US 6,686,363 B2Granted

Cyclopropyl containing oxazolidinone antibiotics and derivatives thereof

AssigneeKyorin Pharmaceutical Co., Ltd.

InventorYasumichi Fukuda

Life of this patent

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Abstract

This invention relates to new oxazolidinones having a cyclopropyl moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as Mycobacterium tuberculosis and other mycobacterial species. The compounds are represented by structural formula I: its enantiomer, diastereomer, or pharmaceutically acceptable salt or ester thereof.

Claims32

Dependent claims

A compound of the following formula I:

its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
R1 represents
i) hydrogen,
ii) NR5NR6,
iii) CR7R8R9, C(R)2OR14, CH2NHR14, C(═O)R13, C(═NOH)H, C(═NOR13)H, C(═NOR13)R13, C(═NOH)R13, C(═O)N(R13)2, C(═NOH)N(R13)2, NHC(═X1)N(R13)2, (C═NH)R7, N(R13)C(═X1)N(R13)2, COOR13, SO2R14, N(R13)SO2R14, N(R13)COR14, or (C1-6alkyl)CN, CN, CH═C(R)2, OH, C(═O)CHR13, C(═NR13)R13, NHC(═X1)R13;
or
iv) C5-10 heterocycle optionally substituted with 1-3 groups of R7, which may be attached through either a carbon or a heteroatom;
represents aryl or heteroaryl, heterocycle, heterocyclyl or heterocyclic, provided that in the case of a heteroaryl, heterocycle, heterocyclyl or heterocyclic, the cyclopropyl is not attached to a nitrogen atom on the ring;
R3 represent
i) NR13(C=X2)R12,
ii) NR13(C=X1)R12,
iii) NR13SO2R14,
iv) NR13(CHR13)0-4aryl,
v) NR13(CHR13)0-4heteroaryl,
vi) S(CHR13)0-4aryl,
vii) S(CHR13)0-4heteroaryl,
viii) O(CHR13)0-4aryl, or
ix) O(CHR13)0-4heteroaryl;
x) OCR13═NR16
R4 and R4a independently represent
i) hydrogen,
ii) halogen,
iii) C1-6 alkoxy,
iv) C1-6 alkyl,
v) CN,
vi) Aryl, or
vii) heteroaryl
r and s independently are 1-3, with the provision that when (R4a)s and (R4)r are attached to an Ar or HAr ring the sum of r and s is less than or equal to 4;
represents an optionally substituted aromatic heterocyclic group containing at least one nitrogen in the ring and which is attached through a bond on any nitrogen, and which is unsubstituted or contains 1 to 3 substituents of R16;
R5 and R6 independently represent
i) hydrogen,
ii) C1-6 alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C1-6 alkoxy, amino, imino, hydroxyamino, alkoxyamino, C1-6 acyloxy, C1-6 alkylsulfenyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, C1-6 alkylaminosulfonyl, C1-6 dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethylenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF3, C1-6 alkyl or C1-6 alkoxy;
iii) C1-6 acyl optionally substituted with 1-3 groups of halogen, OH, SH, C1-6 alkoxy, naphthalenoxy, phenoxy, amino, C1-6 acylamino, hydroxylamino, alkoxylamino, C1-6 acyloxy, aralkyloxy, phenyl, pyridine, C1-6 alkylcarbonyl, C1-6 alkylamino, C1-6 dialkylamino, C1-6 hydroxyacyloxy, C1-6 alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3 groups of halo, OH, CN, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
iv) C1-6 alkylsulfonyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, amino, hydroxylamino, alkoxylamino, C1-6 acyloxy, or phenyl;
said phenyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
v) arylsulfonyl optionally substituted with 1-3 of halogen, C1-6 alkoxy, OH or C1-6 alkyl;
vi) C1-6 alkoxycarbonyl optionally substituted with 1-3 of halogen, OH, C1-6 alkoxy, C1-6 acyloxy, or phenyl, said phenyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
vii) aminocarbonyl, C1-6 alkylaminocarbonyl or C1-6 dialkylaminocarbonyl, said alkyl groups optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy or phenyl;
viii) five to six membered heterocycles optionally substituted with 1-3 groups of halogen, OH, CN, amino, C1-6 acylamino, C1-6 alkylsulfonylamino, C1-6 alkoxycarbonylamino, C1-6 alkoxy, C1-6 acyloxy or C1-6 alkyl, said alkyl optionally substituted with 1-3 groups of halogen, or C1-6 alkoxy;
ix) C3-6 cycloalkylcarbonyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy or CN;
x) benzoyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, C1-6 alkyl, CF3, C1-6 alkanoyl, amino or C1-6 acylamino;
xi) pyrrolylcarbonyl optionally substituted with 1-3 of C1-6 alkyl;
xii) C1-2 acyloxyacetyl where the acyl is optionally substituted with amino, C1-6 alkylamino, C1-6 dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl;
or
R5 and R6 taken together with any intervening atoms can form a 3 to 7 membered heterocyclic ring containing carbon atoms and 1-2 heteroatoms independently chosen from O, S, SO, SO2, N, or NR8;
R7 represent
hydrogen, halogen, OH, C1-6 alkoxy, C1-6 alkyl, alkenyl,
amino, C1-6 alkylamino, C1-6 dialkylamino, hydroxylamino or C1-2 alkoxyamino all of which can be optionally substituted on the nitrogen with C1-6 acyl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl, said acyl and alkylsulfonyl optionally substituted with 1-2 of halogen or OH;
R8 and R8 independently represents
H, CN,
C1-6 alkyl optionally substituted with 1-3 halogen, CN, OH, C1-6 alkoxy, C1-6 acyloxy, or amino,
phenyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy;
or
R7 and R8 taken together can form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, NH, and NR8;
X1 represents O, S or NR13, NCN, or NSO2R14
X2 represents O, S, NH or NSO2R14;
R10 represents hydrogen, C1-6 alkyl or CO2R15;
R11 represents hydrogen, C1-6 alkyl, C1-6 alkanoyl, halogen, amino, C1-6 cylamino, C1-6 alkoxy, OH or CF3,;
NHC1-6 alkyl, or N(C1-6 alkyl)2, where said alkyl may be substituted with 1-3 groups of halo, OH or C1-6 alkoxy;
R12 represents hydrogen, C1-6 alkyl, C3-6 cycloalkyl, NH2, heteroaryl, wherein said heteroaryl may be substituted with 1-2 groups of C1-6 alkyl, C1-6 alkylamino, C1-6 alkoxy or C1-6 dialkylamino, where said alkyl may be substituted with 1-3 groups of halo, OH, or C1-6 alkoxy;
alkylthio, alkylsufinyl, alkylsulfonyl, or cyano;
Each R13 represents independently hydrogen, C1-6 alkyl, NR5NR6, SR8, S(O)R8, S(O)2R8, CN, C1-6 alkylS(O)R, OH, C1-6 alkoxycarbonyl, C6-C10 aryl carboxy, hydroxycarbonyl, C1-6 acyl,
C3-7 membered carbon ring optionally interrupted with 1-4 heteroatoms chosen from O, S, SO, SO2, NH and NR8 where said C1-6 alkyl or C1-6 acyl groups may be independently substituted with 0-3 halogens, hydroxy, N(R)2, CO2R, C6-10 aryl,
C5-10 heteroaryl, or C1-6 alkoxy groups;
When two R13 groups are attached to the same atom or two adjacent atoms they may be taken together to form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, NH, and NR8;
R represents hydrogen or C1-6 alkyl;
R14 represents amino, C1-6 alkyl, C1-6 haloalkyl, five to six membered heterocycles or phenyl, said phenyl and heterocycles optionally substituted with 1-3 group of halo, C1-6 alkoxy, C1-6 acylamino, or C1-6 alkyl, hydroxy and/or amino, said amino and hydroxy optionally protected with an amino or hydroxy protecting group;
R15 is C1-6 alkyl or benzyl said benzyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, or C1-6 alkyl;
and
R16 represents CN, NH2, OH, hydroxy C1-6 alkyl, C1-6 alkyl, COOC1-6 alkyl, COOH, CONH2, CON(C1-6 alkyl)2, CONHC1-6 alkyl, CHO, C═NOH, C═NOC1-6 alkyl, (CH2)1-3NH2, (CH2)1-6 NHOC1-6 alkyl, or (CH2)1-6N(C1-6 alkyl)2,
m, n, and q represents 0-1.

68 more elements

A compound which is:

N-[5(S)-3-[4-[(1-t-Butoxycarbonyl)cyclopropan-1-yl]-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Carboxycyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3-Fluoro-4-(1-hydroxymethylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Aminocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Aminocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Aminocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3-Fluoro-4-(1-formylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3-Fluoro-4-(1-(hydroxyimino)methylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]methanesulfonylamide,
N-[5(S)-3-[4-[(1-t-Butoxycarbonyl)cyclopropan-1-yl]-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3,5-Difluoro-4-(1-hydroxymethylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3,5-Difluoro-4-(1-formylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]-3-[4-(1-cyanocyclopropan-1-yl)-3-fluorophenyl]aminomethyloxazolidin-2-one,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2-isoxadiazolyl-3-yl)]-3-[4-(1-cyanocyclopropan-1-yl)-3-fluorophenyl]aminomethyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-5-[N-(1,2,3,4-thiatriazolyl-5-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-5-[N-(1,2,3,4-thiatriazolyl-5-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,2,3,4-thiatriazolyl-5-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-5-[N-(1,2-isoxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-5-[N-(1,2-isoxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thioacetamide,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2,4-oxadiazolyl-3-yl)]-3-[4-(1-cyanocyclopropan-1-yl)phenyl]aminomethyloxazolidin-2-one,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,2-isoxadiazolyl-3-yl)]-3-[4-(1-cyanocyclopropan-1-yl)phenyl]aminomethyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,2,4-oxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,2-isoxadiazolyl-3-yl)amino]methyloxazolidin-2-one,
5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,2-isoxadiazolyl-3-yl)oxy]methyloxazolidin-2-one,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,3-thiazolyl-2-yl)]-3-[4-(1-cyanocyclopropan-1-yl)phenyl]aminomethyloxazolidin-2-one,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(1,3,4-thiadiazolyl-2-yl)]-3-[4-(1-cyanocyclopropan-1-yl)phenyl]aminomethyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,3-thiazolyl-2-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-5-[N-(1,3-thiazolyl-2-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-5-[N-(1,3-thiazolyl-2-yl)amino]methyloxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(1,3,4-thiadiazolyl-2-yl)amino]methyloxazolidin-2-one,
S-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]dithiocarbamate,
S-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]dithiocarbamate,
S-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]dithiocarbamate,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
O-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbonate,
O-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbonate,
N′-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
N′-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3,5-difluorophenyl]-2-oxooxazolidin-5-ylmethyl]thiourea,
N′-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thiourea, O-Methyl N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]thiocarbonate,
N′-Cyano N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamidine,
N′-Cyano N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]acetamidine, or
its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof.

52 more elements

A compound which is:

1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,
5-Amino-4-cyano-1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-5-methyl-1,2,3-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-4-methyl-1,2,3-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,5-triazole,
5(R)-3-[4-[(1-Cyanocyclopropan-1-yl)phenyl]-5-methanesulfonyloxymethyloxazolidin-2-one,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,5-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,4-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2-prazole,
2-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]tetrazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,3-imidazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]tetrazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-4-hydroxymethyl-1,2,3-triazole and 1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-5-hydroxymethyl-1,2,3-triazole,
t-Butyl 1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole-4-carboxylate,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole-4-carboxylic Acid,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole-4-carboxamide,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-N-methyl-1,2,3-triazole-4-carboxamide,
1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-N,N-dimethyl-1,2,3-triazole-4-carboxamide,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole-4-carboxaldehyde,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-4-(hydroxyimino)methyl-1,2,3-triazole,
4-Cyano-1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-4-(methoxyimino)methyl-1,2,3-triazole,
4-Aminomethyl-1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,
4-Azidomethyl-1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,
4-Aminomethyl-1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole, 4-Acetoamidomethyl-1-[5(R)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,3-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-4-dimethylaminomethyl-1,2,3-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-4-methanesulfonyloxymethyl-1,2,3-triazole,
1-[5(R)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-4-dimethylaminomethyl-1,2,3-triazole,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,
5(S)-Aminomethyl-3-[4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-one,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]difluoroacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]cyclopropanecarboxamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]methoxyacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]furan-3-carboxamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]pyrazine-2-carboxamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]isoxazole-5-carboxamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-1,2,5-thiadiazole-3-carboxamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-(4-methyl-1,3-thiazole)-5-carboxamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]formamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]propionamide,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(methoxycarbonyl)]aminomethyloxazolidin-2-one,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]dichloroacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]methylthioacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]cyanoacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]methylsulfonylacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-(2,2-dichloro)cyclopropane-1-carboxamide (diastereomers A and B),
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]methylsulfinylacetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-2(R)-chloropropionamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-2(S)-chloropropionamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-N-methylacetamide,
N-Benzoyloxy-N-[5(S)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide and N-benzoyloxy-O-[5(S)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetimidate,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-N-hydroxyacetamide,
O-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-N-hydroxyacetimidate,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1-cyanocyclopropane-1-carboxamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]-1-hydroxycyclopropane-1-carboxamide,
N′-Cyano-N-[5(S)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]-S-methylisothiourea, N′-Cyano-N-[5(S)-3-[4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]urea,
5(S)-5-[N-(t-Butoxycarbonyl)-N-(pyridin-2-yl)]aminomethyl-3-[4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-one,
5(S)-3-[4-(1-Cyanocyclopropan-1-yl)phenyl]-5-[N-(pyridin-2-yl)]aminomethyloxazolidin-2-one,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-methylphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
5(R)-3-[4-(1-Cyanocyclopropan-1-yl)-3-methylphenyl]-5-hydroxymethyloxazolidin-2-one,
5(R)-Azidomethyl-3-[4-(1-cyanocyclopropan-1-yl)-3-methylphenyl]oxazolidin-2-one,
5(S)-Aminomethyl-3-[4-(1-cyanocyclopropan-1-yl)-3-methylphenyl]oxazolidin-2-one,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-methylphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)]-3-methylphenyl]-2-oxooxazolidin-5-ylmethyl]propionamide,
5(R)-3-[3-Bromo-4-(1-Cyanocyclopropan-1-yl)phenyl]-5-hydroxymethyloxazolidin-2-one,
5(R)-Azidomethyl-3-[3-bromo-4-(1-cyanocyclopropan-1-yl)phenyl]oxazolidin-2-one,
N-[5(S)-3-[3-Bromo-4-(1-Cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[3-Cyano-4-(1-cyanocyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-phenylphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
N-[5(S)-3-[4-(1-Cyanocyclopropan-1-yl)-3-(pyridin-3-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide and N-[5(S)-3-[4-(1-cyanocyclopropan-1-yl)-3-ethylphenyl]-2-oxooxazolidin-5-ylmethyl]acetamide,
5(R)-[4-(1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]-5-hydroxymethyloxazolidin-2-one,
5(R)-[4-(1-(2-Methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]-5-phenylsulfonyloxymethyloxazolidin-2-one,
5(R)-Azidomethyl-3-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]oxazolidin-2-one,
N-[5(S)-3-[4-(1-Acetylcyclopropan-1-yl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide.

72 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/305,368Filed 27 Nov 2002 · us provisional application
Priority: 29 Nov 2001
Published: US 2003/0225107 A14 Dec 2003
Granted: 3 Feb 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 263/20
Oxygen atoms: attached in position 2
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 413/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms

Family

Application60/333,741Us provisional application · filed 29 Nov 2001
US 2003/0225107 A1Pre-grant publication · published 4 Dec 2003
US 6,686,363 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the following formula I:

its enantiomer, diastereomer, or pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein:
R1 represents
i) hydrogen,
ii) NR5NR6,
iii) CR7R8R9, C(R)2OR14, CH2NHR14, C(═O)R13, C(═NOH)H, C(═NOR13)H, C(═NOR13)R13, C(═NOH)R13, C(═O)N(R13)2, C(═NOH)N(R13)2, NHC(═X1)N(R13)2, (C═NH)R7, N(R13)C(═X1)N(R13)2, COOR13, SO2R14, N(R13)SO2R14, N(R13)COR14, or (C1-6alkyl)CN, CN, CH═C(R)2, OH, C(═O)CHR13, C(═NR13)R13, NHC(═X1)R13;
or
iv) C5-10 heterocycle optionally substituted with 1-3 groups of R7, which may be attached through either a carbon or a heteroatom;
represents aryl or heteroaryl, heterocycle, heterocyclyl or heterocyclic, provided that in the case of a heteroaryl, heterocycle, heterocyclyl or heterocyclic, the cyclopropyl is not attached to a nitrogen atom on the ring;
R3 represent
i) NR13(C=X2)R12,
ii) NR13(C=X1)R12,
iii) NR13SO2R14,
iv) NR13(CHR13)0-4aryl,
v) NR13(CHR13)0-4heteroaryl,
vi) S(CHR13)0-4aryl,
vii) S(CHR13)0-4heteroaryl,
viii) O(CHR13)0-4aryl, or
ix) O(CHR13)0-4heteroaryl;
x) OCR13═NR16
R4 and R4a independently represent
i) hydrogen,
ii) halogen,
iii) C1-6 alkoxy,
iv) C1-6 alkyl,
v) CN,
vi) Aryl, or
vii) heteroaryl
r and s independently are 1-3, with the provision that when (R4a)s and (R4)r are attached to an Ar or HAr ring the sum of r and s is less than or equal to 4;
represents an optionally substituted aromatic heterocyclic group containing at least one nitrogen in the ring and which is attached through a bond on any nitrogen, and which is unsubstituted or contains 1 to 3 substituents of R16;
R5 and R6 independently represent
i) hydrogen,
ii) C1-6 alkyl optionally substituted with 1-3 groups of halogen, CN, OH, C1-6 alkoxy, amino, imino, hydroxyamino, alkoxyamino, C1-6 acyloxy, C1-6 alkylsulfenyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, aminosulfonyl, C1-6 alkylaminosulfonyl, C1-6 dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl, pyridine, 5-isoxazolyl, ethylenyloxy, or ethynyl, said phenyl and pyridine optionally substituted with 1-3 halogen, CN, OH, CF3, C1-6 alkyl or C1-6 alkoxy;
iii) C1-6 acyl optionally substituted with 1-3 groups of halogen, OH, SH, C1-6 alkoxy, naphthalenoxy, phenoxy, amino, C1-6 acylamino, hydroxylamino, alkoxylamino, C1-6 acyloxy, aralkyloxy, phenyl, pyridine, C1-6 alkylcarbonyl, C1-6 alkylamino, C1-6 dialkylamino, C1-6 hydroxyacyloxy, C1-6 alkylsulfenyl, phthalimido, maleimido, succinimido, said phenoxy, phenyl and pyridine optionally substituted with 1-3 groups of halo, OH, CN, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
iv) C1-6 alkylsulfonyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, amino, hydroxylamino, alkoxylamino, C1-6 acyloxy, or phenyl;
said phenyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
v) arylsulfonyl optionally substituted with 1-3 of halogen, C1-6 alkoxy, OH or C1-6 alkyl;
vi) C1-6 alkoxycarbonyl optionally substituted with 1-3 of halogen, OH, C1-6 alkoxy, C1-6 acyloxy, or phenyl, said phenyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, CF3 or C1-6 alkyl;
vii) aminocarbonyl, C1-6 alkylaminocarbonyl or C1-6 dialkylaminocarbonyl, said alkyl groups optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy or phenyl;
viii) five to six membered heterocycles optionally substituted with 1-3 groups of halogen, OH, CN, amino, C1-6 acylamino, C1-6 alkylsulfonylamino, C1-6 alkoxycarbonylamino, C1-6 alkoxy, C1-6 acyloxy or C1-6 alkyl, said alkyl optionally substituted with 1-3 groups of halogen, or C1-6 alkoxy;
ix) C3-6 cycloalkylcarbonyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy or CN;
x) benzoyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy, C1-6 alkyl, CF3, C1-6 alkanoyl, amino or C1-6 acylamino;
xi) pyrrolylcarbonyl optionally substituted with 1-3 of C1-6 alkyl;
xii) C1-2 acyloxyacetyl where the acyl is optionally substituted with amino, C1-6 alkylamino, C1-6 dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl;
or
R5 and R6 taken together with any intervening atoms can form a 3 to 7 membered heterocyclic ring containing carbon atoms and 1-2 heteroatoms independently chosen from O, S, SO, SO2, N, or NR8;
R7 represent
hydrogen, halogen, OH, C1-6 alkoxy, C1-6 alkyl, alkenyl,
amino, C1-6 alkylamino, C1-6 dialkylamino, hydroxylamino or C1-2 alkoxyamino all of which can be optionally substituted on the nitrogen with C1-6 acyl, C1-6 alkylsulfonyl or C1-6 alkoxycarbonyl, said acyl and alkylsulfonyl optionally substituted with 1-2 of halogen or OH;
R8 and R8 independently represents
H, CN,
C1-6 alkyl optionally substituted with 1-3 halogen, CN, OH, C1-6 alkoxy, C1-6 acyloxy, or amino,
phenyl optionally substituted with 1-3 groups of halogen, OH, C1-6 alkoxy;
or
R7 and R8 taken together can form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, NH, and NR8;
X1 represents O, S or NR13, NCN, or NSO2R14
X2 represents O, S, NH or NSO2R14;
R10 represents hydrogen, C1-6 alkyl or CO2R15;
R11 represents hydrogen, C1-6 alkyl, C1-6 alkanoyl, halogen, amino, C1-6 cylamino, C1-6 alkoxy, OH or CF3,;
NHC1-6 alkyl, or N(C1-6 alkyl)2, where said alkyl may be substituted with 1-3 groups of halo, OH or C1-6 alkoxy;
R12 represents hydrogen, C1-6 alkyl, C3-6 cycloalkyl, NH2, heteroaryl, wherein said heteroaryl may be substituted with 1-2 groups of C1-6 alkyl, C1-6 alkylamino, C1-6 alkoxy or C1-6 dialkylamino, where said alkyl may be substituted with 1-3 groups of halo, OH, or C1-6 alkoxy;
alkylthio, alkylsufinyl, alkylsulfonyl, or cyano;
Each R13 represents independently hydrogen, C1-6 alkyl, NR5NR6, SR8, S(O)R8, S(O)2R8, CN, C1-6 alkylS(O)R, OH, C1-6 alkoxycarbonyl, C6-C10 aryl carboxy, hydroxycarbonyl, C1-6 acyl,
C3-7 membered carbon ring optionally interrupted with 1-4 heteroatoms chosen from O, S, SO, SO2, NH and NR8 where said C1-6 alkyl or C1-6 acyl groups may be independently substituted with 0-3 halogens, hydroxy, N(R)2, CO2R, C6-10 aryl,
C5-10 heteroaryl, or C1-6 alkoxy groups;
When two R13 groups are attached to the same atom or two adjacent atoms they may be taken together to form a 3-7 membered carbon ring optionally interrupted with 1-2 heteroatoms chosen from O, S, SO, SO2, NH, and NR8;
R represents hydrogen or C1-6 alkyl;
R14 represents amino, C1-6 alkyl, C1-6 haloalkyl, five to six membered heterocycles or phenyl, said phenyl and heterocycles optionally substituted with 1-3 group of halo, C1-6 alkoxy, C1-6 acylamino, or C1-6 alkyl, hydroxy and/or amino, said amino and hydroxy optionally protected with an amino or hydroxy protecting group;
R15 is C1-6 alkyl or benzyl said benzyl optionally substituted with 1-3 groups of halo, OH, C1-6 alkoxy, amino, C1-6 acylamino, or C1-6 alkyl;
and
R16 represents CN, NH2, OH, hydroxy C1-6 alkyl, C1-6 alkyl, COOC1-6 alkyl, COOH, CONH2, CON(C1-6 alkyl)2, CONHC1-6 alkyl, CHO, C═NOH, C═NOC1-6 alkyl, (CH2)1-3NH2, (CH2)1-6 NHOC1-6 alkyl, or (CH2)1-6N(C1-6 alkyl)2,
m, n, and q represents 0-1.

68 more elements

Facts

Application

10/305,368Filed 27 Nov 2002 · us provisional application

Priority

29 Nov 2001

Published

US 2003/0225107 A14 Dec 2003

Granted

3 Feb 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 263/20
Oxygen atoms: attached in position 2
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 413/06
Containing two hetero rings: linked by a carbon chain containing only aliphatic carbon atoms