US 8,785,452 B2Granted

Anti-infective compounds

AssigneesInstitut National de la Sante et de la Recherche Medicale, Institut Pasteur Korea

InventorsPriscille Brodin, Thierry Christophe, Zaesung No, Jaeseung Kim, Auguste Genovesio, Denis Philippe Cedric Fenistein, Heekyoung Jeon, Fanny Anne Ewann, Sunhee Kang, Saeyeon Lee, Min Jung Seo, Eunjung Park, Monica Contreras Dominguez, Ji Youn Nam, Eun Hye Kim

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Abstract

The present invention relates to 4H-pyrido[1,2-a]pyrimidin-4-one compounds and their use in the treatment of bacterial infections, in particular Tuberculosis.

Claims27

Dependent claims

A compound having the general formula VIIIa:

wherein
X5 is selected from the group consisting of CH2 and C═O;
Z1 is selected from the group consisting of alkoxy, alkylamino, alkylether, alkylthio, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cyano, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, and hydroxyl, any of which is optionally substituted;
Z2 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkylether, alkylthio, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cyano, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydroxyl, and hydrogen, any of which is optionally substituted;
R27 and R28 are each independently selected from the group consisting of alkoxy, alkyl, alkyl amino, alkeny, alkylether, alkylthio, alkynyl, amido, amino, aryl, arylether, arylalkoxy, arylamino, arylthio, carboxy, cyano, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydroxyl, hydrogen, nitro, thiol, sulfonate, sulfonyl and sulfonylamino, any of which is optionally substituted;
and
R29 and R30 are each independently selected from the group consisting of alkoxy, alkyl, alkylamino, alkenyl, alkylether, alkylthio, alkynyl, amido, amino, aryl, arylether, arylalkoxy, arylamino, arylthio, carboxy, cyano, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydroxyl, hydrogen, nitro, thiol, sulfonate, sulfonyl and sulfonylamino, or two groups are connected to each other to make five or six membered cyclic, heterocyclic, aryl, and heteroaryl rings, any of which is optionally substituted,
wherein Z1 and Z2 may be connected to each other to make five or six membered cyclic, heterocyclic and heteroaryl rings, any of which is optionally substituted.

5 more elements

A compound having a formula selected from the group consisting of the following formulae 147-173, 188-189, 198, 205 and 231-298:

9-Methyl-4-oxo-2-(phenylamino)-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (147)
2-(3-Chlorophenylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (148)
2-(3-Chlorophenylamino)-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (149)
2-(3-Chlorophenylamino)-7-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (150)
2-(3-Chlorophenylamino)-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (151)
2-(3-Fluorophenylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (152)
9-Methyl-4-oxo-2-(3-(trifluoromethyl)phenylamino)-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (153)
9-Methyl-4-oxo-2-(3-(trifluoromethoxy)phenylamino)-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (154)
9-Methyl-2-(3-nitrophenylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (155)
2-(3-(Methoxycarbonyl)phenylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (156)
2-(3-Hydroxyphenylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (157)
2-(4-Hydroxyphenylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (158)
2-(4-tert-Butylphenylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (159)
2-(3-Chlorobenzylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (160)
2-(Diethylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (161)
2-(Isobutylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (162)
2-(Cyclohexylmethylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (163)
2-(Cyclohexylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (164)
2-(Cyclopentylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (165)
2-(Cycloheptylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (166)
2-(1-(tert-Butoxycarbonyl)piperidin-4-ylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (167)
2-(2-(4-Fluorophenoxy)ethylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (168)
9-Methyl-4-oxo-2-(2-(4-(trifluoromethoxy)phenoxy)ethylamino)-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (169)
9-Methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (170)
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (171)
2-(4-(2-Chlorophenyl)piperazin-1-yl)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (172)
2-(3-Chlorophenylamino)-8-(4-methylpiperazin-1-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid (173)
Methyl 2-(3-chlorophenylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (188)
Methyl 2-(3-chlorobenzylamino)-9-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (189)
2-(3-Chloro-4-fluorophenylamino)-9-methoxy-N-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide (198)
2-(3-Chlorophenylamino)-3-((cyclohexylamino)methyl)-8-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (205)
3-(Hydroxymethyl)-9-methyl-2-(phenylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (231)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (232)
2-((3-Chlorophenyl)(methyl)amino)-3-(hydroxymethyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (233)
2-((3-Chlorophenyl)(methyl)amino)-3-(methoxymethyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (234)
3-(Hydroxymethyl)-9-methyl-2-(3-(trifluoromethoxy)phenylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (235)
3-(Hydroxymethyl)-2-(3-hydroxyphenylamino)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (236)
3-(Hydroxymethyl)-2-(4-hydroxyphenylamino)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (237)
2-(4-tert-Butylphenylamino)-3-(hydroxymethyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (238)
2-(3-Chlorobenzylamino)-3-(hydroxymethyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (239)
3-(Hydroxymethyl)-2-(isobutylamino)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (240)
2-(Diethylamino)-3-(hydroxymethyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (241)
2-(Cyclohexylmethylamino)-3-(hydroxymethyl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (242)
3-(Hydroxymethyl)-9-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (243)
3-(Hydroxymethyl)-9-methyl-2-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride (244)
7-Bromo-2-(3-chlorophenylamino)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (245)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-7-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (246)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-8-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (247)
8-Chloro-2-(3-chlorophenylamino)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (248)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-8-(methylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (249)
2-(3-Chlorophenylamino)-8-(diethylamino)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (250)
3-(Hydroxymethyl)-8-morpholino-2-(phenylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (251)
2-(3-Fluorophenylamino)-3-(hydroxymethyl)-8-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (252)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-8-morpholino-4H-pyrido[1,2-a]pyrimidin-4-one (253)
3-(Hydroxymethyl)-8-(4-methylpiperazin-1-yl)-2-(phenylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (254)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-8-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (255)
2-(3-Fluorophenylamino)-3-(hydroxymethyl)-8-(4-methylpiperazin-1-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (256)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-8-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (257)
2-(4-Chlorophenylamino)-3-(hydroxymethyl)-8-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (258)
2-(4-Fluorophenylamino)-3-(hydroxymethyl)-8-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (259)
2-(3,4-Dichlorophenylamino)-3-(hydroxymethyl)-8-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (260)
2-(3-Chloro-4-fluorophenylamino)-3-(hydroxymethyl)-8-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (261)
9-Chloro-2-(3-chlorophenylamino)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (262)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-9-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (263)
2-(3-Chlorophenylamino)-9-fluoro-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (264)
2-(4-Chlorophenylamino)-9-fluoro-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (265)
9-Fluoro-2-(4-fluorophenylamino)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (266)
2-(3-Chloro-4-fluorophenylamino)-9-fluoro-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (267)
2-(3,4-Difluorophenylamino)-9-fluoro-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (268)
2-(3,4-Dichlorophenylamino)-9-fluoro-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (269)
2-(1H-Indol-5-ylamino)-9-fluoro-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (270)
3-(Hydroxymethyl)-9-methoxy-2-(phenylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (271)
2-(3-Chlorophenylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (273)
2-(4-Chlorophenylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (274)
2-(4-Fluorophenylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (275)
3-(Hydroxymethyl)-9-methoxy-2-(4-(trifluoromethoxy)phenylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (276)
3-(Hydroxymethyl)-9-methoxy-2-(4-(trifluoromethyl)phenylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (277)
2-(3-Chloro-4-fluorophenylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (278)
2-(3,4-Difluorophenylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (279)
2-(3-Chloro-4-hydroxyphenylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (280)
2-(3,4-Dichlorophenylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (281)
3-(Hydroxymethyl)-9-methoxy-2-(4-methyl-3-(trifluoromethyl)phenylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (282)
2-(4-Fluoro-3-(trifluoromethyl)phenylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (283)
2-(2,3-Dihydro-1H-inden-5-ylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (284)
2-(Benzo[d][1,3]dioxol-5-ylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (285)
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-ylamino)-3-(hydroxymethyl)-9-methoxy-4H-pyrido[1,2-a]pyrimidin-4-one (286)
3-(Hydroxymethyl)-9-methoxy-2-(1-methyl-1H-indol-5-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (287)
3-(Hydroxymethyl)-9-methoxy-2-(1-methyl-1H-benzo[d]imidazol-5-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (288)
3-(Hydroxymethyl)-9-methoxy-2-(1-methyl-1H-indazol-5-ylamino)-4H-pyrido[1,2-a]pyrimidin-4-one (289)
9-(Difluoromethoxy)-2-(4-fluorophenylamino)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (290)
2-(4-Chlorophenylamino)-9-(difluoromethoxy)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (291)
9-(Difluoromethoxy)-2-(3,4-difluorophenylamino)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (292)
2-(3,4-Dichlorophenylamino)-9-(difluoromethoxy)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (293)
2-(3-Chloro-4-fluorophenylamino)-9-(difluoromethoxy)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (294)
2-(1H-Indol-5-ylamino)-9-(difluoromethoxy)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (295)
2-(3-chlorophenylamino)-3-(hydroxymethyl)-6,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (296)
7,9-Dichloro-2-(3-chlorophenylamino)-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (297)
and
2-(3-Chlorophenylamino)-7,9-difluoro-3-(hydroxymethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (298)

96 more elements

A compound having the general formula VIIIa:

wherein
X5 is C═O;
Z1 and Z2 are each independently selected from the group consisting of alkoxy, alkyl, alkylamino, alkenyl, alkylether, alkylthio, alkynyl, amido, amino, aryl, arylalkoxy, arylamino, arylthio, carboxy, cyano, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydroxyl, and hydrogen, or any two groups are connected to each other to make five or six membered cyclic, heterocyclic and heteroaryl rings, any of which is optionally substituted;
R27 is selected from the group consisting of alkoxy, alkyl, alkyl amino, alkenyl, alkylether, alkylthio, alkynyl, amido, amino, aryl, arylether, arylalkoxy, arylamino, arylthio, carboxy, cyano, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydroxyl, hydrogen, nitro, thiol, sulfonate, sulfonyl and sulfonylamino, any of which is optionally substituted;
R28 is selected from the group consisting of alkoxy, alkyl, alkylamino, alkenyl, alkylether, alkylthio, alkynyl, amido, amino, aryl, arylether, arylalkoxy, arylamino, arylthio, carboxy, cyano, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydroxyl, nitro, thiol, sulfonate, sulfonyl and sulfonylamino, any of which is optionally substituted;
and
R29 and R30 are each independently selected from the group consisting of alkoxy, alkyl, alkylamino, alkenyl, alkylether, alkylthio, alkynyl, amido, amino, aryl, arylether, arylalkoxy, arylamino, arylthio, carboxy, cyano, cycloalkyl, ester, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylamino, heterocycloalkyl, hydroxyl, hydrogen, nitro, thiol, sulfonate, sulfonyl and sulfonylamino, or two groups are connected to each other to make five or six membered cyclic, heterocyclic, aryl, and heteroaryl rings, any of which is optionally substituted.

4 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/999,095Filed 17 Jun 2009 · us provisional application
Priority: 17 Jun 2008
Published: US 2011/0178077 A121 Jul 2011
Granted: 22 Jul 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification19 codes

A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
C12Q 1/18
Involving viable microorganisms: testing for antimicrobial activity of a material
A61P 31/06
Antibacterial agents: for tuberculosis
C07C 255/66
With the nitrogen atoms further bound to nitrogen atoms: having cyano groups and nitrogen atoms being part of hydrazine or hydrazone groups bound…

Family

Application61/132,285Us provisional application · filed 17 Jun 2008
US 2011/0178077 A1Pre-grant publication · published 21 Jul 2011
US 8,785,452 B2This patent

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

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