IP Library › Granted Patent US 12,383,548
Granted Patent B2
US 12,383,548 · App. 17/789,472 · Granted Aug 12, 2025

Antibacterial quinolines

Inventors: Augusto Eugénio Pardal Filipe (Sintra, PT); Carla Patrícia Da Costa Pereira Rosa (Sintra, PT); Ana Vanessa Cordeiro Simões (Sintra, PT); João Carlos Ramos Damil (Sintra, PT); João Pedro Silva Serra (Sintra, PT); Ana Lúcia Almeida Ferreira (Sintra, PT); Rita Isabel Gomes Neves (Sintra, PT); Sara Alexandra Marques Homem E Sousa Dos Santos (Sintra, PT)
Assignee: Tecnimede—Sociedade Técnico-Medicinal, SA
A61K31/4709A61P31/06
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Quick Facts
Patent No.
US 12,383,548
App. No.
17/789,472
Granted
Aug 12, 2025
Kind
B2
Abstract

The present disclosure relates to 6-substituted quinoline-2-piperidine derivatives for use in the treatment and/or prevention of tuberculosis.

Claims (154)

1. A compound of general formula I or a pharmaceutically acceptable salt, hydrate, solvate, N-oxide, stereoisomer, diastereoisomer, enantiomer or atropisomer, polymorph or ester thereof:

wherein

R 1 , R 2 , X, Y, Z, W, are independently selected from each other;

R 1 is selected from H or C 1 -C 6 alkyl;

R 2 is selected from H or C 1 -C 6 alkyl;

X is selected from N, O, S or CR 3 , and R 3 is selected from H, halogen, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl;

Y is selected from N or CR 4 , and R 4 is selected from H, C 1 -C 6 haloalkoxy, OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, halogen or C 1 -C 6 alkyl;

Z is selected from N or CR 5 , and R 5 is selected from H, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, OH, NO 2 or C 1 -C 6 alkyl;

W is selected from N, or CR 6 , and R 6 is selected from H, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, halogen, or C 1 -C 6 haloalkoxy;

m and n are independently selected from 0 or 1;

further wherein halogen is F or Cl;

and wherein the group connected to the quinoline moiety on C 6 is a substituted aryl, a substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, benzothiophenyl, indolyl or phenyl,

and the piperidine ring that is connected to the quinoline moiety on C 2 , has its C 3 or C 4 substituted with carboxylate group.

2. The compound of claim 1 , wherein

R1 is selected from H, CH 2 CH 3 or CH 3 ;

R2 is selected from H or CH 3 ;

X is selected from N, O, S or CR 3 , and R 3 is selected from H, Cl, F, CF 3 or OCH 3 ;

Y is selected from N or CR 4 , and R 4 is selected from H, F, Cl, CH 3 , OH, CF 3 , OCF 3 , OCH(CH 3 ) 2 or OCH 3 ;

Z is selected from N or CR 5 , and R 5 is H, OH, F, OCF 3 , OCH 3 , NO 2 , CF 3 or CH 3 ;

W is selected from N or CR 6 and R 6 is H, F, Cl, CF 3 , OCH 3 or OCF 3 ;

m and n are independently selected from 0 or 1;

and wherein the group connected to the quinoline moiety on C 6 is a substituted aryl, a substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, furan-2-yl, benzothiophenyl, indolyl or phenyl.

3. The compound of claim 1 , of Formula II wherein

R 1 is selected from H or CH 2 CH 3 ;

R 3 is selected from H, Cl, F, CF 3 or OCH 3 ;

R 4 is selected from H, OH, Cl, F, OCF 3 , CH 3 , CF 3 , OCH(CH 3 ) 2 or OCH 3 ;

R 5 is selected from H, OH, F, OCF 3 , CF 3 , CH 3 , OCH 3 or NO 2 ;

R 6 is selected from H, Cl, F, CF 3 , OCF 3 or OCH 3 ;

further wherein that the group connected to the quinoline moiety on C 6 is a substituted aryl, substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from indolyl or phenyl.

4. The compound of claim 1 , of Formula III, wherein

R1 is selected from H, CH 2 CH 3 or CH 3 ;

R2 is selected from H and CH 3 ;

X is selected from N, or CR 3 , and R 3 is H;

Y is selected from N or CR 4 , and R 4 is selected from H, CH 3 , F, CF 3 or OCH 3 ;

Z is selected from N or CR 5 , and R 5 is selected from H or CH 3 ;

W is selected from N or CR 6 , and R 6 is selected from H or F;

m is selected from 0 or 1;

further wherein the group connected to the quinoline moiety on C 6 is a substituted aryl, substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl or pyrimidin-5-yl.

5. The compound of claim 1 , of Formula IV, wherein

X is O or S;

R1 is selected from H or CH 2 CH 3 ;

further wherein the group connected to the quinoline moiety on C 6 is a substituted or unsubstituted heteroaryl or fused heteroaroaryl ring selected from furan-2-yl or benzothiophenyl.

6. The compound according to claim 3 , wherein R 3 is H, Cl, F or CF 3 .

7. The compound according to claim 3 , wherein R 4 is H, Cl, F, OCF 3 , OCH(CH 3 ) 2 or OCH 3 , R 5 is H, Cl, F, OH, OCF 3 or CF 3 , and R 6 is H, Cl, CF 3 or OCH 3 .

8. The compound according to claim 4 , wherein one or more of Y, Z or W is N.

9. The compound according to claim 8 , wherein R 4 is OCH 3 or CH 3 and Z is N.

10. The compound according to claim 8 , wherein W is N.

11. The compound of claim 1 , wherein the salt is a hydrochloride.

12. The compound of claim 1 , wherein the compound is:

Ethyl 1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-(Trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(4-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(2-Methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-Isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-Hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-Fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-Fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(6-Methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride;

Ethyl 1-(6-(furan-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(Furan-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(Pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

Ethyl 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-Methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-Methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(2-Chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride;

Ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-Hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-Methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-(Trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(4-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3-nitrophenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(6-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-(Trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(2-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(6-Fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

1-(6-(3-Nitrophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(2-methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3,5-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(1H-indol-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(6-(trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(1H-Indol-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

1-(6-(3,5-Dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(4-Fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(Pyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(Pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(2-Fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

1-(6-(6-(Trifluoromethyl)pyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride;

1-(6-(2-Methylpyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylate;

Ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

1-(4-Methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

Ethyl 1-(4-methyl-6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3,4-dimethoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(Pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(Pyridin-4-yl)quinolin-2-yl)piperidine-3-carboxylic acid hydrochloride;

Ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(4-chlorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(pyridin-4-yl)quinolin-2-yl)pyrrolidine-3-carboxylate;

Ethyl 1-(6-(benzo[b]thiophen-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(2-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(4-methoxy-3-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(4-chloro-3-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3-chloro-4-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(2-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(5-fluoropyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

Ethyl 1-(6-(3-fluoropyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate;

Methyl 1-(6-(pyridin-4-yl)quinolin-2-yl)piperidine-4-carboxylate; or

1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride.

13. The compound of claim 1 , wherein the compound is selected from:

1-(6-(4-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(2-methoxypyrimidin-5-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-fluoro-4-isopropoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

1-(6-(3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methoxypyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-chloro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(4-methoxy-2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate hydrochloride;

ethyl 1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-hydroxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

1-(6-(3-(trifluoromethoxy)phenyl)quinolin-2-yl)piperidine-4-carboxylic acid;

ethyl 1-(6-(6-methylpyridin-3-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(pyridin-2-yl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(3-fluoro-4-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(4-chloro-3-fluorophenyl)quinolin-2-yl)piperidine-4-carboxylate;

ethyl 1-(6-(2-(trifluoromethyl)phenyl)quinolin-2-yl)piperidine-4-carboxylate; or

ethyl 1-(6-(4-fluoro-2-methoxyphenyl)quinolin-2-yl)piperidine-4-carboxylate.

14. A method for treating tuberculosis in a subject, the method comprising administering the compound of claim 1 to the subject.

15. The method of claim 14 , further comprising administering at least one anti-HIV agent to the subject.

16. The method of claim 15 , wherein the anti-HIV agent is selected from an HIV protease inhibitor, an HIV nucleoside reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and an HIV integrase inhibitor.

17. The method of claim 14 , further comprising administering a further tuberculosis drug.

18. The method of claim 17 , wherein the further tuberculosis drug is selected from the group of isoniazid, rifamycin and derivatives, pyrazinamide, ethambutol, cycloserine, ethionamide, streptomycin, amikacin, kanamycin, rifampin (rifampicin), aminoglycosides, capreomycin, p-aminosalicyclic acid, levofloxacin, moxafloxacin or gatifloxacin, or mixtures thereof.

19. The method of claim 15 , wherein the anti-HIV is administered simultaneously, separately or sequentially.

20. A pharmaceutical composition comprising (i) a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof; and (ii) a pharmaceutically acceptable excipient.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2022
From: PARDAL FILIPE, AUGUSTO EUGÉNIO; DA COSTA PEREIRA ROSA, CARLA PATRÍCIA; CORDEIRO SIMÕES, ANA VANESSA; RAMOS DAMIL, JOÃO CARLOS; SILVA SERRA, JOÃO PEDRO; ALMEIDA FERREIRA, ANA LÚCIA; GOMES NEVES, RITA ISABEL; MARQUES HOMEM E SOUSA DOS SANTOS, SARA ALEXANDRA
To: TECNIMEDE - SOCIEDADE TÉCNICO-MEDICINAL, SA
Reel/Frame 060325/0556 →
Priority Claims (3)
PT 116028 · Dec 27, 2019 · national
EP 20163200 · Mar 13, 2020 · regional
PT 116168 · Mar 13, 2020 · national
Continuity (1)
Related Publication 20230106913A1 · Apr 6, 2023
References Cited (20)
US 7868022B2 · Baxter et al. · 2011 [cited by applicant]
US 7989628B2 · Kolczewski et al. · 2011 [cited by applicant]
US 8163756B2 · Flynn · 2012 [cited by examiner]
US 9856208B2 · Lumb · 2018 [cited by examiner]
US 20160113919A1 · Banaei et al. · 2016 [cited by applicant]
EP 0694543A1 · 1996 [cited by applicant]
EP 1527050B1 · 2010 [cited by applicant]
WO 2009001060A2 · 2008 [cited by applicant]
WO 2012025237A9 · 2012 [cited by applicant]
WO 2017001661A1 · 2017 [cited by applicant]
WO 2017027768A1 · 2017 [cited by applicant]
WO 2019243971A1 · 2019 [cited by applicant]
International Search Report and Written Opinion for corresponding PCT Application No. PCT/IB2020/062483 dated Mar. 11, 2021 (8 pages). [cited by applicant]
Comas et al., “Out-of-Africa migration and Neolithic co-expansion of [cited by applicant]
Hoagland et al., “New agents for the treatment of drug-resistant [cited by applicant]
SJ Tantry et al., “Scaffold Morphing Led to Evolution of 2,4-Diaminoquinolines and Aminopyrazolopyrimidines As Inhibitors of ATP Synthesis Pathway”, MedChemComm, Mar. 2016. [cited by applicant]
Ann H. Cory et al., “Use of an Aqueous Soluble Tetrazolium/Formazan Assay for Cell Growth Assays in Culture”, Cancer communications. Jul. 1991, pp. 207-212. [cited by applicant]
Juan-Carlos Palomino et al., “Resazurin Microtiter Assay Plate: Simple and Inexpensive Method for Detection of Drug Resistance in [cited by applicant]
Vivekkumar K. Redasani et al., “Prodrug Design: Perspectives, Approaches and Applications in Medicinal Chemistry”, Academic Press, Jul. 2015. [cited by applicant]
World Health Organization, “Global Tuberculosis Report”, 2017. [cited by applicant]