US 2004/0072873 A1Published application

N-Aryl-2-oxazolidinones and their derivatives

AssigneePharmacia & Upjohn Company

InventorsRobert C. Gadwood, Jason M. Ochoada

Life of this patent

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Abstract

The present invention provides antibacterial agents of formula I described herein.

Claims21

Dependent claims

A compound of formula I

47
or a pharmaceutically acceptable salt thereof wherein:
A is structure i, ii, iii, or iv
48
X1 and Y1 together form the group —C(═O)N(R5)— wherein X1 is either C(═O) (and Y1 is NR5) or X1 is NR5 (and Y1 is C(═O)).
Z1 is
(a) NHC(═O)R1,
(b) NHC(═S)R1,
(c) NH-het1,
(d) O-het1,
(e) S-het1, or
(f) het2;
R1 is
(a) NH2,
(b) NHC1-4alkyl,
(c) C1-4alkyl,
(d) C2-4alkenyl,
(e) —CH2C(═O)C1-4alkyl,
(f) OC1-4alkyl,
(g) SC1-4alkyl, or
(h) C3-6cycloalkyl;
Each X, Y, and Z is independently selected from
(e) H,
(f) Cl,
(g) F, or
(h) CH3
R4 is
(a) H,
(b) C1-4alkyl,
(c) OC1-4alkyl,
(d) SC1-4alkyl, or
(e) NHC1-4alkyl;
R5 is
(a) H,
(b) C1-4alkyl, or
(c) —(CH2)n—W1—(CH2)n—Z3;
W1 is
(a) —CH2—,
(b) —CH═CH—,
(c) —C≡C—, or
49
Z3 is
50
W2 is
(a) —O—,
(b) —N(R25)—, or
(c) —C(═O)—N(R25)—, wherein either the carbon or the nitrogen atom of the amide may be bound to a carbon atom of the phenyl ring of Z3;
R22 is (CH2)tNR23R24, H, halo, C1-4alkyl, —CN, —OH, —O—C1-4alkyl, —S(O)C1-4alkyl, and —C(═O)NH2
R23 is H or C1-4 alkyl;
R24 is is H, C1-4 alkyl, —S(O)2—C1-4alkyl, —C(═O)—C1-4alkyl, —C(═NH)—NH2, —C(═O)—C(HR26)—NR27R28;
R25 is H or C1-4 alkyl;
R26 is H, C1-4 alkyl which can be optionally substituted by —OH, —NH2, —NH—C(═NH)—NH2, —SH, —SCH3, —COOH, —C(O)NH2, and phenyl which can be optionally substituted with —OH, imidazole, indole, or R26 and R27 together with the carbon atom to which R26 attaches and the nitrogen atom to which R27 attaches form a heterocycloalkyl;
R27 is H or C1-4 alkyl;
R28 is H, C1-4 alkyl, —S(O)2—C1-4alkyl, —C(═O)-C1-4 alkyl, —C(═NH)—NH2, —C(═O)—C(HR26)—NR27R27
t is 0, 1;
u is 0, 1, 2;
n is 1 or 2;
het1 is a C-linked five-(5) or six-(6) membered heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen;
het1 being optionally substituted on one or more carbon atoms by 1-2 substituents selected from C1-C4alkyl, amino, C1-C4alkylamino, C1-C4-C4alkyloxy, halogen —CN, ═O, ═S, and being optionally substituted with C1-C4alkyl;
het2 is a N-linked five-(5) or six-6) membered heterocyclic ring having at least one nitrogen atom, and optionally having one oxygen or sulfur atom;
het2 being optionally substituted on one or more carbon atoms by 1-2 substituents selected from C1-C4alkyl, amino, C1-C4alkylamino, C1-C4alkyloxy, halogen N, ═O, S, and being optionally substituted with C1-C4alkyl;
heterocycloalkyl is a four (5) or seven (7) membered saturated heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen;
heterocycloalkyl being optionally substituted on one or more carbon atoms by 1-2 substituents selected from C1-C4alkyl, amino, C1-C4alkylamino, C1-C4alkyloxy, halogen —CN, ═O, ═S, and being optionally substituted with C1-C4alkyl;
at each occurrence, alkyl, alkenyl, or cycloalkyl is optionally substituted with 13 halo, —OH, —OC1-4alkyl, and
Aryl refers to phenyl, biphenyl, or naphthyl, optionally substituted with halo, C1-4 alkyl, OH, OC1-4 alkyl, —CH2NH2, —CH2NH(C1-4alkyl), and S(O)uC1-4alkyl.

62 more elements

A compound selected from the group consisting of

N-({(5S)-3-[3-fluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
N-({(5S)-3-[3-fluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)propanamide;
2,2-dichloro-N-({(5S)-3-[3-fluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3 oxazolidin-5-yl}methyl)ethanethioamide;
2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
N-({(5S)-3-[3,5-difluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
2,2-dichloro-N-({(5S)-3-[3,5-difluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
N-({(5S)-3-[3,5-difluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2,2-difluoroethanethioamide;
N-({(5S)-3-[3,5-difluoro-4-(6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2,2-difluoroacetamide;
N-({(5S)-2-oxo-3-[4-(6-oxopiperidin-3-yl)phenyl]-1,3-oxazolidin-5-yl}methyl) acetamide;
N-({(5S)-2-oxo-3-[4-(6-oxopiperidin-3-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)propanamide;
2,2-dichloro-N-({(5S)-2-oxo-3-[4-(6-oxopiperidin-3-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide;
2,2-difluoro-N-({(5S)-2-oxo-3-[4-(6-oxopiperidin-3-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
2,2-difluoro-N-({(5S)-2-oxo-3-[4-(6-oxopiperidin-3-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
({(5S)-3-[4-(1-methyl-6-oxopiperidin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
N-({(5S)-3-[3-fluoro-4-(2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide;
N-({(5S)-3-[3-fluoro-4-(2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)propanamide;
2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3 oxazolidin-5-yl}methyl)ethanethioamide;
N-({(5S)-3-[3,5-difluoro-4-(2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl) acetamide;
N-({(5S)-3-[3,5-difluoro-4-(2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)propanamide;
N-({(5S)-3-[3,5-difluoro-4-(2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2,2-difluoroethanethioamide;
N-({(5S)-2-oxo-3-[4-(2-oxopiperidin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide;
2,2-difluoro-N-({(5S)-2-oxo-3-[4-(2-oxopiperidin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)ethanethioamide;
N-({(5S)-2-oxo-3-[4-(2-oxopiperidin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)propanamide;
and
N-({(5S)-3-[4-(1-methyl-2-oxopiperidin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl) acetamide.

23 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/632,742Filed 1 Aug 2003
Priority: 12 Aug 2002
Published: 15 Apr 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 405/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C07D 413/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
C07D
Heterocyclic compounds

Family

Application60/402,783Us provisional application · filed 12 Aug 2002
US 7,094,900 B2Related patent
US 2004/0072873 A1This patent

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

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A compound of formula I

47
or a pharmaceutically acceptable salt thereof wherein:
A is structure i, ii, iii, or iv
48
X1 and Y1 together form the group —C(═O)N(R5)— wherein X1 is either C(═O) (and Y1 is NR5) or X1 is NR5 (and Y1 is C(═O)).
Z1 is
(a) NHC(═O)R1,
(b) NHC(═S)R1,
(c) NH-het1,
(d) O-het1,
(e) S-het1, or
(f) het2;
R1 is
(a) NH2,
(b) NHC1-4alkyl,
(c) C1-4alkyl,
(d) C2-4alkenyl,
(e) —CH2C(═O)C1-4alkyl,
(f) OC1-4alkyl,
(g) SC1-4alkyl, or
(h) C3-6cycloalkyl;
Each X, Y, and Z is independently selected from
(e) H,
(f) Cl,
(g) F, or
(h) CH3
R4 is
(a) H,
(b) C1-4alkyl,
(c) OC1-4alkyl,
(d) SC1-4alkyl, or
(e) NHC1-4alkyl;
R5 is
(a) H,
(b) C1-4alkyl, or
(c) —(CH2)n—W1—(CH2)n—Z3;
W1 is
(a) —CH2—,
(b) —CH═CH—,
(c) —C≡C—, or
49
Z3 is
50
W2 is
(a) —O—,
(b) —N(R25)—, or
(c) —C(═O)—N(R25)—, wherein either the carbon or the nitrogen atom of the amide may be bound to a carbon atom of the phenyl ring of Z3;
R22 is (CH2)tNR23R24, H, halo, C1-4alkyl, —CN, —OH, —O—C1-4alkyl, —S(O)C1-4alkyl, and —C(═O)NH2
R23 is H or C1-4 alkyl;
R24 is is H, C1-4 alkyl, —S(O)2—C1-4alkyl, —C(═O)—C1-4alkyl, —C(═NH)—NH2, —C(═O)—C(HR26)—NR27R28;
R25 is H or C1-4 alkyl;
R26 is H, C1-4 alkyl which can be optionally substituted by —OH, —NH2, —NH—C(═NH)—NH2, —SH, —SCH3, —COOH, —C(O)NH2, and phenyl which can be optionally substituted with —OH, imidazole, indole, or R26 and R27 together with the carbon atom to which R26 attaches and the nitrogen atom to which R27 attaches form a heterocycloalkyl;
R27 is H or C1-4 alkyl;
R28 is H, C1-4 alkyl, —S(O)2—C1-4alkyl, —C(═O)-C1-4 alkyl, —C(═NH)—NH2, —C(═O)—C(HR26)—NR27R27
t is 0, 1;
u is 0, 1, 2;
n is 1 or 2;
het1 is a C-linked five-(5) or six-(6) membered heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen;
het1 being optionally substituted on one or more carbon atoms by 1-2 substituents selected from C1-C4alkyl, amino, C1-C4alkylamino, C1-C4-C4alkyloxy, halogen —CN, ═O, ═S, and being optionally substituted with C1-C4alkyl;
het2 is a N-linked five-(5) or six-6) membered heterocyclic ring having at least one nitrogen atom, and optionally having one oxygen or sulfur atom;
het2 being optionally substituted on one or more carbon atoms by 1-2 substituents selected from C1-C4alkyl, amino, C1-C4alkylamino, C1-C4alkyloxy, halogen N, ═O, S, and being optionally substituted with C1-C4alkyl;
heterocycloalkyl is a four (5) or seven (7) membered saturated heterocyclic ring having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen;
heterocycloalkyl being optionally substituted on one or more carbon atoms by 1-2 substituents selected from C1-C4alkyl, amino, C1-C4alkylamino, C1-C4alkyloxy, halogen —CN, ═O, ═S, and being optionally substituted with C1-C4alkyl;
at each occurrence, alkyl, alkenyl, or cycloalkyl is optionally substituted with 13 halo, —OH, —OC1-4alkyl, and
Aryl refers to phenyl, biphenyl, or naphthyl, optionally substituted with halo, C1-4 alkyl, OH, OC1-4 alkyl, —CH2NH2, —CH2NH(C1-4alkyl), and S(O)uC1-4alkyl.

62 more elements

Facts

Application

10/632,742Filed 1 Aug 2003

Priority

12 Aug 2002

Published

15 Apr 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 405/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C07D 413/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
C07D
Heterocyclic compounds