ZA200101505B - Novel isoxazolinone antibacterial agents. - Google Patents
Novel isoxazolinone antibacterial agents. Download PDFInfo
- Publication number
- ZA200101505B ZA200101505B ZA200101505A ZA200101505A ZA200101505B ZA 200101505 B ZA200101505 B ZA 200101505B ZA 200101505 A ZA200101505 A ZA 200101505A ZA 200101505 A ZA200101505 A ZA 200101505A ZA 200101505 B ZA200101505 B ZA 200101505B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- optionally substituted
- phenyl
- alkoxy
- halo
- Prior art date
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- 239000003242 anti bacterial agent Substances 0.000 title description 5
- JGRCHNVLXORPNM-UHFFFAOYSA-N 1,2-oxazol-4-one Chemical compound O=C1CON=C1 JGRCHNVLXORPNM-UHFFFAOYSA-N 0.000 title description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 142
- 229910052739 hydrogen Inorganic materials 0.000 claims description 74
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 125000003545 alkoxy group Chemical group 0.000 claims description 64
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- 125000005843 halogen group Chemical group 0.000 claims description 43
- 229910052717 sulfur Inorganic materials 0.000 claims description 37
- 125000002252 acyl group Chemical group 0.000 claims description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 31
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 150000002431 hydrogen Chemical group 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- -1 imidazoly Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical group CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 6
- 239000000126 substance Substances 0.000 claims 5
- 241000124008 Mammalia Species 0.000 claims 3
- 208000035143 Bacterial infection Diseases 0.000 claims 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 125000005331 diazinyl group Chemical group N1=NC(=CC=C1)* 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims 1
- 125000004306 triazinyl group Chemical group 0.000 claims 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- KGVKJWSKLMEQHR-UHFFFAOYSA-N 1,2-dimethyl-4-[3-methyl-2-(trifluoromethyl)phenyl]pyrazol-3-one Chemical compound CC1=CC=CC(C=2C(N(C)N(C)C=2)=O)=C1C(F)(F)F KGVKJWSKLMEQHR-UHFFFAOYSA-N 0.000 description 1
- JOYDADHPZUCADO-UHFFFAOYSA-N 2-methyl-4-[3-methyl-2-(trifluoromethyl)phenyl]-1,2-oxazol-5-one Chemical compound CC1=CC=CC(C=2C(ON(C)C=2)=O)=C1C(F)(F)F JOYDADHPZUCADO-UHFFFAOYSA-N 0.000 description 1
- NCTCGHLIHJJIBK-UHFFFAOYSA-N 3-phenyl-1,3-oxazolidin-2-one Chemical class O=C1OCCN1C1=CC=CC=C1 NCTCGHLIHJJIBK-UHFFFAOYSA-N 0.000 description 1
- ZCBVFCKHSBEAKF-UHFFFAOYSA-N 4-(2-chloro-3-methylphenyl)-2-methyl-1,2-oxazol-5-one Chemical compound CC1=CC=CC(C=2C(ON(C)C=2)=O)=C1Cl ZCBVFCKHSBEAKF-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000012272 crop production Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000002241 furanones Chemical class 0.000 description 1
- 125000003844 furanonyl group Chemical group 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002547 isoxazolines Chemical class 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
NOVEL ISOXAZOLINONE ANTIBACTERIAL AGENTS
1S .
1. Field of the Invention : 15 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 0} (op H
SNR
L or a pharmaceutically acceptable salt thereof wherein:
Ry is a) H, b) C4.g alkyl optionally substituted with one or more F, Cl, OH,
C1.g alkoxy, or C4_g acyloxy,
c) C3. cycloalkyl, or d) C4.g alkoxy;
L is oxygen or sulfur;
Ais a) k 0
Ra b)
Ry 3A
Re Rs c) a 5S-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is . bonded via a carbon atom and can additionally have a fused-on benzene or naphthyl ring, and wherein the : heteroaromatic moiety is optionally substituted with one to three Rg, d) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three Ra, e) a B-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rg,
f) : Rit R : : aE
Rig K x 13, or e)
R11 Ry fod 1A
TX
Ria: wherein R; and Rj are each independently a) H, b) F, c) Cl, d) Br, e) C1. alkyl, f) NO,, 9 ) h) C14.s alkoxy, i) OH i) amino, k) cyano, or
D R2 and Rj taken together are -O(CH,),-O; wherein R, is a) H, b) C42 alkyl, c) F, or d) OH;
Rg is a) H, b) CF3, oo c) C1.3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) Rs and Rg taken together are a 5-, 6-, or 7-membered ring of the formula, 0= osc! h
SP f) in which D is S, O or NRgg in which Rgg is H or
C4.5 alkyl, or a) Rs and Rg taken together are -(CH,)i-, when Ry is an electron-withdrawing group;
Re and Ry at each occurrence are the same or different and are a) an electron-withdrawing group, b) H, ’ c) CFs, d) C4.3 alkyl optionally substituted with one halo, : e) phenyl, provided at least one of Rg and R; is an electron- withdrawing group, or f) Rg and Ry; taken together are a 5-, 6-, or 7-membered ring of the formula, iz ~c
Gm :
Uis a) CHo, b) 0,
C) Sor, d) NR1g;
Rig is a) Hor b) Cy. alkyl wherein Rg is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF3, g) NO, h) C1.¢ alkoxy, i) C1.¢ alkoxycarbonyl, i) C4 alkythio, k) Cypacyl, -NRy7R4s,
NOH : m) —C-Rg7 in which Rg is H or C4_g alkyl, n) C16 alkyl optionally substituted with OH, sulfamoyl, C4_5 alkoxy, Cq_5 acyl, or —NR17R 1s, 0) Co.g alkyl optionally substituted with one or two Rg, p) phenyl optionally substituted with one or two Ryg, q) 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 Rg, OF .
R17 and R4g at each occurrence are the same or different and are a) H, b) Cy alkyl,
Cc) Cs.g cycloalkyl, or d) R47 and R4g 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, C4_3 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety 2 containing 1-3 O, N or S, —C~NRggRge in which Rgg and
Rgg are each independently hydrogen or C4_g alkyl, SOsRgg in which Rgq is H or C4_g alkyl, or C4_3 acyl optionally substituted with 1 or more F, Cl or OH; Rygis a) carboxyl, ‘ b) halo, c) -CN, d) mercapto, e) formyl, f) CFa, 9) NO,, h) = Cy alkoxy, i) C14.g alkoxycarbonyl, )) C1-g alkythio, k) C4. acyl, )) C4.s alkyl optionally substituted with OH, C4_s alkoxy, C4.5 acyl, or -NR47R4g,
m) phenyl, n) -C(=O)NRyR24, 0) -NRg7Rqg,
P) -N(Rg)(-SOzR3), q) -S05-NRygRo4, Or
Nn -S(=0)Ra;
Rog and R,4 at each occurrence are the same or different and are a) H, b) C1 alkyl, or
Cc) phenyl;
Rp is a) C414 alkyl, or b) phenyl optionally substituted with C44 alkyl; wherein Rg is : 15 a) carboxyl, b) halo, : : ¢ ON, d) mercapto, e) formyl, f) CF3, 9) NO, h) C1.g alkoxy, i) C1. alkoxycarbonyl,
I) C4. alkythio, k) C45 acyl, ) ~~ -NRy3Rp4, m) C4 alkyl optionally substituted with OH, C4_s alkoxy, C45 acyl, or -NRy3R»4,
: n) Co.g alkenylphenyl optionally substituted with one or two oo Ras, 0) phenyl optionally substituted with one or two Ros, 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 Rpg, or q) o
Rpz and Ry, at each occurrence are the same or different and are a) H, b) formyl, c) C14 alkyl, d) C44 acyl, 3 e) phenyl, : f) Cs. cycloalkyl, or g) R23 and Ry, 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, C4_3 alkyl, or C4_5 acyl;
Ros is a) carboxyl, b) halo, 0) -CN, d) mercapto, e) formyl,
f) CFs, : a) NO,, h) C15 alkoxy, i) C4. alkoxycarbonyl, )] C1. alkythio, kK} ~~ Cqgacyl,
I) phenyl, m) C4 alkyl optionally substituted with OH, azido, C4_5 alkoxy,
C15 acyl, -NR3pR33 -SR34, -O-SO,R35, OF
Ru )—Hncoo. , n) -C(=O)NRzgRy7, 0) -NRz3R4,
P) -N(Rxg)}-SOzR2), qQ) -SO2-NRygRy7, or r -S(=0)iR22, s) -CH=N-Ryg, or t) -CH(OH)-SO3Rs4;
Rgpz is the same as defined above;
Ros and Rpy at each occurrence are the same or different and are a) H, b) Cyg alkyl, c) phenyl, or d) tolyl;
Rog is a) OH, b) benzyloxy, c) -NH-C(=0)-NH,,
d) -NH-C(=S)-NH,, or e) -NH-C(=NH)-NR3gR3g;
Rag and Rj at each occurrence are the same or different and are a) H, or b) C1-4 alkyl optionally substituted with phenyl or pyridyl;
Raq is a) H, or b) a sodium ion;
R32 and R33 at each occurrence are the same or different and are a) H, b) formyl, c) C14 alkyl, d) C44 acyl, e) phenyl, f) C35 cycloalkyl, ag) R32 and R33 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, C4_3 alkyl, or C4_3 acy, h) -P(O)(OR37)(ORgg), or i) -S02-Rag;
Rag is
N-N NN N N ho a CL or Lo :
CHa CH; CHj
Rgjsis Cq.3 alkyl;
Rag is a) C14. alkoxycarbonyl, or b) carboxyl; ’ R37 and Rag at each occurrence are the same or different and are a) H, or b) C14.3 alkyl;
Rjgis a) methyl, b) phenyl, or 9) tolyl; wherein K is a) O, b) S, or c) NR40 in which Rg is hydrogen, formyl, C44 alkyl, C4_4 acyl, phenyl, Cg cycloalkyl, -P(O)(OR37)(OR3g) or =SO5-R3g in which R37, Rag and Rag are as defined above;
Ryp, R11, R12, R13, Ry4 and Ry5 at each occurrence are the same or different and are : a) H, b) formyl,
Cc) carboxyl, . d) C4 alkoxycarbonyl, e) C1.g alkyl, f) Cog alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with
OH, halo, C_g alkoxyl, C4_g acyl, C4_g alkylthio or C4_g alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF3, NO5, C44 alkyl, C4. alkoxy, C4.g acyl, C4_g alkylthio, or C1 ¢ alkoxycarbonyl;
h) ~~ -NR42R43, i) OR4g4, ) -S(=0)-Rys, kK) ~~ -SO2-N(Rgg)(Ra7), Or )] a radical of the following formulas:
Oe On OO rf Cont, 0 ruran— Rso 5 — —_ . Rs
Rs3 ww N— Rey—(CHt—N N— NENan _/ , 4, , or re”) . ;
R1g is the same as defined above;
Tis : a) oO, b) S, or *
Cc) SOy;
R42 and R43 at each occurrence are the same or different and are a) H, b) C3.5 cycloalkyl, c) phenyl, d) C4. acyl, e) C1.g alkyl optionally substituted with OH, C4_4 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, halo, -NO,, C44 . ' 0 NN > alkoxy,-NR4gR4g, or o , f) “re
Res~CH— of 9)
VV N-(cgt— —/ :
Vis a) 0, b) CH,, or c) NRsg; :
R4g and Ryg at each occurrence are the same or different and are a) H, or b) C14 alkyl, : Rg4 is a) OH, b) C44 alkoxy, or ¢) -NRs7Rgs;
Rss is a) H, or b) C4.7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NHj, -CO5H, or -C(=NH)-NH,; :
Rsg is a) H, b) phenyl, or
Cc) C1. alkyl optionally substituted by OH;
Rs7 and Rgg at each occurrence are the same or different and are a H, b) Cys alkyl, c) C1.3 cycloalkyl, or d) phenyl;
Ryq is a) C+.g alkyl! optionally substituted with C4_.g alkoxy or C44 hydroxy, C3.g cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -NO,, CFj, halo, -CN, OH, C4_5 alkyl, C4_5 alkoxy, or
Cy.5 acyl, b)
Vo Ne(chgt— c) phenyl, or d) pyridyi; :
Rys is a) Cq.g alkyl, b) C,_1g alkenyl, wherein the substituents (a) and (b) can be optionally substituted with : C4. 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, -NO,,
C45 alkyl, C4 alkoxy, C1.¢ acyl, C1. akkyithio, or C45 : alkoxycarbonyl;
R46 and R47 at each occurrence are the same or different and are a) H, b) phenyl, c) C16 alkyl, or d) benzyl;
Rgp and Rg¢ at each occurrence are the same or different and are a) H, b) OH, c) C+. alkyl optionally substituted with -NR4gR4g in which
R4gand Ryg are as defined above, d) Rs and Rs4 taken together are =O;
Rsa 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 -NO,, CF3, halo, -CN, OH, phenyl, C45 alkyl, C4.5 alkoxy, or C4_5 acyl, c) morpholinyl, d) OH, e) C46 alkoxy, f) -NR4gR4g in which R4qgand Ryg are as defined above, 9) -C(=0)-Rsp, or h)
O— a>
Rs3 is a) H, b) formyl,
Cc) Cq4 alkyl, d) C44 acyl, e) phenyl, f) Cag cycloalkyl, 9) -P(O)}ORg37)(ORgg), or h) -SO7R3g, in which R37, R3g and Rag are as defined above;
Rsgis a) morpholinyl, b) OH, or
Cc) C46 alkoxy; his1,2,0or3; iis 0,1,0r2; jis 0, or 1; kis 3, 4, or 5; : ris1,2,3,4,50r6; tis0,1,2,3,4,5,0r6; uis1or2; and
Qis a) hydrogen, b) halo,
Cc) NO, d) Ns, e) C4-Cg alkylthio,
Q
) CyCgalkyl—§—,
0 9) Cy-Cgalkyl—§—
Oo ’ : h) C1-Cg alkyl, i) C4-Cg alkoxy, )] formyl, k) C4-Cg alkyl—C—, 9 ) C4-Cg alkkyl—0-C—, m) -sulfamoyl (H,NSO,-), n) -NHOH, 0 o) CrCealkyl—C-0—
Q p) heteroaryl —C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, Nor S,
Q
: q) CeHs-C—, r amino, s) C4-Cg alkylamino-, t) di(C4-Cgalkylamino-, 0 u) (C4-Cg) alkyl—C-NRgoRg, in which Rgg and Rg are each independently hydrogen or C4-Cgq alkyl, v) OH, w) cyano,
X) hydroxy (C4-Cg alkyl), 9 y) C4-Cg alkyl—S-C—,
Q z) + NC—(CH,)—C— in whichris 1-6,
Q aa) CgHsCH,-O—-C—,
Q bb) CgHs-0O-C—,
Nes cc) Cy-Cealkyl—C— in which Rgy is hydrogen or Cy.¢ alkyl,
Q dd) RgsO—(CH,)16—C— in which Rg is hydrogen, C4. alkyl optionally substituted with one or more F, Cl, OH, C4_g alkoxy or C4_g acyloxy, C3.g cycloalkyl or C4_g alkoxy;
N-ORg,4 ee) H-C— inwhich Rg is hydrogen or Cq_g alkyl, ff) a substituted or unsubstituted Cg-C4q aryl moiety, gg) a substituted or unsubstituted monocyclic or bicyclic, } saturated or unsaturated, heterocyclic moiety having 1-3 atoms selected from O, N or S, said ring being bonded via a . ring carbon or nitrogen to the phenyl substituent, hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic moiety having 1-3 hetero atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent and wherein the heteroaromatic moiety can additionally have a fused-on benzene or naphthalene ring; 20. the substituents for such p, q, ff, gg and hh moieties being selected from 1 or 2 of the following: 1) halo, 2) C4. alkyl, 3) NO,, 4) Na,
Q
. 5) C4-Cg alkyl —S—, 6) C.-Cs alkyl—S§— o 7) formyl,
Q
8) C4-Cg alkyl—C—,
Q
9) C4-Cg alkkyl—0-C— ) 0 10) heteroaryl—C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, Nor S, 0 . 11) CgHs—C—,
Q
12) -(C4-Ce) alkyl—C-NRgoRg4 in which Rgg and Rg are each independently hydrogen or C4-Cg alkyl, 13) OH, 14) hydroxy (C4-Cg alkyl),
Q
15) C4-Cgalkyl—S-C—,
Q
16) NC—(CH,), —O-C— in which ris 1-6,
Q
17) CgHsCH,—O-C—., 18) -CHy-Rgpin which Rgq is a) -OR3z in which Rj; is as defined above, b) -SR35 in which R35 is as defined above,
Cc) -NR32R33 in which Rg; and R33 are as defined above, or d) 9- or 6-membered heteroaromatic containing 1-4 O,
S or N atoms,
ORe 19) C;-Cgalkyl—C— in which Rey is as defined above, 20) cyano, 21) carboxyl, 22) CFs, } 0 23) C4-Cg alkyl—C-0—
Q
24) CgHs~0-C— in which the phenyl moiety may be optionally substituted by halo or (C4-Cg)alkyl, 2? 25) NRgoRz—C— in which Rg and Rg are as defined above, 0 Q 26) Rgy~NH-C— or Rg;~C-NH— in which Rg is a 5- or 6- membered aromatic heterocyclic group having 1-3 O, N or
S,
Q
27) CgHs(CH,);s—0-C—,
Q
28) RgsO—(CH,);s—0-C— in which Rgg is as defined above,
Q
29) SiRggRgoR191—0-CH,—C— in which Rgg, R1gp and Ryg4 are each independently C44 alkyl; or
Q and either R4 and Ry taken together form —O-CH,-O.
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. 2. Description of the Prior Art
The literature contains a limited number of isoxazolinones used as pre-emergence herbicides. For example in U.S. Patent 4,065,463, 2- methyl-4-(trifluoromethyl-m-tolyl)-3-isoxazolin-5-one and 2-methyl-4- (chloro-m-tolyl)-3-isoxazolin-5-one are disclosed as being useful in preventing the growth of weeds which have a deleterious effect an crop production.
Od 04 [o] \ JS 7
AW : \ AW
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.
Q
' \ _ CHa
Nery
The applicant is not aware of any literature which discloses the use of these compounds as broad spectrum anti-bacterial agents. A different ring system is disclosed in WO 98/07708, which discusses the use of isoxazoline derivatives as anti-bacterial agents,
W, AN hog \'J ba where W is a substituted aryl or heteroaryl system and V is H, or C4-C4 alky! optionally substituted with F, Cl, OH, C4-C4 alkoxy, or acyloxy.
Oxazolidinones Il 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. 4,948,801; 5,254,577; and 5,130,316 (arylbenzene oxazolidinyl compounds), and European Patent Applications 0,697,412; 0,694,544, 0694,543; and 0,693,491 (5 to 9-membered heteroaryl substituted oxazolidinones). 0 “ON
TN n 0
Additionally, certain compounds containing a substituted furanone ring have been reported to possess antibiotic activity. WO 97/14690 discloses 6
EO
IO
L
— where T is hydroxy or NHC(O)C1-C4 alkyl, M and L are each independently hydrogen or fluoro, G and H are are each independently hydrogen or methyl, K-J is of the formula C=CH, CHCH2 or C(OH)CH2, is O, SO, SO2 or a substituted nitrogen, and Q-R is CH,-CH2 or CH=CH.
Other substituted furanones are discussed in U.S. Patent 5,708,169, WO 97/43280 and WO 97/10235.
Claims (1)
- LE WO 00/10566 PCT/US99/19265 CLAIMS We claim:1. A compound of the formula . 0 ' (op H ENR L 1 or a pharmaceutically acceptable salt thereof wherein: Ryis a) H, b) C1.g alkyl optionally substituted with one or more F, Cl, OH, C1-g alkoxy, or C4_g acyloxy, c) C3. cycloalkyl, or d) C4.g alkoxy; L is oxygen or sulfur; Ais a) 2 R3 b) Ry LAD c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a fused-on benzene or naphthyl ring, and wherein the heteroaromatic moiety is optionally substituted with one to three Rg, d) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three Ry, e) a B-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rg, f) Rui Xe , or ¢)) R11 Ryy ed TAS TX Riz wherein Ry and Rj; are each independently a) H, b) F, c) Cl, d) Br, e) C15 alkyl, f) NO,, :: h) C1. alkoxy, . | | ) OH )] amino, . 5 k) cyano, or )) Rz and Rj taken together are -O(CHo)n-0; wherein Ry is : a) H, b) C1 alkyl, Cc) F, or d) OH; Rs is a) H, b) CF3, c) C1.3 alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) Rs and Rg taken together are a 5-, 6-, or 7-membered ring . of the formula, / 0g Jorn -/ ’ f) in which D is S, O or NRgg in which Rgg is H orC1. alkyl, or )) Rs and Rg taken together are -(CH,),-, when Ryis an electron-withdrawing group; Rg and Ry at each occurrence are the same or different and are a) an electron-withdrawing group, b) H,c) CF3, ’ d) C1.3 alkyl optionally substituted with one halo, e) phenyl, provided at least one of Rg and Ry; is an electron- withdrawing group, or f) Re and Ry taken together are a 5-, 6-, or 7-membered ring of the formula, is -c C Schalke Uis a) CHa, b) O, c) Sor, d) NR: Rig is a) H or b) C1.5 alkyl; wherein Rg is a) carboxyl, b) halo, ¢) -CN, d) mercapto, e) formyl, f) CFj, 9) NO, h) C4 alkoxy, )) C4.5 alkoxycarbonyl, )) C4. alkythio, k) Ci acyl,) -NRyzR4g, NOH : oo m) ~~ —C-Rg; in which Rgz is H or C45 alkyl, n) C16 alkyl optionally substituted with OH, sulfamoyl, C4_s alkoxy, C45 acyl, or -NR47R4g, 0) C,_g alkyl optionally substituted with one or two Ryg, p) phenyl optionally substituted with one or two Rig, q) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of §, N, and O, optionally substituted with one or two Rg, or o} R17 and R4g at each occurrence are the same or different and are a) H, j b) C14 alkyl, c) Cs cycloalkyl, or d). R47 and Rqg 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, Cq3 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety : 2 containing 1-3 O, N or S, —C—NRggRgs in which Rgg and Rag are each independently hydrogen or C1. alkyl, SO;Rgg in which Rgg is H or C4_g alkyl, or C4_5 acyl optionally substituted with 1 or more F, Cl or OH;Rig is a) carboxyl, b) halo, ¢) -CN, d) mercapto, e) formyl, f) CFs, 9) NOz h) C45 alkoxy, i) C1. alkoxycarbonyl, i) C4. alkythio, k} Cspacyl, )) C1.6 alkyl optionally substituted with OH, C4_s alkoxy, Cis acyl, or -NR¢7R 4s, m) phenyl, n) -C(=0)NRygR54, : 0) -NR¢7Rqs, P) -N(R20)(-SOzR22), q) -SO2-NRygR»4, OF Nn -S(EO)R2; R20 and Ry4 at each occurrence are the same or different and are a) H, b) C1. alkyl, or Cc) phenyl; Rapjis a) C44 alkyl, or b) phenyl! optionally substituted with C4_4 alkyl;wherein Rg is a) carboxyl, b) halo, Cc) -CN, d) mercapto, e) formyl, f) CF 9) NO,, h) C,.s alkoxy, i) C1.g alkoxycarbonyl, ) C1. alkythio, k) C4 acyl, ) -NR23R24, m) Cy alkyl optionally substituted with OH, C1.5 alkoxy, C4.5 acyl, or -NRy3R54, n) C,.g alkenylphenyl optionally substituted with one or two Ras, o) phenyl optionally substituted with one or two R2s, 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 Ras, or q) Lo} Rpg and Ry, at each occurrence are the same or different and are a) H, b) formyl,c) C14 alkyl, d) Cygqacyl, e) phenyl, f) Cs_g cycloalkyl, or g) R23 and Ry4 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 §, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C4_3 alkyl, or C4.3 acyl; Ros is a) carboxyl, b) halo, Cc) -CN, d) mercapto, e) formyl, f) CFj, 9) NO, h) Cy alkoxy, i) C1. alkoxycarbonyl, i) Cg alkythio, kK} Cigacyl ) phenyl, m) C4 alkyl optionally substituted with OH, azido, C4.5 alkoxy,C1.5 acyl, -NR3pR33 -SRgy4, -0-SO,R35, or Ru—(_)—coo. n) -C(=O)NRzgRz7, 0) -NRa3RasBE a. - 144 - P) -N(Rge)(-SO2Rpy), q) -S05-NRygRo7, or nN -S(=O)Ry, Ss) -CH=N-Ryg, or t) -CH(OH)-SO3R3; Rog is the same as defined above; Ros and Ry7 at each occurrence are the same or different and are a) H, b) C1. alkyl, Cc) phenyl, or d) tolyl; Rog is a) OH, b) benzyloxy, c) -NH-C(=0)-NH,, d) -NH-C(=S)-NH,, or e) -NH-C(=NH)-NRygR3g; : Rag and Rj3q at each occurrence are the same or different and are a) H, or b) C14 alkyl optionally substituted with phenyl or pyridyl; R31 is a) H, or b) a sodium ion; R32 and Rj3 at each occurrence are the same or different and are a) H, b) formyl, c) C14 alkyl, d) C14 acyl, ~e) phenyi,f) Cag cycloalkyl,9) R32 and R33 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, C4_3 alkyl, or C4_3 acyl,h) ~~ -P(O)(OR37)(OR3g), or i) -S0,-Rgg;Raq is C3 ane, CO.N > (CH3)C” “g ’ N Lor N ; CHs CHa CH Ras is Cq.3 alkyl; Rag is a) C4. alkoxycarbonyl, or b) carboxyl; Rgyand Rag at each occurrence are the same or different and are a) H, or b) Cyzalkyl; Rag is a) methyl, b) phenyl, or c) tolyl; wherein K is a) 0, b) S, or Cc) NR4o in which R4q is hydrogen, formyl, C4_4 alkyl, C4_4 acyl, phenyl, C3_¢ cycloalkyl, -P(O)(OR37)(OR3g) or -S05-R3g in which R37, Rag and Rg are as defined above;R10, R11, R12, R13 R44 and Rs at each occurrence are the same or different and are a) H, b) formyl, : x) ¢) carboxyl, d) C4. alkoxycarbonyl, e) C1.g alkyl, f) C,.g alkenyl, wherein the substitutents (e) and (f) can be optionally substituted with OH, halo, C4_g alkoxyl, C4_g acyl, C4 alkylthio or C4 alkoxycarbonyl, or - phenyl optionally substituted with halo, : 9) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF3, NO, Cg alkyl, C4. alkoxy, C1. acyl, C4 alkylthio, or Cis alkoxycarbonyl; h) ~~ -NRjs2Rg3, i) ORy4, I) -S(=0);-R4s. k) -SO2-N(R46)(Ray), or J) a radical of the following formulas: om Ge OO = cont ° ara Nie Fos = , Rsq , Rs3 WARE Rer—(CHt~N Ne Nan~~. pe R1g is the same as defined above:Tis : a oO, b) S,or Cc) SO,; Ryo and R43 at each occurrence are the same or different and are a) H, b) C3. cycloalkyl, c) phenyl, d) Cigacyl, e) C.g alkyl optionally substituted with OH, C,_g alkoxy which can be substituted with OH, a 5- or 6- membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF3, halo, -NO,, C4_4 OX GC alkoxy,-NR4gR4g, OF o , n *\-Re Res-CH— of a) { h—(ongt— Vis a) 0, b) CHo, or c) NRgg; Rag and R4g at each occurrence are the same or different and are a) H, or b) C44 alkyl,Rs4 is a) OH, b) C1.4 alkoxy, or ¢) -NRs7Rsg; ; 5 Rssis a) H, or . b) C4.7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C(=0)-NH,, -CO,H, or -C(=NH)-NH; Rsgis a) H, b) phenyl, or c) C1. alkyl optionally substituted by OH; : Rs7 and Rsg at each occurrence are the same or different and are a) H, b) Cy.5alkyl, c) C14.3 cycloalkyl, or : d) phenyl; : Raq is a) C4. alkyl optionally substituted with C4_g alkoxy or C46 hydroxy, C3_g cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -NO,, CFj3, halo, -CN, OH, C4_5 alkyl, C1_5 alkoxy, orC1.5 acyl, b) VN (oHpt— —/ ’ Cc) phenyl, or d) pyridyl; : Rus is a) Cyqgalkyl, b) C.16 alkenyl, : wherein the substituents (a) and (b) can be optionally substituted withC1.s 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, Cc) 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,, C16 alkyl, C46 alkoxy, C4_¢ acyl, C4 alkylthio, or Cis 16 alkoxycarbonyl; R46 and R47 at each occurrence are the same or different and are a) H, b) phenyl, Cc) C46 alkyl, or d) benzyl; Rso and Rg4 at each occurrence are the same or different and are a) H, b) OH, c) C1.6 alkyl optionally substituted with -NR4gR 4g in which Rag and Ryg are as defined above, d) Rs and Rg4 taken together are =O; Rso 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 -NO,, CF3, halo, -CN, OH, phenyl, Cis alkyl, C4_g alkoxy, or C4_5 acyl, c) morpholinyl, . d) OH, e) Cyg alkoxy, f) -NR4gR4g in which R4g and Rg are as defined above, g) -C(=0)-Rsg, or h) 0" XX Jo Rs3 is a) H, b) formyl, c) C14 alkyl, d) C14 acyl, e) phenyl, f) Cs. cycloalkyl, g) -P(0)(OR37)(OR3g), or h) -SO2R3g, in which R37, Rag and Raq are as defined above: Rsg is a) morpholinyl, b) OH, or c) C4. alkoxy; his 1, 2, or 3; iis 0,1, 0r2;jis 0,0r1; kis 3, 4, or 5; ris1,2,3,4,50r6; tis0,1,2,3,4,5,0r6; wuis1or2; and Qis a) hydrogen, b) halo, c) NO,, d) Ns, e) C4-Cg alkylthio, : Q f) C,-Cg alkyl—S§—, 0 9) CyCealkyl—§— oS h) C4-Cg alkyl, i) C4-Cg alkoxy, J) formyl, Q kK) C,-Cg alkyl—C—, o h C4-Cg alkyl—0-C—, m) -sulfamoyl (H,NSO,-), n) -NHOH, 0 0) CyCealkyl—C-0— Q p) heteroaryl —C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, Nor S,PCT/US99/19265Q q) CgHs—C—, BB r) amino, S) C4-Cg alkylamino, t) di(C4-Cg alkyl)amino-, Q u) (C4-Cg) alkyl—C-NRggRg4 in which Rgg and Rg1 are each independently hydrogen or C4-Cg alkyl, v) OH, w) cyano, X) hydroxy (C4-Cg alkyl), 0 y) C,-Cg alkyl—-S-C—, 2 z) NC—(CH,),—C~— in which ris 1-6, Q aa) CeHsCH,-O—C— ) ) 0 bb) CgHs-O-C—, Noes cc) Cy-Cgalkyl—C— in which Rg is hydrogen or C4_5 alkyl, 0 16 dd) RgsO—(CH,)s.—C— in which Rs is hydrogen, C4.g alkyl optionally substituted with one or more F, CI, OH, Cis alkoxy or C4_g acyloxy, C3 g cycloalkyl or C1.g alkoxy; N-ORg, ee) H-C— inwhich Rg, is hydrogen or Cy alkyl, ff) a substituted or unsubstituted Cg-C1q aryl moiety, gg) a substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, heterocyclic moiety having 1-3 atoms selected from O, N or S, said ring being bonded via a } ring carbon or nitrogen to the phenyl substituent, hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic moiety having 1-3 hetero atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent and wherein the heteroaromatic moiety can additionally have a fused-on benzene or naphthalene ring; the substituents for such p, q, ff, gg and hh moieties being selected from 1 or 2 of the following: 1) halo, 2) C46 alkyl, 3) NO,, 4 Ns, Q 5) C,-Cg alkyl —S—, 0 6) Ci-Cealkyl—§— . O ' 7) formyl, Q 8) C4-Cg alkyl—C—, 0 9) Cy-Csakyl—0-C—,0 . 10) heteroaryl—C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, Nor S, 0 11) CgHs—C—, 0 12) -(C4-Ce) alkyl—C-NRgoRg4 in which Rgg and Rg4 are each independently hydrogen or C4-Cg alkyl,PCT/US99/1926513) OH, . 14) hydroxy (C4-Cg alkyl), , 15) C4-Cgalkyl—S-C—, ? 16) NC—(CH,), —O-C— in which ris 1-6, Q 17) CgHsCH,—0O-C—, 18) -CH3-Rgg in which Rgq is a) -OR3; in which Rg; is as defined above, b) -SR3; in which Rg, is as defined above, ¢) -NR3;Rg33 in which Ry, and R33 are as defined above, or d) 5- or 6-membered heteroaromatic containing 1-4 O, S or N atoms, N _ORg, 19) C4-Cgalkyl—c— in which Rgy is as defined above, 20) cyano, 21) carboxyl, 22) CFs, 0 23) C.-Cg alkkyl—Cc-0— : 2 24) CgHs-0-C~ in which the phenyl moiety may be optionally substituted by halo or (C4-Cg)alkyl, Q 25) NRgoRs—C— in which Rgy and Rg are as defined above, 2 ? 26) Rgi~NH-C— or Rgs—~C-NH— in which Rg is a §- or 6- membered aromatic heterocyclic group having 1-3 O, N or S,PCT/US99/192650 . 27) CgHs(CHy)4.6~0-C— ’ 9 28) RgsO—(CH,)1.5—0-C— in which Rgs is as defined above, 0 29) SiRggR100R101—0-CHy—C— in which Rgg, R100 and R101 are each independently C4 alkyl; or Q and either Ry and R; taken together form —O-CH,-O.2. A compound of claim 1 wherein A is R at y Ras in which Q, R and Rj are as defined in claim 1.3. A compound of the formula >) 0) 3 O ¢ OH x R3 ~Y ! mw © or a pharmaceutically acceptable salt thereof, in which R1 is H, C4_g alkyl optionally substituted with one or more F, Cl, OH, C4.g alkoxy, or C4_g acyloxy, C3.g cycloalkyl or C4_g alkoxy; Ry and R3 are each independently a) H,b) F c Cl d Br e) C1. alkyl, f) NO,, a h) C1. alkoxy, i) OH )] amino, or Kk) cyano; and Qis a) hydrogen, b) halo, c) NO,, : dN, e) C4-Cg alkylthio, 0 f) C,-Cg alkyl —S—, : 0 9) CiCealkyl—s—, 0] h) C4-Cg alkyl, i) C4-Cg alkoxy, )) formyl, Q k) C.-Cg alkyl—Cc—, Q 1) C,-Cg alkyl—0-C—, 0) m) C4-Cg alkkyl—C-0—.,0 i n) heteroaryl —C— in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, Nor S, Q 0) CgHs-C— , p) amino, qQ) C4-Cg alkylamino-, r) di(C4-Cg alkyl)amino-, 0 s) (C4-Ce) alkyl—C-NRgoRg1,in which Reso and Rg4 are each independently hydrogen or C4-Cg alkyl, t) OH, u) cyano, Vv) hydroxy (C4-Cg alkyl), Q : w) C,-Cg alkyl —S-C—, ? X) NC—(CH,), —O-C— in which ris 1-6, 0 y) CgHsCH;—0O-C—, 0 2) CeHs-O-C— , \ _ORg,4 aa) Cy-Cgalkyl—C— wherein Rg, is hydrogen or C4_g alkyl, 0 bb) RgsO-(CH,).s—C— in which Rgg is hydrogen, C,_g alkyl optionally substituted with one or more F, CI, OH, C4.g alkoxy or C4_g acyloxy, C34 cycloalkyl or C4_g alkoxy, N-ORg,4 cc) H-C— in which Rg, is as defined above,dd) JO Se ee) \s|Ny X ] ff) YY W= X aN SX ag)yy. NT X YY \'e M H hh) X vl : "N Ne ii) x N ~ N N Mm 1 I) x ZN Sw Mm 1} kk) X JY 7h N SV m YI) : o N—N X mm) : Nx sn Ny N= nn) Y N Hd NX X, 00) NN ALN \ Rez in which Rg, is H or C44 alkyl, PP) s (2x | N-N qq) X NY N We Y, Ir) NX —N~ 5 \=|= Y 16 ss) No —N _N \A:N x ?PCT/US99/19265 t X EN —N \=4N Y 3 uu) Ss —\ N N—YX wv)N. AN KY X Hi ww) X a Zn N SV Y t] XX) X H [T% B v 2” , yy) ORg2 0 AS 0) zz) (CHa), / rg, (CHa)p 16 aaa) a diazinyl group optionally substituted with X and Y, bbb) a triazinyl group optionally substituted with X and Y, ccc) a quinolinyl group optionally substituted with X and Y, ddd) a quinoxalinyl group optionally substituted with X and , eee) a naphthyridinyl group optionally substituted with X and ,ff) + Aq (CHw 2" y hd 14 agg) 2 0 PN N a yy Res” “ieHi J hhh)af . N ZO hd , or ii) Res N Lo A B is an unsaturated 4-atom linker having one nitrogen and three carbons; : 10 Mis a) H, b) C4_g alkyl, Cc) C4_g cycloalkyl, d) -(CH2)mORegg, or e) -(CH,),NRgs7Rgs; Zis a) oO, b) Sor ()] NM; Wis a) CH, b) NorCc) S or O when Z is NM; X and Y are each independently a) hydrogen, b) halo, ¢ NO, d Ns e) C4 alkythio, ? f) C,-Cs alkyl —S—, 0 9) Ci-Ceakyl—s—, 0) h) C4-Cg alkyl, i) C,-Cg alkoxy, i) formyl, Q Kk) C4-Cs alkyl—C— : 0 )] C4-Cg alkyl—0-C— : Q m) 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, Q n) CgHs—C—, 0) amino, Pp) C1-Cg alkylamino-, q) di (C4-Cg alkyl)amino-,Q r -(C4-Cg) alkyl—C-NRggRg; in which Rg and Rg are each independently hydrogen or C4-Cg alkyl, s) OH, t) hydroxy (C4-Cg alkyl), 2 u) C4-Cs alkyl —S-C—, 2 )] NC—(CH,), —0-C— in which ris 1-6, 0 w) CeHsCH,—0O-C— , Q X) CegHs-0O-C—, \ _ORg, y) Cq-Cgalkyl—C— in which Rg, is as defined above, z) cyano, aa) carboxyl,bb). CFj, cc) mercapto, Q dd) C4-Cqalkyl—C-0-— Q ee) CgHs~0O-C— in which the phenyl moiety may be optionally substituted by halo or C4-Cg alkyl, Q ff) ~~ CgHs(CHy)1s—0O-C—, Q 99) RgsO—(CH,)..s—C— in which Rgs is as defined above, or Q hh) SiRggR1ggR191—0-CH,—C— in which Rgo. R100 and R101 are each independently C4_g alkyl; or Q and either Ry and Rj taken together form —-O-CH,-O;Rg2 is a) H, b) C4.g alkyl optionally substituted with one or more halos, or C) C1.g alkyl optionally substituted with one or more OH, orC1.g alkoxy; Eis a) NRgg, b) -S(=0); in which iis 0, 1 or 2, or C) oO; Regis a) H, b) Cys alkyl, c) -(CHy)q-aryl, or d) halo; Rggis Hor Cq4 alkyl; : : Rg7 and Rgg are each independently H or C4_4 alkyl, or NRg7Rgg taken together are ~(CHj)-; : Reg is a) H, b) C4. alkyl, Cc) ~(CHa)q-aryl, d) -CO5Rg4, e) CORagy, f) -C(=0)-(CHp)q-C(=O)Rgy, g) -S(=0),-C4 5 alkyl, h) -S(=0),-(CHp)q-aryl, or i) -(C=0);-Het in which jis 0 or 1;Zyis a) -CHs-, or b) -CH(R7o}-CHy; Zyis a) -05S-, by -O-, c) -S-, d) -SO-, or e) -N(Rzqp)~ Zjis a) S, b) SO, c) SO,, or d) oO; Aqis Hor CHg; Apis : a) H, b) OH-, c) CH3COo-, d) CHsz-, : e) CH30-, f) Ry20-CHy-C(O)-NH-, 9) Ry30-C(O)-NH-, h) ~~ Ry73-C(O)-NH-, i) (C41-Co)alkyl-O-C(0)-, or J) HO-CHoy; or A, and A, taken together are:a) Ra1 Le or b) O=; Re4 is H or CHs-; mis4or5; nis0, 1,2 3,4o0r5; yisOor 1; pis0,1,2 3, 40r5; wis 1,2or3; qis1,2,30r4; zisOor 1; Regs is a) R740C(R75)(R76)-C(O)-, b) ~~ Rz70C(0)-, ¢) Ryg(0), d) R79-SO,-, or e) Rgg-NH-C(0)-; Ryo is H or (C4-C3)alky!; R74 is a) R740C(R75)(R76)-C(O)-, b) R770-C(O)-, ¢) Ryg-CO)-, I A e) I SSL f) HzC-C(0)-(CH,),-C(0)-, 8) Ry9-SOo-, h) o) ° 7 oo i) Rgo-NH-C(O)-, Ryo is a) H, b) CHj, c) phenyl -CH,-, or : d) CH3C(O)- R73 is (C4-Cg)alkyl or phenyl; ’ R74 is H, CH3, phenyl-CH,- or CH3-C(O)-; Rys and Ryg are each independently H or CH3, or R75 and Ry taken together are ~CH,CHo-; R77 is (C4-C3)alkyl or phenyl; Rg is H, (C1-Cg)alkyl, ary-(CHa)p1, CIH,C, ClgHC, FH,C-, FoHC- or (C3-Cg)cycloalkyl; Rygis CHa; -CH,CI, -CH,CH=CH,, aryl or -CH,CN; Rgg is =(CH»),1-aryl where nis 0 or 1; Rgq is a) H,b) C1. alkyl optionally substituted with one or more OH, halo or CN, 0 -(CHg)q—aryl in which q is as defined above, or d) -(CHy)q—ORgs in which q is as defined above: Rep is a) C4.6 alkyl optionally substituted with one or more OH, halo or CN, b) -(CHp)q-aryl in which q is as defined above, or c) ~(CH3)q-ORg3 in which q is as defined above: Rgjis a) H, b) C16 alkyl, Cc) -(CHy)q-aryl in which q is as defined above: or d) -C(=0) Cg alkyl; and | : aryl is phenyl, pyridyl or naphthyl, said phenyl, pyridyl or naphthyl : moieties being optionally substituted by one or more halo, -CN, OH, SH, C4. alkoxy or C4 alkylthio. )4. A compound of the formula Rz o] & ~My IA ° or a pharmaceutically acceptable salt thereof, in which RyisH, C4_g alkyl optionally substituted with one or more F, Cl, OH, Cy _g alkoxy or C4_g acyloxy, Ca. cycloalkyl or C4_g alkoxy;PCT/US99/19265Rz and Rj are each independently H or F; or R, and R taken together ’ represent ou > Qis a) hydrogen, b) halo, c) Ns d) NO,, e) C4-Cg alkylthio, Q f) C4-Cg alkyl—s— . 0 9) C,-Cgakyl—S— (0) Hl h) C4-Cg alkyl, i) C4-Cg alkoxy, J) formyl, Q kK) C4-Cg alkyl—Cc— , Q 0) C-Ce alky-0-C— Q m) C4+-Ce alkyl-Cc-0— , n) (C4-Ce alkoxy),N-, 0) 5- or 6-membered 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 Reg, OH N p) C4-Cg alkyl—CPCT/US99/19265 q) phenyl optionally substituted by Rgg, 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 Rgg, and Reg is a) C4-Cg alkyl-OH, b) C4-Csalkyl—0-c—, oO Q c) CH3—c— C,-Cg alkyl—C—, Oo d) cyano, e) formyl, - ’ NOH f) H-C— ’ : Q a) C4-Cs alkyl-O-C— , 0 : h) SiRg4RasReg~0-C— in which Rgy, Rgs and Rgg are each 16 independently C4-Cg alkyl, Q 0 ) CHy—s— C;-Cgalkyl—S—, oO 0) 2 )] HC=CCH,0C—, Q k) CeHs~0-C— here the phenyl may be optionally substituted by halo, Q ) HO-CH,-C—, m) (C1-Cg alkyl)oN-,‘ | PCT/US99/19265 n) C4-Cg alkyb-NH-, 0) amino. 9 : Pp) C4-Cgalkyl—S—, Q q) CeHsCH,O0C—, or rn Rgg—C— in which Rgg is phenyl, 5- or 6-membered heteroaryl containing 1-3 O, N or S and linked to the phenyl substituent via a ring carbon atom or 5- or 8-membered saturated or unsaturated heterocyclic containing 1-4 O, N or S and linked to the phenyl substituent via a ring carbon atom.5. A compound selected from the group consisting of the compounds of Examples 1-87 described in the specification.6. A pharmaceutical composition comprising a compound of Claim 1 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.7. Use of a compound of Claim 1 in the manufacture of a medicament for treating a bacterial infection in a mammal.8. A substance or composition for use in a method of treating a bacterial infection in a mammal, said substance or composition comprising a compound of Claim 1, and said method comprising administering to a mammal a therapeutically effective amount of said substance or composition. AMENDED SHEET; PCT/US99/192659. A compound according to Claim 1, Claim 3, or Claim 4, substantially as herein described and illustrated.10. A pharmaceutical composition according to Claim 6, substantially as herein described and illustrated.11. Use according to Claim 7, substantially as herein described and illustrated.12. A substance or composition for use in a method of treatment according to Claim 8, substantially as herein described and illustrated.13. A new compound, a new composition, new use of a compound as claimed in Claim 1 or of a pharmaceutically acceptable salt thereof, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
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US6465456B2 (en) | 2000-06-29 | 2002-10-15 | Bristol-Myers Squibb Company | Isoxazolinone antibacterial agents |
JP2002020366A (en) * | 2000-07-05 | 2002-01-23 | Sumitomo Seika Chem Co Ltd | Method for producing alkylthiophenylacetic acid |
PE20030044A1 (en) | 2000-11-17 | 2003-02-09 | Upjohn Co | BICYCLE ISOXAZOLINONES OF FORMULA I |
PE20020689A1 (en) | 2000-11-17 | 2002-08-03 | Upjohn Co | OXAZOLIDINONES WITH A HETEROCYCLE OF 6 OR 7 MEMBERS UNITED WITH ANNULAR LINK TO BENZENE |
US6861433B2 (en) | 2000-12-15 | 2005-03-01 | Pharmacia & Upjohn Company | Oxazolidinone photoaffinity probes |
EP1349853B1 (en) | 2000-12-21 | 2006-03-08 | Pharmacia & Upjohn Company LLC | Antimicrobial quinolone derivatives and use of the same to treat bacterial infections |
ES2180456B1 (en) * | 2001-07-20 | 2004-05-01 | Laboratorios S.A.L.V.A.T., S.A. | SUBSTITUTED ISOXAZOLS AND ITS USE AS ANTIBIOTICS. |
WO2003031443A1 (en) | 2001-10-04 | 2003-04-17 | Morphochem Aktiengesellschaft für kombinatorische Chemie | Dual actions antibiotics comprising a oxazoldinone and a quinolone or naphthyridinone moiety |
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 |
WO2004033449A1 (en) * | 2002-10-10 | 2004-04-22 | Pharmacia & Upjohn Company Llc | Antimicrobial 1-aryl dihydropyridone compounds |
WO2004069832A2 (en) * | 2003-02-07 | 2004-08-19 | Warner-Lambert Company Llc | Antibacterial agents |
CA2529347C (en) | 2003-04-30 | 2011-09-06 | Morphochem Aktiengesellschaft Fur Kombinatorische Chemie | Use of oxazolidinone-quinoline hybrid antibiotics for the treatment of anthrax and other infections |
US8324398B2 (en) | 2003-06-03 | 2012-12-04 | Rib-X Pharmaceuticals, Inc. | Process for the synthesis of biaryl oxazolidinones |
CN101429170B (en) * | 2003-06-03 | 2015-05-13 | 梅林塔医疗有限公司 | Biaryl heterocyclic compounds preparation and uses |
AR045690A1 (en) | 2003-06-03 | 2005-11-09 | Rib X Pharmaceuticals Inc | HETEROCICLIC BIARIL COMPOUNDS AND METHODS TO PREPARE AND USE THE SAME |
EP1664001A2 (en) * | 2003-07-29 | 2006-06-07 | Rib-X Pharmaceuticals, Inc. | Biaryl heterocyclic amines, amides, and sulfur-containing compounds and methods of making and using the same |
DE10340485B4 (en) * | 2003-09-03 | 2015-05-13 | Morphochem AG Aktiengesellschaft für kombinatorische Chemie | Process for the preparation of oxazolidinone-quinolone hybrids |
US7304050B2 (en) * | 2003-09-16 | 2007-12-04 | Pfizer Inc. | Antibacterial agents |
WO2005061468A1 (en) | 2003-12-17 | 2005-07-07 | Rib-X Pharmaceuticals, Inc. | Halogenated biaryl heterocyclic compounds and methods of making and using the same |
US8158797B2 (en) | 2003-12-18 | 2012-04-17 | Morphochem Aktiengesellschaft Fur Kombinatorische Chemie | Oxazolidinone-quinolone hybrid antibiotics |
PT1709044E (en) | 2003-12-18 | 2008-10-27 | Morphochem Aktiengese Fur Komb | Oxazolidinone-quinolone hybrid antibiotics |
WO2005082900A2 (en) * | 2004-01-28 | 2005-09-09 | Pharmacia & Upjohn Company Llc | Oxazolidinone amidoximes as antibacterial agents |
US8399660B2 (en) | 2005-06-08 | 2013-03-19 | Rib-X Pharmaceuticals, Inc. | Process for the synthesis of triazoles |
AT503354B1 (en) * | 2006-02-22 | 2008-07-15 | Dsm Fine Chem Austria Gmbh | METHOD FOR THE PRODUCTION OF 3,4-DISUBSTITUTED PHENYL ACETIC ACIDS, AND NEW INTERMEDIATE COMPOUNDS |
JP4518066B2 (en) * | 2006-10-25 | 2010-08-04 | 宇部興産株式会社 | Dialkoxynitrile derivative and process for producing the same |
CN110423610B (en) * | 2019-08-29 | 2023-05-12 | 浙江理工大学 | Fluorescent probe for detecting two-photon mercury ions and preparation method and use method thereof |
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US4000155A (en) * | 1975-12-11 | 1976-12-28 | Eli Lilly And Company | Herbicidal 2-methyl-4-phenyl-5-pyrazolinones[and isoxazolinones] |
DK0673370T3 (en) * | 1992-12-08 | 1998-09-07 | Upjohn Co | Tropon-substituted phenyloxazolidinones as antibacterial agents |
WO1997010235A1 (en) * | 1995-09-15 | 1997-03-20 | Pharmacia & Upjohn Company | 5-AMIDOMETHYL α, β-SATURATED AND -UNSATURATED 3-ARYL BUTYROLACTONE ANTIBACTERIAL AGENTS |
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EP0920421B1 (en) * | 1996-08-21 | 2002-11-06 | PHARMACIA & UPJOHN COMPANY | Isoxazoline derivatives useful as antimicrobials |
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AU748750B2 (en) | 2002-06-13 |
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EP1107756A1 (en) | 2001-06-20 |
AR020250A1 (en) | 2002-05-02 |
HUP0103433A3 (en) | 2002-08-28 |
WO2000010566A1 (en) | 2000-03-02 |
JP2002523369A (en) | 2002-07-30 |
CZ2001669A3 (en) | 2001-08-15 |
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HUP0103433A2 (en) | 2002-01-28 |
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