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WO2000010566A1 - Nouveaux agents antibacteriens a base d'isoxazolinone - Google Patents

Nouveaux agents antibacteriens a base d'isoxazolinone Download PDF

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Publication number
WO2000010566A1
WO2000010566A1 PCT/US1999/019265 US9919265W WO0010566A1 WO 2000010566 A1 WO2000010566 A1 WO 2000010566A1 US 9919265 W US9919265 W US 9919265W WO 0010566 A1 WO0010566 A1 WO 0010566A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
phenyl
alkoxy
halo
Prior art date
Application number
PCT/US1999/019265
Other languages
English (en)
Inventor
Lawrence B. Snyder
Zhizhen Zheng
Original Assignee
Bristol-Myers Squibb Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to AU57833/99A priority Critical patent/AU748750B2/en
Priority to BR9913225-7A priority patent/BR9913225A/pt
Priority to IL14154299A priority patent/IL141542A0/xx
Priority to JP2000565887A priority patent/JP2002523369A/ja
Priority to HU0103433A priority patent/HUP0103433A3/hu
Priority to CA002341271A priority patent/CA2341271A1/fr
Priority to EP99945157A priority patent/EP1107756A4/fr
Priority to NZ509867A priority patent/NZ509867A/en
Priority to KR1020017002377A priority patent/KR20010072945A/ko
Publication of WO2000010566A1 publication Critical patent/WO2000010566A1/fr
Priority to NO20010916A priority patent/NO20010916L/no

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Classifications

    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links
    • 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
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
    • C07D261/12—Oxygen 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
    • C07D413/10—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

Definitions

  • the present invention is directed toward new isoxazolinones, methods for their use, and processes for their production.
  • the present invention provides for a compound represented by the general formula
  • R-l is a) H, b) C-
  • L is oxygen or sulfur
  • A is a)
  • R 2 and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C
  • R 2 and R 3 taken together are -0(CH ) -0; wherein R4 is a) H, b) C-
  • R 5 is a) H, b) CF 3 , c) C-
  • D is S, O or NR 8 e in which R 8 e is H or
  • R 6 and R7 at each occurrence are the same or different and are a) an electron-withdrawing group, b) H, c) CF 3 , d) C-
  • U is a) CH 2 , b) 0, c) S or, d) NR 16 00/10566
  • R 16 is a) H or b) C-1.5 alkyl; wherein Ra is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) N0 2 , h) C-
  • C 2 _8 alkyl optionally substituted with one or two R ⁇ g, p) phenyl optionally substituted with one or two R-
  • i7 and R-JS at each occurrence are the same or different and are a) H, b) C-]_ alkyl, c ) 5 _e cycloalkyl, or d) R-i 7 and R 18 taken together with the nitrogen atom is a 5- or
  • 6-membered saturated or unsaturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, C- ⁇ . $ alkyl, formyl, a 5- or 6-membered heteroaromatic moiety
  • R-i 9 ' s a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) N0 2 , h) C ⁇ _e alkoxy, i) C ⁇ _e alkoxycarbonyl, j) C-
  • R 20 and R 21 at each occurrence are the same or different and are a) H, b) C-
  • R 2 is a) C
  • R 25- o phenyl optionally substituted with one or two R 2 5, p) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R 2 5, or q)
  • R 2 3 and R 4 at each occurrence are the same or different and are a) H, b) formyl, c) C- ] _4 alkyl, d) C- ) _4 acyl, e) phenyl, f) C3.6 cycloalkyl, or g) R 2 and R 2 taken together with the nitrogen atom is a 5- or
  • 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C-
  • R 25 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) N0 2 , h) C ⁇ alkoxy, i) C-
  • R 22 is the same as defined above;
  • R 26 and F ⁇ 2 ⁇ at each occurrence are the same or different and are a) H, b) C ⁇ e alkyl, c) phenyl, or d) tolyl;
  • R 2g and R30 at each occurrence are the same or different and are a) H, or b) C1.4 alkyl optionally substituted with phenyl or pyridyl;
  • R31 is a) H, or b) a sodium ion
  • R 32 and R33 at each occurrence are the same or different and are a) H, b) formyl, c) C-
  • R 35 is Ci.3 alkyl
  • R36 is a) C-
  • R 37 and R 38 at each occurrence are the same or different and are a) H, or b) C
  • Ri3 , 14 and R15 at each occurrence are the same or different and are a) H, b) formyl, c) carboxyl, d) C-
  • R ⁇ g is the same as defined above;
  • T is a) O, b) S, or c) S0 2 ;
  • R 2 and R43 at each occurrence are the same or different and are a) H, b) C 3 _e cycloalkyl, c) phenyl, d) C ⁇ _e acyl, e) C-
  • V is a) O, b) CH 2 , or c) NR 56 ;
  • R48 and R4g at each occurrence are the same or different and are a) H, or b) C.
  • R 54 is a) OH, b) C-
  • R ⁇ 6 is a) H, b) phenyl, or c) C ⁇ _6 alkyl optionally substituted by OH;
  • R 57 and R58 at each occurrence are the same or different and are a) H, b) Ci.5 alkyl, c) C-]_ 3 cycloalkyl, or d) phenyl;
  • R44 is a) C-
  • R 45 is a) C- ⁇ alkyl, b) C 2 _ ⁇ e alkenyl, wherein the substituents (a) and (b) can be optionally substituted with C ⁇ e alkoxycarbonyl, or a 5-, 6-, or 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-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF3, -NO , C-
  • R 50 and R51 at each occurrence are the same or different and are a) H, b) OH, c) C-
  • _e alkyl optionally substituted with -NR 8 R4g in which R 4 8and R4g are as defined above, d) R 50 and R51 taken together are 0;
  • R 52 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) can in turn be optionally substituted with one or three -N0 2 , CF 3 , halo, -CN, OH, phenyl, C ⁇ s alkyl, C-
  • R53'S a) H, b) formyl, c) C-
  • R59'S a) morpholinyl, b) OH, or c) C-
  • heteroaryl — C— in which heteroaryl is a 5- or 6-member aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S,
  • R 85 0-(CH 2 ) ⁇ _ 6 -C— in which Rss is hydrogen, C-j_ 8 alkyl optionally substituted with one or more F, Cl, OH, C-
  • heteroaryl— C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S,
  • R 8u is a) -OR in which R 32 is as defined above, b) -SR3 2 in which R 82 is as defined above, c) -NR3 2 R33 in which R 32 and R 33 are as defined above, or d) 5- or 6-membered heteroaromatic containing 1-4 0, S or N atoms,
  • These derivatives are useful as antimicrobial agents which are effective against a number of human and veterinary pathogens, including gram positive bacteria such as multiply-resistant staphylococci, streptococci, and enterococci, such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium.
  • gram positive bacteria such as multiply-resistant staphylococci, streptococci, and enterococci, such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium.
  • the literature contains a limited number of isoxazolinones used as pre-emergence herbicides.
  • isoxazolinones used as pre-emergence herbicides.
  • 2- methyl-4-(trifluoromethyl-/r7-tolyl)-3-isoxazolin-5-one and 2-methyl-4- (chloro- -tolyl)-3-isoxazolin-5-one are disclosed as being useful in preventing the growth of weeds which have a deleterious effect on crop production.
  • U.S. Patent 4,000,155 discloses the related compound 1 ,2- dimethyl-4-(trifluoromethyl-m-tolyl)-3-pyrazolin-5-one for the same utility.
  • W is a substituted aryl or heteroaryl system and V is H, or C1-C4 alkyl optionally substituted with F, Cl, OH, C1-C4 alkoxy, or acyloxy.
  • Oxazolidinones II shown below are a well known class of orally active antibacterial agents. The prior art contains numerous references to these compounds where Y and Z can include a wide variety of substituents. Specific substituted oxazolidinones are discussed in U.S. Patent Nos. 4,705,799 and 5,523,403 (substituted phenyl 2- oxazolidinones), U.S. Patent Nos.
  • T is hydroxy or NHC(0)C-
  • M and L are each independently hydrogen or fluoro
  • G and H are are each independently hydrogen or methyl
  • 1 is O, SO, S02 or a substituted nitrogen
  • Other substituted furanones are discussed in U.S. Patent 5,708,169, WO 97/43280 and WO 97/10235.
  • Ri is a) H, b) C ⁇ s alkyl optionally substituted with one or more F, Cl, OH,
  • L is oxygen or sulfur
  • A is a)
  • R 2 and R3 are each independently a) H, b) F, c) Cl, d) Br, e) C
  • R 5 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) R5 and Re taken together are a 5-, 6-, or 7-membered ring of the formula,
  • _6 alkyl or g) R5 and Re taken together are -(CH 2 )
  • U is a) CH 2 , b) 0, c) S or, d) NR 16 ;
  • R 16 is a) H or b) C-1.5 alkyl; wherein R 8 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) N0 2 , h) C-1.5 alkoxy, i) C ⁇ _e alkoxycarbonyl, j) C ⁇ _e alkythio, k) Ci ⁇ acyl,
  • R 8 7 is H or C-
  • n C-
  • 8 alkyl optionally substituted with one or two R-
  • 8 at each occurrence are the same or different and are a) H, b) C-,. 4 alkyl, c ) C5.6 cycloalkyl, or d) R17 and R-
  • 6-membered saturated or unsaturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, C1.3 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety
  • R k i1o9 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) N0 2 , h) C _ Q alkoxy, i) C ⁇ _e alkoxycarbonyl, j) C-
  • _e alkyl optionally substituted with OH, C-
  • _ 5 alkoxy, C-1.5 acyl, or -NR 17 R 18 , m) phenyl, n) -C( O)NR 20 R 21 , o) -N R 17 R-
  • R 20 and R 2 - I at each occurrence are the same or different and are a) H, b) C ⁇ e alkyl, or c) phenyl;
  • R 22 is a) C-
  • Rg is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, ) CF 3 , g) N0 2 , h) C-
  • R 23 and R 24 at each occurrence are the same or different and are a) H, b) formyl, c) C ⁇ _4 alkyl, d) C-
  • 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C-
  • R 25 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) N0 2 , h) C-
  • Ci_e alkyl optionally substituted with OH, azido, C ⁇ _ 5 alkoxy,
  • R 2 is the same as defined above;
  • R 2 e and R 2 7 at each occurrence are the same or different and are a) H, b) C ⁇ _e alkyl, c) phenyl, or d) tolyl;
  • R 29 and R 30 at each occurrence are the same or different and are a) H, or bb)) C C ⁇ __44 aallkkyyll ooppttiioonnaallllyy ssuubbssttiittuutteedd wwiitthh pphheennyyll oorr ppyyrriiddyyl;
  • R 31 is a) H, or b) a sodium ion
  • R 32 and R 33 at each occurrence are the same or different and are a) H, b) formyl, c) C ⁇ _4 alkyl, d) C ⁇ _4 acyl, e) phenyl, f) C3 ⁇ cycloalkyl, g) R 32 and R 33 taken together are a 5- or 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C1.3 alkyl, or C ⁇ _ 3 acyl, h) -P(0)(OR 37 )(OR 38 ), or i) -S0 2 -R3 ;
  • R35 is C1.3 alkyl; 36 is a) C _e alkoxycarbonyl, or b) carboxyl; R37 and R3 8 at each occurrence are the same or different and are a) H, or b) Ci_ 3 alkyl;
  • R39 is a) methyl, b) phenyl, or c) tolyl; wherein K is a) O, b) S, or cc)) NNRR4400 iinn wwhich R40 is hydrogen, formyl, C1. alkyl, C ⁇ _4 acyl, phenyl, C 3 .
  • R-6 cycloalkyl, -P(O)(OR 37 )(OR 38 ) or -SO 2 -R 39 in which R37, R 38 and R 89 are as defined above;
  • R-10, 11 , i2' Ri3, R14 and R15 at each occurrence are the same or different and are a) H, b) formyl, c) carboxyl, d) C ⁇ _e alkoxycarbonyl, e) C ⁇ ⁇ alkyl, f) C 2 .
  • R 9 is the same as defined above; T is a) O, b) S, or c) S0 2 ; R4 2 and R43 at each occurrence are the same or different and are a) H, b) C3.6 cycloalkyl, c) phenyl, d) C ⁇ _e acyl, e) C _ 8 alkyl optionally substituted with OH, C ⁇ _ 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 3 , halo, -N0 2 , C 1-4
  • V is a) O, b) CH 2 , or c) NR 56 ;
  • R4 8 and R4g at each occurrence are the same or different and are a) H, or b) C-
  • R 54 is a) OH, b) C ⁇ _4 alkoxy, or c) -NR57R5 8 ;
  • R 56 is a) H, b) phenyl, or c) C ⁇ _e alkyl optionally substituted by OH;
  • R 57 and R ⁇ 8 at each occurrence are the same or different and are a) H, b) Ci_ 5 alkyl, c) C1.3 cycloalkyl, or d) phenyl;
  • R44 is a) C ⁇ _ 8 alkyl optionally substituted with C . 6 alkoxy or C ⁇ _ 6 hydroxy, C 3 _e 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 2 , CF 3 , halo, -CN, OH, C ⁇ _ 5 alkyl, C ⁇ _ 5 alkoxy, or C ⁇ s acyl, b)
  • R 45 is a) C ⁇ _ 16 alkyl, b) C 2 _ ⁇ e alkenyl, wherein the substituents (a) and (b) can be optionally substituted with Ci_e alkoxycarbonyl, or a 5-, 6-, or 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-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF 3 , -N0 2 ,
  • Ci_e alkyl C 1 ⁇ alkoxy, C ⁇ _ 6 acyl, C _ 8 alkylthio, or C ⁇ alkoxycarbonyl;
  • R 46 and R47 at each occurrence are the same or different and are a) H, b) phenyl, c) C _e alkyl, or d) benzyl;
  • R 52 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) can in turn be optionally substituted with one or three -N0 2 , CF 3 , halo, -CN, OH, phenyl, C ⁇ _ 5 alkyl, C .5 alkoxy, or C-
  • R ⁇ 3 is a) H, b) formyl, c) C ⁇ _ alkyl, d) C ⁇ _4 acyl, e) phenyl, f) C 3 . 6 cycloalkyl, g) -P(0)(OR 37 )(OR 38 ), or h) -S0 R 3g , in which R 37 , R 38 and R 39 are as defined above;
  • R 85 0-(CH 2 ) ⁇ _ 6 -C— in which R 85 is hydrogen, C _ 8 alkyl optionally substituted with one or more F, Cl, OH, C ⁇ _ 8 alkoxy or C _ 8 acyloxy, C3.5 cycloalkyl or C ⁇ _ 8 alkoxy;
  • heteroaryl— C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S,
  • R 8 Q is a) -OR3 2 in which R 3 is as defined above, b) -SR3 2 in which R 32 is as defined above, c) -NR3 2 R33 in which R 32 and R33 are as defined above, or d) 5- or 6-membered heteroaromatic containing 1-4 0,
  • the compounds of this invention are novel and represent a new class of antibacterial agents. They are distinct from both the previously reported oxazolidinone and isoxazoline antibiotics since they incorporate the isoxazolinone ring system. They differ from the prior art isoxazolinone herbicides since the ring nitrogen must be substituted with an amide moiety as defined above.
  • the compounds of formula I are antibacterial agents useful in the treatment of infections in humans and other animals caused by a variety of bacteria, particularly methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium.
  • salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p- toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like. These salts may be in hydrated form.
  • halo or halogen includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro.
  • alkyl groups as used herein means straight or branched chains having the specified number of carbon atoms, e.g. in the case of Ci-Ce alkyl, the alkyl group may have from 1 to 6 carbon atoms.
  • C -C 8 alkenyl refers to at least one double bond alkenyl group having the specified number of carbon atoms
  • C 2 -C 8 alkenyl refers to at least one triple bond alkynyl group having the specified number of carbons, etc.
  • acyloxy refers to a group of O the type CH 3 C-0— where the alkyl group can have the specified number of carbon atoms, e.g. C ⁇ Ce alkoxy would have 1-6 carbons. Where not specified the carbon length is from 1-6 carbons.
  • aryl refers to aromatic carbocyclic rings, i.e. phenyl and naphthyi.
  • Heteroaromatic refers to an aromatic heterocyclic moiety having one or more atoms selected from O, N, S, e.g.
  • a saturated or unsaturated heterocyclic group can have 1-3 atoms selected from O, N and S, e.g. dioxolane, imidazolidine, dithiolane, oxathiolane, oxazolidine, piperidinyl, piperazinyl, morpholino or thiomorpholino, or the corresponding unsaturated heterocyclic groups.
  • nitrogen and/or sulfur atoms in such heterocyclic moieties may be oxidized and such oxidized compounds are intened to be encompassed within the formula I compounds.
  • Preferred embodiments of the present invention are the compounds of formula I wherein A is in which Q , R , and R 3 are as defined above.
  • Ri is H, Ci _ 8 alkyl optionally substituted with one or more F, Cl, OH, C ⁇ _ 8 alkoxy, or C ⁇ _ 8 acyloxy, C3.6 cycloalkyl or C ⁇ _ 8 alkoxy;
  • R 2 and R 3 are each independently a) H, b) F, c) Cl, d) Br, e) C ⁇ _e alkyl, f) N0 2 , g) I, h) C ⁇ _6 alkoxy, i) OH j) amino, or k) cyano; and Q is a) hydrogen, b) halo, c) N0 2 , d) N 3 , e) C r C 6 alkylthio,
  • heteroaryl— C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S,
  • B is an unsaturated 4-atom linker having one nitrogen and three carbons;
  • M is a) H, b) C ⁇ _ 8 alkyl, c) C3- 8 cycloalkyl, d) -(CH 2 ) m OR 66 , or e) -(CH 2 ) n NR 67 R 68 ;
  • Z is a) 0, b) S or c) NM;
  • W is a) CH, b) N or c) S or O when Z is NM
  • X and Y are i each independently a) hydrogen, b) halo, c) N0 2 , d) N 3 . e) C ⁇ _ 6 alkythio, -- 52 -
  • heteroaryl— C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S,
  • R ⁇ and R 3 taken together form -O-CH 2 -0;
  • Re is a) H, b) C _s alkyl optionally substituted with one or more halos, or c) C ⁇ _ 8 alkyl optionally substituted with one or more OH, or C ⁇ _ 8 alkoxy;
  • R63 is a) H, b) Ci ⁇ alkyl, c) -(CH 2 ) q -aryl, or d) halo;
  • Re6 is H or C _4 alkyl
  • R 67 and R 68 i are each independently H or C ⁇ alkyl, or NR67R68 taken together are -(CH 2 ) m -;
  • ⁇ is a) -CH 2 -, or b) -CH(R 70 )-CH 2 -;
  • Z 2 is a) -0 2 S-, b) -0-, c) -S-, d) -SO-, or e) -N(R 71 )-;
  • Z 3 is a) s, b) so, c) S0 2 , or d) O;
  • Ai is H or CH 3 ;
  • a 2 is a) H, b) OH-, c) CH 3 C0 2 -, d) CH 3 -, e) CH3O-, f) R 72 0-CH 2 -C(0)-NH-, g) R 73 0-C(0)-NH-, h) R 73 -C(0)-NH-, i) (C r C 2 )alkyl-0-C(0)-, or j) HO-CH 2 ; or
  • Re4 is H or CH 3 -; m is 4 or 5; nisO, 1,2, 3, 4 or 5; y is 0 or 1 ; pisO, 1,2, 3, 4 or 5; w is 1 , 2 or 3; q is 1,2, 3 or 4; z is 0 or 1 ;
  • R65 is a) R74 ⁇ C(R 7 5)(R76)-C(0)-, b) R 77 OC(0)-, c) R 8 (0)-, d) R 79 -S0 2 -, or e) R 80 -NH-C(O)-;
  • R70 is H or (CrCealkyl
  • R71 is a) R 7 4OC(R75)(R 76 )-C(O)-, b) R 77 O-C(0)-, c) R 78 -C(0)-, d)
  • R 72 is a) H, b) CH 3 , c) phenyl -CH 2 -, or d) CH 3 C(0)-;
  • R 3 is (C -C 3 )alkyl or phenyl;
  • R 74 is H, CH 3 , phenyl-CH 2 - or CH 3 -C(0)-;
  • R75 and R 6 are each independently H or CH , or R 75 and R 76 taken together are -CH 2 CH 2 -;
  • R77 is (C -C3)alkyl or phenyl;
  • R 78 is H, (C r C )alkyl, aryl-(CH 2 ) n ⁇ , CIH 2 C, CI 2 HC, FH 2 C-, F 2 HC- or (C 3 -Ce)cycloalkyl;
  • R 79 is CH 3 ;
  • -CH 2 CI, -CH 2 CH CH 2 , aryl or -CH 2 CN;
  • R 80 is -(CH 2 ) n ⁇ -aryl where n 1 is 0 or 1 ;
  • R 81 is a) H, b) Ci_e alkyl optionally substituted with one or more OH, halo or CN, c) -(CH 2 )q-aryl in which q is as defined above, or d) -(CH 2 ) q -OR 8 3 in which q is as defined above;
  • R 82 is a) C _e alkyl optionally substituted with one or more OH,
  • aryl is phenyl, pyridyl or naphthyi, said phenyl, pyridyl or naphthyi moieties being optionally substituted by one or more halo, -CN, OH, SH, C ⁇ _e alkoxy or C ⁇ alkylthio.
  • Ri is H, C ⁇ _ 8 alkyl optionally substituted with one or more F, Cl, OH, C ⁇ _ 8 alkoxy or C ⁇ _ 8 acyloxy, C3.6 cycloalkyl or C ⁇ _ 8 alkoxy; R 2 and R 3 are each independently H or F; or R 2 and R 3 taken together represent
  • Q is a) hydrogen, b) halo, c) N 3 . d) N0 2 , e) C C 6 alkylthio, O f) C C 6 alkyl-s- , O g) C C 6 alkyl— s—
  • Rg 6 P) q) phenyl optionally substituted by Rg 6 , or r) 5- or 6-membered saturated or unsaturated heterocyclic containing 1-3 O, N or S and linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being optionally substituted by Rg 6 , and R 96 is a) C r C 6 alkyl-OH, b) C C 6 alkyl- -0-C II-.
  • the compounds of the present invention can be made by the methods summarized below.
  • Isoxazolinones 5 of the present invention are preferably prepared via the sequence outlined in Scheme 1.
  • Aryl acetic acids 1 are either commercially available or prepared by one of many well known methods in the chemical literature including but not limited to the sequence shown in Scheme 2 or 3.
  • Isoxazolinone 3 is prepared by methods described by Marchesini [J. Org. Chem. 1984, 49, p. 4287-4290]. Reaction of 1 with sodium hydride and ethyl formate provides 2 which is in turn reacted with hydroxylamine yielding 3.
  • aryl acetic esters 1 of the present invention is shown in Scheme 3.
  • a mild base preferably potassium carbonate, and a primary or secondary amine or thiolate
  • a suitable solvent preferably acetonitrile or N, N- dimethylformamide
  • Conversion of 11 to 12 can also be accomplished by various methods known in the chemical literature including but not limited to treatment with acid in hot alcohol.
  • Sulfoxides and sulfones 14 and 16 are prepared by treating sulfides 13 and 15, respectively with an oxidizing agent such as m- chloroperoxybenzoic acid or osmium tetroxide by methods known by those skilled in the art and exemplified by Barbachyn [J. Med. Chem., 1996, 39, 680-685].
  • an oxidizing agent such as m- chloroperoxybenzoic acid or osmium tetroxide
  • the triazole-substituted compounds 27 and 28 are prepared by cyclization of the azide 25 with acetylenes 26 (Scheme 7). This is a standard 3+2 cycloaddition which is well documented in the chemical literature.
  • the acetylenes 26 are either commercially available or prepared by literature procedures. For example, cyanoacetylene is prepared according to Murahashi [J.Chem. Soc. Jap., 1956, 77, 1689].
  • the cyclization reaction was usually carried out in a suitable solvent such as DMF, at a temperature between 25°C and 80°C.
  • suitable solvents include but are not limited to DMSO, NMP, and DMA.
  • the two cyclization adducts 27 and 28 were separated using preparative HPLC or by triturating with a suitable solvent such as ethyl acetate.
  • suitable solvents for trituration include but are not limited to methanoi, ethanol, diethyl ether, and acetone.
  • the azidophenylisoxazolinone 25 is reduced to aminophenylisoxazolinone 29 via one of the many well known methods in the chemical literature including but not limited to the treatment with stannous chloride in a suitable solvent such as a 2:1 combination of ethyl acetate and methanoi .
  • a suitable solvent such as a 2:1 combination of ethyl acetate and methanoi .
  • Treatment of aminophenylisoxazolinones 29 with 2,5-dimethoxytetrahydrofurans 30 in acetic acid provide pyrrole- substituted isoxazolinones 31 (Scheme 8).
  • N-thioacetates 33 may be prepared from the corresponding N- acetates 32 using a variety of well known literature methods, for instance by refluxing in benzene with Lawesson's reagent. Other solvents such as toluene and xylene are also suitable.
  • the final product may be recovered in the form of a pharmaceutically acceptable acid addition salt, e.g. by addition of the appropriate acid such as HCI, HI or methane-sulfonic acid to the amine.
  • the compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans.
  • the novel isoxazolinone derivatives of general formula I or pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics active against gram-positive bacteria. While they may be used, for example, as animal feed additives for promotion of growth, as preservatives for food, as bactericides in industrial applications, for example in waterbased paint and in the white water of paper mills to inhibit the growth of harmful bacteria, and as disinfectants for destroying or inhibiting the growth of harmful bacteria on medical and dental equipment, they are especially useful in the treatment of bacterial infections in humans and other animals caused by the gram- positive bacteria sensitive to the new derivatives.
  • compositions comprising, in addition to the active isoxazolinone ingredient, a pharmaceutically acceptable carrier or diluent.
  • the compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or intramuscular injection).
  • the pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions.
  • Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents.
  • the compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
  • a method of treating a bacterial infection which comprises administering a therapeutically effective amount of the compound to a host, particularly a mammalian host and most particularly a human patient.
  • a host particularly a mammalian host and most particularly a human patient.
  • the use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of bacterial infections are also provided.
  • the dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 25 mg/day to about 2 g/day.
  • MIC Minimum Inhibitory Concentrations
  • NCLS National Committee for Clinical Laboratory Standards
  • Mueller-Hinton medium was used except for Streptococci which was tested in Todd Hewitt broth.
  • the final bacterial inoculate contained approximately 5 x 10 5 cfu/ml and the plates were incubated at 35°C for 18 hours in ambient air (Streptococci in 5% CO2).
  • the MIC was defined as the lowest drug concentration that prevented visible growth.
  • Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of 5 doublets; dt, doublet of triplets; and app d, apparent doublet, etc.
  • Infrared spectra were determined on a Perkin-Elmer 1800 FT-IR spectrometer from 4000 cm" 1 to 400 cm- 1 , calibrated to 1601 cm- 1 absorption of a polystyrene film, and are reported in reciprocal centimeters (cm- 1 ).
  • Mass spectra were recorded on a Kratos MS-50 or a Finnegan 4500 instrument 0 utilizing direct chemical ionization (DCI, isobutene), fast atom bombardment (FAB), or electron ion spray (ESI). Ultraviolet spectra were determined on a Hewlett Packard 8452 diode array spectrophotometer in the solvent indicated.
  • Analytical thin-layer chromatography was carried out on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapors, and/or staining by heating with methanolic phosphomolybdic acid.
  • Column chromatography also referred to as flash chromatography, was performed in a glass column using finely divided silica gel at pressures somewhat above atmospheric pressure with the indicated solvents.
  • Reversed-phase analytical thin-layer chromatography was carried out on precoated reverse phase plates and visualized using UV light or iodine vapors.
  • the aqueous layer was extracted twice with 20% methanol/chloroform, and the combined organics were then washed successively with 1 N sodium hydroxide, saturated sodium bicarbonate, and brine.
  • the organic layer was then dried over magnesium sulfate, filtered, and concentrated to an amorphous yellow solid which was dissolved in 20% methanol/chloroform. Ether was added and the mixture was stored at 0°C for 18 hours. The resultant precipitate was filtered to provide 2.48 g (70%) of the title compound as a pale pink solid.
  • reaction mixture was capped and allowed to stir at ambient temperature for 8 hours, at which time it was diluted with 20% methanol/chloroform, filtered thru celite and concentrated. The residue was suspended in chloroform, loaded onto a Biotage flash 40i chromatography module (12M) thru a frit, and eluted with 50% hexane/ethyl acetate providing a solid which was triturated with chloroform/ether to provide 132 mg (53%) of the title compound as a colorless solid.
  • Nitrogen was bubbled through a mixture of N-[[4-(4-iodophenyl)-5- oxo-2-hydroisoxazol-2-yl]methyl ⁇ acetamide (300 mg, 0.84 mmol), 2- tributylstannylthiophene (0.27 mL, 0.84 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF.
  • reaction mixture was capped and allowed to stir at ambient temperature for 8 hours, at which time it was diluted with 20% methanol/chloroform, filtered thru celite and concentrated. The residue was suspended in chloroform, loaded onto a Biotage flash 40i chromatography module (12M) thru a frit, and eluted with 15% acetone/chloroform providing a solid which was triturated with chloroform/ether to provide 165 mg (63%) of the title compound as a colorless solid.
  • the reaction mixture was capped and allowed to stir at ambient temperature for 16 hours, at which time it was diluted with 20% methanol/chloroform, 10% aqueous potassium fluoride was added and the mixture was allowed to rapidly stir for 1 hours.
  • the reaction mixture was filtered thru celite and concentrated.
  • the resultant black oil was dissolved in 20% methanol/chloroform, adsorbed onto silica gel and loaded into a Biotage flash 40i chromatography module SIM. Chromatography was performed using a 12M silica gel cartridge eluting with 20% acetone/chloroform providing an amber oil which was triturated with ether, yielding 115 mg (44%) of the title compound as a tan solid.
  • Nitrogen was bubbled through a mixture of N- ⁇ [4-(4-iodophenyl)-5- oxo-2-hydroisoxazol-2-yl]methyl ⁇ acetamide (300 mg, 0.84 mmol), 2- (tributylstannyl)pyrazine (340 mg, 0.92 mmol), tris(dibenzylideneacetone)dipalladium(0) (77 mg, 0.08 mmol), triphenylarsine (51 mg, 0.17 mmol), and lithium chloride (106 mg, 2.51 mmol) in 5 mL DMF.
  • reaction mixture was capped and allowed to stir at ambient temperature for 16 hours, at which time it was diluted with 20% methanol/chloroform, 10% aqueous potassium fluoride was added and the mixture was allowed to rapidly stir for 1 hour.
  • the reaction mixture was filtered thru celite and concentrated.
  • the resultant black oil was dissolved in 20% methanol/chloroform, adsorbed onto silica gel and loaded into a Biotage flash 40i chromatography module SIM. Chromatography was performed using a 12M silica gel cartridge eluting with 25% acetone/chloroform providing an amber oil which was triturated with ether, yielding 52 mg (44%) of the title compound as a colorless solid.
  • 1 H NMR (DMSO-d 6 ; 300MHz) ⁇ 9.28 (d, J 1.4 Hz, 1 H), 9.11 (s,
  • the starting materials were prepared as follows:
  • Nitrogen was bubbled through a mixture of methyl-4- (trifluoromethylsulfonyloxy)phenyl acetate (1.0 g, 3.35 mmol), cesium carbonate (1.6 g, 4.69 mmol), palladium (II) acetate (22 mg, 0.10 mmol), (S)-BINAP (93 mg, 0.15 mmol), and morpholine (0.35 mL, 4.02 mmol) in 8 mL toluene and the reaction mixture was heated to 80°C for 6 hours. The reaction was then cooled, celite was added, and the mixture was concentrated.
  • N- ⁇ [4-(4-hydrazinylphenyl)-5-oxo-2- hydroisoxazol-2-yl]methyl ⁇ acetamide hydrochloride was prepared as follows. Sodium nitrite (112 mg, 1.6 mmol) in 2 mL of water was added to a solution of N- ⁇ [4-(4-aminophenyl)-5-oxo-2-hydroisoxazol-2- yl]methyl ⁇ acetamide (400 mg, 1.6 mmol) in concentrated hydrochloric acid at 0°C over 5 minutes.

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Abstract

L'invention concerne des dérivés d'isoxazolinone qui exercent une activité antibactérienne et qui conviennent au traitement de maladies bactériennes. D'une manière plus spécifique, l'invention concerne de nouveaux isoxazolinones représentés par la formule générale (I), dans laquelle A et R1 sont décrits dans le descriptif.
PCT/US1999/019265 1998-08-24 1999-08-23 Nouveaux agents antibacteriens a base d'isoxazolinone WO2000010566A1 (fr)

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AU57833/99A AU748750B2 (en) 1998-08-24 1999-08-23 Novel isoxazolinone antibacterial agents
BR9913225-7A BR9913225A (pt) 1998-08-24 1999-08-23 Novos agentes antibacterianos de isoxazolinona
IL14154299A IL141542A0 (en) 1998-08-24 1999-08-23 Novel isoxazolinone antibacterial agents
JP2000565887A JP2002523369A (ja) 1998-08-24 1999-08-23 新規イソオキサゾリノン抗菌剤
HU0103433A HUP0103433A3 (en) 1998-08-24 1999-08-23 Novel isoxazolinone antibacterial agents, their use and process for preparation the compounds
CA002341271A CA2341271A1 (fr) 1998-08-24 1999-08-23 Nouveaux agents antibacteriens a base d'isoxazolinone
EP99945157A EP1107756A4 (fr) 1998-08-24 1999-08-23 Nouveaux agents antibacteriens a base d'isoxazolinone
NZ509867A NZ509867A (en) 1998-08-24 1999-08-23 Isoxazolinone antibacterial agents
KR1020017002377A KR20010072945A (ko) 1998-08-24 1999-08-23 신규한 이소옥사졸리논 항균제
NO20010916A NO20010916L (no) 1998-08-24 2001-02-23 Nye antibakterielle isoksazolinoner

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JP2002020366A (ja) * 2000-07-05 2002-01-23 Sumitomo Seika Chem Co Ltd アルキルチオフェニル酢酸類の製造方法
WO2002102785A1 (fr) * 2000-11-17 2002-12-27 Pharmacia & Upjohn Company Nouvelles isoxazolinones bicycliques utilisees comme agents antibacteriens
WO2003008395A1 (fr) * 2001-07-20 2003-01-30 Laboratorios S.A.L.V.A.T., S.A. Isoxazoles substitues et utilisation comme antibiotiques
WO2002048139A3 (fr) * 2000-12-15 2003-10-02 Upjohn Co Sonde de photo-affinite a base d'oxazolidinone
US6689769B2 (en) 2000-12-21 2004-02-10 Pharmacia & Upjohn Company Antimicrobial quinolone derivatives and use of the same to treat bacterial infections
WO2004033449A1 (fr) * 2002-10-10 2004-04-22 Pharmacia & Upjohn Company Llc Composes de 1-aryl dihydropyridone antimicrobiens
WO2004069832A3 (fr) * 2003-02-07 2004-10-21 Warner Lambert Co Agents antibacteriens
WO2005023801A1 (fr) * 2003-09-03 2005-03-17 Morphochem Aktiengesellschaft für kombinatorische Chemie Produits intermediaires destines a la fabrication d'hybrides oxazolidinone-chinolone
WO2005026161A1 (fr) * 2003-09-16 2005-03-24 Warner-Lambert Company Llc Agents antibacteriens
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WO2005070904A3 (fr) * 2003-06-03 2006-07-20 Rib X Pharmaceuticals Inc Composes de sulfamide, procedes de preparation et d'utilisation de ces derniers
US7081538B1 (en) 1999-12-03 2006-07-25 Astrazeneca Ab Substituted isoxazolines and their use as antibacterial agents
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JP2007500707A (ja) * 2003-07-29 2007-01-18 リブ−エックス ファーマシューティカルズ，インコーポレイテッド ビアリールヘテロ環状のアミン、アミドおよび硫黄−含有化合物、並びに該化合物の製造方法および使用方法
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US8158797B2 (en) 2003-12-18 2012-04-17 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Oxazolidinone-quinolone hybrid antibiotics
US8268812B2 (en) 2003-04-30 2012-09-18 Morphochem Aktiengesellschaft fül Kombinatorische Chemie Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections
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US8329908B2 (en) 2001-10-04 2012-12-11 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Dual action antibiotics
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US7141583B2 (en) 2000-04-25 2006-11-28 Astrazeneca Ab Oxazolidinone derivatives with antibiotic activity
WO2002002555A1 (fr) * 2000-06-29 2002-01-10 Bristol-Myers Squibb Company Nouveaux agents antibacteriens, les isoxazolinones
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WO2002102785A1 (fr) * 2000-11-17 2002-12-27 Pharmacia & Upjohn Company Nouvelles isoxazolinones bicycliques utilisees comme agents antibacteriens
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US6861433B2 (en) 2000-12-15 2005-03-01 Pharmacia & Upjohn Company Oxazolidinone photoaffinity probes
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ES2180456A1 (es) * 2001-07-20 2003-02-01 S A L V A T Lab Sa Isoxazoles sustituidos y su utilizacion como antibioticos.
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US8329908B2 (en) 2001-10-04 2012-12-11 Morphochem Aktiengesellschaft Fur Kombinatorische Chemie Dual action antibiotics
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US6875784B2 (en) 2002-10-09 2005-04-05 Pharmacia & Upjohn Company Antimibicrobial [3.1.0.] bicyclic oxazolidinone derivatives
US7105547B2 (en) 2002-10-10 2006-09-12 Pharmacia And Upjohn Company Antimicrobial 1-aryl dihydropyridone compounds
WO2004033449A1 (fr) * 2002-10-10 2004-04-22 Pharmacia & Upjohn Company Llc Composes de 1-aryl dihydropyridone antimicrobiens
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US9550783B2 (en) 2003-06-03 2017-01-24 Melinta Therapeutics, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US8895741B2 (en) 2003-06-03 2014-11-25 Melinta Therapeutics, Inc. Process for the synthesis of biaryl oxazolidinones
US7705026B2 (en) 2003-06-03 2010-04-27 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US7148219B2 (en) 2003-06-03 2006-12-12 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
US8324398B2 (en) 2003-06-03 2012-12-04 Rib-X Pharmaceuticals, Inc. Process for the synthesis of biaryl oxazolidinones
US7456206B2 (en) 2003-06-03 2008-11-25 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic compounds and methods of making and using the same
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US8124772B2 (en) 2003-09-03 2012-02-28 Morphochem Aktiengesellschaft für kombinatorische Chemie Intermediate products for producing oxazolidinone-quinolone hybrids
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JP2002523369A (ja) 2002-07-30
IL141542A0 (en) 2002-03-10
HUP0103433A3 (en) 2002-08-28
HUP0103433A2 (hu) 2002-01-28
CO5160266A1 (es) 2002-05-30
AU5783399A (en) 2000-03-14
TR200100672T2 (tr) 2001-07-23
PE20001063A1 (es) 2000-12-24
EP1107756A4 (fr) 2003-02-26
ZA200101505B (en) 2002-02-22
CN1314813A (zh) 2001-09-26
TW572757B (en) 2004-01-21
ID27690A (id) 2001-04-19
KR20010072945A (ko) 2001-07-31
NO20010916L (no) 2001-04-10
CA2341271A1 (fr) 2000-03-02
NO20010916D0 (no) 2001-02-23
AR020250A1 (es) 2002-05-02
BR9913225A (pt) 2001-05-22
NZ509867A (en) 2003-08-29
PL346267A1 (en) 2002-01-28
CZ2001669A3 (cs) 2001-08-15
EP1107756A1 (fr) 2001-06-20
AU748750B2 (en) 2002-06-13

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