sub.13)--(CH.sub.2).sub.h--NR.sub.27R.sub.28, q)
--NR.sub.27R.sub.28, r) --N(R.sub.27)C(.dbd.O)R.sub.7, s)
--N(R.sub.27)--S(.dbd.O).sub.iR.sub.7, t)
--C(OR.sub.14)(OR.sub.15)R.sub.- 28, u)
--C(R.sub.25)(R.sub.16)--NR.sub.27R.sub.26, or v) C.sub.1-8 alkyl
substituted with one or more halos, OH, .dbd.O other than at alpha
position, --S(.dbd.O).sub.i--R.sub.17, --NR.sub.27R.sub.28,
C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, or C.sub.3-8 cycloalkyl;
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.13, R.sub.14, R.sub.15,
R.sub.16, and R.sub.17 are the same as defined above; R.sub.25 is
a) H, b) C.sub.1-4 alkyl optionally substituted with one or more
halos, C.sub.3-8 cycloalkyl, C.sub.1-4 alkyl substituted with one
or more of --S(.dbd.O).sub.iR.sub.17- , --OR.sub.13, or
OC(.dbd.O)R.sub.13, NR.sub.27R.sub.28, or c) C.sub.2-5 alkenyl
optionally substituted with CHO, or CO.sub.2R.sub.13; R.sub.26 is
a) R.sub.28, or b) NR.sub.27N.sub.28; R.sub.27 and R.sub.28 at each
occurrence are the same or different and are a) H, b) C.sub.1-8
alkyl, c) C.sub.3-8 cycloalkyl, d) --(CH.sub.2).sub.mOR.sub.13, e)
--(CH.sub.2).sub.h--NR.sub.21R.sub.22, or f) R.sub.27 and R.sub.28
taken together are --(CH.sub.2).sub.2O(CH.sub.2).sub.2--,
--(CH.sub.2).sub.hCH(COR.sub.7)--, or
--(CH.sub.2).sub.2N(CH.sub.2).sub.2- (R.sub.7); R.sub.29 is a)
--NR.sub.27R.sub.28, b) --OR.sub.27, or c) --NHC(.dbd.O)R.sub.28;
wherein R.sub.30 is a) H, b) C.sub.1-8 alkyl optionally substituted
with one or more halos, or c) C.sub.1-8 alkyl optionally
substituted with one or more OH, or C.sub.1-6 alkoxy, wherein E is
a) NR.sub.39, b) --S(.dbd.O).sub.i, or c) O; R.sub.38 is a) H, b)
C.sub.1-6 alkyl, c) --(CH.sub.2).sub.q-aryl, or d) halo; R.sub.39
is a) H, b) C.sub.1-6 alkyl optionally substituted with one or more
OH, halo, or --CN, c) --(CH.sub.2).sub.q-aryl, d)
--CO.sub.2R.sub.40, e) --COR.sub.41, f)
--C(.dbd.O)--(CH.sub.2).sub.q--C(.dbd.O)R.sub.40, g)
--S(.dbd.O).sub.2--C.sub.1-6 alkyl, h)
--S(.dbd.O).sub.2--(CH.sub.2).sub.- q-aryl, or i)
--(C.dbd.O).sub.j-Het; R.sub.40 is a) H, b) C.sub.1-6 alkyl
optionally substituted with one or more OH, halo, or --CN, c)
--(CH.sub.2).sub.q-aryl, or d) --(CH.sub.2).sub.q--OR.sub.42;
R.sub.41 is a) C.sub.1-6 alkyl optionally substituted with one or
more OH, halo, or --CN, b) -(CH.sub.2).sub.q-aryl, or c)
--(CH.sub.2).sub.q--OR.sub.42; R.sub.42 is a) H, b) C.sub.1-6
alkyl, c) --(CH.sub.2).sub.q-aryl, or d) --C(.dbd.O)--C.sub.1-6
alkyl; aryl is a) phenyl, b) pyridyl, or c) napthyl; a to c
optionally substituted with one or more halo, --CN, OH, SH,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkylthio; wherein
R.sub.43 is a) H, b) C.sub.1-2 alkyl, c) F, or d) OH; R.sub.44 is
a) H, b) CF.sub.3, c) C.sub.1-3 alkyl optionally substituted with
one or more halo, d) phenyl optionally substituted with one or more
halo, e) R.sub.44 and R.sub.45 taken together are a 5-, 6-, or
7-membered ring of the formula, 344 or f) R.sub.44 and R.sub.45
taken together are --(CH.sub.2).sub.k--, when R.sub.46is an
electron-withdrawing group; R.sub.45 and R.sub.46at each occurrence
are the same or different and are a) an electron-withdrawing group,
b) H, c) CF.sub.3, d) C.sub.1-3 alkyl optionally substituted with
one halo, e) phenyl provided at least one of R.sub.45 or R.sub.46
is an electron-withdrawing group, or f) R.sub.45 and R.sub.46 taken
together are a 5-, 6-, 7-membered ring of the formula 345U is a)
CH.sub.2, b) O, c) S, or d) NR.sub.47; R.sub.47 is a) H, or b)
C.sub.1-5 alkyl; wherein R.sub.48 is a) carboxyl, b) halo, c) --CN,
d) mercapto, e) formyl, f) CF.sub.3, g) --NO.sub.2, h) C.sub.1-6
alkoxy, i) C.sub.1-6 alkoxycarbonyl, j) C.sub.1-6 alkythio, k)
C.sub.1-6 acyl, l) --NR.sub.49 R.sub.50, m) C.sub.1-6 alkyl
optionally substituted with OH, C.sub.1-5 alkoxy, C.sub.1-5 acyl,
or --NR.sub.49R.sub.50, n) C.sub.2-8 alkenylphenyl optionally
substituted with one or two R.sub.51, o) phenyl optionally
substituted with one or two R.sub.51, 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 R.sub.51, or 346R.sub.49 and R.sub.50
at each occurrence are the same or different and are a) H, b)
C.sub.1-4 alkyl, c) C.sub.5-6 cycloalkyl, or d) R.sub.49 and
R.sub.50 taken together with the nitrogen atom is a 5-, 6-membered
saturated heterocyclic moiety which optionally has a farther 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.sub.1-3 alkyl, or C.sub.1-3 acyl; R.sub.51 is a)
carboxyl, b) halo, c) --CN, d) mercapto, e) formyl, f) CF.sub.3, g)
--NO.sub.2, h) C.sub.1-6 alkoxy, i) C.sub.1-6 alkoxycarbonyl, j)
C.sub.1-6 alkythio, k) C.sub.1-6 acyl, l) C.sub.1-6 alkyl
optionally substituted with OH, C.sub.1-5 alkoxy, C.sub.1-5 acyl,
or --NR.sub.49R.sub.50, m) phenyl, n) --C(.dbd.O)NR.sub.52
R.sub.53, o) --NR.sub.49R.sub.50, p)
--N(R.sub.52)(--SO.sub.2R.sub.54), q)
--SO.sub.2--NR.sub.52R.sub.53, or r) --S(.dbd.O).sub.iR.sub.54;
R.sub.52 and R.sub.53 at each occurrence are the same or different
and are a) H, b) C.sub.1-6 alkyl, or c) phenyl; R.sub.54 is a)
C.sub.1-4 alkyl, or b) phenyl optionally substituted with C.sub.1-4
alkyl; wherein R.sub.55 is a) carboxyl, b) halo, c) --CN, d)
mercapto, e) formyl, f) CF.sub.3, g) --NO.sub.2, h) C.sub.1-6
alkoxy, i) C.sub.1-6 alkoxycarbonyl, j) C.sub.1-6 alkythio k)
C.sub.1-6 acyl, l) --NR.sub.56 R.sub.57, m) C.sub.1-4 alkyl
optionally substituted with OH, C.sub.1-5 alkoxy, C.sub.1-5 acyl,
or --NR.sub.56R.sub.57, n) C.sub.2-8 alkenylphenyl optionally
substituted with one or two R.sub.58, o) phenyl optionally
substituted with one or two R.sub.58, 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 R.sub.58, or 347R.sub.56 and R.sub.57
at each occurrence are the same or different and are a) H, b)
formyl, c) C.sub.1-4 alkyl d) C.sub.1-4 acyl, e) phenyl, f)
C.sub.3-6 cycloalkyl, or g) R.sub.56 and R.sub.57 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, phenyl,
pyrimidyl, C.sub.1-3 alkyl or C.sub.1-3 acyl; R.sub.58 is a)
carboxyl, b) halo, c) --CN, d) mercapto, e) formyl, f) CF.sub.3, g)
--NO.sub.2, h) C.sub.1-6 alkoxy, i) C.sub.1-6 alkoxycarbonyl, j)
C.sub.1-6 alkythio, k) C.sub.1-6 acyl, l) phenyl, m) C.sub.1-6
alkyl optionally substituted with OH, azido, C.sub.1-5 alkoxy,
C.sub.1-5 acyl, --NR.sub.65R.sub.56, --SR.sub.57,
--O--SO.sub.2R.sub.68, or 348n) --C(.dbd.O)NR.sub.59 R.sub.60, o)
--NR.sub.56R.sub.57, p) --N(R.sub.59)(SO.sub.2R.sub.54), q)
--SO.sub.2--NR.sub.59R.sub.60, r) --S(.dbd.O).sub.i--R.sub.54, s)
--CH.dbd.N--R.sub.61, or t) --CH(OH)--SO.sub.3R.sub.64; R.sub.54 is
the same as defined above; R.sub.59 and R.sub.60 at each occurrence
are the same or different and are a) H, b) C.sub.1-6 alkyl, c)
phenyl, or d) tolyl; R.sub.61 is a) OH, b) benzyloxy, c)
--NH--C(.dbd.O)--NH.sub.2, d) --NH--C(.dbd.S)--NH.sub.2, or e)
--NH--C(.dbd.NH)--NR.sub.62R.sub.63; R.sub.62 and R.sub.63 at each
occurrence are the same or different and are a) H, or b) C.sub.1-4
alkyl optionally substituted with phenyl or pyridyl; R.sub.64 is a)
H, or b) a sodium ion; R.sub.65 and R.sub.66 at each occurrence are
the same or different and are a) H, b) formyl, c) C.sub.1-4 alkyl,
d) C.sub.1-4 acyl, e) phenyl, f) C.sub.3-6 cycloalkyl, g) R.sub.65
and R.sub.66 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.sub.1-3 alkyl,
or C.sub.1-3 acyl, h) --P(O)(OR.sub.70)(OR.sub.71), or i)
--SO.sub.2--R.sub.72; R.sub.67 is 349R.sub.68 is C.sub.1-3 alkyl;
R.sub.69 is a) C.sub.1-6 alkoxycarbonyl, or b) carboxyl; R.sub.70
and R.sub.71 at each occurrence are the same or different and are
a) H, or b) C.sub.1-3 alkyl; R.sub.72 is a) methyl, b) phenyl, or
c) tolyl; wherein K is a) O, or b) S; R.sub.73, R.sub.74, R.sub.75,
R.sub.76, and R.sub.77 at each occurrence are the same or different
and are a) H, b) carboxyl, c) halo, d) --CN, e) mercapto, f)
formyl, g) CF.sub.3, h) --NO.sub.2, i) C.sub.1-6 alkoxy, j)
C.sub.1-6 alkoxycarbonyl, k) C.sub.1-6 alkythio, l) C.sub.1-6 acyl,
m) --NR.sub.78 R.sub.79, n) C.sub.1-6 alkyl optionally substituted
with OH, C.sub.1-5 alkoxy, C.sub.1-5 acyl, --NR.sub.78R.sub.79,
--N(phenyl)(CH.sub.2--CH.sub- .2--OH),
--O--CH(CH.sub.3)(OCH.sub.2CH.sub.3), or --O-phenyl-[para-NHC(.db-
d.O)CH.sub.3], o) C.sub.2-8 alkenylphenyl optionally substituted
with R.sub.51, p) phenyl optionally substituted with R.sub.51, 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 R.sub.51; R.sub.51 is the same as
defined above; R.sub.78 and R.sub.79 at each occurrence are the
same or different and are a) H, b) C.sub.1-4 alkyl, c) phenyl, or
d) R.sub.78 and R.sub.79 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 nitrogen atom, C.sub.1-3 alkyl,
or C.sub.1-3 acyl; further wherein T is a) O, b) S, or c) SO.sub.2;
R.sub.75, R.sub.76, and R.sub.77 are the same as defined above;
R.sub.80 is a) H, b) formyl, c) carboxyl, d) C.sub.1-6
alkoxycarbonyl, e) C.sub.1-8 alkyl, f) C.sub.2-8 alkenyl, wherein
the substituents (e) and (f) can be optionally substituted with OH,
halo, C.sub.1-6 alkoxy, C.sub.1-6 acyl, C.sub.1-6 alkylthio or
C.sub.1-6 alkoxycarbonyl, or phenyl optionally substituted with
halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally
substituted with carboxyl, halo, --CN, formyl, CF.sub.3,
--NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 acyl,
C.sub.1-6 alkylthio, or C.sub.1-6 alkoxycarbonyl; h)
--NR.sub.81R.sub.82, i) --OR.sub.90, j)
--S(.dbd.O).sub.i--R.sub.91, k) --SO.sub.2--N(R.sub.92)(R.sub.93),
or l) a radical of the following formulas: R.sub.81 and R.sub.82 at
each occurrence are the same or different and are a) H, b)
C.sub.3-6 cycloalkyl, c) phenyl, d) C.sub.1-6 acyl, e) C.sub.1-8
alkyl optionally substituted with OH, C.sub.1-6 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, CF.sub.3,
halo, --NO.sub.2, C.sub.1-4alkoxy, --NR.sub.83R.sub.84, or 350V is
a) O, b) CH.sub.2, or c) NR.sub.87; R.sub.83 and R.sub.84 at each
occurrence are the same or different and are a) H, or b) C.sub.1-4
alkyl; R.sub.85 is a) OH, b) C.sub.1-4 alkoxy, or c) --NR.sub.88
R.sub.89; R.sub.86 is a) H, or b) C.sub.1-7 alkyl optionally
substituted with indolyl, OH, mercaptyl, imidazoly, methylthio,
amino, phenyl optionally substituted with OH,
--C(.dbd.O)--NH.sub.2, --CO.sub.2H, or --C(.dbd.NH)--NH.sub.2;
R.sub.87 is a) H, b) phenyl, or c) C.sub.1-6 alkyl optionally
substituted by OH; R.sub.88 and R.sub.89 at each occurrence are the
same or different and are a) H, b) C.sub.1-6 alkyl c) C.sub.1-6
cycloalky, or d) phenyl; R.sub.90 is a) C.sub.1-8 alkyl optionally
substituted with C.sub.1-6 alkoxy or C.sub.1-6 hydroxy, C.sub.3-6
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.sub.2, CF.sub.3, halo,
--CN, OH, C.sub.1-5 alkyl, C.sub.1-5 alkoxy, or C.sub.1-5 acyl;
351c) phenyl, or d) pyridyl; R.sub.91 is a) C.sub.1-16 alkyl, b)
C.sub.2-16 alkenyl, wherein the substituents (a) and (b) can be
optionally substituted with C.sub.1-6 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 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.sub.3, --NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.1-6 acyl, C.sub.1-6 alkylthio, or C.sub.1-6
alkoxycarbonyl; R.sub.92 and R.sub.93 at each occurrence are the
same or different and are a) H, b) phenyl, c) C.sub.1-6 alkyl, or
d) benzyl; R.sub.94 and R.sub.95 at each occurrence are the same or
different and are a) H, b) OH, c) C.sub.1-6 alkyl optionally
substituted with --NR.sub.83 R.sub.84, or d) R.sub.94 and R.sub.95
taken together are .dbd.O; R.sub.96 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 with one or three
--NO.sub.2, CF.sub.3, halo, --CN, OH, phenyl, C.sub.1-5 alkyl,
C.sub.1-5 alkoxy, or C.sub.1-5 acyl, c) morpholinyl, d) OH, e)
C.sub.1-6 alkoxy, f) --NR.sub.83R.sub.84, g) --C(.dbd.O)--R.sub.97,
or 352R.sub.97 is a) morpholinyl, b) OH, or c) C.sub.1-6 alkoxy; h
is 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5; l 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.
2. A compound of claim 1 which is: a)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl-
)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide; b)
(S)-N-[[3-[3-Fluoro-4-[4-(5-methyl1,3,4-thiadiazol2-yl)-1-piperazinyl]phe-
nyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide; c)
(S)-N-[[3-[3-Fluoro-4-[-
2',6'-dioxospiro[piperidine-4,4'-imidazolidine]1-yl]phenyl]-2-oxo-5-oxazol-
idinyl]methyl]thioacetamide; d)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)pheny-
l]-2-oxo-5-oxazolidinyl]methyl]thioacetamide; e)
(S)-N-[[3-[3-Fluoro-4-(4--
morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiourea; f)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
-N'-methylthiourea; g)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo--
5-oxazolidinyl]methyl]-thioformamide; h)
(S)-N-[[3-[3-Fluoro-4-(4-morpholi-
nyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thiopropion-amide; i)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
-2-chlorothioacetamide; j)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2--
oxo-5-oxazolidinyl]methyl]-.alpha.,.alpha.,.alpha.-trifluorothioacetamide;
k)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]-.alpha.-fluorothioacetamide; l)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)p-
henyl]-2-oxo-5-oxazolidinyl]methyl]-.alpha.,.alpha.-difluorothioacetamide;
m)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]-.alpha.-cyanothioacetamide; n)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)ph-
enyl]-2-oxo-5-oxazolidinyl]methyl]-.alpha.,.alpha.-dichlorothioacetamide;
o)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]-.alpha.-(methoxycarbonyl)thioacetamide; p)
(S)-N-[[3-[4-[1-[1,2,4]Tria-
zolyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide; q)
(S)-N-[[3-[4-[1-[1,2,4]Triazolyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thio-
acetamide; r))
(S)-N-[[3-[1-(Hydroxyacetyl)-5-indolinyl]-2-oxo-5-oxazolidi-
nyl]methyl]thioacetamide; s)
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-pi-
perazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide; t)
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]thio-acetamide; u)
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2--
oxo-5-oxazolidinyl]methyl]thioacetamide, thiomorpholine S-oxide; v)
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]thio-acetamide, thiomorpholine S, S-dioxide; w)
(S)-N-[[3-[3,5-Difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo--
5-oxazolidinyl]methyl]thioacetamide; x)
(S)-N-[[3-[4-[1-[1,2,4]Triazolyl]p-
henyl]-2-oxo-5-oxazolidinyl]methyl]thiourea; y)
(S)-N-[[3-[3-Fluoro-4-[4-(-
hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thiourea;
z)
(S)-N-[[3-[1-(Hydroxyacetyl)-5-indolinyl]-2-oxo-5-oxazolidinyl]methyl]-
thiourea; aa)
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxa-
zolidinyl]methylthiourea, thiomorpholine S-oxide; bb)
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
-S-methyldithiocarbamate;
3. A compound of claim 1 which is
(S)-trans-N-[[3-[3-fluoro-4-(tetrahydro--
1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioam-
ide.
4. A compound of claim 1 which is
(S)-N-[[3-[3-fluoro-4-(4-thiomorpholinyl-
)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide, thiomorpholine
S-oxide.
5. A method for treating microbial infections in patients
comprising administering to a patient in need thereof an effective
amount of a compound of Formula I.
6. A compound of claim 1 wherein G is 353
7. A compound of claim 1 wherein A is 354
8. A compound of claim 7 wherein Q is 355
9. A compound of claim 1 wherein G is 356
10. A compound of claim 9 wherein Z.sup.2 is --O.sub.2S--.
11. A compound of claim 10 which is
(5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-
-thiazepin-4(5H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide,
thiazepine S,S-dioxide.
12. A compound of claim 9 wherein Z.sup.2 is --OS--.
13. A compound of claim 12 which is
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholin-
yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide,
thiomorpholine S-oxide;
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazoli-
dinyl]methyl]-2-methylpropanethioamide, thiomorpholine S-oxide;
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]cyclopropanecarbothio-amide, thiomorpholine S-oxide;
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]-O-methylthiocarbamate, thiomorpholine S-oxide;
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]-O-ethylthiocarbamate, thiomorpholine S-oxide;
(S)-N-[[3-[3-Fluoro-4-(-
4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-O-isopropylthiocarb-
amate, thiomorpholine S-oxide;
(5S)-N-[[3-[3-Fluoro-4-tetrahydro-1,4-thiaz-
epin-4(5H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide,
thiazepine S-oxide,
(5S)-N-[[3-[3-Fluoro-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-N',N'-dimethylthiourea, thiomorpholine
S-oxide, or
(5S)-N-[[3-[3-Fluoro-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]-1-azetidinecarbothioamide, thiomorpholine S-oxide.
14. A compound of claim 9 wherein Z.sup.2 is O.
15. A compound of claim 14 which is
(S)-N-[[3-[3-Fluoro-4-morpholinyl)phen-
yl]-2-oxo-5-oxazolidinyl]methyl]-O-ethylthiocarbamate;
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
-2-methylpropanethioamide;
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2--
oxo-5-oxazolidinyl]methyl]cyclopropane-carbothioamide
16. A compound of claim 9 wherein Z.sup.2 is --S--.
17. A compound of claim 9 which is
(5S)-N-[[3-[4-(tetrahydro-1,4-thiazepin-
e-4(5H)-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide.
18. A compound of claim 9 wherein Z.sup.2 is --N(R.sup.107)--.
19. A compound of claim 16 which is
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacety-
l)-1-piperazinyl]phenyl-2-oxo-5-oxazolidinyl]methyl]propanethiomide;
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-ox-
azolidinyl]methyl]-2-methylpropanethioamide;
(S)-N-[[3-[3-Fluoro-4-[4-(hyd-
roxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropane-
carbothioamide;
(S)-N-[[3-[3-Fluoro-4-acetyl-1-piperazinyl)phenyl]-2-oxo-5-
-oxazolidinyl]methyl]thioacetamide;
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-pipe-
razinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide;
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]-2-oxo-5-oxazolidiny-
l]methyl]cyclopropanecarbothioamide;
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-pip-
erazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbothioamide;
(S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)-1-piperazinyl]phenyl]-2-oxo-5--
oxazolidinyl]methyl]-2-methylpropanethioamide;
(S)-N-[[3-[3-Fluoro-4-[4-(m-
ethanesulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopro-
panecarbothioamide;
(S)-N-[[3-[3-Fluoro-4-(4-formyl-1-piperazinyl)phenyl]--
2-oxo-5-oxazolidinyl]methyl]thioacetamide;
(S)-N-[[3-[3-Fluoro-4-(4-formyl-
-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethioamide;
(S)-N-[[3-[3-Fluoro-4-(4-formyl-1-piperazinyl)phenyl]-2-oxo-5-oxazolidiny-
l]methyl]-2-methylpropanethioamide;
(S)-N-[[3-[3-Fluoro-4-(4-formyl-1-pipe-
razinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropanecarbothioamide;
or
(S)-N-[[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]m-
ethyl]thioacetamide.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of co-pending
application U.S. Ser. No. 09/080,751, filed May 18, 1998, which
claims the benefit of provisional application U.S. Ser. No.
60/048,342, filed May 30, 1997, under 35 USC 119(e)(i).
BACKGROUND OF THE INVENTION
[0002] 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(O)--R is converted to a thiocarbonyl
functionality, such as a thiourea --NH--C(S)--NH.sub.2, an alkyl
thiourea --NH--C(S)--NH--(C.sub.1-4 alkyl), thioamide
--NH--C(S)--(C.sub.1-4 alkyl) or --NH--C(S)--H.
[0003] 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
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
infection in persons with AIDS.
SUMMARY OF THE INVENTION
[0004] In one aspect the subject invention is a compound of the
Formula I 2
[0005] or pharmaceutical acceptable salts thereof wherein:
[0006] G is 3
[0007] R.sub.1 is
[0008] a) H,
[0009] b) NH.sub.2,
[0010] c) NH--C.sub.1-4 alkyl,
[0011] d) C.sub.1-4 alkyl,
[0012] e) --OC.sub.1-4 alkyl,
[0013] f) --S C.sub.1-4 alkyl,
[0014] g) C.sub.1-4 alkyl substituted with 1-3 F, 1-2 Cl, CN or
--COOC.sub.1-4 alkyl,
[0015] h) C.sub.3-6 cycloalkyl,
[0016] i) N(C.sub.1-4 alkyl).sub.2 or
[0017] j) N(CH.sub.2).sub.2-5;
[0018] A is 4
[0019] d) a 5-membered heteroaromatic moiety having one to three
atoms selected from the group consisting of S, N, and O,
[0020] wherein the 5-membered heteroaromatic moiety is bonded via a
carbon atom,
[0021] wherein the 5-membered heteroaromatic moiety can
additionally have a fused-on benzene or naphthyl ring,
[0022] wherein the heteroaromatic moiety is optionally substituted
with one to three R.sub.48,
[0023] e) a 6-membered heteroaromatic moiety having at least one
nitrogen atom,
[0024] wherein the heteroaromatic moiety is bonded via a carbon
atom,
[0025] wherein the 6-membered heteroaromatic moiety can
additionally have a fused-on benzene or naphthyl ring,
[0026] wherein the heteroaromatic moiety is optionally substituted
with one to three R.sub.55,
[0027] f) a .beta.-carbolin-3-yl, or indolizinyl bonded via the
6-membered ring, optionally substituted with one to three R.sub.55,
5
[0028] wherein R.sub.2 is
[0029] a) H,
[0030] b) F,
[0031] c) Cl,
[0032] d) Br,
[0033] e) C.sub.1-3 alkyl,
[0034] f) NO.sub.2, or
[0035] g) R.sub.2 and R.sub.3 taken together are
--O--(CH.sub.2).sub.h--O-- -;
[0036] R.sub.3 is
[0037] a) --S(.dbd.O).sub.i R.sub.4,
[0038] b) --S(.dbd.O).sub.2--N.dbd.S(O).sub.jR.sub.5R.sub.6,
[0039] c) --SC(.dbd.O)R.sub.7,
[0040] d) --C(.dbd.O)R.sub.8,
[0041] e) --C(.dbd.O)R.sub.9,
[0042] f) --C(.dbd.O)NR.sub.10R.sub.11,
[0043] g) --C(.dbd.NR.sub.12)R.sub.8,
[0044] h) --C(R.sub.8)(R.sub.11)--OR.sub.13,
[0045] i) --C(R.sub.9)(R.sub.11)--OR.sub.13,
[0046] j) --C(R.sub.8)(R.sub.11)--OC(.dbd.O)R.sub.13,
[0047] k) --C(R.sub.9)(R.sub.11)--OC(.dbd.O)R.sub.13,
[0048] l) --NR.sub.10R.sub.11,
[0049] m) --N(R.sub.10)--C(.dbd.O)R.sub.7,
[0050] n) --N(R.sub.10)--S(.dbd.O).sub.iR.sub.7,
[0051] o) --C(OR.sub.14)(OR.sub.15)R.sub.8,
[0052] p) --C(R.sub.8)(R.sub.16)--NR.sub.10R.sub.11, or
[0053] q) C.sub.1-8 alkyl substituted with one or more .dbd.O other
than at alpha position, --S(.dbd.O).sub.iR.sub.17,
--NR.sub.10R.sub.11, C.sub.2-5 alkenyl, or C.sub.2-5 alkynyl;
[0054] R.sub.4 is
[0055] a) C.sub.1-4 alkyl optionally substituted with one or more
halos, OH, CN, NR.sub.10R.sub.11, or --CO.sub.2R.sub.13,
[0056] b) C.sub.2-4 alkenyl,
[0057] c) --NR.sub.16R.sub.18,
[0058] d) --N.sub.3,
[0059] e) --NHC(.dbd.O)R.sub.7,
[0060] f) --NR.sub.20C(.dbd.O)R.sub.7,
[0061] g) --N(R.sub.19).sub.2,
[0062] h) --NR.sub.16R.sub.19, or
[0063] i) --NR.sub.19R.sub.20,
[0064] R.sub.5 and R.sub.6 at each occurrence are the same or
different and are
[0065] a) C.sub.1-2 alkyl, or
[0066] b) R.sub.5 and R.sub.6 taken together are
--(CH.sub.2).sub.k--;
[0067] R.sub.7 is C.sub.1-4 alkyl optionally substituted with one
or more halos;
[0068] R.sub.8 is
[0069] a) H, or
[0070] b) C.sub.1-8 alkyl optionally substituted with one or more
halos, or C.sub.3-8 cycloalkyl;
[0071] R.sub.9 is C.sub.1-4 alkyl substituted with one or more
[0072] a) --S(.dbd.O)R.sub.17,
[0073] b) --OR.sub.13,
[0074] c) --OC(.dbd.O)R.sub.13,
[0075] d) --NR.sub.10R.sub.11, or
[0076] e) C.sub.1-5 alkenyl optionally substituted with CHO;
[0077] R.sub.10 and R.sub.11 at each occurrence are the same or
different and are
[0078] a) H,
[0079] b) C.sub.1-4 alkyl, or
[0080] c) C.sub.3-8 cycloalkyl;
[0081] R.sub.12 is
[0082] a) --NR.sub.10R.sub.11,
[0083] b) --OR.sub.10; or
[0084] c) --NHC(.dbd.O)R.sub.10;
[0085] R.sub.13 is
[0086] a) H, or
[0087] b) C.sub.1-4 alkyl;
[0088] R.sub.14 and R.sub.15 at each occurrence are the same or
different and are
[0089] a) C.sub.1-4 alkyl, or
[0090] b) R.sub.14 and R.sub.15 taken together are
--(CH).sub.l--;
[0091] R.sub.16 is
[0092] a) H,
[0093] b) C.sub.1-4 alkyl, or
[0094] c) C.sub.3-8 cycloalkyl;
[0095] R.sub.17 is
[0096] a) C.sub.1-4 alkyl, or
[0097] b) C.sub.3-8 cycloalkyl;
[0098] R.sub.18 is
[0099] a) H,
[0100] b) C.sub.1-4 alkyl,
[0101] c) C.sub.2-4 alkenyl,
[0102] d) C.sub.3-4 cycloalkyl,
[0103] e) --OR.sub.1-3 or
[0104] f) --NR.sub.21R.sub.22;
[0105] R.sub.19 is
[0106] a) Cl,
[0107] b) Br, or
[0108] c) I;
[0109] R.sub.20 is a physiologically acceptable cation;
[0110] R.sub.21 and R.sub.22 at each occurrence are the same or
different and are
[0111] a) H,
[0112] b) C.sub.1-4 alkyl, or
[0113] c) --NR.sub.21R.sub.22 taken together are
--(CH.sub.2).sub.m--;
[0114] wherein R.sub.23 and R.sub.24 at each occurrence are the
same or different and are
[0115] a) H,
[0116] b) F,
[0117] c) Cl,
[0118] d) C.sub.1-2 alkyl,
[0119] e) CN
[0120] f) OH,
[0121] g) C.sub.1-2 alkoxy,
[0122] h) nitro, or
[0123] i) amino;
[0124] Q is 6
[0125] m) a diazinyl group optionally substituted with X and Y,
[0126] n) a triazinyl group optionally substituted with X and
Y,
[0127] o) a quinolinyl group optionally substituted with X and
Y,
[0128] p) a quinoxalinyl group optionally substituted with X and
Y,
[0129] q) a naphthyridinyl group optionally substituted with X and
Y, 7
[0130] Q and R.sub.24 taken together are 8
[0131] wherein Z.sup.1 is
[0132] a) --CH.sub.2--,
[0133] b) --CH(R.sup.104)--CH.sub.2--,
[0134] c) --C(O)--, or
[0135] d) --CH.sub.2CH.sub.2CH.sub.2--;
[0136] wherein Z.sup.2 is
[0137] a) --O.sub.2S--,
[0138] b) --O--,
[0139] c) --N(R.sup.107)--,
[0140] d) --OS--, or
[0141] e) --S--;
[0142] wherein Z.sup.3 is
[0143] a) --O.sub.2S--,
[0144] b) --O--,
[0145] c) --OS--, or
[0146] d) --S--;
[0147] wherein A.sup.1 is
[0148] a) H--, or
[0149] b) CH.sub.3;
[0150] wherein A.sup.2 is
[0151] a) H--,
[0152] b) HO--,
[0153] c) CH.sub.3--,
[0154] d) CH.sub.3O--,
[0155] e) R.sup.102O--CH.sub.2--C(O)--NH--
[0156] f) R.sup.103O--C(O)--NH--,
[0157] g) (C.sub.1-C.sub.2)alkyl-O--C(O)--,
[0158] h) HO--CH.sub.2--,
[0159] i) CH.sub.3O--NH--,
[0160] j) (C.sub.1-C.sub.3)alkyl-O.sub.2C--
[0161] k) CH.sub.3--C(O)--,
[0162] l) CH.sub.3--C(O)--CH.sub.2--, 9
[0163] A.sup.1 and A.sup.2 taken together are: 10
[0164] wherein R.sup.102 is
[0165] a) H--,
[0166] b) CH.sub.3--,
[0167] c) phenyl-CH.sub.2--, or
[0168] d) CH.sub.3C(O)--;
[0169] wherein R.sup.103 is
[0170] a) (C.sub.1-C.sub.3)alkyl-, or
[0171] b) phenyl-;
[0172] wherein R.sup.104 is
[0173] a) H--, or
[0174] b) HO--;
[0175] wherein R.sup.105 is
[0176] a) H--,
[0177] b) (C.sub.1-C.sub.3)alkyl-,
[0178] c) CH.sub.2.dbd.CH--CH.sub.2--, or
[0179] d) CH.sub.3--O--(CH.sub.2).sub.2--;
[0180] wherein R.sup.106 is
[0181] a) CH.sub.3--C(O)--,
[0182] b) H--C(O)--,
[0183] c) Cl.sub.2CH--C(O)--,
[0184] d) HOCH.sub.2--C(O)--,
[0185] e) CH.sub.3SO.sub.2--, 11
[0186] g) F.sub.2CHC(O)--, 12
[0187] i) H.sub.3C--C(O)--O--CH.sub.2--C(O)--,
[0188] j) H--C(O)--O--CH.sub.2--C(O)--, 13
[0189] l) HC.ident.C--CH.sub.2O--CH.sub.2--C(O)--, or
[0190] m) phenyl-CH.sub.2--O--CH.sub.2--C(O)--;
[0191] wherein R.sup.107 is
[0192] a) R.sup.102O--C(R.sup.110)(R.sup.111)--C(O)--,
[0193] b) R.sup.103O--C(O)--,
[0194] c) R.sup.108--C(O)--, 14
[0195] f) H.sub.3C--C(O)--(CH.sub.2).sub.2--C(O)--,
[0196] g) R.sup.109--SO.sub.2--, 15
[0197] i) HO--CH.sub.2--C(O)--,
[0198] j) R.sup.116--(CH.sub.2).sub.2--,
[0199] k) R.sup.113--C(O)--O--CH.sub.2--C(O)--,
[0200] l) (CH.sub.3).sub.2N--CH.sub.2--C(O)--NH--,
[0201] m) NC--CH.sub.2--,
[0202] n) F.sub.2--CH--CH.sub.2--, or
[0203] o) R.sup.150R.sup.151NSO.sub.2
[0204] wherein R.sup.108 is
[0205] a) H--,
[0206] b) (C.sub.1-C.sub.4)alkyl,
[0207] c) aryl --(CH.sub.2).sub.p,
[0208] d) ClH.sub.2C--,
[0209] e) Cl.sub.2HC--,
[0210] f) FH.sub.2C--,
[0211] g) F.sub.2HC--,
[0212] h) (C.sub.3-C.sub.6)cycloalkyl, or
[0213] i) CNCH.sub.2--.
[0214] wherein R.sup.109 is
[0215] a) alkylC.sub.1-C.sub.4,
[0216] b) --CH.sub.2Cl
[0217] c) --CH.sub.2CH.dbd.CH.sub.2,
[0218] d) aryl, or
[0219] e) --CH.sub.2CN;
[0220] wherein R.sup.110 and R.sup.111 are independently
[0221] a) H--,
[0222] b) CH.sub.3--; or
[0223] wherein R.sup.112 is
[0224] a) H--,
[0225] b) CH.sub.3O--CH.sub.2O--CH.sub.2--, or
[0226] c) HOCH.sub.2--;
[0227] wherein R.sup.113 is
[0228] a) CH.sub.3--,
[0229] b) HOCH.sub.2--,
[0230] c) (CH.sub.3).sub.2N-phenyl, or
[0231] d) (CH.sub.3).sub.2N--CH.sub.2--;
[0232] wherein R.sup.114 is
[0233] a) HO--,
[0234] b) CH.sub.3O--,
[0235] c) H.sub.2N--,
[0236] d) CH.sub.3O--C(O)--O--,
[0237] e) CH.sub.3--C(O)--O--CH.sub.2--C(O)--O--,
[0238] f) phenyl-CH.sub.2--O--CH.sub.2--C(O)--O--,
[0239] g) HO--(CH.sub.2).sub.2--O--,
[0240] h) CH.sub.3O--CH.sub.2--O--(CH.sub.2).sub.2--O--, or
[0241] i) CH.sub.3O--CH.sub.2--;
[0242] wherein R.sup.113 is
[0243] a) CH.sub.3--,
[0244] b) HOCH.sub.2--,
[0245] c) (CH.sub.3).sub.2N-phenyl, or
[0246] d) (CH.sub.3).sub.2N--CH.sub.2--;
[0247] wherein R.sup.115 is
[0248] a) H--, or
[0249] b) Cl--;
[0250] wherein R.sup.116 is
[0251] a) HO--
[0252] b) CH.sub.3O--, or
[0253] c) F;
[0254] wherein R.sup.150 and R.sup.151 are each H or alkyl
C.sub.1-C.sub.4 or R.sup.150 and R.sup.151 taken together with the
nitrogen atom to which each is attached form a monocyclic
heterocyclic ring having from 3 to 6 carbon atoms;
[0255] B is an unsaturated 4-atom linker having one nitrogen and
three carbons;
[0256] M is
[0257] a) H,
[0258] b) C.sub.1-8 alkyl,
[0259] c) C.sub.3-8 cycloalkyl,
[0260] d) --(CH.sub.2).sub.mOR.sub.13, or
[0261] e) --(CH.sub.2).sub.h--NR.sub.21R.sub.22;
[0262] Z is
[0263] a) O,
[0264] b) S, or
[0265] c) NM;
[0266] W is
[0267] a) CH,
[0268] b) N, or
[0269] c) S or O when Z is NM;
[0270] Y is
[0271] a) H,
[0272] b) F,
[0273] c) Cl,
[0274] d) Br,
[0275] e) C.sub.1-3 alkyl, or
[0276] f) NO.sub.2;
[0277] X is
[0278] a) H,
[0279] b) --CN,
[0280] c) OR.sub.27,
[0281] d) halo,
[0282] e) NO.sub.2,
[0283] f) tetrazoyl,
[0284] g) --SH,
[0285] h) --S(.dbd.O).sub.iR.sub.4,
[0286] i) --S(.dbd.O).sub.2--N.dbd.S(O).sub.jR.sub.5R.sub.6,
[0287] j) --SC(.dbd.O)R.sub.7,
[0288] k) --C(.dbd.O)R.sub.25,
[0289] l) --C(.dbd.O)NR.sub.27R.sub.28,
[0290] m) --C(.dbd.NR.sub.29)R.sub.25,
[0291] n) --C(R.sub.25)(R.sub.28)--OR.sub.13,
[0292] o) --C(R.sub.25)(R.sub.28)--OC(.dbd.O)R.sub.13,
[0293] p)
--C(R.sub.28)(OR.sub.13)--(CH.sub.2).sub.h--NR.sub.27R.sub.28,
[0294] q) --NR.sub.27R.sub.28,
[0295] r) --N(R.sub.27)C(.dbd.O)R.sub.7,
[0296] s) --N(R.sub.27)--S(.dbd.O).sub.iR.sub.7,
[0297] t) --C(OR.sub.14)(OR.sub.15)R.sub.28,
[0298] u) --C(R.sub.25)(R.sub.16)--NR.sub.27R.sub.26, or
[0299] v) C.sub.1-8 alkyl substituted with one or more halos, OH,
.dbd.O other than at alpha position, --S(.dbd.O).sub.iR.sub.17,
--NR.sub.27R.sub.28, C.sub.2-5 alkenyl, C.sub.2-5 alkynyl, or
C.sub.3-8 cycloalkyl;
[0300] R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.13, R.sub.14,
R.sub.15, R.sub.16, and R.sub.17 are the same as defined above;
[0301] R.sub.25 is
[0302] a) H,
[0303] b) C.sub.1-8 alkyl optionally substituted with one or more
halos, C.sub.3-8 cycloalkyl, C.sub.1-4 alkyl substituted with one
or more of --S(.dbd.O).sub.iR.sub.17, --OR.sub.13, or
OC(.dbd.O)R.sub.13, NR.sub.27R.sub.28, or
[0304] c) C.sub.2-5 alkenyl optionally substituted with CHO, or
CO.sub.2R.sub.13;
[0305] R.sub.26 is
[0306] a) R.sub.28, or
[0307] b) NR.sub.27N.sub.28;
[0308] R.sub.27 and R.sub.28 at each occurrence are the same or
different and are
[0309] a) H,
[0310] b) C.sub.1-8 alkyl,
[0311] c) C.sub.3-8 cycloalkyl,
[0312] d) --(CH.sub.2).sub.mOR.sub.13,
[0313] e) --(CH.sub.2).sub.h--NR.sub.21R.sub.22, or
[0314] f) R.sub.27 and R.sub.28 taken together are
--(CH.sub.2).sub.2O(CH.- sub.2).sub.2--,
--(CH.sub.2).sub.hCH(COR.sub.7)--, or
--(CH.sub.2).sub.2N(CH.sub.2).sub.2(R.sub.7);
[0315] R.sub.29 is
[0316] a) --NR.sub.27R.sub.28,
[0317] b) --OR.sub.27, or
[0318] c) --NHC(.dbd.O)R.sub.28;
[0319] wherein R.sub.30 is
[0320] a) H,
[0321] b) C.sub.1-8 alkyl optionally substituted with one or more
halos, or
[0322] c) C.sub.1-8 alkyl optionally substituted with one or more
OH, or C.sub.1-6 alkoxy;
[0323] wherein E is
[0324] a) NR.sub.39,
[0325] b) --S(.dbd.O).sub.i, or
[0326] c) O;
[0327] R.sub.38 is
[0328] a) H,
[0329] b) C.sub.1-6 alkyl,
[0330] c) --(CH.sub.2).sub.q-aryl, or
[0331] d) halo;
[0332] R.sub.39 is
[0333] a) H,
[0334] b) C.sub.1-6 alkyl optionally substituted with one or more
OH, halo, or --CN,
[0335] c) --(CH.sub.2).sub.q-aryl,
[0336] d) --CO.sub.2R.sub.40,
[0337] e) --COR.sub.41,
[0338] f) --C(.dbd.O)--(CH.sub.2).sub.q--C(.dbd.O)R.sub.40,
[0339] g) --S(.dbd.O).sub.2--C.sub.1-6 alkyl,
[0340] h) --S(.dbd.O).sub.2--(CH.sub.2).sub.q-aryl, or
[0341] i) --(C.dbd.O).sub.j-Het;
[0342] R.sub.40 is
[0343] a) H,
[0344] b) C.sub.1-6 alkyl optionally substituted with one or more
OH, halo, or --CN,
[0345] c) --(CH.sub.2).sub.q-aryl, or
[0346] d) --(CH.sub.2).sub.q--OR.sub.42;
[0347] R.sub.41 is
[0348] a) C.sub.1-6 alkyl optionally substituted with one or more
OH, halo, or --CN,
[0349] b) --(CH.sub.2).sub.q-aryl, or
[0350] c) --(CH.sub.2).sub.q--OR.sub.42;
[0351] R.sub.42 is
[0352] a) H,
[0353] b) C.sub.1-6 alkyl,
[0354] c) --(CH.sub.2).sub.q-aryl, or
[0355] d) --C(.dbd.O)--C.sub.1-6 alkyl;
[0356] aryl is
[0357] a) phenyl,
[0358] b) pyridyl, or
[0359] c) napthyl; a to c optionally substituted with one or more
halo, --CN, OH, SH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or C.sub.1-6
alkylthio;
[0360] wherein R.sub.43 is
[0361] a) H,
[0362] b) C.sub.1-2 alkyl,
[0363] c) F, or
[0364] d) OH;
[0365] R.sub.44 is
[0366] a) H,
[0367] b) CF.sub.3,
[0368] c) C.sub.1-3 alkyl optionally substituted with one or more
halo,
[0369] d) phenyl optionally substituted with one or more halo,
[0370] e) R.sub.44 and R.sub.45 taken together are a 5-, 6-, or
7-membered ring of the formula, 16
[0371] or
[0372] f) R.sub.44 and R.sub.45 taken together are
--(CH.sub.2).sub.k--, when R.sub.46 is an electron withdrawing
group;
[0373] R.sub.45 and R.sub.46 at each occurrence are the same or
different and are
[0374] a) an electron-withdrawing group,
[0375] b) H,
[0376] c) CF.sub.3,
[0377] d) C.sub.1-3 alkyl optionally substituted with one halo,
[0378] e) phenyl, provided at least one of R.sub.45 or R.sub.46 is
an electron-withdrawing group, or
[0379] f) R.sub.45 and R.sub.46 taken together are a 5-, 6-,
7-membered ring of the formula 17
[0380] U is
[0381] a) CH.sub.2,
[0382] b) O,
[0383] c) S, or
[0384] d) NR.sub.47;
[0385] R.sub.47 is
[0386] a) H, or
[0387] b) C.sub.1-5 alkyl;
[0388] wherein R.sub.48 is
[0389] a) carboxyl,
[0390] b) halo,
[0391] c) --CN,
[0392] d) mercapto,
[0393] e) formyl,
[0394] f) CF.sub.3,
[0395] g) --NO.sub.2,
[0396] h) C.sub.1-6 alkoxy,
[0397] i) C.sub.1-6 alkoxycarbonyl,
[0398] j) C.sub.1-6 alkythio,
[0399] k) C.sub.1-6 acyl,
[0400] l) --NR.sub.49 R.sub.50,
[0401] m) C.sub.1-6 alkyl optionally substituted with OH, C.sub.1-5
alkoxy, C.sub.1-5 acyl, or --NR.sub.49R.sub.50,
[0402] n) C.sub.2-8 alkenylphenyl optionally substituted with one
or two R.sub.51,
[0403] o) phenyl optionally substituted with one or two
R.sub.51,
[0404] 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 R.sub.51, or
18
[0405] R.sub.49 and R.sub.50 at each occurrence are the same or
different and are
[0406] a) H,
[0407] b) C.sub.1-4 alkyl,
[0408] c) C.sub.5-6 cycloalkyl, or
[0409] d) R.sub.49 and R.sub.50 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.sub.1-3
alkyl, or C.sub.1-3 acyl;
[0410] R.sub.51 is
[0411] a) carboxyl,
[0412] b) halo,
[0413] c) --CN,
[0414] d) mercapto,
[0415] e) formyl,
[0416] f) CF.sub.3,
[0417] g) --NO.sub.2,
[0418] h) C.sub.1-6 alkoxy,
[0419] i) C.sub.1-6 alkoxycarbonyl,
[0420] j) C.sub.1-6 alkythio,
[0421] k) C.sub.1-6 acyl,
[0422] l) C.sub.1-6 alkyl optionally substituted with OH, C.sub.1-5
alkoxy, C.sub.1-5 acyl, or --NR.sub.49R.sub.50,
[0423] m) phenyl,
[0424] n) --C(.dbd.O)NR.sub.52 R.sub.53,
[0425] o) --NR.sub.49R.sub.50,
[0426] p) --N(R.sub.52)(--SO.sub.2R.sub.54),
[0427] q) --SO.sub.2--NR.sub.52R.sub.53, or
[0428] r) --S(.dbd.O).sub.1R.sub.54;
[0429] R.sub.52 and R.sub.53 at each occurrence are the same or
different and are
[0430] a) H,
[0431] b) C.sub.1-6 alkyl, or
[0432] c) phenyl;
[0433] R.sub.54 is
[0434] a) C.sub.1-4 alkyl, or
[0435] b) phenyl optionally substituted with C.sub.1-4 alkyl;
[0436] wherein R.sub.55 is
[0437] a) carboxyl,
[0438] b) halo,
[0439] c) --CN,
[0440] d) mercapto,
[0441] e) formyl,
[0442] f) CF.sub.3,
[0443] g) --NO.sub.2,
[0444] h) C.sub.1-6 alkoxy,
[0445] i) C.sub.1-6 alkoxycarbonyl,
[0446] j) C.sub.1-6 alkythio
[0447] k) C.sub.1-6 acyl,
[0448] l) --NR.sub.56 R.sub.57,
[0449] m) C.sub.1-6 alkyl optionally substituted with OH, C.sub.1-5
alkoxy, C.sub.1-5 acyl, or --NR.sub.56R.sub.57,
[0450] n) C.sub.2-8 alkenylphenyl optionally substituted with one
or two R.sub.58,
[0451] o) phenyl optionally substituted with one or two
R.sub.58,
[0452] 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 R.sub.58, or
19
[0453] R.sub.56 and R.sub.57 at each occurrence are the same or
different and are
[0454] a) H,
[0455] b) formyl,
[0456] c) C.sub.1-4 alkyl,
[0457] d) C.sub.1-4 acyl,
[0458] e) phenyl,
[0459] f) C.sub.3-6 cycloalkyl, or
[0460] g) R.sub.56 and R.sub.57 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, phenyl,
pyrimidyl, C.sub.1-3 alkyl, or C.sub.1-3 acyl;
[0461] R.sub.58 is
[0462] a) carboxyl,
[0463] b) halo,
[0464] c) --CN,
[0465] d) mercapto,
[0466] e) formyl,
[0467] f) CF.sub.3,
[0468] g) --NO.sub.2,
[0469] h) C.sub.1-6 alkoxy,
[0470] i) C.sub.1-6 alkoxycarbonyl,
[0471] j) C.sub.1-6 alkythio,
[0472] k) C.sub.1-6 acyl,
[0473] l) phenyl,
[0474] m) C.sub.1-6 alkyl optionally substituted with OH, azido,
C.sub.1-5 alkoxy, C.sub.1-5 acyl, --NR.sub.65R.sub.66, --SR.sub.67,
--O--SO.sub.2R.sub.68, or 20
[0475] n) --C(.dbd.O)NR.sub.59 R.sub.60,
[0476] o) --NR.sub.56R.sub.57,
[0477] p) --N(R.sub.59)(--SO.sub.2R.sub.54),
[0478] q) --SO.sub.2--NR.sub.59R.sub.60,
[0479] r) --S(.dbd.O).sub.iR.sub.54,
[0480] s) --CH.dbd.N--R.sub.61, or
[0481] t) --CH(OH)--SO.sub.3R.sub.64;
[0482] R.sub.54 is the same as defined above;
[0483] R.sub.59 and R.sub.60 at each occurrence are the same or
different and are
[0484] a) H,
[0485] b) C.sub.1-6 alkyl,
[0486] c) phenyl, or
[0487] d) tolyl;
[0488] R.sub.61 is
[0489] a) OH,
[0490] b) benzyloxy,
[0491] c) --NH--C(.dbd.O)--NH.sub.2,
[0492] d) --NH--C(.dbd.S)--NH.sub.2, or
[0493] e) --NH--C(.dbd.NH)--NR.sub.62R.sub.63;
[0494] R.sub.62 and R.sub.63 at each occurrence are the same or
different and are
[0495] a) H, or
[0496] b) C.sub.1-4 alkyl optionally substituted with phenyl or
pyridyl;
[0497] R.sub.64 is
[0498] a) H, or
[0499] b) a sodium ion;
[0500] R.sub.65and R.sub.66 at each occurrence are the same or
different and are
[0501] a) H,
[0502] b) formyl,
[0503] c) C.sub.1-4 alkyl,
[0504] d) C.sub.1-4 acyl,
[0505] e) phenyl,
[0506] f) C.sub.3-6 cycloalkyl,
[0507] g) R.sub.65 and R.sub.66 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.sub.1-3
alkyl, or C.sub.1-3 acyl,
[0508] h) --P(O)(OR.sub.70)(OR.sub.71), or
[0509] i) --SO.sub.2--R.sub.72;
[0510] R.sub.67 is 21
[0511] R.sub.68 is C.sub.1-3 alkyl;
[0512] R.sub.69 is
[0513] a) C.sub.1-6 alkoxycarbonyl, or
[0514] b) carboxyl;
[0515] R.sub.70 and R.sub.71 at each occurrence are the same or
different and are
[0516] a) H, or
[0517] b) C.sub.1-3 alkyl;
[0518] R.sub.72 is
[0519] a) methyl,
[0520] b) phenyl, or
[0521] c) tolyl;
[0522] wherein K is
[0523] a) O, or
[0524] b) S;
[0525] R.sub.73, R.sub.74, R.sub.75, R.sub.76, and R.sub.77 at each
occurrence are the same or different and are
[0526] a) H,
[0527] b) carboxyl,
[0528] c) halo,
[0529] d) --CN,
[0530] e) mercapto,
[0531] f) formyl,
[0532] g) CF.sub.3,
[0533] h) --NO.sub.2,
[0534] i) C.sub.1-6 alkoxy,
[0535] j) C.sub.1-6 alkoxycarbonyl,
[0536] k) C.sub.1-6 alkythio,
[0537] l) C.sub.1-6 acyl,
[0538] m) --NR.sub.78 R.sub.79,
[0539] n) C.sub.1-6 alkyl optionally substituted with OH, C.sub.1-5
alkoxy, C.sub.1-5 acyl, --NR.sub.78R.sub.79,
--N(phenyl)(CH.sub.2--CH.sub- .2--OH),
--O--CH(CH.sub.3)(OCH.sub.2CH.sub.3), or --O-phenyl-[para-NHC(.db-
d.O)CH.sub.3],
[0540] o) C.sub.2-8 alkenylphenyl optionally substituted with
R.sub.51,
[0541] p) phenyl optionally substituted with R.sub.51, or
[0542] 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 R.sub.51;
[0543] R.sub.51 is the same as defined above;
[0544] R.sub.78 and R.sub.79 at each occurrence are the same or
different and are
[0545] a) H,
[0546] b) C.sub.1-4 alkyl,
[0547] c) phenyl, or
[0548] d) R.sub.78 and R.sub.79 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.sub.1-3
alkyl, or C.sub.1-3 acyl;
[0549] wherein T is
[0550] a) O,
[0551] b) S, or
[0552] c) SO.sub.2;
[0553] R.sub.75, R.sub.76, and R.sub.77 are the same as defined
above;
[0554] R.sub.80 is
[0555] a) H,
[0556] b) formyl,
[0557] c) carboxyl,
[0558] d) C.sub.1-6 alkoxycarbonyl,
[0559] e) C.sub.1-8 alkyl,
[0560] f) C.sub.2-8 alkenyl,
[0561] wherein the substituents (e) and (f) can be optionally
substituted with OH, halo, C.sub.1-6 alkoxy, C.sub.1-6 acyl,
C.sub.1-6 alkylthio or C.sub.1-6 alkoxycarbonyl, or phenyl
optionally substituted with halo,
[0562] g) an aromatic moiety having 6 to 10 carbon atoms optionally
substituted with carboxyl, halo, --CN, formyl, CF.sub.3,
--NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 acyl,
C.sub.1-6 alkylthio, or C.sub.1-6 alkoxycarbonyl;
[0563] h) --NR.sub.81R.sub.82,
[0564] i) --OR.sub.90,
[0565] j) --S(.dbd.O).sub.i--R.sub.91,
[0566] k) --SO.sub.2--N(R.sub.92)(R.sub.93), or
[0567] l) a radical of the following formulas:
[0568] R.sub.81 and R.sub.82 at each occurrence are the same or
different and are
[0569] a) H,
[0570] b) C.sub.3-6 cycloalkyl,
[0571] c) phenyl,
[0572] d) C.sub.1-6 acyl,
[0573] e) C.sub.1-8 alkyl optionally substituted with OH, C.sub.1-6
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, CF.sub.3, halo, --NO.sub.2, C.sub.1-4 alkoxy,
--NR.sub.83R.sub.84, or 22
[0574] V is
[0575] a) O,
[0576] b) CH.sub.2, or
[0577] c) NR.sub.87;
[0578] R.sub.83 and R.sub.84 at each occurrence are the same or
different and are
[0579] a) H, or
[0580] b) C.sub.1-4 alkyl;
[0581] R.sub.85 is
[0582] a) OH,
[0583] b) C.sub.1-4 alkoxy, or
[0584] c) --NR.sub.88 R.sub.89;
[0585] R.sub.86 is
[0586] a) H, or
[0587] b) C.sub.1-7 alkyl optionally substituted with indolyl, OH,
mercaptyl, imidazoly, methylthio, amino, phenyl optionally
substituted with OH, --C(.dbd.O)--NH.sub.2, --CO.sub.2H, or
--C(.dbd.NH)--NH.sub.2;
[0588] R.sub.87 is
[0589] a) H,
[0590] b) phenyl, or
[0591] c) C.sub.1-6 alkyl optionally substituted by OH;
[0592] R.sub.88 and R.sub.89 at each occurrence are the same or
different and are
[0593] a) H,
[0594] b) C.sub.1-5 alkyl
[0595] c) C.sub.3-6 cycloalky, or
[0596] d) phenyl;
[0597] R.sub.90 is
[0598] a) C.sub.1-8 alkyl optionally substituted with C.sub.1-6
alkoxy or C.sub.1-6 hydroxy, C.sub.3-6 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.sub.2, CF.sub.3, halo, --CN, OH, C.sub.1-5 alkyl,
C.sub.1-5 alkoxy, or C.sub.1-5 acyl; 23
[0599] c) phenyl, or
[0600] d) pyridyl;
[0601] R.sub.91 is
[0602] a) C.sub.1-16 alkyl,
[0603] b) C.sub.2-16 alkenyl,
[0604] wherein the substituents (a) and (b) can be optionally
substituted with C.sub.1-6 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,
[0605] c) an aromatic moiety having 6 to 10 carbon atoms, or
[0606] d) a 5-, 6-, 7-membered aromatic heterocyclic moiety having
one to three atoms selected from the group consisting of S, N, and
O,
[0607] wherein the substituents (c) and (d) can be optionally
substituted with carboxyl, halo, --CN, formyl, CF.sub.3,
--NO.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 acyl,
C.sub.1-6 alkylthio, or C.sub.1-6 alkoxycarbonyl;
[0608] R.sub.92 and R.sub.93 at each occurrence are the same or
different and are
[0609] a) H,
[0610] b) phenyl,
[0611] c) C.sub.1-6 alkyl, or
[0612] d) benzyl;
[0613] R.sub.94 and R.sub.95 at each occurrence are the same or
different and are
[0614] a) H,
[0615] b) OH,
[0616] c) C.sub.1-6 alkyl optionally substituted with --NR.sub.83
R.sub.84, or
[0617] d) R.sub.94 and R.sub.95 taken together are .dbd.O;
[0618] R.sub.96 is
[0619] a) an aromatic moiety having 6 to 10 carbon atoms,
[0620] 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,
[0621] wherein the substituents (a) and (b) which can in turn be
substituted with one or three --NO.sub.2, CF.sub.3, halo, --CN, OH,
phenyl, C.sub.1-5 alkyl, C.sub.1-5 alkoxy, or C.sub.1-5 acyl,
[0622] c) morpholinyl,
[0623] d) OH,
[0624] e) C.sub.1-6 alkoxy,
[0625] f) --NR.sub.83R.sub.84,
[0626] g) --C(.dbd.O)--R.sub.97, or 24
[0627] R.sub.97 is
[0628] a) morpholinyl,
[0629] b) OH, or
[0630] c) C.sub.1-6 alkoxy;
[0631] h is 1, 2, or 3;
[0632] i is 0, 1, or 2;
[0633] j is 0 or 1;
[0634] k is 3, 4, or 5;
[0635] l is 2 or 3;
[0636] m is 4 or 5;
[0637] n is 0, 1, 2, 3, 4, or 5;
[0638] p is 0, 1, 2, 3, 4, or 5; with the proviso that n and p
together are 1, 2, 3, 4, or 5;
[0639] q is 1, 2, 3, or 4;
[0640] r is 2, 3, or 4;
[0641] t is 0, 1, 2, 3, 4, 5, or 6;
[0642] u is 1 or 2;
[0643] w is 0, 1, 2, or 3.
DETAILED DESCRIPTION OF THE INVENTION
[0644] The new compounds of the invention can be prepared using
known compounds and intermediates of oxazolidinones, isoxazolines
and butyolactones as intermediates and synthetic methods known in
the art. Thioamides of the invention can typically be prepared by
the reaction of the corresponding amide with Lawesson's
reagent.
[0645] Compounds disclosed in the following publications are
suitable intermediates for preparation of the compounds of this
invention and are hereby incorporated by reference for their
disclosure of suitable compounds that can be converted to the
subject thiocarbonyl derivatives.
[0646] U.S. Pat. Nos. 5,225,565; 5,182,403; 5,164,510; 5,247,090;
5,231,188; 5,565,571; 5,547,950; and 5,523,403.
[0647] PCT Application and publications PCT/US93/04850, WO94/01110;
PCT/US94/08904, WO95/07271; PCT/US95/02972, WO95/25106;
PCT/US95/10992, WO96/13502; PCT/US96/05202, WO96/35691;
PCT/US96/12766; PCT/US96/13726; PCT/US96/14135; PCT/US96/17120;
PCT/US96/19149; PCT/US97/01970; PCT/US95/12751, WO96/15130; and
PCT/US96/00718, WO96/23788.
[0648] Chemical conversion techniques for converting various
intermediates having a CH.sub.2NH.sub.2 on the oxazolidinone ring
to CH.sub.2NH--C(S)--CH.sub.3 is disclosed by Hartke, K, Barrmeyer,
S., J. prakt. Chem. 1996, 338, 251-6. Similarly, conversion of
CH.sub.2NHC(.dbd.O)CH.sub.3 to CH.sub.2NHC(S)NHCH.sub.3 is reported
by Cava, M. P.; Levinson, M. I., Thionation Reactions of Lawesson's
Reagents, Tetrahedron 1985, 41, 5061-87.
[0649] For the purpose of the present invention, the carbon content
of various hydrocarbon containing moieties is indicated by a prefix
designating the minimum and maximum number of carbon atoms in the
moiety, i.e., the prefix C.sub.i-j defines the number of carbon
atoms present from the integer "i" to the integer "j", inclusive.
Thus, C.sub.1-4 alkyl refers to alkyl of 1-4 carbon atoms,
inclusive, or methyl, ethyl, propyl, butyl and isomeric forms
thereof.
[0650] The terms "C.sub.1-2 alkyl", "C.sub.1-3 alkyl", "C.sub.1-4
alkyl", "C.sub.1-5 alkyl", "C.sub.1-6 alkyl", "C.sub.1-8 alkyl",
and "C.sub.1-16 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.
[0651] The terms "C.sub.2-4 alkenyl", "C.sub.2-5 alkenyl",
"C.sub.2-8 alkenyl", "C.sub.2-14 alkenyl" and "C.sub.2-16 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.
[0652] The terms "C.sub.2-5 alkynyl", "C.sub.2-8 alkynyl", and
"C.sub.2-10 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.
[0653] The terms "C.sub.3-4 cycloalkyl", "C.sub.3-6 cycloalkyl",
"C.sub.5-6 cycloalkyl", and "C.sub.3-8 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.
[0654] The terms "C.sub.1-4 alkoxy", "C.sub.1-6 alkoxy", and
"C.sub.1-8 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.
[0655] The terms "C.sub.1-6 alkylamino", and "C.sub.1-8 alkylamino"
refer to an alkyl group 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.
[0656] The terms "C.sub.1-6 dialkylamino", and "C.sub.1-8
dialkylamino" refer to two alkyl 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.
[0657] The terms "C.sub.1-3 acyl", "C.sub.1-4 acyl", "C.sub.1-5
acyl", "C.sub.1-6 acyl", "C.sub.1-8 acyl", and "C.sub.2-8 acyl"
refer to a carbonyl group having an alkyl group of one to three,
one to four, one to five, one to six, one to eight, or two to eight
carbon atoms.
[0658] The terms "C.sub.1-4 alkoxycarbonyl", "C.sub.1-6
alkoxycarbonyl", and "C.sub.1-8 alkoxycarbonyl" refer to an ester
group having an alkyl group of one to four, one to six, or one to
eight carbon atoms.
[0659] The term "C.sub.1-8 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.
[0660] The term "C.sub.2-8 alkenyl phenyl" refers to a at least one
double bond alkenyl group having one to eight carbon atoms and
isomeric forms thereof which is substituted with at least one
phenyl radical.
[0661] The term "C.sub.1-8alkyl 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.
[0662] The term "C.sub.1-8 hydroxyl" refers to an alkyl group
having one to eight carbon atoms and isomeric forms thereof
attached to a hydroxy group.
[0663] The term "C.sub.1-8 alkylsulfonyl" refers to an alkyl group
having one to eight carbon atoms and isomeric forms thereof
attached to a SO.sub.2 moiety.
[0664] The term "C.sub.1-6 alkylthio" refers to an alkyl group
having one to six carbon atoms and isomeric forms thereof attached
to a sulfur atom.
[0665] 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, pyrimidine, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl,
1-isoquinolyl, 3-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-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-1-oxide, 1,2,4-oxadiazol-3-yl,
1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,
3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl,
2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl,
1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl,
1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl,
1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl,1-purinyl,
3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl,
1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or
5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione,
1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties
may be substituted as appropriate.
[0666] The term halo refers to fluoro, chloro, bromo, or iodo.
[0667] The compounds of the present invention can be converted to
their salts, where appropriate, according to conventional
methods.
[0668] The term "pharmaceutically 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.
[0669] When Q is the structure of 25
[0670] 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.sub.39 group will not be present.
[0671] 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 chiral centers and other isomeric forms may be present
in any of A or R.sub.1 group, and this invention embraces all
possible stereoisomers and geometric forms in these groups.
[0672] The compounds of this invention are useful for treatment of
microbial infections in humans and other warm blooded animals,
under both parenteral and oral administration.
[0673] The pharmaceutical compositions of this invention may be
prepared by combining the compounds of this invention with a solid
or liquid pharmaceutically acceptable carrier and, optionally, with
pharmaceutically acceptable adjuvants and excipients employing
standard and conventional techniques. Solid form compositions
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, 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 agents, stabilizers and thickening agents.
[0674] 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.
[0675] The quantity of active component, that is the compound
according to this 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.
[0676] In therapeutic use for treating, or combatting, bacterial
infections in warm-blooded animals, the compounds or pharmaceutical
compositions thereof will be administered orally, parenterally
and/or topically at a dosage to obtain and maintain 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 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 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.
[0677] When the compounds according to this invention are
administered parenterally, i.e., by injection, for example, by
intravenous injection or by other parenteral routes of
administration. Pharmaceutical compositions for parenteral
administration will generally contain a pharmaceutically acceptable
amount of the compound or a soluble salt (acid addition salt or
base salt) dissolved in a pharmaceutically acceptable liquid
carrier such as, for example, water-for-injection and a buffer to
provide a suitably buffered isotonic solution, for example, having
a 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 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.
[0678] As a topical treatment an effective amount of Formula I is
admixed in a 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.
[0679] MIC Test Method
[0680] The in vitro MICs of test compounds were determined by a
standard agar dilution method. A stock drug solution of each analog
is prepared in the preferred solvent, usually DMSO:H.sub.2O (1:3).
Serial 2-fold dilutions of each sample are made 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.times.100 mm petri
dishes, and allowed to solidify and dry prior to inoculation.
[0681] 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.degree. 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 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
10.sup.4 to 10.sup.5 cells per spot. The plates are incubated
overnight at 35.degree. C.
[0682] Following incubation the Minimum Inhibitory Concentration
(MIC .mu.g/ml), the lowest concentration of drug that inhibits
visible growth of the organism, is read and recorded. The data is
shown in Tables I and II.
1TABLE 1 Oxazolidinone MIC Values (Gram+) SAUR SEPI EFAE SPNE SPYO
Structure 9213 12084 9217 9912 152 Comparison* 26 16 4 8 .5 1
Example 3 27 4 1 2 .25 .5 Comparison* 28 2 1 2 .5 1 Example 1 29 1
.25 .5 .13 .13 Example 5 30 1 .25 .5 <.125 .25 Example 6 31 2 1
2 .5 1 Comparison* 32 .5 .25 1 .13 .25 Example 2 33 8 2 4 2 4 SAUR:
S. aureus SEPI: S. epidermidis EFAE: E. faecalis SPNE: S.
pneumoniae SPYO: S. pyogenes *not a compound of the subject
invention
[0683]
2TABLE II SAUR SEPI EFAB SPNE SPYO HINF MCAT EFAE Example No. 9213
MIC 30593 MIC 12712 MIC 9912 MIC 152 MIC 30063 MIC 30610 MIC 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 1 1 0.25 0.5 16 4 2 5 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 0.5 9 0.5 0.25 0.25 <0.125 <0.125 2
0.5 0.25 10 2 1 0.5 <0.125 0.25 2 1 1 11 0.25 0.25 0.25
<0.125 0.25 2 1 0.25 12 1 0.5 0.25 <0.125 <0.125 1 0.5 0.5
13 1 1 2 0.5 1 >16 8 2 14 1 0.5 1 0.25 0.5 8 1 1 15 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 <0.125 0.25
4 2 0.5 25 0.5 0.25 0.5 <0.125 <0.125 2 2 0.5 26 1 0.5 1 0.25
0.5 16 2 1 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 0.25 0.25 0.25 <0.125 <0.125 2 0.5 0.25 30 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 1 0.25 0.25 4 2 4 34 2 1 2 0.5 1 >16 4 2
35 1 0.5 1 0.25 0.5 16 2 1 Key: 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 catarrhalis EFAE 9217: Enterococcus faccalis
[0684] 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.
[0685] 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
1,1'-thiocarbonyldi-2(1H)-pyridone in solvents such as methylene
chloride at 0 to 25.degree. C. The thioureas (Ia, R'=H,
alkyl.sub.1-4) can then be prepared as shown in Step 2 by the
reaction of III with ammonia or the appropriate primary amines in
solvents such as 1,4-dioxane or tetrahydrofuran at 0-50.degree. C.
Alternatively, as illustrated in Example 6 and shown in Step 3, the
thioureas can be prepared by allowing II to react with an
appropriate isothiocyanate (R'--N.dbd.C.dbd.S) in solvents such as
tetrahydrofuran at 0-50.degree. C. Thioamides (Ib, R"=H,
alkyl.sub.1-4) are prepared by allowing II to react with an
appropriate dithioester (R'" S--C(.dbd.S)--R", Step 4 as
illustrated in Example 4. This reaction is carried out in
aqueous-alcoholic solvents at 0-50.degree. C. in the presence of an
equivalent of an alkali metal hydroxide. This reaction, especially
when R'" is methyl or ethyl, can be catalyzed by an alkali metal
fluoride.
[0686] The reaction of II with R'"--S--C(S)--R'" (R'"=CH.sub.3,
C.sub.2H.sub.5) to give Ib (Step 4) can also be carried out in the
presence of a tertiary amine base such as triethylamine in solvents
such as THF, dioxane or methylene chloride at 10-50.degree. C. for
3-48 hr.
[0687] When the reaction conditions are tolerated by the
substituents on R (see, for example, Examples 1-3) the thioamides
(Ib, R"--H, alkyl.sub.1-4) can also be conveniently prepared (Step
5) by allowing the appropriate amide intermediates (IV) to react
with reagents such as
2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide
(Lawesson's Reagent) in 1,4-dioxane, benzene, toluene or
tetrahydrofuran at 60-110.degree. C.; phosphorus decasulfide and
sodium carbonate in tetrahydrofuran at 20-50.degree. C. [Brillon,
D., Synthetic Communications, 20, 3085 (1990)] or phosphorus
decasulfide and sodium fluoride in 1,2-dimethoxyethane at
20-50.degree. C. [Hartke, K., Gerber, H.-D., J. Prakt. Chem., 338,
763 (1996)].
[0688] 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.degree. C. for 5-24 hours. The
resulting intermediate is treated with an alkylating agent (R"" X
where X represents bromo, iodo, alkylsulfonyloxy or
arylsulfonyloxy) at 0-30.degree. 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. 34
[0689] 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]t-
hioacetamide (I)
[0690] 35
[0691] A stirred mixture of II (PCT/US94/08904, 3.37 g, 10.0 mmol)
in dry dioxane (100 mL), under nitrogen was treated with Lawesson's
Reagent (4.04 g, 10.0 mml), 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.sub.3. It was kept at ambient temperature for
18 h and concentrated in vacuo. Chromatography of the residue on
silica gel with 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.degree. C.; HRMS theory
for C.sub.16H.sub.20FN.sub.3O.sub.3S (M.sup.+): 353.1209; found:
353.1212. Anal. calcd for C.sub.16H.sub.20FN.sub.3O.sub.3S: C,
54.38; H, 5.38; N, 11.89; S, 9.07. Found: C, 54.21; H, 5.58; N,
11.78; S, 8.93.
EXAMPLE 2
(S)-N-[[3-[3-Fluoro-4-[4-(5-methyl-1,3,4-thiadiazol-2-yl)-1-piperazinyl]ph-
enyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (2)
[0692] 36
[0693] 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.degree. C.; HRMS theory for
C.sub.19H.sub.24FN.sub.6O.sub.2S.sub.2 (M+H.sup.+): 451.1386; found
451.1381.
EXAMPLE 3
(S)-N-[[3-[3-Fluoro-4-[2',5'-dioxospiro[piperidine-4,4'-imidazolidine]-1-y-
l]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (3)
[0694] Step A:
(S)-N-[[3-[3Fluoro-4-[2',5'-dioxospiro[piperidine-4,4'-imid-
azolidine]-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (32)
37
[0695] A stirred suspension of 31 (WO95/25106, 0.349 g, 1.00 mmol)
in 1:1 EtOH:H.sub.2O (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 65-60.degree. C. for 5 h 15 min and
kept at ambient temperature for 17 h 15 min. It was then
chromatographed on silica gel with mixtures of
MeOH--NH.sub.4OH--CHCl.sub.3 containing 5-20% MeOH and 0.5%
NH.sub.4OH to give 0.280 g of 32: HRMS calcd for
C.sub.19H.sub.22FN.sub.5O.sub.5: 419.1605 (M.sup.+); found
419.1613; Anal. calcd for C.sub.19H.sub.22FN.sub.5O.sub.5.1
H.sub.2O: C, 52.17; H. 5.53; N. 16.01. Found: C, 52.44; H, 5.30; N,
16.11.
[0696] Step B:
(S)-N-[[3-[3-Fluoro-[2',5'-doxospiro[piperidine-4,4'-imidaz-
olidine]-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (3)
38
[0697] 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--NH.sub.4OH--CHCl.sub- .3 containing 1-10% MeOH and 0.1-0.5%
NH.sub.4OH and the resulting product was crystallized from
MeOH--CHCl.sub.3EtOAc to give 0.0491 g of 3: mp 218.5.degree. C.;
HR FAB MS theory for C.sub.19H.sub.22FN.sub.5O.sub.4S (M.sup.+):
435.1376; found 435.1370. Anal. calcd for
C.sub.19H.sub.22FN.sub.5O.sub.4S.0.5 H.sub.2O: 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]t-
hioacetamide (4)
[0698] 39
[0699] 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 .mu.L, 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 .mu.L) was added after 1 h 55 min and additional 0.97 M KOH (40
mL) and sodium fluoride (6 mg) were added to the mixture after 3h 5
min. The reaction was followed by TLC on silica gel with 10%
MeOH--CHCl.sub.3 and 30% acetone-CH.sub.2Cl.sub.2. The major
product had an R.sub.f on TLC that was the same as that of 4.
EXAMPLE 5
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]t-
hiourea (5)
[0700] 40
[0701] A solution of 51 (PCT/US94/08904, 2.07 g, 7.00 mmol) in
CH.sub.2Cl.sub.2 was added, dropwise during 30 min, under nitrogen
to an ice cold, stirred solution of
1,1'-thiocarbonyldi-2(1H)-pyridone (1.95 g, 8.40 mmol) in
CH.sub.2Cl.sub.2 (70 mL). The mixture was warmed slowly to ambient
temperature and kept for 18 h. It was then diluted with
CH.sub.2Cl.sub.2, washed with water and aqueous NaCl, dried
(Na.sub.2SO.sub.4) and concentrated. Chromatography of the residue
on silica gel with 10% acetonitrile-CH.sub.2Cl.sub.2 gave 1.60 g of
the isothiocyanate: HRMS theory for
C.sub.15H.sub.16FN.sub.3O.sub.3S (M.sup.+): 337.0896; found
337.0888. 41
[0702] 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.degree. C.; MS m/z
354 (M.sup.+). Anal. calcd for C.sub.15H.sub.19FN.sub.4O.sub.3S: 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-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]--
N'-methylthiourea (6)
[0703] 42
[0704] 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 concentrated in vacuo. The residue
was recrystallized from EtOAc-hexane to give 246 mg of 6: mp
158-160.degree. C.; MS m/z 368 (M.sup.+). Anal. calcd for
C.sub.16H.sub.21FN.sub.4O.sub.3S: C, 52.16; H, 5.74; N, 15.21.
Found: C, 52.20; H, 5.85; N, 15.17.
EXAMPLE 7
(S)-cis-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2--
oxo-5-oxazolidinyl]methyl]ethanethioamide
[0705] 43
[0706] Step 1: A mixture of
(S)-(-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thio-
pyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide S-oxide
(4.50 g, can be obtained 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 a gradient of
methanol/methylene chloride (3/97-7/93). Pooling and concentration
of those fractions with an R.sub.f=0.44 by TLC
(methanol/chloroform, 10/90) gives
(S)-cis-(-)-N-[[3-[3-Fluoro-4-(tetrahy-
dro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamid-
e, mp 203-204.degree. C.
[0707] 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.degree.
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, 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.times.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 chloride (6/94-10/90). Pooling and concentration
of those fractions with an R.sub.f=0.14 by TLC
(methanol/chloroform, 10/90) gives
(S)-cis-3-[3-fluoro-4-(tetrahydro-1-ox-
ido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, mp
159-161.degree. C.
[0708] Step 3: A solution of ethyl dithioacetate (105 mL, 0.919
mmol) and sodium fluoride (39 mg, 0.919 mmol) in ethanol (9.2 mL)
under a nitrogen atmosphere was treated with a mixture of
(S)-cis-3-[3-fluoro-4-(tetrahydr-
o-1-oxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone,
as prepared in Step 2,(300 mg, 0.919 mmol) and aqueous potassium
hydroxide (1M, 0.92 mL) in ethanol (46 mL). The resulting solution
was stirred at ambient temperature for 4 hours and was then diluted
with methylene chloride (150 mL) and washed with water (50 mL),
aqueous potassium hydrogen sulfate (1M, 50 mL) and brine (25 mL).
The organic phase was dried over anhydrous sodium sulfate and
concentrated in vacuo, and the crude product was triturated with
methylene chloride/diethyl ether and filtered to give the title
compound, mp 176-177.degree. C. (dec.).
EXAMPLE 8
(S)-cis-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]thiourea
[0709] 44
[0710] Step 1: A solution of 1,1'-thiocarbonyldi-2(1H)-pyridone
(235 mg, 1.01 mmol) in anhydrous methylene chloride (10 mL) at
0.degree. C. under a nitrogen atmosphere was treated with a
solution of
(S-cis-3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-5-amin-
omethyl-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.degree. C. for 30
minutes and at ambient 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 R.sub.f=0.07 by TLC
(acetonitrile/methylene chloride, 30/70) were pooled and
concentrated to give
(S)-cis-3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thi-
opyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone, mp
187-190.degree. C. (dec.).
[0711] Step 2: A solution of
(S)-cis-3-[3-fluoro-4-(tetrahydro-1-oxido-2H--
thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone (Step
1, 290 mg, 0.787 mmol) in anhydrous tetrahydrofuran (39 mL) at
0.degree. 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.degree. 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 methanol/methylene chloride/diethyl
ether gave the title compound, mp 206-208.degree. C. (dec.).
EXAMPLE 9
(S)-trans-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]--
2-oxo-5-oxazolidinyl]methyl]ethanethioamide
[0712] 45
[0713] Step 1:
(S)-(-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thiopyran-4-yl)ph-
enyl]-2-oxo-5ox azolidinyl]methyl]acetamide S-oxide (disclosed in
International Publication No. 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 NaIO.sub.4 or meta-chloroperoxybenzoic acid
in solvent to provide the cis and trans-sulfoxides. Alternatively,
the sulfide byproduct acn be oxidized selectively to the trans
isomer using t-butyl hydroperoxide and a catalyst such as Ti(OiPr)4
and D-diisopropyl tartrate in a suitable solvent. The isomeric
mixture can then be separated by chromatography to isolate the
trans-sulfoxide, mp 211-212.degree. C. (dec.). A mixture of the
trans-sulfoxide,
(S)-trans-(-)-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido--
2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
(0.90 g) and hydroxylamine hydrochloride (0.85 g) in pyridine (11.0
mL) and ethanol (1.2 mL) is stirred in a screw-cap vial at
100.degree. 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 extracted with
methanol/methylene chloride (10/90, 6.times.100 mL). The combined
organic phase is concentrated under reduced pressure, and the crude
product is 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 R.sub.f=0.14 by TLC (methanol/chloroform, 10/90) gives
(S)-trans-3-[3-fluoro-4-(tetrahydro-1--
oxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, mp
138-140.degree. C.
[0714] 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-(tetrahy-
dro-1-oxido-2H-thiopyran-4-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.times.50 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, 35 g), eluting with
methanol/methylene chloride (3/97), and those fractions with an
R.sub.f=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.degree. C. (dec.).
EXAMPLE 10
(S)-trans-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2--
oxo-5-oxazolidinyl]methyl]thiourea
[0715] 46
[0716] Step 1: A solution of 1,1'-thiocarbonyldi-2(1H)-pyridone
(192 mg, 0.827 mmol) in anhydrous methylene chloride (8.3 mL) at
0.degree. C. under a nitrogen atmosphere was treated with a
solution of
(S)-trans-3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-5-a-
minomethyl-2-oxazolidinone, as prepared in Example 9, Step 1, (225
mg, 0.689 mmol) in anhydrous methylene chloride (28 mL) over 30
minutes. The resulting mixture was stirred at 0.degree. 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 N.sub.2,
and those fractions with an R.sub.f=0.12 by TLC
(acetonitrile/methylene chloride, 30/70) were pooled and
concentrated to give
(S)-trans-3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-5-i-
sothiocyanatomethyl-2-oxazolidinone, mp 165-167.degree. C.
[0717] Step 2: A solution of
(S)-trans-3-[3-fluoro-4-(tetrahydro-1-oxido-2-
H-thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone
(Step 1, 230 mg, 0.624 mmol) in anhydrous tetrahydrofuran (31.2 mL)
at 0.degree. 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.degree. C. for 1
hour. The excess ammonia was then removed under a stream of
nitrogen, and the reaction mixture was concentrated in vacuo to
give the crude product. Trituration with methanol/methylene
chloride/diethyl ether gave the title compound, mp 209-210.degree.
C. (dec.).
EXAMPLE 11
(S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-2--
oxo-5-oxazolidinyl]methyl]ethanethioamide
[0718] 47
[0719] Step 1: Starting with
(S)-cis-(-)-N-[[3-[3-Fluoro-4-(tetrahydro-1-o-
xido-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)phenyl]-2-oxo-5-o-
xazolidinyl]methyl]acetamide S,S-dioxide (disclosed in
International Publication No. WO 97/09328) for
(S)-cis-(-)-N-[[3-[3-fluoro-4-(tetrahydr-
o-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide,
the product
(S)-(-)-3-[3-Fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4--
yl)phenyl]-5-aminomethyl-2-oxazolidinone is obtained, mp
194.degree. C. (dec.).
[0720] 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-(tetrahydr-
o-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone,
as prepared in Step 1, (300 mg, 0.876 mmol) and aqueous potassium
hydroxide (1M, 0.88 mL) in ethanol (43.8 mL). The resulting mixture
was stirred at 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 (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.degree. C. (dec.).
EXAMPLE 12
(S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-2--
oxo-5-oxazolidinyl]methyl]thiourea
[0721] 48
[0722] Step 1: A solution of 1,1'-thiocarbonyldi-2(1H)-pyridone
(304 mg, 1.31 mmol) in anhydrous methylene chloride (13 mL) at
0.degree. C. under a nitrogen atmosphere was treated with a
solution of
(S)-(-)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-5-
-aminomethyl-2-oxazolidinone, as prepared in Example 11, Step 1,
(375 mg, 1.09 mmol) in anhydrous methylene chloride (88 mL) over 30
minutes. The resulting mixture was stirred at 0.degree. 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 fractions
with an R.sub.f=0.64 by TLC (acetonitrile/methylene chloride,
20/80) were pooled and concentrated to give
(S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thi-
opyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone, mp
158-162.degree. C. (dec.).
[0723] Step 2: A solution of
(S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H--
thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone (Step
1, 380 mg, 0.988 mmol) in anhydrous tetrahydrofuran (49 mL) at
0.degree. 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.degree. 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 methanol/methylene chloride/diethyl
ether gave the title compound, mp 196-198.degree. C. (dec.).
EXAMPLE 13
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]--
thioformamide (7)
[0724] 49
[0725] 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.degree. C. for 2 h, cooled to ambient temperature
and treated, portionwise during 2 min, with 39.sup.8 (0.45 g,
0.0015 mol). The suspension was kept at ambient temperature for 4 h
and the resulting solution was treated with Et.sub.2O (1 mL) and
kept at ambient temperature for 18 h. The mixture was diluted with
additional Et.sub.2O (10 mL) and the solid was collected by
filtration, washed with Et.sub.2O and dried to give 0.38 g of
6.sup.9: MS (ES) m/z 324 (M+H.sup.+), 346 (M+Na.sup.+); .sup.1H NMR
(300 mHz, CDCl.sub.3) d 3.08 (m, 4H), 3.72 (m, 2H), 3.77 (d,d, 1H),
3.89 (m, 4H), 4.04 (t, 1H), 4.80 (m, 1H), 6.33 (s, 1H), 7.05 (m,
2H), 7.45 (d,d, 1H), 8.27 (s, 1H). 50
[0726] 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 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--CH.sub.2Cl.sub.2
and the slightly impure product was rechromatographed on silica gel
with 25% EtOAc-CH.sub.2Cl.sub.2. The resulting product was
crystallized from EtOAc-methyl tert-butyl ether to give 0.114 g of
7: mp 150-155.degree. C. (dec); IR (DRIFT) 3322, 1752 cm.sup.-1;
MS(ES) m/z 340 (M+H.sup.+), 362 (M+Na.sup.+); .sup.1HNMR [300 MHz,
(CD.sub.3).sub.2SO] d 2.94 (m, 4H), 3.72 (m, 4H), 3.77 (d,d, 1H),
3.94 (t, 2H), 4.12 (t, 1H), 4.93 (m, 1H), 7.05 (t, 1H), 7.16 (d,d,
1H), 7.47 (d,d, 1H), 9.33 (d, 1H), 10.59 (s, 1H). Anal. calcd for
C.sub.15H.sub.18FN.sub.3O.sub.3S: 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]t-
hiopropion-amide (9)
[0727] 51
[0728] An ice cold, stirred solution of 39 (0.395 g, 0.00134 mol)
and triethyl amine (0.186 mL, 0.0027 mol) in CH.sub.2Cl.sub.2 (20
mL), under nitrogen was treated, dropwise during 2 min, with a
solution of propionyl chloride (0.128 mL, 0.00147 mol) in
CH.sub.2Cl.sub.2 (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.sub.2Cl.sub.2, washed with saturated NaHCO.sub.3, water and
brine, dried (MgSO.sub.4) and concentrated. The residue (8) was
used without further purification in the next reaction. 52
[0729] 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--CHCl.sub.3 and the
product was crystallized from methyl tert-butyl ether to give 0.259
g of 9: mp 138-139.degree. C.; MS(ES) m/z 368 (M+H.sup.+), 390
(M+Na.sup.+); IR (DRIFT) 3284, 3266, 1748, 1744 cm.sup.-1;
[.alpha.].sup.24.sub.D +20.degree. (MeOH); 1H NMR[300 MHz,
(CD.sub.3).sub.2SO] d 1.12 (t, 3H), 2.56 (q, 2H), 2.94 (m, 4H),
3.72 (m, 4H), 3.78 (d,d, 1H), 3.90 (t, 2H), 4.11 (t, 1H), 4.93 (m,
1H), 7.05 (t, 1H), 7.16 (d,d, 1H), 7.47 (d,d, 1H), 10.30 (broad s,
1H). Anal. calcd for C.sub.17H.sub.22FN.sub.3O.sub.3S: 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-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]--
2-chlorothioacetamide (11)
[0730] 53
[0731] A stirred solution of 39 (1.54 g, 5.2 mmol) and
triethylamine (750 mg, 7.5 mmol) in CH.sub.2Cl.sub.2 (50 mL), under
nitrogen, was treated, dropwise, during 15 min with a solution of
chloroacetyl chloride (465 mL, 5.8 mmol) in CH.sub.2Cl.sub.2 (30
mL) and kept at ambient temperature for 18 h. It was then washed
with saturated NaHCO.sub.3 and dilute NaCl, dried
(Na.sub.2SO.sub.4) and concentrated. The residue was flash
chromatographed on silica gel with 20-30% acetone-CH.sub.2Cl.sub.2
to give 1.49 g of 10.sup.9 which was used in the next reaction
without further purification. 54
[0732] 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%
acetone-CH.sub.2Cl.sub.2 to give 0.143 g of 11: MS (CI) m/z 388
(M+H.sup.+); .sup.1H NMR (300 MHz, CDCl.sub.3) d 3.07 (m, 4H), 3.77
(d,d, 1H), 3.88 (m, 4H), 4.04 (m, 1H), 4.12 (t, 1H), 4.35 (m, 1H),
4.61 (s, 2H), 4.98 (m, 1H), 6.96 (t, 1H), 7.08 (d,d, 1H), 7.44
(d,d, 1H), 8.69 (s, 1H). Anal. calcd for
C.sub.16H.sub.19ClFN.sub.3O.sub.3S: 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-moropholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
-.alpha.,.alpha.,.alpha.-trifluorothioacetamide (13)
[0733] 55
[0734] An ice cold stirred solution of 39 (0.590 g, 2.0 mmol) and
triethylamine (640 mL, 4.6 mmol) in CH.sub.2Cl.sub.2 (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-CH.sub.2Cl.sub.2. Additional trifluoroacetic anhydride and
triethylamine were added after 3 d (64 mL/125 mL), 4 d (100 mL/220
mL) and 6 d (325 mL/1.0 mL). The reaction was complete 1 h after
the last addition; it was mixed with CH.sub.2Cl.sub.2, washed with
water and dilute NaCl, dried (Na.sub.2SO.sub.4) and concentrated.
The solid residue was recrystallized from acetone-heptane to give
0.566 g of 12: mp 161-164.degree. C. (dec); MS(EI) m/z 391
(M.sup.+). Anal. calcd for C.sub.16H.sub.17F.sub.4N.sub.3O- .sub.4:
C, 49.11; H, 4.38; N, 10.74. Found: C, 48.99; H, 4.56; N, 10.73.
56
[0735] 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 chromatographed on
silica gel with 5-15% acetone-CH.sub.2Cl.sub.2 and the product was
crystallized from acetone-heptane to give 0.249 g of 13: mp
151-152.degree. C.; MS(EI) m/z 407 (M.sup.+), 363, 209, 151, 95;
.sup.1H NMR (300 MHz, CDCl.sub.3) d 3.05 (m, 4H), 3.75 (d,d, 1H),
3.87 (m, 4H), 3.95 (m, 1H), 4.14 (t, 1H), 4.32 (m, 1H), 5.01 (m,
1H), 6.92 (t, 1H), 7.05 (d,d, 1H), 7.38 (d,d, 1H), 9.03 (s, 1H).
Anal. calcd for C.sub.16H.sub.17F.sub.4N.sub.3O.sub.3S: C, 47.17;
H, 4.21; N, 10.31. Found: C, 47.09; H, 4.35; N, 10.27.
EXAMPLE 17
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]--
.alpha.-fluorothioacetamide (15)
[0736] 57
[0737] A stirred, ice cold solution of 39 (0.590 g, 2.0 mmol) and
triethylamine (611 mL, 4.4 mmol) in CH.sub.2Cl.sub.2 (10 mL), under
nitrogen, was treated, dropwise, with a solution of fluoroacetyl
chloride (220 mL, 2.2 mmol) in CH.sub.2Cl.sub.2 (5 mL), kept in the
ice bath for 10 min and at ambient temperature for 2 h. It was then
diluted with CH.sub.2Cl.sub.2, washed with water and dilute NaCl,
dried (Na.sub.2SO.sub.4) and concentrated. The residue was
chromatographed on silica gel with 10-30% acetone-CH.sub.2Cl.sub.2
to give 0.180 g of 14: MS(ES) m/z 356 (M+H.sup.+), 378
(M+Na.sup.+). 58
[0738] 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.degree. C. for 1 h and concentrated in vacuo. The
residue was chromatographed on silica gel with 15%
acetone-CH.sub.2Cl.sub.2 to give 0.161 g of 15: MS(EI) m/z 371
(M.sup.+); .sup.1H NMR (300 MHz, CDCl.sub.3) d 3.05 (m, 4H), 3.78
(d,d, 1H), 3.87 (m, 4H), 4.03 (m, 1H), 4.11 (t, 1H), 4.38 (m, 1H),
4.98 (m, 1H), 5.07 (s, 1H), 5.23 (s, 1H), 6.93 (t, 1H), 7.08 (dd,
1H), 7.42 (d,d, 1H), 8.42 (s, 1H). Anal. calcd for
C.sub.16H.sub.19F.sub.2N.sub.3O.sub.3S: C, 51.74; H, 5.16; N,
11.31. Found: C, 51.79; H, 5.31; N, 11.02.
EXAMPLE 18
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]--
.alpha.,.alpha.-difluorothioacetamide (17)
[0739] 59
[0740] 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 nitrogen, was treated with
1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.843
g, 4.4 mmol) and kept at ambient temperature for 18 h. It was
diluted with CH.sub.2Cl.sub.2, washed with water and dilute NaCl,
dried (Na.sub.2SO.sub.4) and concentrated. The solid residue was
crystallized form EtOAc-heptane to give 0.617 g of 16: mp
149-150.degree. C.; 1H NMR (300 MHz, CDCl.sub.3) d 3.05 (m, 4H),
3.66 (m, 2H), 3.85 (m, 5H), 4.08 (t, 1H), 4.80 (m, 1H), 5.93 (t,
J=53.9 Hz, 1H), 6.92 (t, 1H), 7.06 (m, 2H), 7.39 (d,d, 1H); MS(EI)
m/z 373 (M.sup.+). Anal. calcd for
C.sub.16H.sub.18F.sub.3N.sub.3O.sub.4: C, 51.48; H, 4.86; N, 11.26.
Found: C, 51.59; H, 4.91; N, 11.29. 60
[0741] 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.degree. C. for 1 h and concentrated
in vacuo. Chromatography of the residue on silica gel with 10%
acetone-CH.sub.2Cl.sub.2 and cyrstallization of the product from
EtOAc-heptane gave 0.276 g of 17: mp 125-127.degree. C.; MS(EI) m/z
389 (M.sup.+), 345, 305, 247, 209, 195, 151, 138, 123, 109, 95;
.sup.1H NMR (300 MHz, CDCl.sub.3) d 3.05 (m, 4H), 3.76 (d,d, 1H),
3.86 (m, 4H), 4.01 (m, 1H), 4.12 (t, 1H), 4.30 (m, 1H), 4.99 (m,
1H), 6.20 (t, J=55.9 Hz, 1H), 6.92 (t, 1H), 7.06 (d,d, 1H), 7.38
(d,d, 1H), 8.78 (broad s, 1H). Anal. calcd for
C.sub.16H.sub.18F.sub.3N.sub.3O.sub.3S: C, 49.35; H, 4.66; N,
10.79. Found: C, 49.37; H, 4.71; N, 10.83.
EXAMPLE 19
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]--
.alpha.-cyanothioacetamide (19)
[0742] 61
[0743] 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 nitrogen, was treated with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.997
g, 5.2 mmol) and kept at ambient temperature for 24 h. It was
diluted with CH.sub.2Cl.sub.2, washed with water and dilute NaCl,
dried (Na.sub.2SO.sub.4) and concentrated. The solid residue was
crystallized from EtOAc-heptane to give 0.546 g of 18: mp
172-174.degree. C.: IR (DRIFT) 3316, 2256, 1754, 1684 cm.sup.-1;
MS(EI) m/z 362 (M.sup.+). Anal. calcd for
C.sub.17H.sub.19FN.sub.4O.sub.4: C, 56.35; H, 5.28; N, 15.46.
Found: C, 56.33; H, 5.30; N, 15.36. 62
[0744] A stirred solution of 18 (0.453 mg, 1.25 mmol) in dioxane
(10 mL), under nitrogen, was treated with Lawesson's reagent (0.505
g, 1.25 mmol) and warmed at about 100.degree. C. When the reaction
was over (TLC with 30% acetone-CH.sub.2Cl.sub.2) the mixture was
cooled and concentrated in vacuo. Chromatography of the residue on
silica gel with 10-20% acetone-CH.sub.2Cl.sub.2 and crystallization
of the product from EtOAc-heptane gave 0.110 g of 19: mp
186-187.degree. C. (dec); MS(ES) m/z 379 (M+H.sup.+), 401
(M+Na.sup.+); .sup.1H NMR (300 MHz, CDCl.sub.3) d 3.05 (m, 4H),
3.81 (d,d, 1H), 3.86 (m, 4H), 3.89 (s, 2H), 4.09 (t, 1H), 4.14 (m,
2H), 5.01 (m, 1H), 6.92 (t, 1H), 7.05 (d,d, 1H), 7.34 (d,d, 1H),
9.15 (s, 1H); IR (DRIFT) 3244, 2260, 1754 cm.sup.-1. Anal. calcd
for C.sub.17H.sub.19FN.sub.4O.sub.3S: 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-oxazolidinyl]methyl].-
alpha.,.alpha.-dichlorothioacetamide (21)
[0745] 63
[0746] A stirred, ice cold solution of 39 (0.885 g, 3.00 mmol) and
triethylamine (975 mL, 7 mmol) in CH.sub.2Cl.sub.2 (15 mL), under
nitrogen was treated, dropwise with a solution of dichloroacetic
anhydride (555 mL, 3.5 mmol) in CH.sub.2Cl.sub.2 (5 mL) and kept in
the ice bath for 15 min and at ambient temperature for 18 h. It was
diluted with CH.sub.2Cl.sub.2, washed with water, saturated
NaHCO.sub.3 and dilute NaCl, dried (Na.sub.2O.sub.4) and
concentrated. Chromatography of the residue on silica gel with 10%
acetone-CH.sub.2Cl.sub.2 and crystallization of the product from
acetone-heptane gave 0.463 g of 20: mp 197-198.degree. C. (dec);
MS(ES) m/z 406 (M+H.sup.+), 428 (M+Na.sup.+); .sup.1H NMR (300 MHz,
CDCl.sub.3) d 3.05 (m, 4H), 3.75 (m, 3H), 3.86 (m, 4H), 4.07 (t,
1H), 4.83 (m, 1H), 5.94 (s, 1H), 6.92 (t, 1H), 7.06 (m, 2H), 7.41
(d,d, 1H). 64
[0747] A stirred solution of 20 (0.306 g, 0.75 mmol) in dioxane (5
ml), under nitrogen, was treated with Lawesson's reagent (0.202 g,
0.5 mmol), warmed at about 90.degree. C. for 1 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 0.203 g with 21: mp 143-144.degree. cd.;
HR17S (EI) calculated for C.sub.16H.sub.18cl.sub.2 F N.sub.3
O.sub.3 S(M) 421.0431. Anal. calcd for C.sub.16H.sub.18cl.sub.2 F
N.sub.3 O.sub.3 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)phenyl]-2-oxo-5-oxazolidinyl]methyl]--
.alpha.-(methoxycarbonyl)thioacetamide (23)
[0748] 65
[0749] A stirred solution of 39 (0.955 g, 3.2 mmol) and
triethylamine (650 mL, 4.5 mmol) in CH.sub.2Cl.sub.2 (50 mL), under
nitrogen, was treated, dropwise during 15-20 min with a solution of
methyl malonyl chloride (475 mL, 4.3 mmol) in CH.sub.2Cl.sub.2 (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-CH.sub.2Cl.sub.2 and the product was crystallized form
acetone-hexane to give 0.873 g of 22: mp 150-151.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) d 3.03 (m, 4H), 3.34 (s, 2H),
3.67 (s, 3H), 3.69 (m, 2H), 3.76 (d,d, 1H), 3.85 (m, 4H), 4.00 (t,
1H), 4.78 (m, 1H), 6.90 (t, 1H), 7.06 (d,d, 1H), 7.41 (d,d, 1H),
7.57 (t, 1H); MS(ES) m/z 396 (M+H.sup.+), 418 (M+Na.sup.+); HRMS
(FAB) calcd for C.sub.18H, FN.sub.3O.sub.6 (M+H.sup.+) 396.1571,
found 396.1579. Anal. calcd for C.sub.18H.sub.22FN.sub.3O.sub.6: C,
54.68; H, 5.61; N, 10.63. Found: C, 54.69; H, 5.68; N, 10.58.
66
[0750] 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 temperature for 4 h 10 min and at
80-90.degree. C. for 1.5 h. The reaction was followed by TLC on
silica gel with 10% MeOH--CHCl.sub.3. At this time a new, less
polar product had begun to form. It was kept at ambient temperature
for 18 h and at 80.degree. C. for 2 h; additional Laewsson's
reagent (40 mg, 0.099 mmol) was added and warming at 80.degree. 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.sub.2Cl.sub.2 to give 0.348 g of 23:
.sup.1H NMR (300 MHz, CDCl.sub.3) d 3.05 (m, 4H), 3.71 (s, 3H),
3.81 (d,d, 1H), 3.86 (m, 4H), 3.88 (s, 2H), 4.07 (t, 1H), 4.19 (m,
2H), 4.99 (m, 1H), 6.91 (t, 1H), 7.07 (d,d, 1H), 7.42 (d,d, 1H),
9.52 (s, 1H); IR (DRIFT) 3269, 1743 cm.sup.-1; MS(EI) m/z 411
(M.sup.+). Anal. calcd for C.sub.18H.sub.22FN.sub.3O.sub.5S: C,
52.54; H, 5.39; N, 10.21. Found: C, 52.58; H, 5.43; N, 10.14.
EXAMPLE 22
(S)-N-[[3-[4-[1-[1,2,4]Triazolyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioa-
cetamide (25)
[0751] 67
[0752] 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
chromatography of the residue on silica gel with 5%
MeOH--CHCl.sub.3 gave the product which was crystallized from MeOH
to give 0.100 g (63.4%) of 25: mp 161-163.degree. C.; .sup.1H NMR
[300 MHz, (CD.sub.3).sub.2SO] d 2.43 (s, 3H), 3.87 (m, 3H), 4.22
(t, 1H), 4.99 (m, 1H), 7.51 (d, 1H), 7.77 (m, 2H), 8.26 (s, 1H),
8.97 (d, 1H), 10.35 (broad s, 1H); IR (mull) 3259, 3226, 3044, 1752
cm.sup.-1; MS(ES) m/z 336 (M+H.sup.+), 358 (M+Na.sup.+). Anal.
calcd for C.sub.14H.sub.14FN.sub.5O.sub.2S: C, 50.14; H, 4.21; N,
20.88. Found: C, 50.18; H, 4.26; N, 20.94.
EXAMPLE 23
(S)-N-[[3-[4-[1-[1,2,4]Triazolyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thioa-
cetamide (25)
[0753] 68
[0754] 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
CH.sub.2CL.sub.2 (75 mL), washed with water, 1M KHSO.sub.4, water
and brine and evaporated. The residue was flash chromatographed on
silica gel with 5% MeOH--CHCl.sub.3 and the product was
crystallized from MeOH to give 0.118 g, mp 164-165.degree. C. (dec)
and 0.026 g, mp 162-163.degree. C. (dec) of 25.
EXAMPLE 24
(S)-N-[[3-[1-(Hydroxyacetyl)-5-indolinyl]-2-oxo-5-oxazolidinyl]methyl]thio-
acetamide (28)
[0755] 69
[0756] A stirred, ice cold solution of 52 (8.80 g, 0.0240 mol) in
CH.sub.2Cl.sub.2 (25 mL) was treated during 20 min with a solution
of trifluoroacetic acid (25 mL) in CH.sub.2Cl.sub.2 (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
CH.sub.2Cl.sub.2 was washed with saturated NaHCO.sub.3 and dilute
NaCl, dried (Na.sub.2SO.sub.4) and concentrated. The residue was
used in the next reaction without further purification. A sample of
this material (53) had: .sup.1H NMR (300 MHz, CDCl.sub.3) d 3.00
(t, 2H), 3.54 (t, 2H), 3.85 (broad s, 1H), 5.17 (s, 2H), 6.59 (d,
1H), 6.66 (broad s, 1H), 6.91 (d, 1H), 7.23 (s, 1H), 7.36 (m, 5H);
MS m/z 269 (M+H.sup.+). 70
[0757] An ice cold, stirred mixture of 53 (crude product from the
previous reaction), acetone (200 mL), saturated NaHCO.sub.3 (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 (Na.sub.2SO.sub.4) and
concentrated to give 5.36 g of additional crude product.
Crystallization of the product from EtOAc gave a total of 6.35 g of
54.sup.14, mp 157-159.5.degree. C. The analytical sample had: mp
158-159.5.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
3,16 (t,2H), 4.01(t,2H), 4.21 (s, 2H), 4.69 (s, 2H), 5.19 (s, 2H),
6.67 (s, 1H), 6.97 (d, 1H), 7.36 (m, 10H), 7.50 (braod s, 1H), 8.15
(d, 1H); MS(EI) m/z (relative intensity) 416 (M.sup.+, 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.sup.-1. Anal. calcd
for C.sub.25H.sub.24N.sub.2- O.sub.4: C, 72.10; H, 5.81; N, 6.73.
Found: C, 72.05; H, 5.86; N, 6.68. 71
[0758] A stirred suspension of 54 (1.16 g, 2.78 mmol) in THF (42
mL) was cooled, under nitrogen, to 78.degree. C. and treated,
dropwise, during 5 min with 1.6 M n-BuLi in hexane (1.83 mL). It
was kept at 78.degree. C. for 50 min, treated, dropwise, during 5
min with a solution of (R)-(-)-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 with EtOAc, washed with
saturated NH.sub.4Cl, water and brine, dried (MgSO.sub.4) and
concentrated. Chromatography of the residue on silica gel with 3%
MeOH--0.2% NH.sub.4OH--CHCl.sub.3 gave 0.60 g (56%) of 55.sup.14:
.sup.1H NMR [300 MHz, (CD.sub.3).sub.2SO] .delta. 3.14 (t, 2H),
3.59 (m, 2H), 3.79 (d,d, 1H), 4.03 (m, 3H), 4.29 (s, 2H), 4.58 (s,
2H), 4.65 (m, 1H), 5.20 (t, 1H), 7.31 (m, 6H), 7.55 (s, 1H), 8.03
(d, 1H); MS(ES) m/z 383 (M+H.sup.+), 405 (M+Na.sup.+). 72
[0759] An ice cold, stirred mixture of 55 (0.60 g, 1.57 mmol),
triethylamine (2.2 mL), and CH.sub.2Cl.sub.2 (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 for 60 min. It was then diluted with CH.sub.2Cl.sub.2,
washed with water and brine, dried (Na.sub.2SO.sub.4) and
concentrated. Chromatography of the residue on silica gel with 15%
CH.sub.3CN--CH.sub.2Cl.sub.2 gave 0.70 g of 56: .sup.1H NMR (300
MHz, CDCl.sub.3) d 3.19 (t, J=8.3 Hz, 2H), 3.88 (d,d, 1H), 4.04 (t,
J=8.4 Hz, 2H), 4.14 (t, 1H), 4.23 (s, 2H), 4.42 (m, 2H), 4.70 (s,
2H), 4.84 (m, 1H), 6.97 (m, 1H), 7.34 (m, 5H), 7.58 (s, 1H), 7.81
(t, 1H), 8.22 (m, 2H), 8.53 (m, 1H), 8.73 (m, 1H); MS(ES) m/z 568
(M+H.sup.+), 590 (M+Na.sup.+). 73
[0760] 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.degree. C. for 7h and kept at
ambient temperature for 18 h. It was concentrated in vacuo to an
aqueous residue with was extracted with CH.sub.2Cl.sub.2. The
extract was washed with water and brine, dried (Na.sub.2SO.sub.4)
and concentrated. Chromatography of the residue on silica gel with
8% MeOH0.5% NH.sub.4OH--CHCl.sub.3 gave 1.05 g of 57: .sup.1H NMR
[300 MHz, (CD.sub.3).sub.2SO] d 2.78 (m, 2H), 3.13 (t, 2H), 3.82
(d,d, 1H), 4.01 (m, 3H), 4.29 (s, 2H), 4.58 (s, 2H), 4.58 (m, 1H),
7.31 (m, 6H), 7.54 (broad s, 1H), 8.03 (d, 1H); MS(ES) m/z 382
(M+H.sup.+), 404 (M+Na.sup.+). 74
[0761] A mixture of 57 (0.46 g, 1.21 mmol), MeOH (150 mL), 1 M HCl
(1.2 mL) and 5% palladium-on-carbon catalyst (250 mg) was
hydrogenated at an initial pressure of 49 psi for 5 h. Additional
1M HCl (0.5 mL) and catalyst (100 mg) were added and hydrogenation
was continued for 18 h. The catalyst was removed by filtration and
the filtrate was concentrated to give 0.34 g of 27: .sup.1H NMR
[300 MHz, (CD.sub.3).sub.2SO] .delta. 3.15 (t, 2H), 3.22 (broad s,
2H), 3.84 (d,d, 1H), 4.00 (t, 2H), 4.15 (s, 2H), 4.15 (m, 1H), 4.92
(m, 1H), 7.24 (q, 1H), 7.50 (d, 1H), 8.03 (d, 1H), 8.37 (broad s,
3H); MS(ES) m/z 2.92 (M+H.sup.+). 75
[0762] 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.sub.2Cl.sub.2 (150 mL), washed with water, 1M KHSO.sub.4 and
brine, dried (Na.sub.2SO.sub.4) and concentrated. The residue was
crystallized from acetone to give 0.0404 g of 28: mp
175-176.degree. C. (dec); MS (FAB) m/z 350 (M+H.sup.+), 349
(M.sup.+), 331, 316, 205, 73; HR MS (FAB) calcd for
C.sub.16H.sub.20N.sub.3O.sub.4S (M+H.sup.+) 350.1174, found
350.1183; .sup.1H NMR [300 MHz, (CD.sub.3).sub.2SO] d 2.42 (s, 3H),
3.14 (t, 2H), 3.79 (d,d, 1H), 3.89 (t, 2H), 4.00 (t, 2H), 4.12 (m,
3H), 4.83 (t, 1H), 4.90 (m, 1H), 7.25 (d, 1H), 7.50 (s, 1H), 8.03
(d, 1H), 10.35 (s, 1H); IR (DRIFT) 3255, 3223, 3068, 1747, 1639,
1614 cm.sup.-1.
[0763] EXAMPLE 25:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-
phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide (30) 76
[0764] 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: .sup.1H NMR (300 MHz,
CDCl.sub.3) d 2.16 (broad s), 3.02 (m, 8H), 3.73 (d,d, J=3.9, 12.6
Hz, 1H), 3.96 (m, 3H), 4.72 (m, 1H), 6.92 (t, J=9.2 Hz, 1H), 7.11
(m, 1H), 7.43 (d,d, J=2.6, 14.3 Hz, 1H); MS(ES) m/z 296
(M+H.sup.+). 77
[0765] A stirred, ice cold mixture of 59 (2.67 g from the previous
reaction), acetone (190 mL) and saturated NaHCO.sub.3 (70 mL) was
treated, dropwise during 2-3 min with a 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-CH.sub.2Cl.sub.2 gave 2.64 g
of 60: .sup.1H NMR (300 MHz, CDCl.sub.3) d 2.28 (broad s, 1H), 3.00
(m, 4H), 3.66 (m, 2H), 3.77 (m, 3H), 3.96 (m, 3H), 4.22 (s, 2H),
4.61 (s, 2H), 4.74 (m, 1H), 6.88 (t, J=9.2 Hz, 1H), 7.12 (m, 1H),
7.35 (s, 5H), 7.46 (d,d, J=2.6, 14.2 Hz, 1H); IR (mull) 3406, 1748,
1647 cm.sup.-1; HRMS(EI) calcd for C.sub.23H.sub.26FN.sub.3O.sub.5
(M.sup.+) 443.1856, found 443.1842. 78
[0766] A stirred, ice cold mixture of 60 (2.64 g, 6.00 mmol) and
triethylamine (1.14 mL, 8.16 mmol) in CH.sub.2Cl.sub.2 (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 temperature for 18 h, diluted with CH.sub.2Cl.sub.2 and
washed with water and dilute NaCl, dried (Na.sub.2SO.sub.4) and
concentrated. Chromatography of the residue on silica gel with
40-60% acetone-hexane gave 3.36 g of 77: .sup.1H NMR (300 MHz,
CDCl.sub.3) 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, 1H), 4.09 (t, J=9.2 Hz, 1H), 4.22
(s, 2H), 4.41 (m, 2H), 4.61 (s, 2H), 4.84 (m, 1H), 6.88 (t, J=9.1
Hz, 1H), 7.02 (m, 1H), 7.35 (m, 6H), 7.82 (t, J=8.0 Hz, 1H), 8.23
(m, 1H), 8.53 (m, 1H), 8.73 (m, 1H); MS(ES) m/z 629 (M+H.sup.+).
79
[0767] 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.degree. C., for 18 h, treated
with additional ammonium hydroxide (30 mL), warmed at 40-45.degree.
C. for 8 h, treated with additional ammonium hydroxide (25 mL) and
warmed at 45.degree. C. for 18 h. It was then mixed with water and
extracted with CH.sub.2Cl.sub.2. The extract was washed with dilute
NaCl, dried (Na.sub.2SO.sub.4) and concentrated. Chromatography of
the residue on silica gel with 5% MeOH-0.5% NH.sub.4OH--CHCl.sub.3
gave 2.44 g of 61: .sup.1H NMR (300 MHz, CDCl.sub.3) d 1.50 (broad
s), 3.04 (m, 6H), 3.65 (broad s, 2H), 3.81 (m, 3H), 3.99 (t, 1H),
4.21 (s, 2H), 4.61 (s, 2H), 4.66 (m, 1H), 6.88 (t, 1H), 7.12 (m,
1H), 7.33 (m, 5H), 7.47 (d,d, 1H); MS(ES) m/z 443 (M+H.sup.+).
80
[0768] A solution of 61 (1.45 g, 3.3 mmol) and 1.0 N HCl (3.65 mL)
in 95% EtOH (150 mL) was treated with 5% palladium-on-carbon
catalyst (500 mg) and hydrogenated at an initial pressure of 54 psi
for 20 h 15 min. Additional 1.0 N HCl (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 NH.sub.4OH, filtered and
concentrated in vacuo to give 1.18 g of 29: .sup.1H NMR [300 MHz,
(CD.sub.3).sub.2SO] d 2.94 (broad s, 4H), 3.19 (m, 2H), 3.48 (broad
s, 2H), 3.60 (broad s, 2H), 3.84 (m, 1H), 4.14 (m, 3H), 4.66 (broad
s, 1H), 4.93 (m, 1H), 7.07 (t, 1H), 7.16 (d,d, 1H), 7.48 (d,d, 1H),
8.04 (broad s); IR (mull) 3420, 3099, 3040, 3008, 1755, 1641
cm.sup.-1; MS(ES) m/z 353 (M+H.sup.+). Anal. calcd for
C.sub.16H.sub.22ClFN.sub.4O.sub.4: C, 49.42; H, 5.70; Cl, 9.12; N,
14.41. Found: C, 48.16; H, 5.82; Cl, 10.00; N, 14.28. 81
[0769] 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 CHCl.sub.3, washed with
water and dilute NaCl, dried (Na.sub.2SO.sub.4) and concentrated.
Chromatography of the residue on silica gel with 5% MeOH-0.5%
NH.sub.4OH--CHCl.sub.3 and crystallization of the resulting product
from absolute EtOH gave 0.238 mg (44.9%) 30: mp 163-165.degree. C.;
.sup.1H NMR (300 MHz, CDCl.sub.3) d 2.60 (s, 3H), 3.06 (m, 4H),
3.45 (m, 2H), 3.61 (m, 1H), 3.82 (m, 3H), 4.07 (m, 2H), 4.25 (m,
3H), 4.97 (m, 1H), 6.91 (t, 1H), 7.07 (m, 1H), 7.45 (d,d, 1H), 7.91
(broad s, 1H); MS(FAB) m/z (relative intensity) 411 (M+H+, 100),
410 (M.sup.+, 66.5), 266 (3.1); IR 3292, 1733, 1653 cm.sup.-1.
Anal. calcd for C.sub.18H.sub.23FN.sub.4O.sub.4S: C, 52.67; H,
5.65; N, 13.65. Found: C, 52.76; H, 5.58; N, 13.64.
EXAMPLE 26
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]thioacetamide (32)
[0770] 82
[0771] 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 CH.sub.2Cl.sub.2 was washed with
saturated NaHCO.sub.3, water and brine, dried (MgSO.sub.4) and
concentrated. Crystallization of the residue from EtOAc-hexane gave
0.355 g of 32: mp 155-156.degree. C.; MS(ES) m/z 370 (M+H.sup.+),
392 (M+Na.sup.+); IR (DRIFT) 3206, 3042, 1759, 1738 cm.sup.-1;
.sup.1H NMR (300 MHz, CDCl.sub.3) d 2.60 (s, 3H), 2.95 (s, 4H),
3.43 (m, 4H), 3.82 (d, d, 1H), 4.08 (m, 2H), 4.27 (m, 1H), 4.98 (m,
1H), 7.06 (m, 1H), 7.33 (broad s, 1H), 7.51 (d, 1H), 8.03 (broad s,
1H). Anal. calcd for C.sub.16H.sub.20FN.sub.3O.sub.2S.sub.2: C,
52.01; H, 5.46; N, 11.37. Found: C, 51.86; H, 5.43; N, 11.20.
EXAMPLE 27
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]thio-acetamide, thiomorpholine S-oxide (34)
[0772] 83
[0773] 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.degree. C. for
18 h and at 4.degree. C. for 3 h. It was then treated with
additional sodium metaperiodate (0.1 g), kept at 4.degree. C. for 3
h and extracted with CHCl.sub.3. The extract was dried (MgSO.sub.4)
and concntrated to give 1.4 g of 63: .sup.1H NMR [300 MHz,
(CD.sub.3).sub.2SO] d 2.84 (m, 2H), 3.01 (m, 2H), 3.16 (m, 2H),
3.50 (m, 3H), 3.65 (m, 1H), 3.77 (d,d, 1H), 4.03 (t, 1H), 4.66 (m,
1H), 5.18 (t, 1H), 7.16 (m, 2H), 7.52 (m, 1H); MS(ES) m/z 329
(M+H.sup.+), 351 (M+Na.sup.+). 84
[0774] An ice cold, stirred mixture of 63 (1.27 g, 3.87 mmol) and
triethylamine (0.732 mL, 5.25 mmol) in CH.sub.2Cl.sub.2 (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 CH.sub.2Cl.sub.2, washed with water and brine,
dried (Na.sub.2SO.sub.4) and concentrated to give 78 which was used
in the next reaction without purification. 85
[0775] 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.sub.3) and
kept at 40.degree. C. for 2 h, at ambient temperature for 18 h and
at 40-45.degree. C. for 4 h; it was concentrated to about 50 mL,
diluted with water and extracted with CH.sub.2Cl.sub.2. The
extracts were washed with water and brine, dried (MgSO.sub.4) and
concentrated. Chromatography of the residue on silica gel with 5%
MeOH--CHCl.sub.3 gave 0.58 g of 33: MS(ES) m/z 328 (M+H.sup.+), 350
(M+Na); .sup.1H NMR [300 MHz, (CD.sub.3).sub.2SO] d 2.81 (m, 4H),
3.01 (m, 2H), 3.16 (m, 2H), 3.30 (broad s), 3.49 (m, 2H), 3.80
(d,d, 1H), 4.01 (t, 1H), 4.58 (m, 1H), 7.19 (m, 2H), 7.51 (m, 1H).
86
[0776] 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 concentrated and the residue crystallized from acetonitrile to
give 3.61 g of 34: mp 176-177.degree. C.; .sup.1H NMR [300 MHz,
(CD.sub.3).sub.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, 1H), 3.89 (broad s, 2H),
4.12 (t, 1H), 4.92 (m, 1H), 7.18 (m, 2H), 7.49 (m, 1H), 10.33 (s,
1H); IR (DRIFT) 3186, 3102, 1741 cm.sup.-1; MS(ES) m/z 386
(M+H.sup.+), 408 (M+Na.sup.+). Anal. calcd for
C.sub.16H.sub.20FN.sub.3O.sub.3S.sub.2.smallcircle.0.05 H.sub.2O:
C, 48.71; H, 5.37; N, 10.65; S, 16.26; H.sub.2O, 2.38. Found: C,
48.75; H, 5.17; N, 10.72; S, 16.07; H.sub.2O, 1.72.
EXAMPLE 28
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]thioacetamide, thiomorpholine S, S-dioxide (36)
[0777] 87
[0778] 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 tert-butanol. It was kept
at ambient temperature for 18 h, mixed with saturated NaHSO.sub.3
(50 mL) and extracted with CH.sub.2Cl.sub.2. The extract was washed
with saturated NaHSO.sub.3 and brine, dried (Na.sub.2SO.sub.4) and
concentrated. The residue was mixed with 3.5%
MeOH--CH.sub.2Cl.sub.2 and filtered; the solid was dissolved in 15%
MeOH--CH.sub.2Cl.sub.2 and concentrated to give 0.29 g of 64. The
filtrate was chromatographed on silica gel with 3.5%
MeOH--CH.sub.2Cl.sub.2 to give 0.1 of additional 64: MS(ES) m/z 345
(M+H.sup.+), 367 (M+Na.sup.+); .sup.1H NMR [300 MHz,
(CD.sub.3).sub.2SO] d 3.26 (m, 4H), 3.44 (m, 4H), 3.60 (m, 2H),
3.80 (d,d, 1H), 4.05 (t, 1H), 4.69 (m, 1H), 7.22 (m, 2H), 7.54 (d,
1H). 88
[0779] A stirred mixture of 64 (0.39 g, 0.00113 mol) and
triethylamine (0.214 mL, 0.00154 mol) in CH.sub.2Cl.sub.2 (37 mL)
was cooled, under nitrogen, in an ice bath and treated, 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%
NH.sub.4OH (25 mL), warmed at 50-55.degree. C. for 6 h and kept at
ambient temperature for 48 h. It was concentrated to remove the
organic solvents, diluted with water and extracted with
CH.sub.2Cl.sub.2. The extract was washed with water and brine,
dried (MgSO.sub.4) and concentrated. Flash chromatography of the
residue on silica gel with 6% MeOH--0.4% NH.sub.4OH--CHCl.sub.3
gave 0.29 g of 35: .sup.1H NMR [300 MHz, (CD.sub.3).sub.2SO] d 1.59
(broad s, 2H), 2.78 (m, 2H), 3.24 (m, 4H), 3.43 (m, 4H), 3.81 (d,d,
1H), 4.01 (t, 1H), 4.57 (m, 1H), 7.18 (m, 2H), 7.52 (m, 1H); MS(ES)
m/z 344 (M+H.sup.+), 366 (M+Na.sup.+). 89
[0780] A stirred, ice cold suspension of 35 (0.28 g, 0.85 mmol) in
a mixture of Et.sub.3N (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 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.sub.2Cl.sub.2 (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 ambient temperature for 5 d and
concentrated in vacuo. The residue was mixed with EtOAc, washed
with saturated NaHCO.sub.3, water and brine, dried (MgSO.sub.4) and
concentrated. Crystallization of the residue from MeOH--EtOAc gave
0.209 g of 36: mp 197-198.degree. C.; .sup.1H NMR [300 MHz,
(CD.sub.3).sub.2SO] d 2.42 (s, 3H), 3.24 (m, 4H), 3.43 (m, 4H),
3.78 (d,d, 1H), 3.88 (m, 2H), 4.12 (t, 1H), 4.92 (m, 1H), 7.18 (m,
2H), 7.50 (m, 1H), 10.37 (broad s, 1H); IR (mull) 3300, 3267, 1743
cm.sup.-1; MS(ES) m/z 424 (M+Na.sup.+). Anal. calcd for
C.sub.16H.sub.20FN.sub.3O.sub.4S.sub.2: 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)-1-piperazinyl]phenyl]-2-oxo-5-
-oxazolidinyl]methyl]thioacetamide (38)
[0781] 90
[0782] 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 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 NaHCO.sub.3 and extracted with Et.sub.2O. The extracts
were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated.
Chromatography of the residue on silica gel with 5% MeOH--0.35%
NH.sub.4OH--CHCl.sub.3 gave 0.75 g of recovered 65 and 0.72 g of
66: .sup.1H NMR [300 MHz, (CD.sub.3).sub.2SO] d 1.40 (s, 9H), 1.72
(broad s, 2H), 2.78 (m, 2H), 2.97 (m, 4H), 3.40 (m, 4H), 3.80 (d,d,
1H), 4.00 (t, 1H), 4.59 (m, 1H), 7.27 (d, 2H); MS(ES) m/z 413
(M+H.sup.+), 435 (M+Na.sup.+). 91
[0783] An ice cold, stirred mixture of 66 (0.75 g, 0.0018 mol) and
triethylamine (0.315 mL, 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 CH.sub.2Cl.sub.2 and washed with saturated NaHCO.sub.3,
water and brine, dried (Na.sub.2SO.sub.4) and concentrated. This
residue was mixed with Et.sub.2O and filtered to give 0.939 g of
67: mp 116-118.degree. C.; .sup.1H NMR (300 MHz, CDCl.sub.3) d 1.48
(s, 9H), 3.08 (m, 4H), 3.53 (m, 4H), 3.60 (m, 2H), 3.73 (m, 1H),
3.96 (t, 1H), 4.76 (m, 1H), 5.10 (s, 2H), 5.21 (m, 1H), 7.07 (d,
2H), 7.31 (s, 5H); MS(ES) m/z 547 (M+H.sup.+), 569 (M+Na.sup.+).
92
[0784] 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 NaHCO.sub.3 and
extracted with CH.sub.2Cl.sub.2; the extract was washed with water
and brine, dried (Na.sub.2SO.sub.4) 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
(Na.sub.2SO.sub.4) and conentrated to give additional product. The
combined product amounted to 0.68 g of 68 which was used in the
next reaction without further purification. 93
[0785] An ice cold, stirred mixture of 68 (0.68 g, 0.00152 mol),
saturated NaHCO.sub.3 (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 (MgSO.sub.4) and
concentrated in vacuo to give 0.72 g of 69: MS(ES) m/z 395
(M+H.sup.+), 617 (M+Na.sup.+); 1H NMR (300 MHz, CDCl.sub.3) d 3.12
(m, 4H), 3.59 (m, 4H), 3.74 (m, 3H), 3.96 (t, 1H), 4.22 (s, 2H),
4.62 (s, 2H), 4.75 (broad s, 1H), 5.10 (s, 2H), 5.22 (m, 1H), 7.08
(d, 2H), 7.33 (m, 10H). 94
[0786] A mixture of 69 (0.72 g, 0.0012 mol), MeOH and 5%
palladium-on-carbon catalyst (0.4 g) was hydrogenated at an initial
pressure of 45 psi for 4 h. By TLC (8% MeOH--0.5%
NH.sub.4OH--CHCl.sub.3) 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 concentrated to give
0.40 g of 37: MS(ES) m/z 371 (M+H.sup.+), 393 (M+Na.sup.+); .sup.1H
NMR [300 MHz, (CD.sub.3).sub.2SO] d 3.02 (s, 4H), 3.20 (m, 2H),
3.43 (s, 2H), 3.56 (s, 2H), 3.84 (m, 1H), 3.84 (broad s), 4.10 (s,
2H), 4.14 (t, 1H), 4.96 (m, 1H), 7.26 (d, 2H), 8.41 (broad s, 3H).
95
[0787] A stirred suspension of 37 (0.38 g) in a solution of
Et.sub.3N (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% NH.sub.4OH--CHCl.sub.3). Additional ethyl dithioacetate
(2 drops) was added after 24 h; after 30 h CH.sub.2Cl.sub.2 (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.sub.3
an extracted with CH.sub.2Cl.sub.2. The extract was washed with
water and brine, dried (MgSO.sub.4) and concentrated. The residue
was chromatographed on silica gel with 2.5% MeOH--CH.sub.2Cl.sub.2
and the product was crystallized from MeOH to give 0.182 g of 38:
mp 110-111.degree. C. (dec); MS(ES) m/z 429 (M+H.sup.+), 451
(M+Na.sup.+); HRMS (FAB) calcd for
C.sub.18H.sub.23F.sub.2N.sub.4O.sub.4S (M+H.sup.+) 429.1408, found
429.1415; IR (DRIFT) 1760, 1652, 1639 cm.sup.-1;
[.alpha..sup.24.sub.D 8.degree. (MeOH).
EXAMPLE 30
(S)-N-[[3-[4-[1-[1,2,4]Triazolyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]thiou-
rea (44)
[0788] 96
[0789] A solution of 26 (0.190 g, 0.685 mmol) in CH.sub.2Cl.sub.2
(20 mL) was added, dropwise during 20 min, under nitrogen, to an
ice cold, stirred solution of 1,1-thiocarbonyldi-2(1H)-pyridone
(0.193 g, 0.831 mmol) in CH.sub.2Cl.sub.2 (7 mL). The mixture was
kept in the ice bath for 20 min and at ambient temperature for 2 h,
diluted with CH.sub.2Cl.sub.2, washed with water and brine, dried
(MgSO.sub.4) and concentrated. Chromatography of the residue on
silica gel with 10-15% CH.sub.3CN--CH.sub.2Cl.sub.2 gave 0.11 g of
79 which was used in the next reaction without further
purification: MS(ES) m/z 320 (M+H.sup.+), 342 (M+Na.sup.+). 97
[0790] 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.degree. C.; .sup.1H NMR [300 MHz,
(CD.sub.3).sub.2SO] d 3.82 (m, 3H), 4.18 (t, 1H), 4.89 (broad s,
1H), 7.20 (broad s, 2H), 7.50 (d, 1H), 7.79 (m, 2H), 7.93 (t, 1H),
8.26 (s, 1H), 8.97 (s, 1H); MS(ES) m/z 337 (M+H.sup.+), 359
(M+Na.sup.+). Anal. calcd for C.sub.13H.sub.13FN.sub.6O.sub.2S: C,
46.42; H, 3.90; N, 24.99. Found: C, 46.22; H, 3.98; N, 24.55.
EXAMPLE 31
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxa-
zolidinyl]methyl]thiourea (45)
[0791] 98
[0792] An ice cold, stirred solution of
1,1-thiocarbonyl-2(1H)-dipyridone (0.123 g, 0.530 mmol) in
CH.sub.2Cl.sub.2 (5 mL), under nitrogen, was treated with a
suspension of 29 (0.17 g, 0.4 mmol) in CH.sub.2Cl.sub.2 (20 mL) and
then during 10 min with a solution of triethylamine (0.111 mL, 0.8
mmol) in CH.sub.2Cl.sub.2 (10 mL). It was kept in the ice bath for
30 min, at ambient temperature for 2 h and at <0.degree. C. for
18 h. It was then diluted with CH.sub.2Cl.sub.2, washed with water
and brine, dried (MgSO.sub.4) 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-CH.sub.2Cl.sub.2 had: .sup.1H NMR (300
MHz, CDCl.sub.3) d 1.60 (broad s), 3.07 (m, 4H), 3.45 (m, 2H), 3.85
(m, 4H), 3.97 (d,d, 1H), 4.16 (t, 1H), 4.21 (s, 2H), 4.82 (m, 1H),
6.95 (t, 1H), 7.13 (d,d, 1H), 7.47 (d,d, 1H); MS m/z 395
(M+H.sup.+); 417 (M+Na.sup.+). 99
[0793] 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 ice bath for 90 min and
concentrated under a stream of nitrogen. The residue was
chromatographed on silica gel with 5% MeOH--0.4%
NH.sub.4OH--CHCl.sub.3 and the product was crystallized from
acetonitrile to give 0.0544 g of 45: mp 209-210.degree. C.; .sup.1H
NMR [300 MHz, (CD.sub.3).sub.2SO] d 294 (broad s, 4H), 3.47 (broad
s, 2H), 3.60 (broad s, 2H), 3.78 (broad s, 3H), 4.07 (t, 1H), 4.10
(d, J=5.5 Hz, 2H), 4.63 (t, J=5.5 Hz, 1H), 4.81 (broad s, 1H), 7.05
(t, 1H), 7.16 (d,d, 1H), 7.15 (broad s, 2H), 7.49 (d,d, 1H), 7.91
(t, 1H); IR (mull) 3443, 3403, 3321, 3202, 3081, 1753, 1655, 1648
cm.sup.-1; HRMS (FAB) calcd for C.sub.17H.sub.23FN.sub.6O.sub.4S
(M+H.sup.+) 412.1454, found 412.1447. Anal. calcd for
C.sub.17H.sub.22FN.sub.5O.sub.4S: C, 49.63; H, 5.39; N, 17.02.
Found: C, 49.63; H, 5.48; N, 16.99.
EXAMPLE 32
(S)-N-[[3-[1-(Hydroxyacetyl)-5-indolinyl]-2-oxo-5-oxazolidinyl]methyl]thio-
urea (46)
[0794] 100
[0795] An ice cold, stirred solution of
1,1-thiocarbonyldi-2(1H)-pyridone (0.096 g, 0.41 mmol) in
CH.sub.2Cl.sub.2 (5 mL) was treated with a suspension of 27 (0.10
g, 0.34 mmol) in CH.sub.2Cl.sub.2 (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
CH.sub.2Cl.sub.2, washed with water and brine, dried (MgSO.sub.4)
and concentrated. Chromatography of the residue on silica gel with
20-40% CH.sub.3CN--CH.sub.2Cl.sub.2 gave 0.04 g of 81. 101
[0796] 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 under a stream of
nitrogen. The residue was crystallized from CH.sub.3CN to give
0.0151 g of 46: mp 214-215.degree. C. (dec); MS (FAB) m/z 351
(M+H.sup.+), 350 (M.sup.+), 319, 304, 147; HRMS (FAB) calcd for
C.sub.15H.sub.19N.sub.4O.sub.4S (M+H.sup.+) 351.1127, found
351.1130; IR (DRIFT) 3329, 3296, 3196, 1746, 1655, 1626
cm.sup.-1.
EXAMPLE 33
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]thiourea, thiomorpholine S-oxide (47)
[0797] 102
[0798] A suspension of 33 (0.30 g, 0.92 mmol) in CH.sub.2Cl.sub.2
(7 mL) was added, during 20 min, to an ice cold, stirred mixture of
1,1-thiocarbonyldi-2(1H)-pyridone (0.258 g, 1.11 mmol) and
CH.sub.2Cl.sub.2 (20 mL). The mixture was kept in the ice bath for
20 min and at ambient temperature for 2 h, mixed with
CH.sub.2Cl.sub.2 (50 mL), washed with water and brine, dried
(MgSO.sub.4) and concentrated. Chromatography of the product on
silica gel with 20-50% CH.sub.3CN--CH.sub.2Cl.sub.2 gave 0.27 g of
82 which was used in the next reaction: MS(ES) m/z 370 (M+H.sup.+),
392 (M+Na.sup.+). 103
[0799] A stirred, ice cold solution of 82 (0.27 g, 0.73 mmol) in
THF (15 mL), under nitrogen, was treated with excess anhydrous
ammonia, kept in the ice bath for 1 h and concentrated;
crystallization of the residue from MeOH gave 0.175 g of 47; mp
212-213.degree. C.; .sup.1H NMR [300 MHz, (CD.sub.3).sub.2SO] d
2.83 (m, 2H), 3.01 (m, 2H), 3.17 (m, 2H), 3.50 (t, 2H), 3.78 (broad
s, 3H), 4.08 (t, 1H), 4.80 (broad s, 1H), 7.17 (m, 2H), 7.17 (broad
s, 2H), 7.50 (d, 1H), 7.90 (t, 1H); MS(ES) m /z 409 (M+Na.sup.+);
IR (mull) 3335, 3284, 3211, 3175, 3097, 1750, 1630 cm.sup.-1. Anal.
calcd for C.sub.15H.sub.19FN.sub.4O.sub.3S.sub.2: C, 46.62; H,
4.95; N, 14.50. Found: C, 46.50; H, 4.95; N, 14.40.
EXAMPLE 34
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl-S-
-methyldithiocarbamate (48)
[0800] 104
[0801] 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 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 solution of the residue in EtOAc was washed with
saturated NaHCO.sub.3, water and brine, dried (MgSO.sub.4) and
concentrated. The residue was chromatographed on silica gel with
1.8% MeOH--CH.sub.2Cl.sub.2 and the product was crystallized from
EtOAc to give 0.197 g of 48: mp 154-155.degree. C.; IR (mull) 3354,
3346, 1726 cm.sup.-1. Anal. calcd for
C.sub.16H.sub.20FN.sub.3O.sub.3S.sub.2: C, 49.85; H, 5.23; N,
10.90. Found: C, 49.73; H, 5.25; N, 10.82.
EXAMPLE 35
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl-O-
-methylthiocarbamate (50)
[0802] 105
[0803] A stirred mixture of 48 (0.200 g, 0.518 mmol), sodium
methoxide (0.003 g, 0.06 mmol) and MeOH (5 mL), under nitrogen, was
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 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 KHSO.sub.4 and saturated NaHCO.sub.3 and
the mixture was extracted with CH.sub.2Cl.sub.2. The extract was
washed with water and brine, dried (MgSO.sub.4) and concentrated.
The residue was chromatographed on silica gel with 5%
acetone-CH.sub.2Cl.sub.2 and the product was crystallized from
EtOAc-hexane to give 0.107 g of 50: mp 128-129.degree. C.; MS(ES)
m/z 370 (M+H.sup.+), 392 (M+Na.sup.+); IR (DRIFT) 3282, 3251, 1753,
1735 cm.sup.-1; .sup.1H NMR [300 MHz, (CD.sub.3).sub.2SO] d 2.94
(m, 4H), 3.47, 374 (m,m, 7H), 3.86, 3.91 (s,s, 3H), 4.10 (m, 1H),
4.73, 4.86 (m,m, 1H), 7.05 (t, 1H), 7.16 (d,d, 1H), 7.47 (d,d, 1H),
9.41, 9.50 (s,s, 1H). Anal. calcd for
C.sub.16H.sub.20FN.sub.3O.sub.4S: C, 52.02; H, 5.46; N, 11.38.
Found: C, 51.97; H, 5.49; N, 11.35.
[0804] 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.
[0805] When in the procedure of Example 1 an appropriate amount of
(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]iso-
propylcarboxamide,
(S)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]cyclopropylcarboxamide, or
(S)-N-[[3-[3,5-difluoro-4-morpho-
linyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide was substituted
for
(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-
acetamide (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. Pat. 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. Pat. No. 5,688,792 at Example 4.
[0806] 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.
3TABLE A 106 Example No. Compound R, R' 36
(S)--N-[[3-[3-Fluoro-4-(4-morp- holinyl)-
phenyl]-2-oxo-5-oxazolidinyl]methyl]-O- ethylthiocarbamate; mp
120.degree. C., MS(ES) m/z 384(M + H.sup.+). Anal. calcd for
C.sub.17H.sub.22FN.sub.3O.sub.4S: C, 53.25; H, 5.78; N, 10.96.
Found: C, 53.23; H, 5.82; N, 10.92. R = H, R' = OC.sub.2H.sub.5 37
(S)--N-[[3-[3-Fluoro-4-(4-morpholinyl)-
phenyl]-2-oxo-5-oxazolidinyl]meth- yl]-2- methylpropanethioamide;
mp 152-153.degree. C. (dec.); Anal. calcd for
C.sub.18H.sub.24FN.sub.3O.sub.3S: C, 56.67; H, 6.34; N, 11.02.
Found: C, 56.58; H, 6.41; N, 10.81 R = H, R' = CH(CH.sub.3).sub.2
38 (S)--N-[[3-[3-Fluoro-4-(4-morpholinyl)-
phenyl]-2-oxo-5-oxazolidinyl]- methyl]-
cyclopropane-carbothioamide; mp 155-156.degree. C.; Anal. calcd for
C.sub.18H.sub.22FN.sub.3O.sub.3S: C, 56.98; H, 5.84; N, 11.07.
Found: C, 56.98; H, 5.85; N, 10.97 107 39
(S)--N-[[3-[3,5-Difluoro-4-(4-morpholinyl)-
phenyl]-2-oxo-5-oxazolidinyl]- methyl]- thioacetamide R = F, R' =
CH.sub.3 40 (S)--N-[[3-[3-Fluoro-4-(4-morpholinyl)-
phenyl]-2-oxo-5-oxazolidinyl]meth- yl]-N',N'- dimethylthiourea R =
H, R' = N(CH.sub.3).sub.2 PREPARATION Z Methyl Dithiopropionate
108
[0807] A stirred mixture of magnesium turnings (12.6 g, 0.520 g
atom) and THF (100 mL) 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.degree. C. and
treated, during 10 minutes with carbon disulfide (24.0 mL, 0.40
mol). The mixture is warmed to 15.degree. C., treated with methyl
iodide (28.0 mL, 0.45 mol) and kept at 60.degree. C. for 1 hour. It
is then cooled in an ice bath, treated with ice and extracted with
Et.sub.2O. The extract is washed with brine, dried (MgSO.sub.4) and
concentrated. Distillation of the residue gives 34.0 g of the
titled product, bp 48-52.degree. C. (12 mmHg).
[0808] The following methyl dithio compounds were obtained when the
appropriate alkyl magnesium bromide was substituted for ethyl
magnesium bromide in the above procedure:
[0809] The following methyl dithio compounds were obtained when the
appropriate alkyl magnesium bromide was substituted for ethyl
magnesium bromide in the above procedure:
4TABLE B 109 Rs = (b) (CH.sub.3).sub.2CH-- (h) 110 (c) 111 (i) 112
(d) CH.sub.3CH.sub.2CH.sub.2-- (j) 113 (e) 114 (k) 115 (f) 116 (l)
117 (g) (CH.sub.3).sub.3C--CH.sub.2-- (m) 118
[0810] When following the general procedure of Example 27, step 4,
an appropriate 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.
[0811] 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.
5TABLE C Example Dithio Compound No. Compound Amine (from
Preparation Z) 41 (S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide,
thiomorpholine S-oxide; mp 196-197.degree. C.; #Anal. calcd for
C.sub.17H.sub.22FN.sub.3O.su- b.3S.sub.2: C, 51.11; H, 5.55; N,
10.52; S, 16.05. Found: C, 50.99; H, 5.60; N, 10.55; S, 15.75 119
Z(a) 42 (S)--N-[[3-[3-Fluoro-4-(4- thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylpropanethio- amide,
thiomorpholine S-oxide; mp 195-196.degree. C.; #Anal. calcd for
C.sub.18H.sub.24FN.sub.3O- .sub.3S.sub.2: C, 52.28; H, 5.85; N,
10.16; S, 15.51. Found: C, 52.24; H, 5.97; N, 10.16; S, 15.28 120
Z(b) 43 (S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclopropanecarbothio-
amide, thiomorpholine S-oxide; mp 109-110.degree. C.; Anal. calcd
for #C.sub.18H.sub.22FN.sub.3O.sub.3S.sub.2: C, 52.54; H, 5.39; N,
10.21; S, 15.58. Found: C, 52.48; H, 5.51; N, 10.28; S, 15.29 121
Z(c) 44 (S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- butanethioamide,
thiomorpholine S-oxide 122 Z(d) 45 (S)--N-[[3-[3-Fluoro-4-
(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-3-
methylbutanethioamide, thiomorpholine S-oxide 123 Z(e) 46
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- methylbutanethioamide, thiomorpholine
S-oxide 124 Z(f) 47 (S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- 3,3-dimethylbutanethio-
amide, thiomorpholine S-oxide 125 Z(g) 48 (S)--N-[[3-[3-Fluoro-4-
(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
cyclobutanecarbothio- amide, thiomorpholine S-oxide 126 Z(h) 49
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-1- cyclopentanecarbothio- amide,
thiomorpholine S-oxide 127 Z(i) 50 (S)--N-[[3-[3-Fluoro-4-
(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
cyclohexanecarbothio- amide, thiomorpholine S-oxide 128 Z(j) 51
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- cyclopropylethanethio- amide,
thiomorpholine S-oxide 129 Z(k) 52 (S)--N-[[3-[3-Fluoro-4-
(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
cyclobutylethanethio- amide, thiomorpholine S-oxide 130 Z(l) 53
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- cyclopentylethanethio- amide,
thiomorpholine S-oxide 131 Z(m) 54 (S)--N-[[3-[3,5-Difluoro-
4-(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
thioacetamide, thiomorpholine S-oxide 132 Ethyl dithioacetate 55
(S)--N-[[3-[3,5-Difluoro- 4-(4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- propanethioamide, thiomorpholine S-oxide 133
Z(a) 56 (S)--N-[[3-[3,5-Difluoro- 4-(4-thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylpropanethio- amide,
thiomorpholine S-oxide 134 Z(b) 57 (S)--N-[[3-[3,5-Difluoro-
4-(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
cyclopropanecarbothio- amide, thiomorpholine S-oxide 135 Z(c) 58
(S)--N-[[3-[4-(4- thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- thioacetamide, thiomorpholine S-oxide 136
Ethyl dithioacetate 59 (S)--N-[[3-[4-(4- thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide,
thiomorpholine S-oxide 137 Z(a) 60 (S)--N-[[3-[4-(4-
thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
methylpropanethio- amide, thiomorpholine S-oxide 138 Z(b) 61
(S)--N-[[3-[4-(4- thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopropanecarbothio- amide, thiomorpholine
S-oxide 139 Z(c) 62 (S)--N-[[3-[3,5-Difluoro-
4-(4-hydroxyacetyl)-1- piperazinyl]phenyl]-2- oxo-5-oxazolidinyl]-
methyl]propanethio- amide 140 Z(a) 63 (S)--N-[[3-[3,5-Difluoro-
4-(4-hydroxyacetyl)-1- piperazinyl]phenyl]-2- oxo-5-oxazolidinyl]-
methyl]-2-methyl- propanethioamide 141 Z(b) 64
(S)--N-[[3-[3,5-Difluoro- 4-(4-hydroxyacetyl)-1-
piperazinyl]phenyl]-2- oxo-5-oxazolidinyl]- methyl]cyclopropane-
thioamide 142 Z(c) 65 (S)--N-[[3-[3-[4- (hydroxyacetyl)-1-
piperazinyl]phenyl]-2- oxo-5-oxazolidinyl]- methyl]propanethio-
amide 143 Z(a) 66 (S)--N-[[3-[3-[4- (hydroxyacetyl)-1-
piperazinyl]phenyl]-2- oxo-5-oxazolidinyl]- methyl]-2-methyl-
propanethioamide 144 Z(b) 67 (S)--N-[[3-[3-[4- (hydroxyacetyl)-1-
piperazinyl]phenyl]-2- oxo-5-oxazolidinyl]- methyl]cyclopropane-
carbothioamide 145 Z(c)
[0812] 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.
6TABLE D Example Dithio Compound No. Compound Amine (see
Preparation Z) 68 (S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide,
thiomorpholine S,S- dioxide 146 Z(a) 69 (S)--N-[[3-[3-Fluoro-4-
(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
methylpropanethio- amide, thiomorpholine S,S-dioxide 147 Z(b) 70
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopropanecarbothio- amide, thiomorpholine
S,S-dioxide 148 Z(c) 71 (S)--N-[[3-[3,5-Difluoro-
4-(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]-
methyl]thioacetamide, thiomorpholine S,S- dioxide 149 Ethyl
dithioacetate 72 (S)--N-[[3-[3,5-Difluoro- 4-(4-thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide,
thiomorpholine S,S- dioxide 150 Z(a) 73 (S)--N-[[3-[3,5-Difluoro-
4-(4-thiomorpholinyl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
methylpropanethio- amide, thiomorpholine S,S-dioxide 151 Z(b) 74
(S)--N-[[3-[3,5-Difluoro- 4-(4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopropanecarbothio- amide, thiomorpholine
S,S-dioxide 152 Z(c) 75 (S)--N-[[3-[4-(4-thio-
morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]- methyl]thioacetamide,
thiomorpholine S,S- dioxide 153 Ethyl dithioacetate 76
(S)--N-[[3-[4-(4-thio- morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]-
methyl]propanethio- amide, thiomorpholine S,S-dioxide 154 Z(a) 77
(S)--N-[[3-[4-(4-thio- morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]-
methyl]-2-methyl- propanethioamide, thiomorpholine S,S- dioxide 155
Z(b) 78 (S)--N-[[3-[4-(4-thio- morpholinyl)phenyl]-2-
oxo-5-oxazolidinyl]- methyl]cyclopropane- carbothioamide,
thiomorpholine S,S- dioxide 156 Z(c)
[0813] 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.
7TABLE E Example Dithio Compound No. Compound Amine (See
Preparation Z) 79 (S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide 157 Z(a) 80
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- methylpropanethioamide 158 Z(b) 81
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopropanecarbothio- amide 159 Z(c) 82
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- butanethioamide 160 Z(d) 83
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-3- methylbutanethioamide 161 Z(e) 84
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- methylbutanethioamide 162 Z(f) 85
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- 3,3-dimethylbutanethio- amide 163 Z(g) 86
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclobutanecarbothio- amide 164 Z(h) 87
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopentanecarbothio- amide 165 Z(i) 88
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclohexanecarbothio- amide 166 Z(j) 89
(S)--N-[[3-[3-5 Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- cyclopropylethanethio- amide 167 Z(k) 90
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- cyclobutylethanethio- amide 168 Z(l) 91
(S)--N-[[3-[3-Fluoro-4- (4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- cyclopentylethanethio- amide 169 Z(m) 92
(S)--N-[[3-[3,5-Difluoro- 4-(4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- thioacetamide 170 Ethyl dithioacetate 93
(S)--N-[[3-[3,5-Difluoro- 4-(4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- propanethioamide 171 Z(a) 94
(S)--N-[[3-[3,5-Difluoro- 4-(4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- methylpropanethioamide 172 Z(b) 95
(S)--N-[[3-[3,5-Difluoro- 4-(4-thiomorpholinyl)- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopropanecarbothio- amide 173 Z(c) 96
(S)--N-[[3-[4-(4-thio- morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]-
methyl]thioacetamide 174 Ethyl dithioacetate 97
(S)--N-[[3-[4-(4-thio- morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]-
methyl]propanethio- amide 175 Z(a) 98 (S)--N-[[3-[4-(4-thio-
morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]- methyl]-2-methyl-
propanethioamide 176 Z(b) 99 (S)--N-[[3-[4-(4-thio-
morpholinyl)phenyl]-2- oxo-5-oxazolidinyl]- methyl]cyclopropane-
carbothioamide 177 Z(c)
[0814] 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-thiomorpholinyl)phenyl]-2-oxo-5--
oxazolidinyl]methanol for compound 62 in step 1 of Example 27.
[0815] 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 oxazolidinyl
methanol compound is obtained by following the procedure of Example
1 in U.S. Pat. No. 5,688,792, steps 1 through 3, only substituting
4-fluoronitrobenzene for 3,4-difluoronitrobenzene in step 1
thereof.
[0816] 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. Pat. No. 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. Pat. No. 5,700,799: 178
[0817] The amine utilized in Examples 68 to 70 is prepared as
described in step 2 of Example 28 above.
[0818] 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)p-
henyl]-2-oxo-5-oxazolidinyl]methanol 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. Pat. No. 5,688,792, steps 1 through
4, only substituting thiomorpholine for morpholine in step 1
thereof.
[0819] The amine utilized in Examples 75 to 78 is prepared as
described in Example 28, step 1, above by substituting
(S)-N-[3-[4-(4-thiomorpholinyl)-
phenyl]-2-oxo-5oxazolidinyl]methanol for compound 62 in step 1. The
appropriate oxazolidinyl methanol is obtained by following the
procedure of Example 1 in U.S. Pat. No. 5,688,792, steps 1 through
3, only substituting 4-fluoronitrobenzene for
3,4-difluoronitrobenzene in step 1 thereof.
[0820] The amine utilized in Examples 79 to 91 is prepared as
described in Example 1, step 4, of U.S. Pat. No. 5,688,792. The
amine utilized in Examples 92 to 95 is prepared as described in
Example 4 of U.S. Pat. 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. Pat. No. 5,688,792, only substituting 4-fluoronitrobenzene for
3,4-difluoronitrobenzene in step 1 thereof.
EXAMPLE 100
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]-O-methylthiocarbamate, thiomorpholine S-oxide
[0821] 179
[0822] A solution of 201 mg (0.554 mmol) of
(S)-N-[[3-[3-fluoro-4-(4-thiom-
orpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]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.degree. C.; Anal. calcd for
C.sub.16H.sub.20FN.sub.3O.sub.4S.sub.- 2: C, 47.87; H, 5.02; N,
10.47. Found: C, 47.81; H, 5.04: N, 10.49.
[0823] When in the procedure of Example 100 the thioisocyanate
listed below is substituted for compound 82 the products listed
below as Examples 101 to 109 are obtained.
8TABLE F Isothiocyanate 180 Ex- ample Rc Ra Rb No. Compound OS F F
101 (S)--N-[[3-[3,5-Difluoro-4-(4- thiomorpholinyl)phenyl]-2-o-
xo-5- oxazolidinyl]methyl]-O-methylthio- carbamate, thiomorpholine
S-oxide OS H H 102 (S)-N-[[3-[4-(4-thiomorpholinyl)- phenyl]-
2-oxo-5-oxazolidinyl]methyl]-O-methyl- thio-carbamate,
thiomorpholine S-oxide O.sub.2S H F 103
(S)--N-[[3-[3-Fluoro-4-(4-thiomorpho- linyl)-phenyl]-2-oxo-5-o-
xazolidinyl]meth- yl]-O-methylthiocarbamate, thio- morpholine
S,S-dioxide O.sub.2S F F 104 (S)--N-[[3-[3,5-Difluoro-4- -(4-
thiomorpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-methylthio-
carbamate, thiomorpholin S,S-dioxide O.sub.2S H H 105
(S)--N-[[3-[4-(4-thiomorpholinyl)phen- yl]-
2-oxo-5-oxazolidinyl]methyl]-O-methyl- thiocarbamate,
thiomorpholine S,S-dioxide S H F 106
(S)--N-[[3-[3-Fluoro-4-(4-thio- morpholinyl)-phenyl]-2-oxo-5-o- xa-
zolidinyl]methyl]-O-methylthiocarbamate S F F 107
(S)--N-[[3-[3,5-Difluoro-4-(4-thiomorph-
olinyl)phenyl]-2-oxo-5-oxazolidinyl]- methyl]-O-methylthiocarb-
amate S H H 108 (S)--N-[[3-[4-(4-thiomorpholinyl)phenyl]-
2-oxo-5-oxazolidinyl]methyl]-O-methyl- thiocarbamate 181 H H 109
(S)--N-[[3-[3-Fluoro- 4-(4-(hydroxyacetyl)-1-
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate
[0824] 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:
[0825] EXAMPLE 110:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-O-ethylthiocarbamate, thiomorpholine
S-oxide. m.p. 198-199.degree. C.; Anal. calcd for
C.sub.17H.sub.22FN.sub.3O.sub.4S.sub.- 2: C, 49.14; H, 5.34; N,
10.11. Found: C, 49.06; H, 5.27; N, 10.10.
[0826] EXAMPLE 111:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-O-isopropylthiocarbamate, thiomorpholine
S-oxide. m.p. 180-181.degree. C.; Anal. calcd for
C.sub.18H.sub.24FN.sub.3O.sub.4S- .sub.2: C, 50.33; H, 5.63; N,
9.78. Found: C, 50.29; H, 5.69; N, 9.82.
[0827] When in the procedure of Example 114 an appropriate amount
of
(S)-N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]iso-
thiocyanate is substituted for compound 82 and ethanol or isopropyl
alcohol is substituted for methanol, the following respective
products are obtained:
[0828] EXAMPLE 112:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-O-ethylthiocarbamate;
[0829] EXAMPLE 113:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-O-isopropylthiocarbamate;
[0830] EXAMPLE 114:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]N-methylthiourea, thiomorpholine
S-oxide.
[0831] A stirred suspension of 240 mg (0.650 mmol) of compound 82
from Example 33, step 1 in THF (5 mL) at 0.degree. C. is treated
with a 2M solution of methylamine in THF (0.42 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.
[0832] Following the procedure of Example 114, only substituting an
appropriate amount of dimethylamine and azetidine for methylamine,
the following compounds are obtained:
[0833] 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 C.sub.17H.sub.23FN.sub.4O.sub.3S.sub.2, C,
49.26; H, 5.59; N, 13.52. Found C, 49.11; H, 5.57; N, 13.40; mp
180-182.degree. C.
[0834] EXAMPLE 116:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-1-azetidinecarbothioamide, thiomorpholine
S-oxide; Anal. Calcd for C.sub.18H.sub.23FN.sub.4O.sub.3S.sub.2, C,
50.69; H, 5.43; N, 13.14. Found: C, 50.79; H, 5.45; N, 12.82; mp
213-214.degree. C.
[0835] When in the procedure of Example 114 an appropriate amount
of
(S)-N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]isothiocyanate is substituted for compound 82, the following
compound is obtained:
[0836] EXAMPLE 117:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]methyl-N'-methylthiourea.
[0837] When in the procedure of Example 117 an appropriate amount
of dimethylamine and azetidine are substituted for methylamine, the
following respective products are obtained:
[0838] EXAMPLE 118:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-N',N'-dimethylthiourea;
[0839] EXAMPLE 119:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]-1-azetidinecarbothioamide.
[0840] 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 Example 33 are followed, the
following compound is obtained.
[0841] EXAMPLE 120:
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-
-5-oxazolidinyl]methyl]thiourea.
[0842] EXAMPLE 121:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl-
]phenyl-2-oxo-5-oxazolidinyl]methyl]propanethioamide 182
[0843] 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 (MgSO.sub.4) 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.degree. C.; Anal. calcd for
C.sub.19H.sub.25FN.sub.4O.sub.4S: 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.
[0844] 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.
9TABLE G 183 Ex- ample No. Compound 122
(S)--N-[[3-[3-Fluoro-4-[4-(hydroxy- R = CH(CH.sub.3).sub.2
acetyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2-methylpropane- thioamide; Anal. calcd for
C.sub.20H.sub.27FN.sub.4O.sub.4S: C, 54.78; H, 6.21; N, 12.78; S,
7.31. Found: C, 54.67; H, 6.34; N, 12.41; S, 7.15 123
(S)--N-[[3-[3-Fluoro-4-[4-(hydroxy- acetyl)-1-piperazinyl]phenyl]--
2-oxo-5- oxazolidinyl]methyl]cyclopropane- carbothioamide; mp
179-181.degree. C.; Anal. calcd for
C.sub.20H.sub.25FN.sub.4O.sub.4S: C, 55.03; H, 5.77; N, 12.84; S,
7.34. Found: C, 55.15; H, 5.72; N, 12.76; S, 7.09 184 124
(S)--N-[[3-[3-Fluoro-4-[4-(hydroxy- R =
CH.sub.2--CH.sub.2--CH.sub.3 acetyl)-1-piperazinyl]phenyl]-2-oxo--
5- oxazolidinyl]methyl]butanethioamide 125
(S)--N-[[3-[3-Fluoro-4-[4-(hydroxy-
acetyl)-1-piperazinyl]phenyl]-2-oxo-5- -
oxazolidinyl]methyl]-3-methylbutane- thioamide 185 126
(S)--N-[[3-[3-Fluoro-4-[4-(hydroxy-
acetyl)-1-piperazinyl]phenyl]-2-oxo-5- -
oxazolidinyl]methyl]-2-methylbutane- thioamide 186 127
(S)--N-[[3-[3-Fluoro-4-[4-(hydroxy- R = CH.sub.2--C(CH.sub.3).sub.3
acetyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-3,3-
-dimethyl- butanethioamide 128 (S)--N-[[3-[3-Fluoro-4-[4-(h-
ydroxy- acetyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]cyclobu- tane- carbothioamide 187 129
(S)--N-[[3-[3-Fluoro-4-[4-(hy- droxy-
acetyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]cyclopen- tane- carbothioamide 188 130
(S)--N-[[3-[3-Fluoro-4-[4-(hy- droxy-
acetyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]cyclohex- ane- carbothioamide 189 131
(S)--N-[[3-[3-Fluoro-4-[4-hydr- oxy-
acetyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2-cyclopr- opyl- ethanethioamide 190 132
(S)--N-[[3-[3-Fluoro-4-[4-(h- ydroxy-
acetyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-cycl-
obutyl- ethanethioamide 191 133 (S)--N-[[3-[3-Fluoro-4-[4--
(hydroxy- acetyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2-cy- clopentyl- ethanethioamide 192
[0845] 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:
[0846] EXAMPLE 134:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]-O-ethylthiocarbamate;
[0847] EXAMPLE 135:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]-O-iso-propylthiocarbamate;
[0848] EXAMPLE 136:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]-N'-methylthiourea.
[0849] 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.
[0850] 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:
[0851] EXAMPLE 137:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]-N',N'-dimethylthiourea;
[0852] EXAMPLE 138:
(S)-N-[[3-[3-Fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl-
]phenyl]-2-oxo-5-oxazolidinyl]methyl]-1-azetidinecarbothioamide.
EXAMPLE 139
(S)-N-[[3-[3,5-Difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]2-oxo-5--
oxazolidinyl]methyl]-O-methylthiocarbamate.
[0853] 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-(hydroxyacetyl)-1-pipera-
zinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]isothiocyanate is
obtained.
[0854] Part B: Upon substitution of an appropriate amount of
(S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo--
5-oxazolidinyl]methyl]isothiocyanate for compound 82 in the general
procedure of Example 100, the title compound is obtained.
EXAMPLE 140
(S)-N-[[3-[4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]-O-methylthiocarbamate
[0855] Part A: Following the procedure of Example 33, step 1, only
substituting an appropriate amount of
(S)-N-[[3-[4-[4-(hydroxyacetyl)-1-p-
iperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine for compound
33,
(S)-N-[[3-[4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidiny-
l]methyl]isothiocyanate is obtained.
[0856] Part B: Upon substituting an appropriate amount of
(S)-N-[[3-[4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidiny-
l]methyl]isothiocyanate for compound 82 in the general procedure of
Example 100, the title compound is obtained.
EXAMPLE 141
(S)-N-[[-3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]m-
ethyl]thioacetamide
[0857] 193
[0858] 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
m-nitrobenzenesulfonyl chloride (18.8 g, 84.9 mmol) and kept, under
nitrogen, at ambient temperature (24.degree. C.) for 24 hours.
Additional m-nitrobenzenesulfonyl chloride (1.88 g) and
triethylamine (1.54 mL) are added and the mixture is kept for one
additional day at ambient temperature, washed with water, saturated
sodium bicarbonate and brine, dried (Na.sub.2SO.sub.4) 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. 194
[0859] 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% NH.sub.4OH-1%
MeOH--CH.sub.2Cl.sub.2 gives 22.4 g of the amine, 86. 195
[0860] An ice cold, stirred solution of the amine 86 in THF (650
mL) is treated, during 20 mintues with a solution of di-tert-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.sub.4) 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. 196
[0861] 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.
197
[0862] A stirred solution of compound 88 (1.10 g, 2.79 mmol) in
pyridine (10 mL) is treated with acetic anhydride (289 .mu.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 dilute hydrochloric acid, dried (MgSO.sub.4) and concentrated
to give 1.23 g of compound 89: MS m/z 436 (M.sup.+). 198
[0863] An ice cold, stirred 4N solution of HCl 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. 199
[0864] A stirred mixture of compound P-90 (250 mg), triethylamine
(0.75 mL, 5.36 mmol), ethyl dithioacetate (307 .mu.L, 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.sub.18H.sub.23FN.sub.4O.sub.3S: C, 54.81; H, 5.88; N, 14.20; S,
8.13. Found: C, 54.92; H, 5.95; N, 14.08; S, 7.94; mp 158.degree.
C.
[0865] When in the general procedure of Example 141 an appropriate
amount of 200
[0866] 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 are obtained: 201
[0867] 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 (trifluoromethane) sulfonate and
4-fluoronitrobenzene respectively for 3,4-difluoronitrobenzene in
the preparation of 2a therein.
[0868] 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 are followed, the following Boc protected
compounds listed below are obtained. 202
[0869] 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.
[0870] The amine compound set forth below as P-129 is obtained by
refluxing for 6 days a 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 sulfamoyl 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 general procedure is followed,
Preparations P-130 and P-131 respectively set forth below are
obtained.
[0871] Following the general procedures of steps 5 and 6 of Example
141 only in step 5 substituting chloroacetonitrile or 2-fluoroethyl
bromide respectively for acetic anhydride and using potassium
carbonate in acetonitrile, and using either compound 88, compound
x-b or compound y-b, the respective amines set forth below as
Preparations P-132 to P-137 are obtained.
[0872] 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 1N sodium hydroxide and dilute
sodium chloride, dried (MgSO.sub.4), 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.
10 203 Boc Preparation Reagent Compound R R" R' No.
methoxyacetylchloride 88 x-b y-b 204 H F H F F H P-93 P-94 P-95
cyanoacetyl chloride 88 x-b y-b 205 H F H F F H P-96 P-97 P-98
acetoxyacetyl chloride 88 x-b y-b 206 H F H F F H P-99 P-100 P-101
benzyloxyacetyl chloride 88 x-b y-b 207 H F H F F H P-102 P-103
P-104 methyl chloroformate 88 x-b y-b 208 H F H F F H P-105 P-106
P-107 methanesulfonyl chloride 88 CH.sub.3SO.sub.2-- H F P-108 x-b
F F P-109 y-b H H P-110 ethanesulfonyl chloride 88
CH.sub.3CH.sub.2SO.sub.2-- H F P-111 x-b F F P-112 y-b H H P-113
chloromethaneslfonyl 88 ClCH.sub.2SO.sub.2-- H F P-114 chloride x-b
F F P-115 y-b H H P-116 cyanomethanesulfonyl 88
NCCH.sub.2SO.sub.2-- H F P-117 chloride x-b F F P-118 y-b H H P-119
N-methylsulfamoyl 88 CH.sub.3NHSO.sub.2-- H F P-120 chloride x-b F
F P-121 y-b H H P-122 N,N-dimethylsulfamoyl 88
(CH.sub.3).sub.2NSO.sub.2-- H F P-123 chloride x-b F F P-124 y-b H
H P-125 ethyl chloroformate 88 x-b y-b 209 H F H F F H P-126 P-127
P-128 sulfamide 88 H.sub.2NSO.sub.2-- H F P-129 x-b F F P-130 y-b H
H P-131 chloroacetonitrile 88 NCCH.sub.2-- H F P-132 x-b F F P-133
y-b H H P-134 2-fluoroethyl bromide 88 FCH.sub.2CH.sub.2-- H F
P-135 x-b F F P-136 y-b H H P-137 N-formylbenzotriazole 88 x-b y-b
210 H F H F F H P-138 P-139 P-140
EXAMPLES 142-161
[0873] 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.
11TABLE H Example Dithio No. Product Amine Compound 142
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl- )phenyl]- P-90 Z (a)
2-oxo-5-oxazolidinyl]methyl]propanethioamide- ; mp 161-162.degree.
C.; Anal. calcd for C.sub.19H.sub.25FN.sub.4O- .sub.3S: C, 55.87;
H, 6.17; N, 13.72; S, 7.85. Found: C, 55.79; H, 6.26; N, 13.60; S,
7.71 143 (S)-N-[[3-[3-Fluoro-4-(4-acety- l-1-piperazinyl)phenyl]-
P-90 Z (b) 2-oxo-5-oxazolidinyl]methyl]-- 2-methylpropane-
thioamide 144 (S)-N-[[3-[3-Fluoro-4-(4-ace-
tyl-1-piperazinyl)phenyl]- P-90 Z (c) 2-oxo-5-oxazolidinyl]methyl-
]cyclopropanecarbo- thioamide; mp 159-160.degree. C.; Anal. calcd
for C.sub.20H.sub.25FN.sub.4O.sub.3S: C, 57.13; H, 5.99; N, 13.32;
S, 7.62. Found: C, 57.05; H, 6.01; N, 13.15; S, 7.45. 145
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]- P-90 Z (d)
2-oxo-5-oxazolidinyl]methyl]butanethioamide 146
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]- P-90 Z (e)
2-oxo-5-oxazolidinyl]methyl]-3-methylbutane- thioamide 147
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]- P-90 Z (f)
2-oxo-5-oxazolidinyl]methyl]-2-methylbutane- thioamide 148
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]- P-90 Z (g)
2-oxo-5-oxazolidinyl]methy;]-3,3-dimethylbutane- thioamide 149
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl]- P-90 Z (h)
2-oxo-5-oxazolidinyl]methyl]cyclobutanecarbo- thioamide 150
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phenyl- ]- P-90 Z (i)
2-oxo-5-oxazolidinyl]methyl]cyclopentanecarbo- thioamide 151
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)phe- nyl]- P-90 Z (j)
2-oxo-5-oxazolidinyl]methyl]cyclohexanecarbo- thioamide 152
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperazinyl)p- henyl]- P-90 Z (k)
2-oxo-5-oxazolidinyl]methy;]-2-cyclopropyletha- ne- thioamide 153
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-piperaz- inyl)phenyl]- P-90 Z (l)
2-oxo-5-oxazolidinyl]methyl]-2-cyclobuty- lethane- thioamide 154
(S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-pi- perazinyl)phenyl]- P-90 Z (m)
2-oxo-5-oxazolidinyl]methyl]-2-cycl- opentylethane- thioamide 155
(S)-N-[[3-[3,5-Difluoro-4-(4-a- cetyl-1-piperazinyl)- P-91 Ethyl
phenyl]-2-oxo-5-oxazolidinyl]met- hyl]thioacetamide dithio- acetate
156 (S)-N-[[3-[3,5-Difluoro-4-(4-acetyl-1-piperazinyl)- P-91 Z (a)
phenyl]-2-oxo-5-oxazolidinyl]methyl]propane- thioamide 157
(S)-N-[[3-[3,5-Difluoro-4-(4-acetyl-1-piperazinyl)- P-91 Z (b)
phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methyl- propanethioamide 158
(S)-N-[[3-[3,5-Difluoro-4-(4-acetyl-1-piperazinyl)- P-91 Z (c)
pjhenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopropane- carbothioamide
159 (S)-N-[[3-[4-(4-Acetyl-1-piperazinyl)phenyl]-2-- oxo-5- P-92
Ethyl oxazolidinyl]methyl]thioacetamide dithio- acetate 160
(S)-N-[[3-[4-(4-Acetyl-1-piperazinyl)phenyl]-2-ox- o-5- P-92 Z (a)
oxazolidinyl]methyl]propanethioamide 161
(S)-N-[[3-[4-(4-Acetyl-1-piperazinyl)phenyl]-2-oxo-5- P-92 Z (b)
oxazolidinyl]methyl]-2-methylpropanethioamide 162
(S)-N-[[3-[4-(4-Acetyl-1-piperazinyl)phenyl]-2-oxo-5- P-92 Z (c)
oxazolidinyl]methyl]cyclopropanecarbothioamide 163
(S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-
thioacetamide acetate 164 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl-
)-1- P-93 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
propanethioamide 165 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacet- yl)-1-
P-93 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl- ]-2-
methylpropanethioamide 166 (S)-N-[[3-[3-Fluoro-4-[4-(m-
ethoxyacetyl)-1- P-93 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]- cyclopropanecarbothiamide 167
(S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 Z (d)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- butanethioamide
168 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 Z (e)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-
methylbutanethioamide 169 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-
-1- P-93 Z (f) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
- methylbutanethioamide 170 (S)-N-[[3-[3-Fluoro-4-[4-(metho-
xyacetyl)-1- P-93 Z (g) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-3,3- dimethylbutanethioamide 171
(S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 Z (h)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclobutanecarbothioamide 172 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyace-
tyl)-1- P-93 Z (i) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methy-
l]- cyclopentanecarbothioamide 173 (S)-N-[[3-[3-Fluoro-4-[4-
-(methoxyacetyl)-1- P-93 Z (j) piperazinyl]phenyl]-2-oxo-5-oxazol-
idinyl]methyl]- cyclohexanecarbothioamide 174
(S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 Z (k)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
cyclopropylethanethioamide 175 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyac-
etyl)-1- P-93 Z (l) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]-2- cyclobutylethanethioamide 176
(S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 Z (m)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
cyclopentylethanethioamide 177 (S)-N-[[3-[3,5-Difluoro-[4-[4-(meth-
oxyacetyl)-1- P-94 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]- dithio- thioacetamide acetate 178
(S)-N-[[3-[3,5-Dilfuooro[4-[4-(methoxyacetyl)-1- P-94 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
179 (S)-N-[[3-[3,5-Difluoro-[4-[4-(methoxyacetyl)- -1- P-94 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- -
methylpropanethioamide 180 (S)-N-[[3-[3,5-Difluoro[4-[4-(-
methoxyacetyl)-1- P-94 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]- cyclopropanecarbothioamide 181
(S)-N-[[3-[4-[4-(methoxyacetyl)-1-piperazinyl]phenyl]- P-95 Ethyl
2-oxo-5-oxazolidinyl]methyl]thioacetamide 182
(S)-N-[[3-[4-[4-(methoxyacetyl)-1-piperazinyl]phenyl]- P-95 Z (a)
2-oxo-5-oxazolidinyl]methyl]propanethioamide 183
(S)-N-[[3-[4-[4-(methoxyacetyl)-1-piperazinyl]phenyl]- P-95 Z (b)
2-oxo-5-oxazolidinyl]methyl]-2-methylpropane- thioamide 184
(S)-N-[[3-[4-[4-(methoxyacetyl)-1-piperazinyl]phenyl]- P-95 Z (c)
2-oxo-5- oxazolidinyl]methyl]cyclopropanecarbothioamide 185
(S)-N-[[3-[3-Fluoro-4-[4-(cyanoacetyl)-1-piperazinyl]- P-96 Ethyl
phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide dithio- acetate
186 (S)-N-[[3-[3-Fluoro-4-[4-(cyanoacetyl)-1-piperaziny- l]- P-96 Z
(a) phenyl]-2-oxo-5-oxazolidinyl]methyl]propanethio- amide 187
(S)-N-[[3-[3-Fluoro-4-[4-(cyanoacetyl)-1-piperazin- yl]- P-96 Z (b)
phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-methyl- propanethioamide 188
(S)-N-[[3-[3-Fluoro-4-[4-(cyanoacetyl)-1- -piperazinyl]- P-96 Z (c)
phenyl]-2-oxo-5-oxazolidinyl]methyl]cyc- lopropane- carbothiamide
189 (S)-N-[[3-[3,5-Difluoro-4-[4-(- cyanoacetyl)-1- P-97 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidin- yl]- dithio-
methyl]thioacetamide acetate 190
(S)-N-[[3-[3,5-Difluoro-4-[4-(cyanoacetyl)-1- P-97 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]- methyl]propanethioamide
191 (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanoace- tyl)-1- P-97 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methy- l]-2-
methylpropanethioamide 192 (S)-N-[[3-[3,5-Difluoro-4--
[4-(cyanoacetyl)-1- P-97 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazol-
idinyl]- methyl]cyclopropanecarbothioamide 193
(S)-N-[[3-[4-[4-(Cyanoacetyl)-1-piperazinyl]phenyl]-2- P-98 Ethyl
oxo-5-oxazolidinyl]methyl]thioacetamide dithio- acetate 194
(S)-N-[[3-[4-[4-(Cyanoacetyl)-1-piperazinyl]phenyl]-2- P-98 Z (a)
oxo-5-oxazolidinyl]methyl]propanethioamide 195
(S)-N-[[3-[4-[4-(Cyanoacetyl)-1-piperazinyl]phenyl]-2- P-98 Z (b)
oxo-5-oxazolidinyl]methyl]-2-methylpropanethioamide 196
(S)-N-[[3-[4-[4-(Cyanoacetyl)-1-piperazinyl]phenyl]-2- P-98 Z (c)
oxo-5-oxazolidinyl]methyl]cyclopropanecarbothio- amide 197
(S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide 198
(S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
199 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 200 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxy-
acetyl)-1- P-99 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]- cyclopropanecarbothioamide 201
(S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 Z (d)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- butanethioamide
202 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 Z (e)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-
methylbutanethioamide 203 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-
-1- P-99 Z (f) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
- methylbutanethioamide 204 (S)-N-[[3-[3-Fluoro-4-[4-(aceto-
xyacetyl)-1- P-99 Z (g) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-3,3- dimethylbutanethioamide 205
(S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 Z (h)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclobutanecarbothioamide 206 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyace-
tyl)-1- P-99 Z (i) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methy-
l]- cyclopentanecarbothioamide 207 (S)-N-[[3-[3-Fluoro-4-[4-
-(acetoxyacetyl)-1- P-99 Z (j) piperazinyl]phenyl]-2-oxo-5-oxazol-
idinyl]methyl]- cyclohexanecarbothioamide 208
(S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 Z (k)
piperazinyl]phenyl]-2-oxo-5-oxazlidinyl]methyl]-2-
cyclopropylethanethioamide 209 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyac-
etyl)-1- P-99 Z (l) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]-2- cyclobutylethanethioamide 210
(S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 Z (m)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
cyclopentylethanethioamide 211 (S)-N-[[3-[3,5-Difluoro-4-[4-(aceto-
xyacetyl)-1- P-100 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]- thioacetamide 212 (S)-N-[[3-[3,5-Difluoro-4-[4-(ac-
etoxyacetyl)-1- P-100 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidin-
yl]methyl]- propanethioamide 213 (S)-N-[[3-[3,5-Difluoro-4--
[4-(acetoxyacetyl)-1- P-100 Z (b) piperazinyl]phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]-2- methylpropanethioamide 214
(S)-N-[[3-[3,5-Difluoro-4-[4-(acetoxyacetyl)-1- P-100 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 215 (S)-N-[[3-[4-[4-(Acetoxyacetyl)-1-p-
iperazinyl]phenyl]- P-101 Ethyl 2-oxo-5-oxazolidinyl]methyl]thioac-
etamide dithio- acetate 216 (S)-N-[[3-[4-[4-(Acetoxyacet-
yl)-1-piperazinyl]phenyl]- P-101 Z (a) 2-oxo-5-oxazolidinyl]methyl-
]propanethioamide 217
(S)-N-[[3-[4-[4-(Acetoxyacetyl)-1-piperazinyl- ]phenyl]- P-101 Z
(b) 2-oxo-5-oxazolidinyl]methyl]-2-methylpropane- - thioamide 218
(S)-N-[[3-[4-[4-(Acetoxyacetyl)-1-piperazin- yl]phenyl]- P-101 Z
(c) 2-oxo-5-oxazolidinyl]methyl]cyclopropaneca- rbo- thioamide 219
(S)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacety- l)-1- P-102 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- - dithio-
thioacetamide acetate 220
(S)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacetyl)-1- P-102 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
221 (S)-N-[[3-[3-Fluoro-4-[4-(benzyloxyacetyl)-1- P-102 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanecarbothioamide 222 (S)-N-[[3-[3-Fluoro-4-[4-(be-
nzyloxyacetyl)-1- P-102 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]- cyclopropanecarbothioamide 223
(S)-N-[[3-[3,5-Difluoro-4-[4-(benzyloxyacetyl)-1- P-103 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-
thioacetamide acetate 224 (S)-N-[[3-[3,5-Difluoro-4-[4-(benzyloxy-
acetyl)-1- P-103 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]- propanethioamide 225 (S)-N-[[3-[3,5-Difluoro-4-[4-be-
nzyloxyacetyl)-1- P-103 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]-2- methylpropanethioamide 226
(S)-N-[[3-[3,5-Difluoro-4-[4-(benzyloxyacetyl)-1- P-103 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 227 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyca-
rbonyl)-1- P-105 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio-
oxazolidinyl]methyl]thioacetamide acetate 228
(S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-1- P-105 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
229 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-1- P-105 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 230 (S)-N-[[3-[3-Fluoro-4-[4-(methoxy-
carbonyl)-1- P-105 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]- cyclopropanecarbothioamide 231
(S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-1- P-105 Z (d)
piperazinyl]phenyl]-2-oxo-5-oxazlidinyl]methyl]- butanethioamide
232 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-1- P-105 Z (e)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-
methylbutanethioamide 233 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbony-
l)-1- P-105 Z (f) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
-2- methylbutanethioamide 234 (S)-N-[[3-[3-Fluoro-4-[4-(met-
hoxycarbonyl)-1- P-105 Z (g) piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]-3,3- dimethylbutanethioamide 235
(S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-1- P-105 Z (h)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclobutanecarbothioamide 236 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycar-
bonyl)-1- P-105 Z (i) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]- cyclopentanecarbothioamide 237
(S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-1- P-105 Z (j)
piperazinyl]phenyl]-2-oxo-5-oxaolidinyl]methyl]-
cyclohexanecarbothioamide 238 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycar-
bonyl)-1- P-105 Z (k) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]-2- cyclopropylethanethioamide 239
(S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)-1- P-105 Z (l)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
cyclobutylethanethioamide 240 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycar-
bonyl)-1- P-105 Z (m) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]-2- cyclopentylethanethioamide 241
(S)-N-[[3-[3,5-Difluoro-4-[4-(methoxycarbonyl)-1- P-106 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-
thioacetamide acetate 242 (S)-N-[[3-[3,5-Difluoro-4-[4-(methoxyca-
rbonyl)-1- P-106 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]- propanethioamide 243 (S)-N-[[3-[3,5-Difluoro-4-[4-(m-
ethoxycarbonyl)-1- P-106 Z (b) piperazinyl]phenyl]-2-oxo-5-oxaolid-
inyl]methyl]-2- methylpropanethioamide 244
(S)-N-[[3-[3,5-Difluoro-4-[4-(methoxycarbonyl)-1- P-106 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 245 (S)-N-[[3-[4-[4-(methoxycarbonyl)-1-
- P-107 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
dithio- thioacetamide acetate 246 (S)-N-[[3-[4-[4-(methox-
ycarbonyl)-1- P-107 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]- propanethioamide 247 (S)-N-[[3-[4-[4-(methoxycarb-
onyl)-1- P-107 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]-2- methylpropanethioamide 248 (S)-N-[[3-[4-[4-(methoxyc-
arbonyl)-1- P-107 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]m-
ethyl]- cyclopropanecarbothioamide 249
(S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)-1- P-108 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-
thioacetamide; mp 197-198.degree. C.; Anal. calcd for acetate
C.sub.17H.sub.23FN.sub.4O.sub.4S.sub.2: C, 47.43; H, 5.39; N,
13.01; C, 14.89. Found: C, 47.25; H, 5.40; N, 12.82; S, 14.56. 250
(S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)-1- P-108 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide;
mp 207-208.degree. C.; Anal. calcd for
C.sub.18H.sub.25FN.sub.4O.sub.4S.sub.2: 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
(S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)-1- P-108 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide; mp 204-206.degree. C.; Anal. calcd for
C.sub.19H.sub.27FN.sub.4O.sub.4S.sub.2: C, 49.76; H, 5.93; N,
12.22; S, 13.98. Found: C, 49.63; H, 5.92; N, 14.14; S, 13.91. 252
(S)-N-[[3-[3-Fluoro-4-[4-(methanesulfonyl)-1- P-108 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide; Anal. calcd for
C.sub.19H.sub.25FN.sub.4O.sub.4S.sub.2: 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)-1- P-109 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-
thioacetamide acetate 254 (S)-N-[[3-[3,5-Difluoro-4-[4-(methanesu-
lfonyl)-1- P-109 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]me-
thyl]- propanethioamide 255 (S)-N-[[3-[3,5-Difluoro-4-[4-(m-
ethanesulfonyl)-1- P-109 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazoli-
dinyl]methyl]-2- methylpropanethioamide 256
(S)-N-[[3-[3,5-Difluoro-4-[4-(methanesulfonyl)-1- P-109 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 257 (S)-N-[[3-[4-[4-(methanesulfonyl)-1-
- P-110 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
dithio- thioacetamide 258 (S)-N-[[3-[4-[4-(methanesulfonyl- )-1-
P-110 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
propanethioamide 259 (S)-N-[[3-[4-[4-(methanesulfonyl)-1- P-110 Z
(b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 260 (S)-N-[[3-[4-[4-(methanesulfonyl)- -1-
P-110 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 261 (S)-N-[[3-[3-Fluoro-4-[4-(e-
thanesulfonyl)-1- P-111 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolid-
inyl]methyl]- dithio- thioacetamide acetate 262
(S)-N-[[3-[3-Fluoro-4-[4-(ethanesulfonyl)-1- P-111 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
263 (S)-N-[[3-[3-Fluoro-4-[4-(ethanesulfonyl)-1- P-111 Z (b)
piperazinyl]phenyl]-2-oxo-5-exazolidinyl]methyl]-2-
methylpropanethioamide 264 (S)-N-[[3-[3-Fluoro-4-[4-(ethanes-
ulfonyl)-1- P-111 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]m-
ethyl]- cyclopeopanecarbothioamide 265
(S)-N-[[3-[3,5-Difluoro-4-[4-(ethanesulfonyl)-1- P-112 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-
thioacetamide acetate 266 (S)-N-[[3-[3,5-Difluoro-4-[4-(ethanesul-
fonyl)-1- P-112 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]- propanethioamide 267 (S)-N-[[3-[3,5-Difluoro-4-[4-(et-
hanesulfonyl)-1- P-112 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]-2- methylpropanethioamide 268
(S)-N-[[3-[3,5-Difluoro-4-[4-(ethanesulfonyl)-1- P-112 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 269 (S)-N-[[3-[4-[4-(ethanesulfonyl)-1--
piperazinyl]phenyl]- P-113 Ethyl 2-oxo-5-oxazolifinyl]methyl]thioa-
cetamide dithio- acetate 270 (S)-N-[[3-[4-[4-(ethanesulf-
onyl)-1-piperazinyl]phenyl]- P-113 Z (a) 2-oxo-5-oxazolidinyl]meth-
yl]-2-methylpropanethioamide 271
(S)-N-[[3-[4-[4-(ethanesulfonyl)-1- -piperazinyl]phenyl]- P-113 Z
(b) 2-oxo-5-oxazolidinyl]methyl]-2-m- ethylpropane- thioamide 272
(S)-N-[[3-[4-[4-(ethanesulfonyl- )-1-piperazinyl]phenyl]- P-113 Z
(c) 2-oxo-5-oxazolidinyl]methyl]c- yclopropanecarbothio- amide 273
(S)-N-[[3-[3-Fluoro-4-[4-(c- hloromethanesulfonyl)-1- P-114 Ethyl
piperazinyl]phenyl]-2-oxo-5-o- xazolidinyl]methyl]- dithio-
thioacetamide acetate 274
(S)-N-[[3-[3-Fluoro-4-[4-(chloromethanesulfonyl)-1- P-114 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
275 (S)-N-[[3-[3-Fluoro-4-[4-(chloromethanesulfon- yl)-1- P-114 Z
(b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl- ]-2-
methylpropanethioamide 276 (S)-N-[[3-[3-Fluoro-4-[4-(c-
hloromethanesulfonyl)-1- P-114 Z (c) piperazinyl]phenyl]-2-oxo-5-o-
xazolidinyl]methyl]- cyclopropanecarbothioamide 277
(S)-N-[[3-[3,5-Difluoro-4-[4-(chloromethanesulfonyl)- P-115 Ethyl
1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-
thioacetamide acetate 278 (S)-N-[[3-[3,5-Difluoro-4-[4-(chloromet-
hanesulfonyl)- P-115 Z (a) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]- propanethioamide 279 (S)-N-[[3-[3,5-Difluoro-4-
-[4-(chloromethanesulfonyl)- P-115 Z (b) 1-piperazinyl]phenyl]-2-o-
xo-5-oxazolidinyl]methyl]-2- methylpropanethioamide 280
(S)-N-[[3-[3,5-Difluoro-4-[4-(chloromethanesulfonyl)- P-115 Z (c)
1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 281 (S)-N-[[3-[4-[4-(chloromethanesulfo-
nyl)-1- P-116 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methy-
l]- dithio- thioacetamide 282 (S)-N-[[3-[4-[4-(chlorometha-
nesulfonyl)-1- P-116 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidiny-
l]methyl]- propanethioamide 283 (S)-N-[[3-[4-[4-(chlorometh-
anesulfonyl)-1- P-116 Z (b) piperazinyl]phenyl]-2-oxo-5-pxazolidin-
yl]methyl]-2- methylpropanethioamide 284
(S)-N-[[3-[4-[4-(chloromethanesulfonyl)-1- P-116 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 285 (S)-N-[[3-[3-Fluoro-4-[4-(cyanometh-
ane-sulfonyl)-1- P-117 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio-
oxazolidinyl]methyl]thioacetamide acetate 286
(S)-N-[[3-[3-Fluoro-4-[4-(cyanomethane-sulfonyl)-1- P-117 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
287 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethane-sulfon- yl)-1- P-117 Z
(b) piperazinyl]phenyl]020oxo-5-oxazolidinyl]methyl- ]-2-
methylpropanethioamide 288 (S)-N-[[3-[3-Fluoro-4-[4-(c-
yanomethane-sulfonyl)-1- P-117 Z (c) piperazinyl]phenyl]-2-oxo-5-o-
xazolidinyl]methyl]- cyclopropanecarbothioamide 289
(S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethane-sulfonyl)- P-118 Ethyl
1-piperazinyl]phenyl]-2-oxo-5- dithio- oxazolidinyl]methyl]thioa-
cetamide acetate 290 (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethane-su-
lfonyl)- P-118 Z (a) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]propanethioamide 291 (S)-N-[[3-[3,5-Difluoro-4-[4-(-
cyanomethane-sulfonyl)- P-118 Z (b) 1-piperazinyl]phenyl]-2-oxo-5--
oxazolidinyl]methyl]-2- methylpropanethioamide 292
(S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethane-sulfonyl)- P-118 Z (c)
1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 293 (S)-N-[[3-[4-[4-(Cyanomethanesulfon-
yl)-1- P-119 Ethyl piperazinyl]phenyl]-2-oxo-5- dithio-
oxazolidinyl]methyl]thioacetamide acetate 294
(S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)-1- P-119 Z (a)
piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]propanethioamide
295 (S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)-1- P-119 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 296 (S)-N-[[3-[4-[4-(Cyanomethanesulfonyl)--
1- P-119 Z (c) piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]cyclopropanecarbothioamide 297
(S)-N-[[3-[3-Fluoro-4-[4-(N-methylsulfomaoyl)-1- P-120 Ethyl
piperazinyl]phenyl]-2-oxo-5- dithio- oxazolidinyl]methyl]thioace-
tamide acetate 298 (S)-N-[[3-[3-Fluoro-4-[4-(N-methylsulfamoyl)-1-
P-120 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
propanethioamide 299 (S)-N-[[3-[3-Fluoro-4-[4-(N-methylsulfamo-
yl)-1- P-120 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl-
]-2- methylpropanethioamide 300 (S)-N-[[3-[3-Fluoro-4-[4-(N-
-methylsulfamoyl)-1- P-120 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]- cyclopropanecarbothioamide 301
(S)-N-[[3-[3,5-Difluoro-4-[4-(N-methylsulfamoyl)-1- P-121 Ethyl
piperazinyl]phenyl]-2-oxo-5- dithio- oxazolidinyl]methyl]thioace-
tamide acetate 302 (S)-N-[[3-[3,5-Difluoro-4-[4-(N-methylsulfamoyl-
)-1- P-121 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
propanethioamide 303 (S)-N-[[3-[3,5-Difluoro-4-[4-(N-methy-
lsulfamoyl)-1- P-121 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidiny-
l]methyl]-2- methylpropanethioamide 304
(S)-N-[[3-[3,5-Difluoro-4-[4-(N-methylsulfamoyl)-1- P-121 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 305 (S)-N-[[3-[4-[4-(N-methylsulfamoyl)-
-1- P-122 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
dithio- thioacetamide acetate 306 (S)-N-[[3-[4-[4-(N-meth-
ylsulfamoyl)-1- P-122 Z (a) piperazinyl]phenyl]-2-oxo-5-oxazolidin-
yl]methyl]- propanethioamide 307 (S)-N-[[3-[4-[4-(N-methyls-
ulfamoyl)-1- P-122 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-2- methylpropanethioamide 308
(S)-N-[[3-[4-[4-(N-methylsulfamoyl)-1- P-122 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 309 (S)-N-[[3-[30Fluoro-4-[4-(N,N-dimet-
hylsulfamoyl)-1- P-123 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]- dithio- thioacetamide acetate 310
(S)-N-[[3-[3-Fluoro-4-[4-(N,N-dimethylsulfamoyl)-1- P-123 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
311 (S)-N-[[3-[3-Fluoro-4-[4-(N,N-dimethylsulfamo- yl)-1- P-123 Z
(b) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl- ]-2-
methylpropanethioamide 312 (S)-N-[[3-[3-Fluoro-4-[4-(N-
,N-dimethylsulfamoyl)-1- P-123 Z (c) piperazinyl]phenyl]-2-oxo-5-o-
xazolidinyl]methyl]- cyclopropanecarbothioamide 313
(S)-N-[[3-[3,5-Difluoro-4-[4-(N,N-dimethylsulfamoyl)- P-124 Ethyl
1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- dithio-
thioacetamide 314 (S)-N-[[3-[3,5-Difluoro-4-[4-(N,Ndimethylsulfamo-
yl)- P-124 Z (a) 1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl-
]- propanethioamide 315 (S)-N-[[3-[3,5-Difluoro-4-[4-(N,N-d-
imethylsulfamoyl)- P-124 Z (b) 1-piperazinyl]phenyl]-2-oxo-5-oxazo-
lidinyl]methyl]-2- methylpropanethioamide 316
(S)-N-[[3-[3,5-Difluoro-4-[4-(N,N-dimethylsulfamoyl)- P-124 Z (c)
1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 317 (S)-N-[[3-[4-[4-(N,N-dimethylsulfam-
oyl)-1- P-125 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methy-
l]- dithio- thioacetamide acetate 318
(S)-N-[[3-[4-[4-(N,N-dimethylsulfamoyl)-1- P-125 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
319 (S)-N-[[3-[4-[4-(N,N-dimethylsulfamoyl)-1- P-125 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 320 (S)-N-[[3-[4-[4-(N,N-dimethylsulf-
amoyl)-1- P-125 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]- cyclopropanecarbothioamide 321
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 Ethyl
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- thioacetamide 322
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
323 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 324 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxyc-
arbonyl)-1- P-126 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]m-
ethyl]- cyclopropanecarbothioamide 325
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 Z (d)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- butanethioamide
326 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 Z (e)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-
methylbutanethioamide 327 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl-
)-1- P-126 Z (f) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]--
2- methylbutanethioamide 328 (S)-N-[[3-[3-Fluoro-4-[4-(etho-
xycarbonyl)-1- P-126 Z (g) piperazinyl]phenyl]-2-oxo-5-oxazolidiny-
l]methyl]-3,3- dimethylbutanethioamide 329
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 Z (h)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclobutanecarbothioamide 330 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarb-
onyl)-1- P-126 Z (i) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]meth-
yl]- cyclopentanecarbothioamide 331 (S)-N-[[3-[3-Fluoro-4-[-
4-(ethoxycarbonyl)-1- P-126 Z (j) piperazinyl]phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]- cyclohexanecarboamide 332
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 Z (k)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropylethanethioamide 333 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycar-
bonyl)-1- P-126 Z (l) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]met-
hyl]-2- cyclobutylethanthioamide 334
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 Z (m)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
cyclopentylethanethioamide 335 (S)-N-[[3-[3,5-Difluoro-4-[4-(ethox-
ycarbonyl)-1- P-127 Ethyl piperazinyl]phenyl]-2-oxo-5-oxazolidinyl-
]methyl]- dithio- thioacetamide 336
(S)-N-[[3-[3,5-Difluoro-4-[4-(ethoxycarbonyl)-1- P-127 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
337 (S)-N-[[3-[3,5-Difluoro-4-[4-(ethoxycarbonyl)- -1- P-127 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- -
methylpropanethioamide 338 (S)-N-[[3-[3,5-Difluoro-4-[4-(-
ethoxycarbonyl)-1- P-127 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazoli-
dinyl]methyl]- cyclopropanecarbothioamide 339
(S)-N-[[3-[4-[4-(ethoxycarbonyl)-1-piperazinyl]- P-128 Ethyl
phenyl]-2-oxo-5-oxazolidinyl]methyl]thioacetamide dithio- acetate
340 (S)-N-[[3-[4-[4-(ethoxycarbonyl)-1-piperazinyl]- P-128 Z (a)
phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide 341
(S)-N-[[3-[4-[4-(ethoxycarbonyl)-1-piperaziny- l]- P-128 Z (b)
phenyl]-2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide 342
(S)-N-[[3-[4-[4-(ethoxycarbonyl)-1-pipe- razinyl]- P-128 Z (c)
phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclopro- pane- carbothioamide
343 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- -1-piperazinyl)- P-129
Ethyl phenyl]-2-oxo-5-oxazolidinyl]methyl]t- hioacetamide dithio-
acetate 344 (S)-N-[[3-[3-Fluoro-4-(- 4-sulfamoyl-1-piperazinyl)-
P-129 Z (a) phenyl]-2-oxo-5-oxazolidin- yl]methyl]-
propanethioamide 345 (S)-N-[[3-[3-Fluoro-4-(4-s-
ulfamoyl-1-piperazinyl)- P-129 Z (b) phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-2- methylpropanethioamide 346
(S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1-piperazinyl)- P-129 Z (c)
phenyl]-2-oxo-5-oxazolidinyl]methyl]- cyclopropanecarbothioamide
347 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 Z (d)
piperazinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]butanethioamide
348 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 Z (e)
piper4azinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-3-
methylbutanethioamide 349 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1-
P-129 Z (f) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylbutanethioamide 350 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl- -1-
P-129 Z (g) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-3- ,3-
dimethylbutanethioamide 351 (S)-N-[[3-[3-Fluoro-4-(4-su- lfamoyl-1-
P-129 Z (h) piperazinyl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]cyclobutanecarbothioamide 352
(S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 Z (h)
piperazinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]cyclopentanecarb-
othioamide 353 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 Z (j)
piperazinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]cyclohexane-
carbothioamide 354 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 Z
(k) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
cyclopropylethanethioamide 355 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl--
1- P-129 Z (l) piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
356 (S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 Z (m)
piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
cyclopentylethanethioamide 357 (S)-N-[[3-[3,5-Difluoro-4-(4-sulfam-
oyl-1- P-130 Ethyl piperazinyl)phenyl]-2-oxo-5- dithio-
oxazolidinyl]methyl]thioacetamide acetate 358
(S)-N-[[3-[3,5-Difluoro-4-(4-sulfamoyl-1- P-130 Z (a)
piperazinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]propanethioamide
359 (S)-N-[[3-[3,5-Difluoro-4-(4-sulfamoyl-1- P-130 Z (b)
piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 360 (S)-N-[[3-[3,5-Difluoro-4-(4-sulfamoyl--
1- P-130 Z (c) piperazinyl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]cyclopropanecarbothioamide 361
(S)-N-[[3-[4-(4-sulfamoyl-1-piperazinyl)phenyl]-2-oxo- P-131 Ethyl
5-oxazolidinyl]methyl]thioacetamide dithio- acetate 362
(S)-N-[[3-[4-(4-sulfamoyl-1-piperazinyl)phenyl]-2-oxo- P-131 Z (a)
5-oxazolidinyl]methyl]propanethioamide 363
(S)-N-[[3-[4-(4-sulfamoyl-1-piperazinyl)phenyl]-2-oxo- P-131 Z (b)
5-oxazolidinyl]methyl]-2-methylpropanethioamide 364
(S)-N-[[3-[4-(4-sulfamoyl-1-piperazinyl)phenyl]-2-oxo- P-131 Z (c)
5-oxazolidinyl]methyl]cyclopropanecarbothioamide 365
(S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)-1- P-132 Ethyl
piperazinyl]phenyl]-2-oxo-5- dithio- oxazolidinyl]methyl]thioace-
tamide 366 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)-1- P-132 Z (a)
piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]propanethio- amide
367 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)-1- P-132 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 368 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)--
1- P-132 Z (c) piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]cyclopropanecarbothioamide 369
(S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethyl)-1- P-133 Ethyl
piperazinyl]phenyl]-2-oxo-5- dithio- oxazolidinyl]methyl]thioace-
tamide acetate 370 (S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethyl)-1-
P-133 Z (a) piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]propanethioamide 371 (S)-N-[[3-[3,5-Difluoro-4-
-[4 cyanomethyl)-1- P-133 Z (b) piperazinyl]phenyl]-2-oxo-5-oxazol-
idinyl]methyl]-2- methylpropanethioamide 372
(S)-N-[[3-[3,5-Difluoro-4-[4-(cyanomethyl)-1- P-133 Z (c)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
cyclopropanecarbothioamide 373 (S)-N-[[3-[4-[4-(cyanomethyl)-1-pip-
erazinyl]phenyl]-2- P-134 Ethyl oxo-5-oxazolidinyl]methyl]thioacet-
amide dithio- acetate 374 (S)-N-[[3-[4-[4-(cyanomethyl)--
1-piperazinyl]phenyl]-2- P-134 Z (a) oxo-5-oxazolidinyl]methyl]pro-
panethioamide 375
(S)-N-[[3-[4-[4-(cyanomethyl)-1-piperazinyl]pheny- l]-2- P-134 Z
(b) oxo-5-oxazolidinyl]methyl]-2-methylpropanethioam- ide 376
(S)-N-[[3-[4-[4-(cyanomethyl)-1-piperazinyl]phenyl]- P-134 Z (c)
2-oxo-5-oxazolidinyl]methyl]cyclopropane- carbothioamide 377
(S)-N-[[3-[3-Fluoro-4-[3-(2-fluoroethyl)-1- P-135 Ethyl
piperazinyl]phenyl]-2-oxo-5- dithio-
oxazolidinyl]methyl]thioacetamide acetate 378
(S)-N-[[3-[3-Fluoro-4-[4-(2-fluoroethyl)-1- P-135 Z (a)
piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]propanethioamide
379 (S)-N-[[3-[3-Fluoro-4-[4-(2-fluoroethyl)-1- P-135 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 380 (S)-N-[[3-[3-Fluoro-4-[43-(2-fluoroethy-
l)-1- P-135 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-
- cyclopropanecarbothioamide 381 (S)-N-[[3-[3,5-Difluoro-4--
[4-(2-fluoroethyl)-1- P-136 Ethyl piperazinyl]phenyl]-2-oxo-5-oxaz-
olidinyl]methyl]- dithio- thioacetamide acetate 382
(S)-N-[[3-[3,5-Difluoro-4-[4-(2-fluoroethyl)-1- P-136 Z (a)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]- propanethioamide
383 (S)-N-[[3-[3,5-Difluoro-4-[4-(2-fluoroethyl)-- 1- P-136 Z (b)
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-2-
methylpropanethioamide 384 (S)-N-[[3-[3,5-Difluoro-4-[4-(2-
-fluoroethyl)-1- P-136 Z (c) piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]- cyclopropanecarbothioamide 385
(S)-N-[[3-[4-[4-(2-fluoroethyl)-1-piperazinyl]phenyl]- P-137 Ethyl
2-oxo-5-oxazolidinyl]methyl]thioacetamide dithio- acetate 386
(S)-N-[[3-[4-[4-(2-fluoroethyl)-1-piperazinyl]phenyl]- P-137 Z (a)
2-oxo-5-oxazolidinyl]methyl]propanethioamide 387
(S)-N-[[3-[4-[4-(2-fluoroethyl)-1-piperazinyl]phenyl]- P-137 Z (b)
2-oxo-5-oxazolidinyl]methyl]-2- methylpropanethioamide 388
(S)-N-[[3-[4-[4-(2-fluoroethyl)-1-piperazinyl]phenyl]- P-137 Z (c)
2-oxo-5-oxazolidinyl]methyl]cyclopropane- carbothioamide 389
(S)-N-[[3-[3-Fluoro-4-(4-formyl-1-piperazinyl)phenyl]- P-138 Ethyl
2-oxo-5-oxazolidinyl]methyl]thioacetamide; Ana calcd dithio- for
C.sub.17H.sub.21FN.sub.4O.sub.3S: C, 53.67; H, 5.56; N, 14.73; S,
acetate 8.43. Found: C, 53.14; H, 5.42; N, 14.25; S, 8.18. 390
(S)-N-[[3-[3-Fluoro-4-(4-formyl-1-piperazinyl)phenyl]- P-138 Z (a)
2-oxo-5-oxazolidinyl]methyl]propanethioamide; mp 166-167.degree.
C.; Anal. calcd for C.sub.18H.sub.23FN.sub.4O.sub.3S: 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. 391 (S)-N-[[3-[3-Fluoro-4-(4-formyla-1-piper- azinyl)phenyl]-
P-138 Z (b) 2-oxo-5-oxazolidinyl]methyl]-2-methylp- ropane-
thioamide; mp 157-158.degree. C.: Anal. calcd for
C.sub.19H.sub.25FN.sub.4O.sub.3S: C, 55.87, H, 6.17; N, 13.72; S,
7.85. Found: C, 55.67; H, 6.19; N, 13.50; S, 7.70. 392
(S)-N-[[3-Fluoro-4-(4-formyla-1-piperazinyl)phenyl]- P-138 Z (c)
2-oxo-5-oxazolidinyl]methyl]cyclopropane- carbothioamide; mp
178-179.degree. C.; Anal. calcd for C.sub.19H.sub.23FN.sub.4O.sub-
.3S: C, 56.14; H, 5.70; N, 13.78; S, 7.89. Found: C, 56.13; H,
5.64; N, 13.64; S, 7.75. 393 (S)-N-[[3-[3,5-Difluoro-4-(4-formyl-1-
-piperazinyl)- P-139 Ethyl phenyl]-2-oxo-5-oxazolidinyl]methyl]thi-
oacetamide dithio- acetate 394 (S)-N-[[3-[3,5-Difluoro-4-
-(4-formyl-1-piperazinyl)- P-139 Z (a) phenyl]-2-oxo-5-oxazolidiny-
l]methyl]- propanethioamide 395 (S)-N-[[3-[3,5-Difluoro-4-(-
4-formyla-1-piperazinyl)- P-139 Z (b) phenyl]-2-oxo-5-oxazolidinyl-
]methyl]-2-methyl- propanethioamide 396
(S)-N-[[3-[3,5-Difluoro-4-(4-formyla-1-piperazinyl)- P-139 Z (c)
phenyl]-2-oxo-5-oxazolidinyl]methyl]cyclo- propanecarbothioamide
397 (S)-N-[[3-[4-(4-formyl-1-piperazinyl)phenyl]-2-oxo-5- P-140
Ethyl oxazolidinyl]methyl]thioacetamide dithio- acetate 398
(S)-N-[[3-[4-(4-formyl-1-piperazinyl)phenyl]-2-oxo-5- P-140 Z (a)
oxazolidinyl]methyl]propanethioamide 399
(S)-N-[[3-[4-(4-formyl-1-piperazinyl)phenyl]-2-oxo-5- P-140 Z (b)
oxazolidinyl]methyl]-2-methylpropanethioamide 400
(S)-N-[[3-[4-(4-formyl-1-piperazinyl)phenyl]-2-oxo-5- P-140 Z (c)
oxazolinyl]methyl]cyclopropane-carbothiamide
[0874] 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 are obtained.
[0875] 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.
12TABLE I Isothiocyanate Example Corresponding No. Product to Amine
No. Amine 401 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-1- P-90 methylamine
piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-N'-methylthiourea 402 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-
P-90 dimethylamine piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-N',N'-dimethylthiourea 403 (S)-N-[[3-[3-Fluoro-4-(4-a-
cetyl-1- P-90 azetidine piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
- methyl]-1-azetidinecarbothioamide 404
(S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)- P-90 anhydrous
phenyl]-2-oxo-5-oxazolidinyl]methyl]- ammonia thiourea 405
(S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 methylamine
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-N'-methylthiourea 406 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyace-
tyl)-1- P-93 dimethylamine piperazinyl]phenyl]-2-oxo-5-oxazolidin-
yl]- methyl]-N',N'-dimethylthiourea 407
(S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)-1- P-93 azetidine
piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-1-
azetidinecarbothioamide 408 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacety-
l)-1- P-99 methylamine piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-N'-methylthiourea 409 (S)-N-[[3-[3-Fluoro-4-[4-(ac-
etoxyacetyl)-1- P-99 dimethylamine piperazinyl]phenyl]-2-oxo-5-ox-
azolidinyl]- methyl]-N',N'-dimethylthiourea 410
(S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)-1- P-99 azetidine
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-1-azetidinecarbothioamide 411 (S)-N-[[3-[3-Fluoro-4-[4-(me-
thoxycarbonyl)- P-105 methylamine 1-piperazinyl]phenyl]-2-oxo-5-ox-
azolidinyl]- methyl]-N'-methylthiourea 412
(S)-N-[[3-[3-Fluoro-4-[4-(methoxycarbonyl)- P-105 dimethylamine
1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-N',N'-dimethylthiourea 413 (S)-N-[[3-[3-Fluoro-4-[4-(metho-
xycarbonyl)- P-105 azetidine 1-piperazinyl]phenyl]-2-oxo-5-oxazoli-
dinyl]- methyl]-1-azetidinecarbothioamide 414
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 methylamine
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-N'-methylthiourea 415 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarb-
onyl)-1- P-126 dimethylamine piperazinyl]phenyl]-2-oxo-5-oxazolidi-
nyl]- methyl]-N',N'-dimethylthiourea 416
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycarbonyl)-1- P-126 azetidine
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-1-azetidinecarbothioamide 417 (S)-N-[[3-[3-Fluoro-4-(4-sul-
famoyl-1- P-129 methylamine piperazinyl)phenyl]-2-oxo-5-oxazolidin-
yl]- methyl]-N'-methylthiourea 418 (S)-N-[[3-[3-Fluoro-4-(4-
-sulfamoyl-1- P-129 dimethylamine piperazinyl)phenyl]-2-oxo-5-oxaz-
olidinyl]- methyl]-N',N'-dimethylthiourea 419
(S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 azetidine
piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-1-azetidinecarbothioamide
[0876] 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.
13TABLE J Isothio- cyanate Ex- Corres- am- ponding to ple Amine No.
Product No. Amine 420 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-1- P-90
methanol piperazinyl)phenyl]2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 421 (S)-N-[[3-[3-Fluoro-4-(4-acetyl--
1- P-90 ethanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-ethylthiocarbamate 422 (S)-N-[[3-[3-Fluoro-4-(4-acetyl-1-
- P-90 isopropyl piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]- alcohol
methyl]-O-iso-propylthiocarbamate 423
(S)-N-[[3-[3,5-Difluoro-4-(4-acetyl-1- P-91 methanol
piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 424 (S)-N-[[3-[4-(4-Acetyl-1- P-92
methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 425 (S)-N-[[3-[3-Fluoro-4-[4-(methox-
yacetyl)- P-93 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazoli-
dinyl]-methyl]-O-methylthiocarbamate 426
(S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)- P-93 ethanol
1-piperazinyl]phenyl]-2-oxo-5-oxazoli- dinyl]methyl]-O-ethylthioc-
arbamate 427 (S)-N-[[3-[3-Fluoro-4-[4-(methoxyacetyl)- P-93
isopropyl 1-piperazinyl]phenyl]-2-oxo-5- alcohol
oxazolidinyl]-methyl]-O-iso- propylthiocarbamate 428
(S)-N-[[3-[3,5-Difluoro-[4-[4-(methoxy- P-94 methyl-
acetyl)-1-piperazinyl]phenyl]-2-oxo-5- aminel
oxazolidinyl]methyl]-O-methylthio- carbamate 429
(S)-N-[[3-[4-[4-(methoxyacetyl)-1- P-95 methyl-
piperazinyl]phenyl]-2-oxo-5- amine oxazolidinyl]methyl]-O-methyl-
thio- carbamate 430 (S)-N-[3-[3-Fluoro-4-[4-(cyanoacetyl)-1- - P-96
methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 431 (S)-N-[[3-[3,5-Difluoro-4-[4-(cy-
ano- P-97 methanol acetyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]-methyl]-O-methylthio- carbamate 432
(S)-N-[[3-[4-[4-(Cyanoacetyl)-1- P-98 methanol
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 433 (S)-N-[[3-[3-Fluoro-4-[4-(acetox-
yacetyl)- P-99 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazoli-
dinyl]-methyl]-O-methylthiocarbamate 434
(S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)- P-99 ethanol
1-piperazinyl]phenyl]-2-oxo-5-oxazoli- dinyl]-methyl]-O-ethylthio-
carbamate 435 (S)-N-[[3-[3-Fluoro-4-[4-(acetoxyacetyl)- P-99
isopropyl 1-piperazinyl]phenyl]-2-oxo-5-oxazoli- alcohol
dinyl]-methyl]-O-iso-propylthiocarbamate 436
(S)-N-[[3-[3,5-Difluoro-4-[4-(acetoxy- P-100 methanol
acetyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]-methyl]-O-me-
thylthio- carbamate 437 (S)-N-[[3-[4-[4-(Acetoxyacetyl)-1- P-101
methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 438 (S)-N-[[3-[3-Fluoro-4-[4-(benzyl-
oxy- P-102 methanol acetyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]-methyl]-O-methylthio- carbamate 439
(S)-N-[[3-[3,5-Difluoro-4-[4-(benzyloxy- P-103 methanol
acetyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-met-
hylthio- carbamate 440 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycar- -
P-105 methanol bonyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]-methyl]-O-methylthio- carbamate 441
(S)-N-[[3-[3-Fluoro-4-[4-(methoxycar- P-105 ethanol
bonyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]-methyl]-O-eth-
ylthio- carbamate 442 (S)-N-[[3-[3-Fluoro-4-[4-(methoxycar- P-105
isopropyl bonyl)-1-piperazinyl]phenyl]-2-oxo-5- alcohol
oxazolidinyl]-methyl]-O-iso-propylthio- carbamate 443
(S)-N-[[3-[3,5-Difluoro-4-[4-(methoxy- P-106 methanol
carbonyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-m-
ethylthio- carbamate 444 (S)-N-[[3-[4-[4-(methoxycarbonyl)-- 1-
P-107 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 445 (S)-N-[[3-[3-Fluoro-4-[4-(meth-
anesul- P-108 methanol fonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxa-
zolidinyl]-methyl]-O-methylthiocarbamate 446
(S)-N-[[3-[3,5-Difluoro-4-[4-(methane- P-109 methanol
sulfonyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-m-
ethylthio- carbamate 447 (S)-N-[[3-[4-[4-(methanesulfonyl)-- 1-
P-110 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 448 (S)-N-[[3-[3-Fluoro-4-[4-(etha-
nesulfonyl)- P-111 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazoli-
dinyl]-methyl]-O-methylthiocarbamate 449
(S)-N-[[3-[3,5-Difluoro-4-[4-(ethane- P-112 methanol
sulfonyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]cycl-
opropane- carbothioamide 450 (S)-N-[[3-[4-[4-(ethanesulfony- l)-1-
P-113 methanol piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O-methylthio- carbamate 451
(S)-N-[[3-[3-Fluoro-4-[4-(chloromethane- P-114 methanol
sulfonyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-m-
ethylthio- carbamate 452 (S)-N-[[3-[3,5-Difluoro-4-[4-(chlo- ro-
P-115 methanol methanesulfonyl)-1-piperazinyl]phenyl]-2-
oxo-5-oxazolidinyl]methyl]-O-methyl- thiocarbamate 453
(S)-N-[[3-[4-[4-(chloromethanesulfonyl)- P-116 methanol
1-piperazinyl]phenyl]-2-oxo-5-oxazolidi- nyl]methyl]-O-methylthio-
carbamate 454 (S)-N-[[3-[3-Fluoro-4-[4-(cyanomethane- P-117
methanol sulfonyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O-methylthio- carbamate 455
(S)-N-[[3-[3,5-Difluoro-4-[4-(cyano- P-118 methanol
methane-sulfonyl)-1-piperazinyl]phenyl]- 2-oxo-5-oxazolidinyl]met-
hyl]-O- methylthiocarbamate 456 (S)-N-[[3-[4-[4-(Cyanometha-
nesulfonyl)- P-119 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxazoli-
dinyl]-methyl]-O-methylthiocarbamate 457
(S)-N-[[3-[3-Fluoro-4-[4-(N-methyl- P-120 methanol
sulfamoyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-O--
methylthio- carbamate 458 (S)-N-[[3-[3,5-Difluoro-4-[4-(N-m- ethyl-
P-121 methanol sulfamoyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O-methylthio- carbamate 459
(S)-N-[[3-[4-[4-(N-methylsulfamoyl)-1- P-122 methanol
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 460 (S)-N-[[3-[3-Fluoro-4-[4-(N,N-di-
methyl- P-123 methanol sulfamoyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O-methylthio- carbamate 461
(S)-N-[[3-[3,5-Difluoro-4-[4-(N,N-di- P-124 methanol
methyl-sulfamoyl)-1-piperazinyl]phenyl]- 2-oxo-5-oxazolidinyl]met-
hyl]-O-methyl- thiocarbamate 462 (S)-N-[[3-[4-[4-(N,N-dimet-
hylsulfamoyl)- P-125 methanol 1-piperazinyl]phenyl]-2-oxo-5-oxa-
zolidinyl]methyl]-O-methylthiocarbamate 463
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycar- P-126 methanol
bonyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]-methyl]-O-met-
hylthio- carbamate 464 (S)-N-[[3-[3-Fluoro-4-[4-(ethoxycar- P-126
ethanol bonyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]-methyl]-O-ethylthio- carbamate 465
(S)-N-[[3-[3-Fluoro-4-[4-(ethoxycar- P-126 isopropyl
bonyl)-1-piperazinyl]phenyl]-2-oxo-5- alcohol
oxazolidinyl]-methyl]-O-iso-propylthio- carbamate 466
(S)-N-[[3-[3,5-Difluoro-4-[4-(ethoxy- P-127 methanol
carbonyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-m-
ethylthio- carbamate 467 (S)-N-[[3-[4-[4-(ethoxycarbonyl)-1- -
P-128 methanol piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O-methylthio- carbamate 468
(S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 methanol
piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate, 469 (S)-N-[[3-[3-Fluoro-4-(4-sulfam-
oyl-1- P-129 ethanol piperazinyl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O-ethylthio- carbamate 470
(S)-N-[[3-[3-Fluoro-4-(4-sulfamoyl-1- P-129 isopropyl
piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]- alcohol
methyl]-O-iso-propylthiocarbamate 471 (S)-N-[[3-[3,5-Difluoro-4-(4-
-sulfamoyl-1- P-130 methanol piperazinyl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O-methylthio- carbamate 472
(S)-N-[[3-[4-(4-sulfamoyl-1-piperazinyl)- P-131 methanol
phenyl]-2-oxo-5-oxazolidinyl]methyl]-O- methylthiocarbamate 473
(S)-N-[[3-[3-Fluoro-4-[4-(cyanomethyl)-1- P-132 methanol
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 474 (S)-N-[[3-[3,5-Difluoro-4-[4-(cy-
ano- P-133 methanol methyl)-1-piperazinyl]phenyl]-2-oxo-5-
oxazolidinyl]-methyl]-O-methylthio- carbamate 475
(S)-N-[[3-[4-[4-(cyanomethyl)-1- P-134 methanoll
piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 476 (S)-N-[[3-[3-Fluoro-4-[4-(2-fluo-
roethyl)-1- P-135 methanol piperazinyl]phenyl]-2-oxo-5-oxazolidiny-
l]- methyl]-O-methylthiocarbamate 477
(S)-N-[[3-[3,5-Difluoro-4-[4-(2-fluoro- P-136 methanol
ethyl)-1-piperazinyl]phenyl]-2-oxo-5- oxazolidinyl]-methyl]-O-met-
hylthio- carbamate 478 (S)-N-[[3-[4-[4-(2-fluoroethyl)-1- P-137
methanol piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 479 (S)-N-[[3-[3-Fluoro-4-(4-formyl--
1- P-138 methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 480 (S)-N-[[3-[3,5-Difluro-4-(4-fo-
rmyl-1- P-139 methanol piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyl]-O-methylthiocarbamate 481 (S)-N-[[3-[4-(4-formyl-1-
-piperazinyl)- P-140 methanol phenyl]-2-oxo-5-oxazolidinyl]methyl]-
-O- methylthiocarbamate
EXAMPLE 482
(5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5--
oxazolidinyl]methyl]thioacetamide, thiazepine S-oxide
[0877] 211
[0878] Step 1. Hexahydro-5-oxo-1,4-thiazepine is prepared according
to the procedure described by Gallego (J. Org. Chem. 1993, 58,
3905-3911).
[0879] 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.degree. C. The reaction mixture is stirred at 0.degree. 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.
[0880] 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.sub.2Cl.sub.2 (100 mL)
and washed with saturated aqueous NH.sub.4Cl (35 mL). The phases
are separated and the organics are dried (MgSO.sub.4), 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.degree. C.; Anal. Calcd for
C.sub.11H.sub.13FN.sub.2O.sub.2S: 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.
[0881] 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 CuSO.sub.4 (11.9 mL). The mixture is cooled to 0.degree. C.
and NaBH.sub.4 (4.1 g) is added in portions. The reaction mixture
turns very dark and is stirred at 0.degree. 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.times.200 mL). The combined organics are dried (MgSO.sub.4),
filtered and concentrated to afford the aniline intermediate.
[0882] Step 5. The dark residue from Step 4 is dissolved in 2:1
acetone/water (255 mL) and cooled to 0.degree. C. To this stirred
mixture is added solid NaHCO.sub.3 (5.4 g) followed by
benzylchloroformate (7.7 mL). The reaction mixture is stirred at
0.degree. C. for 10 min, then at room temperature for 24 h. The
reaction mixture is quenched with 10% aqueous NaHSO.sub.4 (200 mL)
and then poured into EtOAc (300 mL). The phases are separated and
the aqueous phase is extracted with EtOAc (2.times.250 mL). The
combined organics are dried (MgSO.sub.4), 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.degree. C.; Anal. Calcd for
C.sub.19H.sub.21FN.sub.2O.sub.2S: C, 63.31; H, 5.87; N, 7.77; S,
8.89. Found: C, 63.31; H, 5.97; N, 7.69; S, 8.79.
[0883] Step 6. To a stirred solution of the carbamate from Step 5
(3.0 g) in dry THF (33 mL) under N.sub.2 cooled to 78.degree. 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.degree. C. for 35
min, then R-glycidyl butyrate (1.2 mL) is added. The reaction
mixture is stirred at 78.degree. C. for 30 min, then at room
temperature overnight during which time a precipitate forms. The
reaction mixture is quenched with saturated aqueous NH.sub.4Cl (33
mL) and poured into EtOAc (100 mL). The phases are separated. The
organic phase is washed with saturated aqueous NaHCO.sub.3 (50 mL),
brine (50 mL), dried (MgSO.sub.4), filtered and concentrated. The
residue is purified by flash chromatography using EtOAc as the
eluent to afford 2.5 g of a hydroxymethyl oxazolidinone. Mp
100-102.degree. C. Anal. Calcd for
C.sub.15H.sub.19FN.sub.2O.sub.3S: 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.
[0884] Step 7. To a stirred solution of the alcohol prepared in
Step 6 (1.7 g) in CH.sub.2Cl.sub.2 (35 mL) cooled to 0.degree. C.,
is added triethylamine (1.1 mL) followed by methanesulfonyl
chloride (0.5 mL). The reaction mixture is stirred at 0.degree. C.
for 10 min, then at room 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.sub.2Cl.sub.2 (35 mL). The
combined organic phases are dried (MgSO.sub.4), 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.degree. C. Anal. Calcd for C.sub.16H.sub.21
FN.sub.2O.sub.5S.sub.2: C, 47.51; H, 5.23; N, 6.93; S, 15.85.
Found: C, 47.18; H, 5.28; N, 6.84; S, 15.60.
[0885] 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.sub.3OH
(40 mL) until saturated (approx. 5 min). The reaction mixture is
heated in a sealed tube at 100.degree. C. for 72 h. The cooled
reaction mixture is concentrated to give the crude amine, which is
immediately suspended in CH.sub.2Cl.sub.2 (35 mL) and cooled to
0.degree. C. To this stirred suspension is added triethylamine
(0.97 mL, 6.9 mmol) followed by di-tert-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
CH.sub.2Cl.sub.2 (75 mL) and washed with H.sub.2O (1.times.50 mL).
The organic phase is dried (MgSO.sub.4), filtered and concentrated.
The resulting residue is purified on a Biotage 40 S column using
30-35% ethyl acetate in CH.sub.3OH as the eluent to afford 867.4 mg
of the protected amine. mp 74-75.degree. C. Anal Cald: C, 56.45; H,
6.63; N, 9.88. Found: C, 56.95; H, 6.85; N, 9.55.
[0886] Step 9. To a stirred suspension of the protected amine
prepared in Step 8 (205.2 mg) in 1:1 CH.sub.3OH/H.sub.2O (6 mL)
cooled to 0.degree. C. is added sodium meta periodate (113.5 mg).
The resulting suspension is stirred at RT for 18 h. The reaction
mixture is filtered and the solid is washed with CH.sub.2Cl.sub.2
(2.times.20 mL). The filtrate is extracted with H.sub.2O
(1.times.10 mL). The phases are separated. The aqueous phase is
extracted with CH.sub.2Cl.sub.2 (1.times.25 mL). The combined
organic phases are dried (MgSO.sub.4), filtered and concentrated.
The white solid residue is purified on a Biotage 12 M column using
5% CH.sub.3OH in CH.sub.2Cl.sub.2 as the eluent to afford 187.3 mg
of the sulfoxide. mp 78-81.degree. C.
[0887] Step 10. Dry HCl gas is passed over the surface of a stirred
solution of the sulfoxide prepared in Step 9 (179.3 mg) in
CH.sub.3OH (2 mL) cooled to 0.degree. C. for 1 minute. The reaction
mixture is stirred at 0.degree. C. for 10 min, then at room
temperature for 15 min, then concentrated. The resulting yellow
residue is suspended in THF (5 mL) and CH.sub.2Cl.sub.2 (5 mL) and
cooled to 0.degree. C. To this stirred suspension is added
triethylamine (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 CH.sub.2Cl.sub.2 (30
mL) and washed with H.sub.2O (2.times.15 mL). The organic phases
are dried (MgSO.sub.4), filtered and concentrated. The dark residue
is purified on a Biotage 12 M column using 5% CH.sub.3OH in
CH.sub.2Cl.sub.2 as the eluent to afford 71.5 mg of the title
compound as a tan solid. mp 85-89.degree. C.
[0888] Following the general procedure outlined in Step 10 of
Example 482, but substituting the dithioesters listed below, the
compounds of Examples 483 to 495 of Table K can be obtained.
14TABLE K Example Dithioester No. Compound Amine (from Preparation
Z) 483 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
propanethioamide, thiazepine S-oxide 212 Z(a) 484
S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylpropanethio- amide,
thiazepine S- oxide. 213 Z(b) 485 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopropanecarbothio- amide, thiazepine S-
oxide. 214 Z(c) 486 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
butanethioamide, thiazepine S-oxide 215 Z(d) 487
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]-3- methylbutanethioamide,
thiazepine S-oxide 216 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
217 Z(f) 489 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
3,3-dimethylbutanethio- amide, thiazepine S- oxide 218 Z(g) 490
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclobutanecarbothio- amide,
thiazepine S- oxide 219 Z(h) 491 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-1- cyclopentanecarbothio- amide, thiazepine S-
oxide 220 Z(i) 492 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
cyclohexanecarbothio- amide, thiazepine S- oxide 221 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 222 Z(k) 494 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- cyclobutylethanethio- amide, thiazepine S-
oxide 223 Z(l) 495 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
cyclopentylethanethio- amide, thiazepine S- oxide 224 Z(m)
EXAMPLE 496
(5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]thioacetamide, thiazepine S-oxide
[0889] 225
[0890] 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-difluoronitrobenzene in Step 1.
[0891] 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.
15TABLE L Example Dithioester No. Compound Amine (from Preparation
Z) 497 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro-
1,4-thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
propanethioamide, thiazepine S-oxide 226 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 227 Z(b) 499 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro-
1,4-thiazepin-4(5H)-yl)- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
cyclopropanecarbothio- amide, thiazepine S- oxide 228 Z(c)
EXAMPLE 500
(5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]thioacetamide, thiazepine S-oxide
[0892] 229
[0893] The title compound can be prepared by the procedure of
Example 482, by substituting an appropriate quantity of
4-fluoronitrobenzene for 3,4-difluoronitrobenzene in Step 1.
[0894] Utilizing the amine prepared in Example 500, but
substituting the dithioester listed below for ethyl dithioacetate
in the final step, the compounds of Examples 501 to 503 of Table M
are obtained
16TABLE M Example Dithioester No. Compound Amine (from Preparation
Z) 501 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide, thiazepine
S-oxide 230 Z(a) 502 (5S)-N-[[3-[4- (Tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
methylpropanethio- amide, thiazepine S- oxide 231 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 232 Z(c)
EXAMPLE 504
(5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5--
oxazolidinyl]methyl]thioacetamide, thiazepine S,S-dioxide
[0895] 233
[0896] Step 1. To a stirred solution of the thiazepine prepared in
Step 8 of Example 482 (243.7 mg) in 25% H.sub.2O/acetone (8 mL) is
added 4methylmorpholine N-oxide (201.5 mg) followed by a solution
of osmium tetroxide in 2methyl-2-propanol (2.5 wt %, 30 .mu.L). 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 CH.sub.2Cl.sub.2 (50 mL). The phases are
separated. The aqueous phase is extracted with CH.sub.2Cl.sub.2
(2.times.25 mL). The combined organic phases are washed with brine
(1.times.25 mL), dried (MgSO.sub.4), filtered and concentrated. The
residue is purified on a Biotage 40 S column using 1% CH.sub.3OH in
CH.sub.2Cl.sub.2 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.degree.
C.
[0897] Step 2. Dry HCl gas is passed over the surface of a stirred
solution of the thiazepine S,S-dioxide prepared in Step 1 (108.2
mg) in CH.sub.3OH(3 mL) at 0.degree. C. for 1 minute. The reaction
mixture is stirred at 0.degree. C. for 10 min and then at room
temperature for 15 min. The reaction is concentrated and the yellow
residue is suspended in CH.sub.2Cl.sub.2 (2 mL) and THF (2 mL).
This stirred suspension is cooled to 0.degree. 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 0.degree. C. for 10 min then at room
temperature for 18 h. The reaction mixture is poured into
CH.sub.2Cl.sub.2 (20 mL) and washed with H.sub.2O (2.times.10 mL).
The organic phase was dried (MgSO.sub.4), filtered and
concentrated. The residue is purified on a Biotage 12 M column
using 2% CH.sub.3OH in CH.sub.2Cl.sub.2 as the eluent to afford
77.3 mg of the title compound as a white solid. mp 88-90.degree.
C.
[0898] 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.
17TABLE N Example Dithioester No. Compound Amine (from Preparation
Z) 505 (5S)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyl]-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide, thiazepine
S,S-dioxide 234 Z(a) 506 (5S)-N-[[3-[3-Fluoro-4-
(4-thiomorpholinyl]- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
methylpropanethio- amide, thiazepine S,S- dioxide 235 Z(b) 507
(5S)-N-[[3-[3-Fluoro-4- (4-thiomorpholinyl]- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopropanecarbothio- amide, thiazepine S,S-
dioxide 236 Z(c)
EXAMPLE 508
(5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4-(5H)-yl)phenyl]-2-o-
xo-5-oxazolidinyl]methyl]thioacetamide, thiazepine S,S-dioxide
[0899] 237
[0900] 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.
[0901] 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.
18TABLE O Example Dithioester No. Compound Amine (from Preparation
Z) 509 (5S)-N-[[3-[3,5- Difluoro-4-(4- thiomorpholinyl]-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- propanethioamide, thiazepine
S,S-dioxide 238 Z(a) 510 (5S)-N-[[3-[3,5- Difluoro-4-(4-
thiomorpholinyl]- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
methylpropanethio- amide, thiazepine S,S- dioxide 239 Z(b) 511
(5S)-N-[[3-[3,5- Difluoro-4-(4- thiomorpholinyl]- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclopropanecarbothio- amide, thiazepine S,S-
dioxide 240 Z(c)
EXAMPLE 512
(5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]thioacetamide, thiazepine S,S-dioxide
[0902] 241
[0903] 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-difluoronitrobenzene in Step 1 of
Example 482.
[0904] 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.
19TABLE P Example Dithioester No. Compound Amine (From Preparation
Z) 513 (5S)-N-[[3-[4- (tetrahydro-1,4- thiazepin-4(5H)-
yl))phenyl]-2-oxo-5- oxazolidinyl]- methyl]propanethio- amide,
thiazepine S,S- dioxide 242 Z(a) 514 (5S)-N-[[3-[4-
(tetrahydro-1,4- thiazepin-4(5H)- yl))phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- methylpropanethio- amide, thiazepine S,S-
dioxide 243 Z(b) 515 (5S)-N-[[3-[4- (tetrahydro-1,4-
thiazepin-4(5H)- yl))phenyl]-2-oxo-5- oxazolidinyl]-
methyl]cyclopropane- carbothioamide, thiazepine S,S-dioxide 244
Z(c)
EXAMPLE 516
(5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4-(5H)-yl)phenyl]-2-oxo-5-
-oxazolidinyl]methyl]thioacetamide
[0905] 245
[0906] This compound is prepared according to the procedure of Step
8 in Example 482, but stubstituting an appropriate quantity of
ethyl dithioacetate for di-tert-butyl dicarbonate; mp
129-131.degree. C.
[0907] Utilizing the amine prepared in Step 8 of Example 482, but
substituting an appropriate quantity of the dithioester listed
below for di-tert-butyl dicarbonate, the compounds of Examples 517
to 529 of Table Q are obtained.
20TABLE Q Example Dithioester No. Compound Amine (From Preparation
Z) 517 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
propanethioamide 246 Z(a) 518 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- methylpropanethioamide 247 Z(b) 519
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclopropanecarbothio- amide
248 Z(c) 520 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
butanethioamide 249 Z(d) 521 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-3- methylbutanethioamide 250 Z(e) 522
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- methylbutanethioamide 251
Z(f) 523 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
3,3-dimethylbutanethio- amide 252 Z(g) 524 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]- cyclobutanecarbothioamide 253 Z(h) 525
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- cyclopentanecarbothio- amide
254 Z(i) 526 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
cylcohexanecarbothio- amide 255 Z(j) 527 (5S)-N-[[3-[3-5 Fluoro-
4-(tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- cyclopropylethanethio- amide 256 Z(k) 528
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]-2- cyclobutylethanethio-
amide 257 Z(l) 529 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-2-
cyclopentylethanethioamide 258 Z(m)
EXAMPLE 530
(5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]thioacetamide
[0908] 259
[0909] 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.
[0910] Utilizing the amine prepared in Example 530, but
substituting an appropriate quantity of the dithioester listed
below for di-tert-butyl dicarbonate, the compounds of Examples 531
to 533 of Table R can be prepared.
21TABLE R Example Dithio Compound No. Compound Amine (from
Preparation Z) 531 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro-
1,4-thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]methyl]-
propanethioamide 260 Z(a) 532 (5S)-N-[[3-[3,5-
Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- methylpropanethioamide 261 Z(b) 533
(5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]methyl]- yclopropanecarbothio- amide
262 (c)
EXAMPLE 534
(5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)yl)phenyl]-2-oxo-5-oxazolidin-
yl]methyl]thioacetamide; mp 129-131.degree. C.
[0911] 263
[0912] This compound can be prepared according to the procedures of
Example 482 and Example 516, but substituting an appropriate
quantity of 4-fluoronitrobenzene for 3,4-difluoronitrobenzene in
Step 1 of Example 482.
[0913] Utilizing the amine prepared in Example 534, but
substituting an appropriate quantity of the dithioester listed
below for di-tert-butyl dicarbonate, the compounds of Examples 535
to 537 of Table S can be prepared.
22TABLE S Example Dithio Compound No. Compound Amine (from
Preparation Z) 535 (5S)-N-[[3-[4- (Tetrahydro-1,4-
thiazepin-4(5H)-yl))- phenyl]-2-oxo-5- oxazolidinyl]-
methyl]propanethio- amide 264 Z(a) 536 (5S)-N-[[3-[4-
(Tetrahydro-1,4- thiazepin-4(5H)-yl))- phenyl]-2-oxo-5-
oxazolidinyl]methyl]-2- methylpropanethioamide 265 Z(b) 537
(5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-yl))-
phenyl]-2-oxo-5- oxazolidinyl]- methyl]cyclopropane- carbothioamide
266 Z(c)
EXAMPLE 538
(5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5--
oxazolidinyl]methyl]thiourea, thiazepine S-oxide
[0914] 267
[0915] This compound can be prepared by the procedure described in
Example 33, but substituting the amine prepared in Example 482 for
the amine 33.
[0916] 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.
23TABLE T Example Amine or No. Compound Isothiocyanate Alcohol 539
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea,
thiazepine S-oxide 268 CH.sub.3NH.sub.2 540 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]- N',N'-dimethylthiourea, thiazepine S-oxide
269 (CH.sub.3).sub.2NH 541 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-1-
azetidinecarbothioamide, thiazepine S-oxide 270 Azetidine 542
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- methylthiocarbamate,
thiazepine S-oxide 271 CH.sub.3OH 543 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- ethylthiocarbamate, thiazepine S-oxide 272
CH.sub.3CH.sub.2OH 544 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-
isopropylthiocarbamate, thiazepine S-oxide 273
(CH.sub.3).sub.2CHOH
EXAMPLE 545
(5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]thiourea, thiazepine S-oxide
[0917] 274
[0918] This compound can be prepared by the procedure described in
Example 33, but substituting the amine prepared in Example 496 for
the amine 33.
[0919] 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.
24TABLE U Example Amine or No. Compound Isothiocyanate Alcohol 546
(5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea,
thiazepine S-oxide 275 CH.sub.3NH.sub.2 547 (5S)-N-[[3-[3,5-
Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]- N',N'-dimethylthiourea, thiazepine S-oxide
276 (CH.sub.3).sub.2NH 548 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro-
1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-1-
azetidinecarbothioamide, thiazepine S-oxide 277 Azetidine 549
(5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- methylthiocarbamate,
thiazepine S-oxide 278 CH.sub.3OH 550 (5S)-N-[[3-[3,5-
Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- ethylthiocarbamate, thiazepine S-oxide 279
CH.sub.3CH.sub.2OH 551 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro-
1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-
isopropylthiocarbamate, thiazepine S-oxide 280
(CH.sub.3).sub.2CHOH
EXAMPLE 552
(5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]thiourea, thiazepine S-oxide
[0920] 281
[0921] This compound can be prepared by the procedure described in
Example 33, but substituting the amine prepared in Example 500 for
the amine 33.
[0922] 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.
25TABLE V Example Amine or No. Compound Isothiocyanate Alcohol 553
(5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea,
thiazepine S-oxide 282 CH.sub.3NH.sub.2 554 (5S)-N-[[3-[4-
(Tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]- N',N'-dimethylthiourea, thiazepine S-oxide
283 (CH.sub.3).sub.2NH 555 (5S)-N-[[3-[4- (Tetrahydro-1,4-
thiazepin-4(5H)- oxazolidinyl]methyl]-1- azetidinecarbothioamide,
thiazepine S-oxide 284 Azetidine 556 (5S)-N-[[3-[4-
(Tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- methylthiocarbamate, thiazepine S-oxide 285
CH.sub.3OH 557 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- ethylthiocarbamate,
thiazepine S-oxide 286 CH.sub.3CH.sub.2OH 558 (5S)-N-[[3-[4-
(Tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- isopropylthiocarbamate, thiazepine S-oxide
287 (CH.sub.3).sub.2CHOH
EXAMPLE 559
(5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5--
oxazolidinyl]methyl]thiourea, thiazepine S,S-dioxide
[0923] 288
[0924] This compound can be prepared by the procedure described in
Example 33, but substituting the amine prepared in Example 504 for
the amine 33.
[0925] 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.
26TABLE W Example Amine or No. Compound Isothiocyanate Alcohol 560
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea,
thiazepine S,S-dioxide 289 CH.sub.3NH.sub.2 561
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]- N',N'-dimethylthiourea,
thiazepine S,S-dioxide 290 (CH.sub.3).sub.2NH 562
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-1-
azetidinecarbothioamide, thiazepine S,S-dioxide 291 Azetidine 563
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- methylthiocarbamate,
thiazepine S,S-dioxide 292 CH.sub.3OH 564 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- ethylthiocarbamate, thiazepine S,S-dioxide
293 CH.sub.3CH.sub.2OH 565 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-
isopropylthiocarbamate, thiazepine S,S-dioxide 294
(CH.sub.3).sub.2CHOH
EXAMPLE 566
(5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]thiourea, thiazepine S,S-dioxide
[0926] 295
[0927] This compound can be prepared by the procedure described in
Example 33, but substituting the amine prepared in Example 508 for
the amine 33.
[0928] 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.
27TABLE X Example Amine or No. Compound Isothiocyanate Alcohol 567
(5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea,
thiazepine S,S-dioxide 296 CH.sub.3NH.sub.2 568 (5S)-N-[[3-[3,5-
Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]- N',N'-dimethylthiourea, thiazepine
S,S-dioxide 297 (CH.sub.3).sub.2NH 569 (5S)-N-[[3-[3,5-
Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-1- azetidinecarbothioamide, thiazepine
S,S-dioxide 298 Azetidine 570 (5S)-N-[[3-[3,5-
Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- methylthiocarbamate, thiazepine S,S-dioxide
299 CH.sub.3OH 571 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro-
1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-
ethylthiocarbamate, thiazepine S,S-dioxide 300 CH.sub.3CH.sub.2OH
572 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- isopropylthiocarbamate,
thiazepine S,S-dioxide 301 (CH.sub.3).sub.2CHOH
EXAMPLE 573
(5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]thiourea, thiazepine S,S-dioxide
[0929] 302
[0930] This compound can be prepared by the procedure described in
Example 33, but substituting the amine prepared in Example 512 for
the amine 33.
[0931] 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.
28TABLE Y Example Amine or No. Compound Isothiocyanate Alcohol 574
(5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea,
thiazepine S,S-dioxide 303 CH.sub.3NH.sub.2 575 (5S)-N-[[3-[4-
(Tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]- N',N'-dimethylthiourea, thiazepine
S,S-dioxide 304 (CH.sub.3).sub.2NH 576 (5S)-N-[[3-[4-
(Tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-1- azetidinecarbothioamide, thiazepine
S,S-dioxide 305 Azetidine 577 (5S)-N-[[3-[4- (Tetrahydro-1,4-
thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-
methylthiocarbamate, thiazepine S,S-dioxide 306 CH.sub.3OH 578
(5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- ethylthiocarbamate,
thiazepine S,S-dioxide 307 CH.sub.3CH.sub.2OH 579 (5S)-N-[[3-[4-
(Tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- isopropylthiocarbamate, thiazepine
S,S-dioxide 308 (CH.sub.3).sub.2CHOH
EXAMPLE 580
(5S)-N-[[3-[3-Fluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5--
oxazolidinyl]methyl]thiourea
[0932] 309
[0933] 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.
[0934] 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.
29TABLE Z Example Amine or No. Compound Isothiocyanate Alcohol 581
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea 310
CH.sub.3NH.sub.2 582 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-
N',N'-dimethylthiourea 311 (CH.sub.3).sub.2NH 583
(5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-1- azetidinecarbothioamide
312 Azetidine 584 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4-
thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-
methylthiocarbamate 313 CH.sub.3OH 585 (5S)-N-[[3-[3-Fluoro-4-
(tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- ethylthiocarbamate 314 CH.sub.3CH.sub.2OH
586 (5S)-N-[[3-[3-Fluoro-4- (tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- isopropylthiocarbamate
315 (CH.sub.3).sub.2CHOH
EXAMPLE 587
(5S)-N-[[3-[3,5-Difluoro-4-(tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-ox-
o-5-oxazolidinyl]methyl]thiourea
[0935] 316
[0936] This compound can be prepared by the procedure described in
Example 33, but substituting the amine prepared in Example 530 for
the amine 33.
[0937] 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.
30TABLE AA Example Amine or No. Compound Isothiocyanate Alcohol 588
(5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea 317
CH.sub.3NH.sub.2 589 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro-
1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-
N',N'-dimethylthiourea 318 (CH.sub.3).sub.2NH 590 (5S)-N-[[3-[3,5-
Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-1- azetidinecarbothioamide 319 Azetidine 591
(5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- methylthiocarbamate 320
CH.sub.3OH 592 (5S)-N-[[3-[3,5- Difluoro-4-(tetrahydro-
1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-
ethylthiocarbamate 321 CH.sub.3CH.sub.2OH 593 (5S)-N-[[3-[3,5-
Difluoro-4-(tetrahydro- 1,4-thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-O- isopropylthiocarbamate 322
(CH.sub.3).sub.2CHOH
EXAMPLE 594
(5S)-N-[[3-[4-(Tetrahydro-1,4-thiazepin-4(5H)-yl)phenyl]-2-oxo-5-oxazolidi-
nyl]methyl]thiourea
[0938] 323
[0939] This compound can be prepared by the procedure described in
Example 33, but substituting the amine prepared in Example 534 for
the amine 33.
[0940] 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.
31TABLE BB Example Amine or No. Compound Isothiocyanate Alcohol 595
(5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-N'- methylthiourea 324
CH.sub.3NH.sub.2 596 (5S)-N-[[3-[4- (Tetrahydro-1,4-
thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-
N',N'-dimethylthiourea 325 (CH.sub.3).sub.2NH 597 (5S)-N-[[3-[4-
(Tetrahydro-1,4- thiazepin-4(5H)- yl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]-1- azetidinecarbothioamide 326 Azetidine 598
(5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- methylthiocarbamate 327
CH.sub.3OH 599 (5S)-N-[[3-[4- (Tetrahydro-1,4- thiazepin-4(5H)-
yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O- ethylthiocarbamate 328
CH.sub.3CH.sub.2OH 600 (5S)-N-[[3-[4- (Tetrahydro-1,4-
thiazepin-4(5H)- yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]-O-
isopropylthiocarbamate 329 (CH.sub.3).sub.2CHOH
* * * * *