US 7,605,157 B2Granted

Tricyclic tetrahydroquinoline antibacterial agents

AssigneePharmacia & Upjohn Company

InventorsMichael Robert Barbachyn, J. Craig Ruble, Arthur Glenn Romero, Lisa Marie Thomasco, Alexander Ross Hurd, John Raymond Palmer, Peter Laurence Toogood, Dennis Joseph McNamara, Debra Ann Sherry, Paul Joseph Dobrowolski

Life of this patent

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Abstract

The invention includes tetrahydroquinoline and related compounds of formula I and pharmaceutical compositions thereof, that exhibit useful antibacterial activity again a wide range of human and veterinary pathogens

Claims22

Dependent claims

A compound of formula I, including enantiomeric, diastereomeric, or tautomeric isomers thereof, or any pharmaceutically acceptable salt thereof;

wherein,
R1 is
(a) R12
(b) C(═O)R6, or
(c) CN;
R2 is
(a) R12
(b) C(═O)R7,
(c) CN,
(d) —CH2—R7,
(e) —NR17R7,
(f) —CH2COR7,
(g) —CH2CH2COR7;
Each R3 is independently
(a) H,
(b) R12,
(c) both R3 taken together are oxo,
(d) C1-7alkyl, C1-7 alkenyl, or C1-7 alkynyl, each of which is optionally substituted by one or more R11,
(e) C3-8cycloalkyl;
C3-8 cycloalkenyl;
or C1-7 cycloalkynyl each of which is optionally substituted by one or more R11,
(f) aryl optionally substituted by one or more R8,
(g) heteroaryl optionally substituted by one or more R8, or
(h) halo;
Each R4 is independently
(a) H,
(b) halo,
(c) OR12,
(d) OC(═O) NR9R10,
(e) SR12,
(f) S(O)mR13,
(g) NR9R10,
(h) NR9S(O)mR13,
(i) NR9C(═O)OR13,
(j) phenyl optionally substituted by one or more R8,
(k) heteroaryl optionally substituted by one or more R8,
(l) cyano,
(m) nitro,
(n) CONR9R10,
(o) CO2R12,
(p) C(═O)R13,
(q) C(═NOR12)R13,
(r) S(O)mNR9R10,
(s) NR9C(═O)—R12,
(t) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(u) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(v) N3,
(w) het1 optionally substituted by one or more R8, or
(x) C(O)O—C1-4alkyl-R12;
Each R5 is independently,
(a) H,
(b) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(c) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(d) aryl optionally substituted by one or more R8, or
(e) heteroaryl optionally substituted by one or more R8;
R6 and R7 are independently;
(a) OR12,
(b) NR9R10,
(c) R13, or
(e) R6 and R7 together with the 2 carbons to which they are attached form cyclohexane-1,3-dione optionally substituted by one or more R13, cyclopentane-1,3-dione optionally substituted by one or more R13, R6 and R7 together form —N(R17)—S(O)m—N(R17)—, —N(R17)—C(O)—N(R17)—, —N(R17)—C(S)—N(R17)—, —N(R17)—N(R17)—, —N(R17)—C(O)—, or —N(R17)—;
R8 is
(a) H,
(b) halo,
(c) OR12,
(d) OCF3,
(e) SR12,
(f) S(O)mR13,
(g) NR9R10,
(h) NR9S(O)mR13,
(i) NR9C(═O)OR13,
(j) phenyl optionally substituted by halo, cyano, C1-7alkyl, or C1-7alkoxy, in the alkyl portion of the C1-7alkyl and C1-7alkoxy is optionally substituted by one or more R11;
(k) heteroaryl optionally substituted by halo, C1-7alkyl, or C1-7alkoxy,
(l) cyano,
(m) nitro,
(n) CONR9R10,
(o) CO2R12,
(p) C(═O)R13,
(q) C(═NOR12)R13,
(r) S(O)mNR9R10,
(s) NR9C(═O)—R12,
(t) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(u) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(v) —C(O)H, or
(w) -het1;
R9 and R10 are independently
(a) H,
(b) OR12,
(c) aryl optionally substituted by one or more R14,
(d) heteroaryl optionally substituted by one or more R14,
(e) C1-7alkyl which is optionally substituted by one or more R11,
(f) C3-8cycloalkyl which is optionally substituted by one or more R11,
(g) (C═O)R13, or
(h) R9 and R10 together with the nitrogen to which they are attached form morpholine, pyrrolidine, piperidine, thiazine, piperazine, each of the morpholine, pyrrolidine, piperidine, thiazine, piperazine being optionally substituted with R11;
R11 is
(a) oxo,
(b) phenyl optionally substituted by one or more R14,
(c) OR12,
(d) SR12,
(e) NR12R12,
(f) halo,
(g) CO2R12 ,
(h) CONR12R12,
(i) C1-7alkyl which is optionally substituted oxo, halo, OR12, SR12, C1-7alkyl, or NR12R12 substituents, or
(j) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more oxo, halo, OR12, SR12, C1-7alkyl, or NR12R12 substituents;
R12 is
(a) H,
(b) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, C1-7alkyl, or C1-7alkoxy substituents,
(c) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more oxo, halo, C1-7alkyl, or C1-7alkoxy substituents,
(d) aryl optionally substituted by one or more halo, C1-7alkyl, or C1-7alkoxy substituents, or
(e) heteroaryl optionally substituted by one or more halo, C1-7alkyl, or C1-7alkoxy substituents;
R13 is
(a) C1-7alkyl which is optionally substituted by one or more by oxo, halo, carboxyl, C1-7alkyl, or C1-7alkoxy substituents,
(b) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more by oxo, halo, C1-7alkyl, or C1-7alkoxy substituents,
(c) aryl optionally substituted by one or more halo, C1-7alkyl, or C1-7alkoxy substituents;
(d) heteroaryl optionally substituted by one or more halo, C1-7alkyl, or C1-7alkoxy substituents,
(e) —C(O)OH
R14 is
(a) H,
(b) halo,
(c) C1-7alkyl,
(d) OR12,
(e) OCF3,
(f) SR12,
(g) S(O)mR13,
(h) NR12R12,
(i) NR12S(O)mR13,
(j) NR12C(═O)OR13,
(k) phenyl optionally substituted by halo, C1-7alkyl, or C1-7alkoxy,
(l) heteroaryl optionally substituted by halo, C1-7alkyl, or C1-7alkoxy,
(m) cyano,
(n) nitro,
(o) CONR12R12,
(p) CO2R12,
(q) C(═O)R13,
(r) C(═NOR12)R13,
(s) S(O)mNR12R12,
(t) NR9C(═O)—R12,
(u) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, OR12, SR12, C1-7alkyl, or NR12R12 substituents, or
(v) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, OR12, SR12, C1-7alkyl, or NR12R12 substituents;
X is
(C(R15)2[m]—O—C(R15)2[k],
Each R15 is independently
(a) H,
(b) OR11,
(d) C1-7 alkyl which is optionally substituted by one or more by one or more R11 substituents,
(e) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more by one or more R11 substituents,
(f) aryl optionally substituted by one or more R8, or
(g) heteroaryl optionally substituted by one or more R8;
R17 is
(a) H,
(b) —OH, and
(c) C1-4alkyl;
R20 is
(a) H,
(b) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(c) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(d) aryl optionally substituted by one or more R8,
(e) heteroaryl optionally substituted by one or more R8,
wherein, “aryl” denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic;
wherein, “heteroaryl” encompasses a radical attached via a ring carbon or ring nitrogen of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms, selected from oxygen (—O—), sulfur (—S—), oxygenated sulfur such as sulfinyl (S═O) and sulfonyl (S(═O)2), or nitrogen N(Z) wherein Z is absent or is H, O, C1-4alkyl, phenyl or benzyl, or a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom;
het1 is a C- or N- linked five- (5), six- (6), seven- (7), or eight- (8) membered mono- or bicyclic ring, each mono- or bicyclic ring being fully saturated or partially unsaturated, and having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen;
het1 being optionally substituted by 1-2 substituents selected from C1-C4alkyl, amino, C1-C4alkylamino, C1-C4alkyloxy, halogen —CN, ═O, ═S;
and
each m is independently 0, 1, or 2;
provided that
when each R4 is H, that R1 and R2 are not simultaneously H, CN, or —C(O)—OCH3 or that R1 is not CN and R2 is not —C(O)—OC1-4alkyl;
when the compound is 1,2,4,4a-Tetrahydro-cis-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′, 6′(1′H,3′H)-trione that the compound is enantiomerically enriched (-) form of (2R,4S,4aS)-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione.

164 more elements

A compound selected from

(2R,4S,4aS)-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)—pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
8-Bromo-1,2,4,4a-tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
8-Fluoro-1,2,4,4a-tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-8-trifluoromethylspiro[[1,4]oxazino]4,3-a] quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,1′,2, 3′4,4′,4a,6′-Octrahydro-2,4′,6′-trioxospiro[[1,4]oxazino[4,3-a] 5(6H),5′(2′H)-pyrimidine]-8-carbonitrile;
1,2,4,4a-Tetrahydro-2,4-dimethyl-8-carboxamidespiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H) -pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H) -pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-1,4a-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
8-Bromo-1,2,4,4a-tetrahydro-cis-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-4′-thioxo-2′,6′(1′H,3′H)-dione;
8-Bromo-1,2,4,4a-tetrahydro-cis-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)pyrimidine]-2′,4′,6′(1′methyl,3′methyl)-trione;
N-[1,1′,2,3′,4,4′,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino [4,3-a]quinolone-5(6H),5′(2′H)-pyrimidin]-8-yl]acetamide;
tert-butyl 1,1′,2,3′,4,4′,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinolone-5(6H),5′(2′H)-pyrimidin]-8-ylcarbamate;
8-Amino-1,2,4,4a-tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinolone-5(6H),5′(2TH)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione monohydrochloride;
9-Bromo-1,2,4,4a-tetrahydro-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
8-Acetyl-1,2,4,4a-tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2H)-pyrimidine)-2′,4′,6′(1′H,3′H)-trione;
8-Ethanone-O-methyloxime-1-1,2,4,4a-tetrahydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2H)-pyrimidine)-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-8-(methylsulfonyl)spiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-8-(methylsulfinyl)spiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-8-(methylthio)spiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-9-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′methyl,3′methyl)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′methyl)-trione;
1,2,4,4a-Tetrahydro-4-methyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2-methyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3's)-trione;
1,1′,2′3′4′4′a-Hexahydro-2′,4′-dimethyl-1,3-dioxospiro[2H-indene-2,5′(6H)-[1,4]oxazino[4,3-a]quinoline]-8′-carbonitrile;
1,2,4,4a-Tetrahydro-2,4-dimethyl[1,4]oxazino[4,3-a]quinoline-5,5,8(6H) -tricarbonitrile;
8-Bromo-1,2,4-4a-tetrhydro-2,4-dimethyl[1,4]oxazino[4,3-a]quinoline-5,5(6H) -dicarbonitrile;
9-(4-Chlorophenyl)-1,2,4,4a-tetryhydro-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-9-(methoxyphenyl)-2,4-dimethylspiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
9-(3-Chloro-4-fluorophenyl)-1,2,4,4a,-tetrahydro-2,4-dimethylsprio[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-9-(3-nitrophenyl)spiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)trione;
1,1′,2,3′,4,4′,4a,6′-Octahydro-2-4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5(2′H)-pyrimidin]-9-yl]benzonitrile;
1,2,4,4a-Tetrahydro-2,4-dimethyl-9-[4-(methylsulfonyl)phenyl]spiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-9-(4-pyridinyl)spiro[[1,4]oxazino[4,3-a]quinoline-5 (6H),5′(2′H)-pyrimidine]-2′,4′,6′(′H,3′H)-trione;
Methyl-1,1′-2,3′,4,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-9-carboxylate;
Methyl-1,1′-2,3′,4,4a,6′-Octahydro-2,4-dimethyl-2′,4′,6′-trioxospiro[[1,4]oxzaino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-8-carboxylate.

35 more elements

A compound selected from

(2S,4R,4aR)-4-isopropyl-2-methyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2R,4S,4aS)-2,4-diethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2R,4S,4aS)-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2R,4S,4aS)-8-acetyl-9,10-difluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H -spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2R,4S,4aS)-10-fluoro-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2R,4S,4aS)-2,4-dimethyl-8-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-1,2,4,4a -tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
1,2,4,4a-Tetrahydro-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2S,4R,4aR)-2-isopropyl-4-methyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1, 4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2S,4R,4aR)-2-isopropyl-4-methyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1, 4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2R,4S,4aS)-2,4-diisopropyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2R,4S,4aS)-2,4-dimethyl-8-(3-methyl-1,2,4-oxadiazol-5-yl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2S,4R,4aR)-8-acetyl-10-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
8-bromo-2,4-dimethyl-10-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
(2R,4S,4aS)-2,4-dimethyl-8-(5-methyl-1,2,4-oxadiazol-3-yl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3H)-trione;
(2S,4S,4aS)-4-methyl-8-nitro-2-(trifluoromethyl)-1,2,4,4a-tetrahydro-2′H,6H -spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione;
4-azido-3-iodobenzyl (2R,4S,4aS)-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4 ′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-8-carboxylate;
or
(2S,4S,4aS)-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione.

15 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/715,213Filed 7 Mar 2007 · continuation
Priority: 7 Oct 2002
Published: US 2007/0161630 A112 Jul 2007
Granted: 20 Oct 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 471/20
In which the condensed system contains three hetero rings: spiro-condensed systems
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents

Family

Application60/416,685Us provisional application · filed 7 Oct 2002
Application60/427,189Us provisional application · filed 18 Nov 2002
Application60/457,622Us provisional application · filed 26 Mar 2003
Application10/677,551Parent of this continuation · filed 2 Oct 2003
US 2007/0161630 A1Pre-grant publication · published 12 Jul 2007
US 7,208,490 B2Parent of this continuation
US 2004/0162279 A1Published application
US 7,605,157 B2This patent

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Abstract

A compound of formula I, including enantiomeric, diastereomeric, or tautomeric isomers thereof, or any pharmaceutically acceptable salt thereof;

wherein,
R1 is
(a) R12
(b) C(═O)R6, or
(c) CN;
R2 is
(a) R12
(b) C(═O)R7,
(c) CN,
(d) —CH2—R7,
(e) —NR17R7,
(f) —CH2COR7,
(g) —CH2CH2COR7;
Each R3 is independently
(a) H,
(b) R12,
(c) both R3 taken together are oxo,
(d) C1-7alkyl, C1-7 alkenyl, or C1-7 alkynyl, each of which is optionally substituted by one or more R11,
(e) C3-8cycloalkyl;
C3-8 cycloalkenyl;
or C1-7 cycloalkynyl each of which is optionally substituted by one or more R11,
(f) aryl optionally substituted by one or more R8,
(g) heteroaryl optionally substituted by one or more R8, or
(h) halo;
Each R4 is independently
(a) H,
(b) halo,
(c) OR12,
(d) OC(═O) NR9R10,
(e) SR12,
(f) S(O)mR13,
(g) NR9R10,
(h) NR9S(O)mR13,
(i) NR9C(═O)OR13,
(j) phenyl optionally substituted by one or more R8,
(k) heteroaryl optionally substituted by one or more R8,
(l) cyano,
(m) nitro,
(n) CONR9R10,
(o) CO2R12,
(p) C(═O)R13,
(q) C(═NOR12)R13,
(r) S(O)mNR9R10,
(s) NR9C(═O)—R12,
(t) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(u) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(v) N3,
(w) het1 optionally substituted by one or more R8, or
(x) C(O)O—C1-4alkyl-R12;
Each R5 is independently,
(a) H,
(b) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(c) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(d) aryl optionally substituted by one or more R8, or
(e) heteroaryl optionally substituted by one or more R8;
R6 and R7 are independently;
(a) OR12,
(b) NR9R10,
(c) R13, or
(e) R6 and R7 together with the 2 carbons to which they are attached form cyclohexane-1,3-dione optionally substituted by one or more R13, cyclopentane-1,3-dione optionally substituted by one or more R13, R6 and R7 together form —N(R17)—S(O)m—N(R17)—, —N(R17)—C(O)—N(R17)—, —N(R17)—C(S)—N(R17)—, —N(R17)—N(R17)—, —N(R17)—C(O)—, or —N(R17)—;
R8 is
(a) H,
(b) halo,
(c) OR12,
(d) OCF3,
(e) SR12,
(f) S(O)mR13,
(g) NR9R10,
(h) NR9S(O)mR13,
(i) NR9C(═O)OR13,
(j) phenyl optionally substituted by halo, cyano, C1-7alkyl, or C1-7alkoxy, in the alkyl portion of the C1-7alkyl and C1-7alkoxy is optionally substituted by one or more R11;
(k) heteroaryl optionally substituted by halo, C1-7alkyl, or C1-7alkoxy,
(l) cyano,
(m) nitro,
(n) CONR9R10,
(o) CO2R12,
(p) C(═O)R13,
(q) C(═NOR12)R13,
(r) S(O)mNR9R10,
(s) NR9C(═O)—R12,
(t) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(u) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(v) —C(O)H, or
(w) -het1;
R9 and R10 are independently
(a) H,
(b) OR12,
(c) aryl optionally substituted by one or more R14,
(d) heteroaryl optionally substituted by one or more R14,
(e) C1-7alkyl which is optionally substituted by one or more R11,
(f) C3-8cycloalkyl which is optionally substituted by one or more R11,
(g) (C═O)R13, or
(h) R9 and R10 together with the nitrogen to which they are attached form morpholine, pyrrolidine, piperidine, thiazine, piperazine, each of the morpholine, pyrrolidine, piperidine, thiazine, piperazine being optionally substituted with R11;
R11 is
(a) oxo,
(b) phenyl optionally substituted by one or more R14,
(c) OR12,
(d) SR12,
(e) NR12R12,
(f) halo,
(g) CO2R12 ,
(h) CONR12R12,
(i) C1-7alkyl which is optionally substituted oxo, halo, OR12, SR12, C1-7alkyl, or NR12R12 substituents, or
(j) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more oxo, halo, OR12, SR12, C1-7alkyl, or NR12R12 substituents;
R12 is
(a) H,
(b) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, C1-7alkyl, or C1-7alkoxy substituents,
(c) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more oxo, halo, C1-7alkyl, or C1-7alkoxy substituents,
(d) aryl optionally substituted by one or more halo, C1-7alkyl, or C1-7alkoxy substituents, or
(e) heteroaryl optionally substituted by one or more halo, C1-7alkyl, or C1-7alkoxy substituents;
R13 is
(a) C1-7alkyl which is optionally substituted by one or more by oxo, halo, carboxyl, C1-7alkyl, or C1-7alkoxy substituents,
(b) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more by oxo, halo, C1-7alkyl, or C1-7alkoxy substituents,
(c) aryl optionally substituted by one or more halo, C1-7alkyl, or C1-7alkoxy substituents;
(d) heteroaryl optionally substituted by one or more halo, C1-7alkyl, or C1-7alkoxy substituents,
(e) —C(O)OH
R14 is
(a) H,
(b) halo,
(c) C1-7alkyl,
(d) OR12,
(e) OCF3,
(f) SR12,
(g) S(O)mR13,
(h) NR12R12,
(i) NR12S(O)mR13,
(j) NR12C(═O)OR13,
(k) phenyl optionally substituted by halo, C1-7alkyl, or C1-7alkoxy,
(l) heteroaryl optionally substituted by halo, C1-7alkyl, or C1-7alkoxy,
(m) cyano,
(n) nitro,
(o) CONR12R12,
(p) CO2R12,
(q) C(═O)R13,
(r) C(═NOR12)R13,
(s) S(O)mNR12R12,
(t) NR9C(═O)—R12,
(u) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, OR12, SR12, C1-7alkyl, or NR12R12 substituents, or
(v) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by oxo, halo, OR12, SR12, C1-7alkyl, or NR12R12 substituents;
X is
(C(R15)2[m]—O—C(R15)2[k],
Each R15 is independently
(a) H,
(b) OR11,
(d) C1-7 alkyl which is optionally substituted by one or more by one or more R11 substituents,
(e) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more by one or more R11 substituents,
(f) aryl optionally substituted by one or more R8, or
(g) heteroaryl optionally substituted by one or more R8;
R17 is
(a) H,
(b) —OH, and
(c) C1-4alkyl;
R20 is
(a) H,
(b) C1-7alkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(c) C3-8cycloalkyl which is optionally partially unsaturated and is optionally substituted by one or more R11,
(d) aryl optionally substituted by one or more R8,
(e) heteroaryl optionally substituted by one or more R8,
wherein, “aryl” denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic;
wherein, “heteroaryl” encompasses a radical attached via a ring carbon or ring nitrogen of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms, selected from oxygen (—O—), sulfur (—S—), oxygenated sulfur such as sulfinyl (S═O) and sulfonyl (S(═O)2), or nitrogen N(Z) wherein Z is absent or is H, O, C1-4alkyl, phenyl or benzyl, or a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom;
het1 is a C- or N- linked five- (5), six- (6), seven- (7), or eight- (8) membered mono- or bicyclic ring, each mono- or bicyclic ring being fully saturated or partially unsaturated, and having 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen;
het1 being optionally substituted by 1-2 substituents selected from C1-C4alkyl, amino, C1-C4alkylamino, C1-C4alkyloxy, halogen —CN, ═O, ═S;
and
each m is independently 0, 1, or 2;
provided that
when each R4 is H, that R1 and R2 are not simultaneously H, CN, or —C(O)—OCH3 or that R1 is not CN and R2 is not —C(O)—OC1-4alkyl;
when the compound is 1,2,4,4a-Tetrahydro-cis-2,4-dimethyl-8-nitrospiro[[1,4]oxazino[4,3-a]quinoline-5(6H), 5′(2′H)-pyrimidine]-2′,4′, 6′(1′H,3′H)-trione that the compound is enantiomerically enriched (-) form of (2R,4S,4aS)-2,4-dimethyl-8-nitro-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione.

164 more elements

Facts

Application

11/715,213Filed 7 Mar 2007 · continuation

Priority

7 Oct 2002

Published

US 2007/0161630 A112 Jul 2007

Granted

20 Oct 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 471/20
In which the condensed system contains three hetero rings: spiro-condensed systems
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 31/00
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents

Family

Application60/416,685Us provisional application · filed 7 Oct 2002

Application60/427,189Us provisional application · filed 18 Nov 2002

Application60/457,622Us provisional application · filed 26 Mar 2003

Application10/677,551Parent of this continuation · filed 2 Oct 2003

US 2007/0161630 A1Pre-grant publication · published 12 Jul 2007

US 7,208,490 B2Parent of this continuation

US 2004/0162279 A1Published application

US 7,605,157 B2This patent

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