WO2000032599A1 - Agents antibacteriens oxazolidinone a fonction thiocarbonyle - Google Patents

Agents antibacteriens oxazolidinone a fonction thiocarbonyle Download PDF

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Publication number
WO2000032599A1
WO2000032599A1 PCT/US1998/025308 US9825308W WO0032599A1 WO 2000032599 A1 WO2000032599 A1 WO 2000032599A1 US 9825308 W US9825308 W US 9825308W WO 0032599 A1 WO0032599 A1 WO 0032599A1
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WIPO (PCT)
Prior art keywords
oxo
phenyl
methyl
oxazolidinyl
fluoro
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PCT/US1998/025308
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English (en)
Inventor
Jackson B. Hester, Jr.
Eldon George Nidy
Salvatore Charles Perricone
Toni-Jo Poel
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Pharmacia & Upjohn Company
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Publication date
Application filed by Pharmacia & Upjohn Company filed Critical Pharmacia & Upjohn Company
Priority to CN98814326A priority Critical patent/CN1322204A/zh
Priority to CA002351062A priority patent/CA2351062A1/fr
Priority to PCT/US1998/025308 priority patent/WO2000032599A1/fr
Priority to AU17053/99A priority patent/AU764980B2/en
Priority to KR1020017006622A priority patent/KR20010107987A/ko
Priority to NZ511963A priority patent/NZ511963A/en
Priority to EP98961822A priority patent/EP1133493A1/fr
Priority to JP2000585241A priority patent/JP2002531455A/ja
Publication of WO2000032599A1 publication Critical patent/WO2000032599A1/fr
Priority to HK02102339.4A priority patent/HK1040707A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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,, an alkyl thiourea -NH-C(S)-NH-(C M alkyl), thioamide -NH-C(S)-(C M alkyl) or -NH-C(S)-H.
  • 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 a ⁇ ium.
  • 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.
  • the subject invention is a compound of the Formula I
  • R j is a) H, b) NH 2 , 0 NH-C 1 4 alkyl, d) C M alkyl, e) -OC M alkyl, f) -S C M alkyl, g ) C M alkyl substituted with 1-3 F, 1-2 Cl, CN or -COOC 1 4 alkyl, h) C 3 . 6 cycloalkyl, i) N(C M alkyl) 2 or j) N(CH 2 ) 2 . 5 ;
  • R 2 is a) H, b) F,
  • R 5 and R 6 at each occurrence are the same or different and are a) C j.2 alkyl, or b) R 5 and R 6 taken together are -(CH 2 ) k -;
  • R 8 is a) H, or b) C,. 8 alkyl optionally substituted with one or more halos, or C 3. , cycloalkyl;
  • R I0 and R n at each occurrence are the same or different and are a) H, b) C[. 4 alkyl, or c) C 3 . 8 cycloalkyl;
  • R 13 is a) H, or b) C M alkyl
  • R 14 and R lf i at each occurrence are the same or different and are a) C alkyl, or b) R 14 and R 15 taken together are -(CH) r ; R 16 is a) H, b) C j . 4 alkyl, or
  • R 17 is a) C M alkyl, or b) C 3.8 cycloalkyl
  • R 18 is a) H, b) C__ 4 alkyl, c) C 2 . 4 alkenyl, d) C 3 . 4 cycloalkyl, e) -OR 13 or f) -NR 21 R 22 ;
  • R 19 is a) Cl, b) Br, or c) I;
  • R 20 is a physiologically acceptable cation
  • R 21 and R 2 at each occurrence are the same or different and are a) H, b) C,. 4 alkyl, or c) -N ,,R 22 taken together are -(CH 2 ) m -; wherein R 23 and R 24 at each occurrence are the same or different and are a) H, b) F, c) Cl, d) C,. 2 alkyl, e) CN f) OH, g) C h2 alkoxy, h) nitro, or i) amino;
  • Z 1 is a) -CH 2 -, b) -CH(R 104 )-CH 2 -, c) -C(O)-, or d) -CH,CH 2 CH,-;
  • Z 2 is a) -O 2 S-, b) -O-, c) -N(R 107 )-, d) -OS-, or e) -S-;
  • Z 3 is a) -O 2 S-, b) -O-, c) -OS-, or d) -S-;
  • a 1 is a) H-, or b) CH 3 ;
  • a 2 is a) H-, b) HO-, c) CH 3 -, d) CH 3 O-, e) R 102 O-CH 2 -C(O)-NH- f) R 103 O-C(O)-NH-, g) (C I -C 2 )alkyl-0-C(0)-, h) HO-CH 2 -, i) CH 3 O-NH-, j) (C r C 3 )alkyl-O 2 C- k) CH 3 -C(O)-;
  • a 1 and A 2 taken together are: a)
  • R 102 is a) H-, b) CH 3 -, c) phenyl-CH 2 -, or d) CH 3 C(O)-; wherein R 103 is a) (C j -C ⁇ alkyl-, or b) phenyl-; wherein R 104 is a) H-, or b) HO-; wherein R 105 is a) H-, b) (C 1 -C !
  • R 106 is a) CH 3 -C(O)-, b) H-C(O)-, c) C1.,CH-C(0)-, d) HOCH,-C(0)-, e) CH 3 S0 2 -,
  • R 107 is a) R 102 O-C(R no )(R )-C(O)-, b) R 103 O-C(O)-, c) R 108 -C(O)-,
  • R 109 is a) alkylC 1 -C 4 , b) -CH 2 C1
  • R 110 and R 111 are independently a) H-, b) CH 3 -; or wherein R 112 is a) H-, b) CH 3 O-CH O-CH 2 -, or
  • R 113 is a) CH 3 -, b) HOCH 2 -, c) (CH 3 ) N-phenyl, or d) (CH ) N-CH -; wherein R 114 is a) HO-, b) CH 3 O-, c) H 2 N-, d) CH :!
  • R 113 is a) CH 3 -, b) HOCH 2 -, c) (CH 3 ) 2 N-phenyl, or d) (CH 3 ) 2 N-CH 2 -;
  • R 115 is a) H-, or b) C1-;
  • R 116 is a) HO- b) CH 3 O-, or c) F;
  • R 150 and R 151 are each H or alkyl C,-C 4 or R 150 and R 151 taken together with the nitrogen atom to which each is attached form a monocyclic heterocyclic ring having from 3
  • 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 ⁇ alkyl, or f) NO 2 ;
  • R 4 , R 5 , R 6 , R 7 , R j j , R 14 , R, 5 , R 16 , and R 17 are the same as defined above;
  • R 7 and R 28 at each occurrence are the same or different and are a) H, b) C_ .a alkyl, c) C 3.8 cycloalkyl, d) -(CH 2 ) m OR 13 , e) -(CH 2 ) h -NR 21 R 22 , or f) R 27 and R 8 taken together are -(CH 2 ) 2 O(CH 2 ) 2 -, JCH ⁇ CH CORM or -(CH 2 ) 2 N(CH 2 ) 2 (R 7 );
  • R 38 is a) H, b) C.. 6 alkyl, c) -(CH ) q -aryl, or d) halo;
  • R 40 is a) H, b) C 1 6 alkyl optionally substituted with one or more OH, halo, or -CN, c) -(CHJ q -aryl, or d) -(CH 2 ) q -OR 42 ;
  • R 41 is a) C [ . 6 alkyl optionally substituted with one or more OH, halo, or -CN, b) -(CH ) q -aryl, or c) -(CH 2 ) q -OR 42 ;
  • aryl is a) phenyl, b) pyridyl, or c) napthyl; a to c optionally substituted with one or more halo, -CN, OH, SH, C j . 6 alkyl, C ⁇ alkoxy, or C 1 6 alkylthio; wherein R 43 is a) H, b) C ⁇ jj alkyl, c) F, or d) OH; R 4 is a) H, b) CF 3 , c) C 1 3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R 44 and R 45 taken together are a 5-, 6-, or 7-membered ring of the formula, or
  • R 44 and R 45 taken together are -(CH 2 ) k -, when R 46 is an electron- withdrawing group; R 45 and R 46 at each occurrence are the same or different and are a) an electron-withdrawing group, b) H,
  • U is a) CH 2 , b) O,
  • R 47 is a) H, or b) C..5 alkyl; wherein R 48 is a) carboxyl, b) halo,
  • R 49 and R 50 at each occurrence are the same or different and are a) H, b) C,. regularly alkyl, c ) C 5 . 6 cycloalkyl, or d) R 49 and R 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 1 alkyl, or C ⁇ acyl;
  • R 51 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) -NO , h) alkoxy, i) Ci. 6 alkoxycarbonyl,
  • R 52 and R 53 at each occurrence are the same or different and are a) H, b) C,. 6 alkyl, or c) phenyl;
  • R 56 and R 57 at each occurrence are the same or different and are a) H, b) formyl, c) C M alkyl, d) C ⁇ . 4 acyl, e) phenyl, ) C 3 . 6 cycloalkyl, or g) R 56 and R 57 taken 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,. 3 alkyl, or C ⁇ acyl;
  • R 58 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) -NO 2 , h) C__ 6 alkoxy, i) C j . 6 alkoxycarbonyl, j) C j .g alkythio, k) C 1 6 acyl,
  • R 54 is the same as defined above;
  • R 59 and R 60 at each occurrence are the same or different and are a) H, b) alkyl, c) phenyl, or d) tolyl;
  • R 62 and R 63 at each occurrence are the same or different and are a) H, or b) C 1 4 alkyl optionally substituted with phenyl or pyridyl;
  • R 64 is a) H, or b) a sodium ion;
  • R 65 and R 66 at each occurrence are the same or different and are a) H, b) formyl, c) C M alkyl, d) C,. 4 acyl, e) phenyl, f) C .6 cycloalkyl, g) R 65 and R 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 1 3 alkyl, or C i acyl, h) -P(OXOR 70 XOR 7] ), or i) -SO ⁇ R,,,; R 67 is
  • R 68 is Ci. 3 alkyl
  • R 69 is a) alkoxycarbonyl, or b) carboxyl
  • Kj 0 and R 71 at each occurrence are the same or different and are a) H, or b) C V3 alkyl;
  • R ⁇ is a) methyl, b) phenyl, or c) tolyl; wherein K is a) O, or b) S;
  • R 76 , and R 77 at each occurrence are the same or different and are a) H, b) carboxyl,
  • halo d) -CN, e) mercapto, f) formyl, g ) CF-, h) -NO 2 , i) alkoxy, j) C j .g alkoxycarbonyl, k) C j . 5 alkythio, 1) C,. 6 acyl, m) -J ⁇ 78 79 , n) C,.g aallkkyyll ooppttiioonnaallllyy substituted with OH, C ⁇ alkoxy, C,.
  • R / g and R- 9 at each occurrence are the same or different and are a) H, b) C M alkyl, c) phenyl, or d) R ⁇ g and R 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 w alkyl, or C j _ 3 acyl; wherein T is a) O, b) S, or 0 SO 2 ;
  • R ⁇ s, R 76 , and R 77 are the same as defined above;
  • R 80 is a) H, b) formyl, c) carboxyl, d) Ci_ 6 alkoxycarbonyl, e) C,. 8 alkyl, f) C 2 .
  • R 81 and R 82 at each occurrence are the same or different and are a) H, b) C 3.6 cycloalkyl, c) phenyl, d) C w acyl, e) Cj. 8 alkyl optionally substituted with OH, C j 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
  • V is a) O, b) CH , or c) NR 87 ;
  • R 83 and R 84 at each occurrence are the same or different and are a) H, or b) C,. 4 alkyl;
  • R 85 is a) OH, b) C M alkoxy, or
  • R 88 and R 89 at each occurrence are the same or different and are a) H, b) C ⁇ . 5 alkyl c) C . 6 cycloalky, or d) phenyl;
  • R 90 is a) C l _ s alkyl optionally substituted with C ⁇ g alkoxy or C ⁇ _ 6 hydroxy,
  • C 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 -N0 , CF 3 , halo, -CN, OH, C ⁇ alkyl, C,. 5 alkoxy, or C 1 5 acyl;
  • Rg 2 and R y ! at each occurrence are the same or different and are a) H, b) phenyl, c) C,. 6 alkyl, or d) benzyl;
  • R g7 is co- a) morpholinyl, b) OH, or c) C,. 6 alkoxy; h is 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5;
  • the new compounds of the invention can be prepared using known compounds and intermediates of oxzolidinones, 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.
  • 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, 1 e
  • the prefix C, j defines the number of carbon atoms present from the integer "1" to the integer "j", inclusive
  • C 1 4 alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and lsomenc forms thereof
  • C, _, alkyl refers 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 lsomenc forms thereof
  • C 2 4 alkenyl refers at least one double bond alkenyl group
  • C 2 _ alkynyl refers 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, octatnynyl, nonynyl, nonediynyl, nonat ⁇ ynyl and their lsomenc forms thereof
  • C J 4 cycloalkyl refers 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 lsomenc forms thereof
  • C, , alkoxy refers 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.
  • C I 6 alkylamino and "C, .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.
  • 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.
  • C,. 3 acyl "C M acyl", “C ⁇ acyl", "C,. 6 acyl", “C,. 8 acyl"
  • C 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.
  • alkoxycarbonyl refer to an ester group having an alkyl group of one to four, one to six, or one to eight carbon atoms.
  • C ⁇ 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.
  • C 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.
  • C [.8 alkyl pyridyl” refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one pyridyl radical.
  • C,. 8 hydroxyl refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a hydroxy group.
  • C,. 8 alkylsulfonyl refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a S0 moiety.
  • C 1 6 alkylthio refers to an alkyl group having one to six carbon atoms and isomeric forms thereof attached to a sulfur atom.
  • Het refers to 5 to 10 membered saturated, unsaturated or aromatic heterocyclic rings containing one or more oxygen, nitrogen, and sulfur forming such groups as, for example, pyridine, thiophene, furan, pyrazoline, pyrimi- dine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3- 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-
  • halo refers to fluoro, chloro, bromo, or iodo.
  • the compounds of the present invention can be converted to their salts, where appropriate, according to conventional methods.
  • 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.
  • 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 39 group will not be present.
  • 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 : group, and this invention embraces all possible stereoisomers and geometric forms in these groups.
  • the compounds of this invention are useful for treatment of microbial infections in humans and other warm blooded animals, under both parenteral and oral administration.
  • 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 composi- tions include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • a solid carrier can be at least one substance which may also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, tablet disintegrating agent, and encapsulating agent.
  • Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials, low melting wax, cocoa butter, and the like.
  • Liquid form compositions include solutions, suspensions and emulsions.
  • 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.
  • the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component, that is, the compound according to this invention.
  • the quantity of active component, that is the compound according to this 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.
  • 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.
  • a concentration that is, an amount, or blood-level of active component in the animal undergoing treatment which will be antibacterially effective.
  • such antibacterially effective amount of dosage of active component will be in the range of about OJ 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.
  • 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.
  • 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.
  • a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection
  • 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.
  • Formula I 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.
  • 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,0 (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 x 100 mm petri dishes, and allowed to solidify and dry prior to inoculation. Vials of each of the test organisms are maintained frozen in the vapor phase of a liquid nitrogen freezer. Test cultures are grown overnight at 35°C on the medium appropriate for the organism.
  • Colonies are harvested with a sterile swab, and cell suspensions are prepared in Trypticase Soy broth (TSB) to equal the turbidity of a 0.5 McFarland standard. A 1:20 dilution of each suspension is made in 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 4 to 10 5 cells per spot. The plates are incubated overnight at 35°C.
  • SEPI S. epidermidia
  • SEPI 30593 S. epidermidis
  • SPNE 9912 S. pneumoniae
  • SPYO 152 S. pyogenes
  • HINF 30063 Haemophilus influenzae
  • 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.
  • the isothiocyanates III can be conveniently prepared by allowing the amine intermediates (II) to react with lJ'-thiocarbonyldi-2(lH)-pyridone in solvents such as methylene chloride at 0 to 25°C.
  • Step 4 as illustrated in Example 4.
  • This reaction is carried out in aqueous-alcoholic solvents at 0-50°C in the presence of an equivalent of an alkali metal hydroxide.
  • This reaction especially when R"' is methyl or ethyl, can be catalyzed by an alkali metal fluoride.
  • the thioamides (lb, R" - H, alkyl,_ 4 ) can also be conveniently prepared (Step 5) by allowing the appropriate amide intermediates (IV) to react with reagents such as 2,4-bis(p-methoxyphenyl)-l,3-dithiadiphosphetane-2,4-disulfide (Lawesson's Reagent) in 1,4-dioxane, benzene, toluene or tetrahydrofuran at 60- 110°C; phosphorus decasulfide and sodium carbonate in tetrahydrofuran at 20-50°C [Brillon, D., Synthetic Communications, 20, 3085 ( 1990)] or phosphorus decasulfide and sodium fluoride in 1,2-dimethoxyethane at 20-50°C [Hartke, K., Gerber, H.-D
  • Compounds Ic are prepared (Step 6) by allowing II to react first with carbon disulfide and a tertiary amine base such as triethylamine in solvent mixtures containing water and methanol, ethanol or isopropanol at 10-50°C for 5-24 hours.
  • the resulting intermediate is treated with an alkylating agent (R"" X where X represents bromo. iodo, alkylsulfonyloxy or arylsulfonyloxy) at 0-30°C to give compounds Ic.
  • R"" X where X represents bromo. iodo, alkylsulfonyloxy or arylsulfonyloxy
  • 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.
  • Example 1 for the preparation of 1, 21 (PCT/US97/01970) was allowed to react with Lawesson's Reagent in refluxing dioxane to give 2: mp 222-223 °C; HRMS theory for C 19 H 24 FN fi O,S, (M+HJ: 451.1386; found 451.1381.
  • STEP B (S)-N-[[3-[3-Fluoro-4-[2',5'-dioxospiro[piperidine-4,4'Jmidazolidine]- l-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl] thioacetamide (3).
  • Step 1 A mixture of (S)J-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thiopyran-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).
  • Step 2 A mixture of the compound prepared in Step 1 (2.50 g) and hydroxylamine hydrochloride (2.36 g) in pyridine (30.6 mL) and ethanol (3.4 mL) is stirred in a screw-cap vial at 100°C for 22 hrs and at ambient temperature for 16 hrs, during which additional hydroxylamine hydrochloride (944 mg) and pyridine (4 mL) is added.
  • the reaction mixture is then concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate (100 mL) and saline (50 mL), adjusted to pH 11 with solid sodium carbonate and extracted with methanol methylene chloride (10/90, 5 x 100 mL).
  • Step 3 A solution of ethyl dithioacetate (105 mL, 0.919 mmol) and sodium fluoride (39 mg, 0.919 mmol) in ethanol (9.2 mL) under a nitrogen atmosphere was treated with a mixture of (S)-cis-3-[3-fluoro-4-(tetrahydro-l-oxido-2H-thiopy ⁇ an-4- yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Step 2,(300 mg, 0.919 mmol) and aqueous potassium hydroxide (IM, 0.92 mL) in ethanol (46 mL).
  • IM aqueous potassium hydroxide
  • Step 1 A solution of l,r-thiocarbonyldi-2(lH)-pyridone (235 mg, 1.01 mmol) in anhydrous methylene chloride (10 mL) at 0°C under a nitrogen atmosphere was treated with a solution of (S)-cis-3-[3-fluoro-4-(tetrahydro-l-oxido- 2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Example 7, Step 2, (275 mg, 0.843 mmol) in anhydrous methylene chloride (34 mL) over 30 minutes.
  • the resulting mixture was stirred at 0°C for 30 minutes and at ambient 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 ⁇ acuo.
  • Step 2 A solution of (S)-cis-3-[3-fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4- yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone (Step 1, 290 mg, 0.787 mmol) in anhydrous tetrahydrofuran (39 mL) at 0°C under a nitrogen atmosphere was treated (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot was sealed, and the resulting mixture was stirred at 0°C for 1 hour. The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture was concentrated in ⁇ acuo to give the crude product. Recrystallization from methanol methylene chloride/diethyl ether gave the title compound, mp 206 - 208°C (dec).
  • Step 1 (S)-(-)-N-[[3-[3-fluoro-4-(3,6-dihydro-2H-thiopyran-4-yl)phenyl]-2-oxo- 5-ox azolidinyl] methyl] acetamide
  • S-oxide (disclosed in International Publication No. WO 97/09328) may be reduced to the corresponding cis- and trans-sulfoxides by catalytic hydrogenation in the presence of a catalyst and solvent.
  • the sulfide by product of this reduction reaction can be oxidized with an oxidizing agent such NaIO 4 or meta-chloroperoxybenzoic acid in solvent to provide the cis- and trans-sulfoxides.
  • 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°C (dec).
  • 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 x 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).
  • Step 2 A solution of ethyl dithioacetate (105 mL, 0.919 mmol) and sodium fluoride (39 mg, 0.919 mmol) in ethanol (9.2 mL) under a nitrogen atmosphere was treated with a mixture of (S)-trans-3-[3-fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4- yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepare in Step 1, (300 mg, 0.919 mmol) and aqueous potassium hydroxide (IM, 0.92 mL) in ethanol (46 mL).
  • IM aqueous potassium hydroxide
  • Step 1 A solution of lJ'-thiocarbonyldi-2(lH)-pyridone (192 mg,
  • the resulting mixture was stirred at 0°C for 30 minutes and at ambient temperature for 40 minutes and was then diluted with methylene chloride (20 mL), washed with water ( 15 mL) and brine ( 15 mL), dried over anhydrous sodium sulfate and concentrated in ⁇ acuo.
  • Step 2 A solution of (S)-trans-3-[3-fluoro-4-(tetrahydro-l-oxido-2H- thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone (Step 1, 230 mg, 0.624 mmol) in anhydrous tetrahydrofuran (31.2 mL) at 0°C under a nitrogen atmosphere was treated (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot was sealed, and the resulting mixture was stirred at 0°C for 1 hour. The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture was concentrated in ⁇ acuo to give the crude product. Trituration with methanol/methylene chloride/diethyl ether gave the title compound, mp 209 - 210°C (dec).
  • Step 1 Starting with (S)-cis-(-)-N-[[3-[3-Fluoro-4-(tetrahydro-l-oxido-
  • Step 2 A solution of ethyl dithioacetate (100 mL, 0.876 mmol) and sodium fluoride (37 mg, 0.876 mmol) in ethanol (8.8 mL) under a nitrogen atmosphere was treated with a mixture of (S)-(-)-3-[3-fluoro-4-(tetrahydro-lJ-dioxido-2H-thiopyran-4- yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Step 1, (300 mg, 0.876 mmol) and aqueous potassium hydroxide (IM, 0.88 mL) in ethanol (43.8 mL).
  • IM aqueous potassium hydroxide
  • Step 1 A solution of l,l'-thiocarbonyldi-2(lH)-pyridone (304 mg, 1.31 mmol) in anhydrous methylene chloride (13 mL) at 0°C under a nitrogen atmosphere was treated with a solution of (S)-(-)-3-[3-fluoro-4-(tetrahydro-lJ-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.
  • Step 2 A solution of (S)-3-[3-fluoro-4-(tetrahydro-lJ-dioxido-2H- thiopyran-4-yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone (Step 1, 380 mg, 0.988 mmol) in anhydrous tetrahydrofuran (49 mL) at 0°C under a nitrogen atmosphere was treated (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot was sealed, and the resulting mixture was stirred at 0°C for 1 hour. The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture was concentrated in ⁇ acuo to give the crude product. Recrystallization from methanol methylene chloride/diethyl ether gave the title compound, mp 196 - 198°C (dec).
  • EXAMPLE 16 (S)-N-[[3-[3-Fluoro-4-(4-moropholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]- ⁇ , ⁇ , ⁇ -trifluorothioacetamide (13).
  • 33 34 A stirred suspension of 33 (3.7 g, 0.011 mol) and triethylamine (3.5 mL, 0.025 mol) in THF ( 120 mL) was cooled, in 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.
  • EXAMPLE 28 (S)-N-[[3-[3-Fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5- oxazolidinyl]methyl]thio-acetamide, thiomorpholine S, S-dioxide (36).
  • Example 35 When in the procedure of Example 35 an appropriate amount of sodium ethoxide was substituted for sodium methoxide, the compound of Example 36 below in Table A was obtained.
  • the isopropylcarboxamide and the cyclopropylcarboxamide are obtained by following the procedure in Example 5 of U.S. Patent No. 5,688,792 only substituting isobutyric anhydride and cyclopropane carbonyl chloride respectively for acetic anhydride in step 7.
  • the acetamide is obtained as described in U.S. Patent No. 5,688,792 at Example 4.
  • 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.
  • R" 37 (S)-N-[[3-[3-Fluoro-4-(4-mo ⁇ holinyD- R H.
  • R' CH(CH- 2 phenyl]-2-oxo-5-oxazohd ⁇ nyl]methyl]-2- methylpropanethioamide; mp 152- 153 °C (dec);
  • 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.
  • Example 41 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-d ⁇ fluoro-4-(4-th ⁇ o- mo ⁇ hol ⁇ nyl)phenyl]-2-oxo-5-oxazohd ⁇ nyl]methanol for compound 62 in step 1 of Example 27
  • Example 27 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-th ⁇ omo ⁇ hohnyl)phenyl]-2- oxo-5-oxazol ⁇ d ⁇ nyl]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 Patent 5 688,792, steps 1 through 3 only substituting 4-fluoron ⁇ trobenzene for 3,4- difluoronitrobenzene in step 1 thereof
  • Example 62 to 64 is prepared as compound 37 in Example 29 from the amide. 65, which is prepared as described in Example 32 of U S Patent No 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 dec ⁇ bed in Example 3 of U S Patent 5.700,799
  • Example 71 to 74 The amine utilized in Examples 71 to 74 is prepared as described in Example 28 by substituting (S)-N-[[3-[3,5-d ⁇ fluoro-4-(4-th ⁇ omo ⁇ hol ⁇ nyl)phenyl]-2-oxo-5- oxazolidinyljmethanol for compound 62 in step 1 and lollowing the procedure of steps 1 and 2
  • the appropriate oxazolidinyl methanol compound is prepared by following the general procedure of Example 4 of U S Patent No 5,688,792, steps 1 through 4, only substituting thiomo ⁇ hohne tor mo ⁇ hohne in step 1 thereot
  • Example 75 to 78 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-th ⁇ omo ⁇ hohnyl)phenyl]-2-oxo-5- oxazo dinyljmethanol for compound 62 in step 1
  • the appropriate oxazolidinyl methanol is obtained by following the procedure of Example 1 in U S Patent No 5,688.792, steps 1 through 3, only substituting 4-fluoron ⁇ trobenzene tor 3,4-d ⁇ fluoromtrobenzene in step 1 thereof
  • the amine utilized in Examples 79 to 91 is prepared as described in Example 1, step
  • EXAMPLE 1 12 (S)-N-[[3-[3-Fluoro-4-(4-th ⁇ omo ⁇ hohnyl)phenyl]-2-oxo-5- oxazohd ⁇ nylJmethyl]-O-ethylth ⁇ ocarbamate;
  • EXAMPLE 1 13 (S)-N-[[3-[3-Fluoro-4-(4-th ⁇ omo ⁇ hol ⁇ nyl)phenylJ-2-oxo-5- oxazohd ⁇ nyl]methyl]-O- ⁇ so-propylth ⁇ ocarbamate,
  • EXAMPLE 1 16 (S)-N-[[3-[3-Fluoro-4-(4-th ⁇ omo ⁇ hohnyl)phenyl]-2-oxo-5- oxazol ⁇ d ⁇ nyl]methylJ- l-azet ⁇ d ⁇ nec ⁇ rboth ⁇ oam ⁇ de, thiomo ⁇ holine S-oxide, Anal Calcd for C, 8 H 2 FN 4 O 3 S2, C, 50 69, H, 5 43, N, 13 14 Found C, 50 79, H, 5 45, N. 12 82, mp 213- 214°C
  • Example 137 and 138 are obtained
  • step 1 Following the procedure of Example 33, step 1, only substituting an appropriate amount of compound 37 from Example 29 step 5 tor compound 33 (5)-N- [[3,5-[3-difluoro-4-[4-(hydroxyacetyl)- l-piperazinyl]phenyl]-2-oxo-5-oxazolidinylJ- methyljisothiocyanate is obtained.
  • Part B Upon substitution of an appropriate amount of (S)-N-[[3-[3,5-difluoro-4-[4- (hydroxyacetyl)- l-piperazinylJphenylJ-2-oxo-5-oxazolidinyl]methylJisothiocyanate for compound 82 in the general procedure of Example 100, the title compound is obtained.
  • step 1 Following the procedure of Example 33, step 1, only substituting an appropriate amount of (S)-N-[[3-[4-[4-(hydroxyacetyl)- 1 -piperazinylJphenyl]-2-oxo-5- oxazolidinyljmethyljamine for compound 33, (S)-N-[[3-[4-[4-(hydroxyacetyl)-l- piperazinyl]phenylJ-2-oxo-5-oxazolidinyl]methyl]isothiocyanate is obtained.
  • Example 25 step 1), and triethylamine ( 15.4 mL, 1 10 mmol) in methylene chloride (2570 mL) is treated with /w-nitrobenzenesulfonyl chloride (18.8 g, 84.9 mmol) and kept, under nitrogen, at ambient temperature (24 °C) for 24 hours. Additional 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 2 SO 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.
  • x and y are prepared according to the procedures of B ⁇ ckner (J Med Chem , 1996, 39, 673-679), by substituting an approp ⁇ ate amount of 2,6-d ⁇ fluoro-4-n ⁇ trobenzene (t ⁇ fluoromethane) sulfonate and 4-fluoron ⁇ trobenzene respectively for 3,4-d ⁇ fluoron ⁇ trobenzene in the preparation of 2a therein
  • the amine compound set forth below as P- 129 is obtained by refluxing tor 6 days a solution of compound 88 ( 1 00 g, 2 54 mmol), sultamide (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 g ⁇ e P- 129
  • Preparations P- 130 and P- 131 respectively set forth below are obtained.
  • Preparation P- 138 The amine compound set forth below as Preparation P- 138 is obtained by combining compound 88 ( 1 J0 g, 2J5 mmol) set forth in step 5 of Example 141 with N- formylbenzotriazole (493 mg, 3J5 mmol) in THF (30 mL) and the mixture is kept at ambient temperature for 18 hours. The mixture is concentrated and the residue in methylene chloride is washed with IN sodium hydroxide and dilute sodium chloride, dried (MgS0 ).

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Abstract

L'invention concerne des composés représentés par la formule (1) ou des sels pharmaceutiquement acceptables de ceux-ci, A, G, et R1 étant tels que défini dans les revendications. Ces composés sont des agents antibactériens.
PCT/US1998/025308 1998-11-27 1998-11-27 Agents antibacteriens oxazolidinone a fonction thiocarbonyle WO2000032599A1 (fr)

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CN98814326A CN1322204A (zh) 1998-11-27 1998-11-27 具有硫代羰基官能团的噁唑烷酮抗菌剂
CA002351062A CA2351062A1 (fr) 1998-11-27 1998-11-27 Agents antibacteriens oxazolidinone a fonction thiocarbonyle
PCT/US1998/025308 WO2000032599A1 (fr) 1998-11-27 1998-11-27 Agents antibacteriens oxazolidinone a fonction thiocarbonyle
AU17053/99A AU764980B2 (en) 1998-11-27 1998-11-27 Oxazolidinone antibacterial agents having a thiocarbonyl functionality
KR1020017006622A KR20010107987A (ko) 1998-11-27 1998-11-27 티오카르보닐 관능기를 갖는 옥사졸리디논 항균제
NZ511963A NZ511963A (en) 1998-11-27 1998-11-27 Oxazolidinone antibacterial agents having a thiocarbonyl functionality
EP98961822A EP1133493A1 (fr) 1998-11-27 1998-11-27 Agents antibacteriens oxazolidinone a fonction thiocarbonyle
JP2000585241A JP2002531455A (ja) 1998-11-27 1998-11-27 チオカルボニル官能基を有するオキサゾリジノン抗細菌剤
HK02102339.4A HK1040707A1 (zh) 1998-11-27 2002-03-27 具有硫代羰基官能團的噁唑烷酮抗菌劑

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042229A1 (fr) * 1999-08-12 2001-06-14 Ortho-Mcneil Pharmaceutical, Inc. Amidinomethyl- et guanidinomethyl-oxazolidinones antibacteriens
WO2002006278A1 (fr) * 2000-07-17 2002-01-24 Ranbaxy Laboratories Limited Derives d'oxazolidinone utilises en tant qu'antimicrobiens
WO2002032857A1 (fr) * 2000-10-17 2002-04-25 Pharmacia & Upjohn Company Procedes de production de composants oxazolidinone
WO2002081469A1 (fr) * 2001-04-07 2002-10-17 Astrazeneca Ab Oxazolidinone-sulfoximines et sulfilimines en tant qu'antibiotiques
WO2004018439A1 (fr) * 2002-08-22 2004-03-04 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux agents antibacteriens
EP1409464A1 (fr) * 2001-07-16 2004-04-21 Ranbaxy Laboratories, Ltd. Derives d'oxazolidinone utilises comme antimicrobiens potentiels
WO2004089944A1 (fr) * 2003-04-07 2004-10-21 Ranbaxy Laboratories Limited Derives d'oxazolidinone comme antimicrobiens
WO2005028473A1 (fr) * 2003-09-23 2005-03-31 Pharmacia & Upjohn Company Llc Bioprecurseurs acyloxymethylcarbamate des oxazolidinones
US6956040B2 (en) 2001-07-16 2005-10-18 Ranbaxy Laboratories Limited Oxazolidinone piperazinyl derivatives as potential antimicrobials
WO2006040614A1 (fr) * 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Derives d'oxazolidinone substitues
WO2006043121A1 (fr) * 2004-10-20 2006-04-27 Ranbaxy Laboratories Limited Derives d'oxazolidinone servant d'antimicrobiens
WO2006056875A1 (fr) * 2004-11-29 2006-06-01 Pharmacia & Upjohn Company Llc Oxazolidinones de thiazepine utilises en tant qu'agents antibacteriens
WO2007000644A1 (fr) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Oxazolidinones d'homomorpholine en tant qu'agents antibacteriens
WO2007040326A1 (fr) * 2005-10-05 2007-04-12 Ildong Pharmaceutical Co., Ltd Nouveau dérivé de formamide oxazolidinone et son procédé de préparation
WO2007114326A1 (fr) 2006-03-31 2007-10-11 Research Foundation Itsuu Laboratory Nouveau composé ayant un hétérocycle
US7435751B2 (en) 2005-04-06 2008-10-14 Vara Prasad Venkata Nagendra Josyula 7-Fluoro-1,3-dihydro-indol-2-one oxazolidinones as antibacterial agents
WO2009044777A1 (fr) 2007-10-02 2009-04-09 Research Foundation Itsuu Laboratory Dérivé d'oxazolidinone avec hétérocycle à 7 chaînons
WO2009001192A3 (fr) * 2007-06-22 2010-05-27 Orchid Research Laboratories Limited Nouveaux composés et leur utilisation
US7825122B2 (en) 2005-12-14 2010-11-02 Amgen Inc. Diaza heterocyclic sulfonamide derivatives and their uses
US10550092B2 (en) * 2015-07-17 2020-02-04 The Global Alliance For Tb Drug Development, Inc. Substituted phenyloxazolidinones for antimicrobial therapy

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GEP20156397B (en) * 2011-05-06 2015-11-10 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Process for the preparation of a rivaroxaban and intermediates formed in said process
WO2017066964A1 (fr) * 2015-10-22 2017-04-27 Merck Sharp & Dohme Corp. Composés oxazolidinone et procédés d'utilisation de ces derniers en tant qu'agents antibactériens

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023384A1 (fr) * 1992-05-08 1993-11-25 The Upjohn Company Oxazolidinones contenant une fraction diazine substituee et leur utilisation comme antimicrobiens
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
WO1998054161A1 (fr) * 1997-05-30 1998-12-03 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone ayant une fonctionnalite thiocarbonyle
WO1999012914A1 (fr) * 1997-09-11 1999-03-18 Hokuriku Seiyaku Co., Ltd. Derives de thiouree

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023384A1 (fr) * 1992-05-08 1993-11-25 The Upjohn Company Oxazolidinones contenant une fraction diazine substituee et leur utilisation comme antimicrobiens
WO1995007271A1 (fr) * 1993-09-09 1995-03-16 The Upjohn Company Agents antimicrobiens oxazolidinone a substitution oxazine et thiazine
WO1998054161A1 (fr) * 1997-05-30 1998-12-03 Pharmacia & Upjohn Company Agents antibacteriens oxazolidinone ayant une fonctionnalite thiocarbonyle
WO1999012914A1 (fr) * 1997-09-11 1999-03-18 Hokuriku Seiyaku Co., Ltd. Derives de thiouree

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001042229A1 (fr) * 1999-08-12 2001-06-14 Ortho-Mcneil Pharmaceutical, Inc. Amidinomethyl- et guanidinomethyl-oxazolidinones antibacteriens
US6734307B2 (en) 2000-07-17 2004-05-11 Ranbaxy Laboratories Limited Oxazolidinone derivatives as antimicrobials
JP2004504321A (ja) * 2000-07-17 2004-02-12 ランバクシー　ラボラトリーズ　リミテッド 抗微生物剤としてのオキサゾリジノン誘導体
WO2002006278A1 (fr) * 2000-07-17 2002-01-24 Ranbaxy Laboratories Limited Derives d'oxazolidinone utilises en tant qu'antimicrobiens
WO2002032857A1 (fr) * 2000-10-17 2002-04-25 Pharmacia & Upjohn Company Procedes de production de composants oxazolidinone
US6833453B2 (en) 2000-10-17 2004-12-21 Pharmacia & Upjohn Company Methods of producing oxazolidinone compounds
WO2002081469A1 (fr) * 2001-04-07 2002-10-17 Astrazeneca Ab Oxazolidinone-sulfoximines et sulfilimines en tant qu'antibiotiques
EP1409465A4 (fr) * 2001-07-16 2005-11-02 Ranbaxy Lab Ltd Derives d'oxazolidinone comme antimicrobiens
EP1409464A1 (fr) * 2001-07-16 2004-04-21 Ranbaxy Laboratories, Ltd. Derives d'oxazolidinone utilises comme antimicrobiens potentiels
EP1409465A2 (fr) * 2001-07-16 2004-04-21 Ranbaxy Laboratories, Ltd. Derives d'oxazolidinone comme antimicrobiens
EP1409464A4 (fr) * 2001-07-16 2005-11-02 Ranbaxy Lab Ltd Derives d'oxazolidinone utilises comme antimicrobiens potentiels
US6956040B2 (en) 2001-07-16 2005-10-18 Ranbaxy Laboratories Limited Oxazolidinone piperazinyl derivatives as potential antimicrobials
WO2004018439A1 (fr) * 2002-08-22 2004-03-04 Orchid Chemicals & Pharmaceuticals Ltd Nouveaux agents antibacteriens
WO2004089944A1 (fr) * 2003-04-07 2004-10-21 Ranbaxy Laboratories Limited Derives d'oxazolidinone comme antimicrobiens
WO2005028473A1 (fr) * 2003-09-23 2005-03-31 Pharmacia & Upjohn Company Llc Bioprecurseurs acyloxymethylcarbamate des oxazolidinones
WO2006040614A1 (fr) * 2004-10-11 2006-04-20 Ranbaxy Laboratories Limited Derives d'oxazolidinone substitues
WO2006043121A1 (fr) * 2004-10-20 2006-04-27 Ranbaxy Laboratories Limited Derives d'oxazolidinone servant d'antimicrobiens
WO2006056875A1 (fr) * 2004-11-29 2006-06-01 Pharmacia & Upjohn Company Llc Oxazolidinones de thiazepine utilises en tant qu'agents antibacteriens
US7435751B2 (en) 2005-04-06 2008-10-14 Vara Prasad Venkata Nagendra Josyula 7-Fluoro-1,3-dihydro-indol-2-one oxazolidinones as antibacterial agents
WO2007000644A1 (fr) 2005-06-29 2007-01-04 Pharmacia & Upjohn Company Llc Oxazolidinones d'homomorpholine en tant qu'agents antibacteriens
WO2007040326A1 (fr) * 2005-10-05 2007-04-12 Ildong Pharmaceutical Co., Ltd Nouveau dérivé de formamide oxazolidinone et son procédé de préparation
US7825122B2 (en) 2005-12-14 2010-11-02 Amgen Inc. Diaza heterocyclic sulfonamide derivatives and their uses
US8148362B2 (en) 2006-03-31 2012-04-03 Research Foundation Itsuu Laboratory Compound having heterocyclic ring
WO2007114326A1 (fr) 2006-03-31 2007-10-11 Research Foundation Itsuu Laboratory Nouveau composé ayant un hétérocycle
US8785625B2 (en) 2006-03-31 2014-07-22 Research Foundation Itsuu Laboratory Compound having heterocyclic ring
EP2181994A1 (fr) 2006-03-31 2010-05-05 Research Foundation Itsuu Laboratory Composés antimicrobiens
WO2009001192A3 (fr) * 2007-06-22 2010-05-27 Orchid Research Laboratories Limited Nouveaux composés et leur utilisation
EP2233484A2 (fr) 2007-10-02 2010-09-29 Research Foundation Itsuu Laboratory Dérivés de oxazolidone ayant un cycle hétérocyclique à sept membre
US8530646B2 (en) 2007-10-02 2013-09-10 Research Foundation Itsuu Laboratory Oxazolidinone derivative having 7-membered hetero ring
EP2669283A1 (fr) 2007-10-02 2013-12-04 Shionogi&Co., Ltd. Dérivé dýoxazolidinone doté dýune bague hétéro composée de 7 éléments
WO2009044777A1 (fr) 2007-10-02 2009-04-09 Research Foundation Itsuu Laboratory Dérivé d'oxazolidinone avec hétérocycle à 7 chaînons
US10550092B2 (en) * 2015-07-17 2020-02-04 The Global Alliance For Tb Drug Development, Inc. Substituted phenyloxazolidinones for antimicrobial therapy
US20200148651A1 (en) * 2015-07-17 2020-05-14 The Global Alliance For Tb Drug Development, Inc. Substituted phenyloxazolidinones for antimicrobial therapy
US11964949B2 (en) * 2015-07-17 2024-04-23 The Global Alliance For Tb Drug Development, Inc. Substituted phenyloxazolidinones for antimicrobial therapy

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EP1133493A1 (fr) 2001-09-19
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CN1322204A (zh) 2001-11-14
KR20010107987A (ko) 2001-12-07
HK1040707A1 (zh) 2002-06-21
AU1705399A (en) 2000-06-19
AU764980B2 (en) 2003-09-04

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