IP Library › Granted Patent US 10,722,520

Granted Patent B2

US 10,722,520 · App. 16/338,355 · Granted Jul 28, 2020

Heterocyclic compounds and their use in preventing or treating bacterial infections

Inventors: Julien Barbion (Sannois, FR); Audrey Caravano (Enghien les Bains, FR); Sophie Chasset (Nandy, FR); Francis Chevreuil (Chantilly, FR); Fabien Faivre (Drancy, FR); Rémi Lebel (Drancy, FR); Nicolas Lecointe (Paris, FR); Benoît Ledoussal (Pommerit Jaudy, FR); Frédéric Le-Strat (Combs la Ville, FR); Christophe Simon (Chevilly Larue, FR); Chrystelle Oliveira (Saint Prix, FR); Géraldine Le Fralliec (Bondy, FR); Julie Brias (Paris, FR); Laurence Farescour (Chelles, FR); Sophie Vomscheid (Malakoff, FR); Sébastien Richard (Romainville, FL)

Assignee: MUTABILIS

A61K31/551 A61K31/439 A61K31/546 A61K45/06 A61P31/04 C07D403/04 C07D403/14 C07D413/14 C07D417/14 C07D471/08

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Quick Facts

Patent No.: US 10,722,520
App. No.: 16/338,355
Granted: Jul 28, 2020
Kind: B2

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Abstract

A compound of formula (I) or a racemate, an enantiomer, a diastereoisomer, a geometric isomer or a pharmaceutically acceptable salt thereof, and its use as antibacterial agent.

Claims (63)

1. A compound of formula (I)

wherein:

R 1 represents a 5-membered heterocycle, optionally substituted by one or more T 1 , that is saturated, partially unsaturated, or aromatic and that comprises a nitrogen atom, wherein said 5-membered heterocycle is linked to the structure by said nitrogen atom, and wherein said nitrogen atom may be quaternized;

R 2 represents —SO 3 H, —CFHCOOH, or —CF 2 COOH;

□T 1 , identical or different, independently represents a fluorine atom; ═O; —C(O)Q 1 ; —(CH 2 ) m —S(O) 2 —NQ 1 Q 2 ; —(CH 2 ) m —C(═NOQ 1 )Q 3 ; —(X)—(CH 2 ) p —S(O) 2 NQ 1 Q 2 ; —C(O)—(CH 2 ) n —S(O) 2 NQ 1 Q 2 ; —(CH 2 ) m —O—(CH 2 ) p —O—(CH 2 ) p —NQ 1 Q 2 ; —(CH 2 ) m OQ 1 ; —(CH 2 ) m —CN; —(CH 2 ) m —OC(O)Q 1 ; —(CH 2 ) m —C(O)OQ 1 ; —(CH 2 ) m —OC(O)OQ 1 ; —(CH 2 ) m —OC(O)NQ 1 Q 2 ; —(CH 2 ) m —C(O)NQ 1 Q 2 ; —(CH 2 ) m —C(O)ONQ 1 Q 2 ; —(CH 2 ) m —C(O)NQ 1 OQ 2 ; —(CH 2 ) m —C(O)NQ 1 -NQ 1 Q 2 ; —(CH 2 ) m —NQ 1 C(O)Q 2 ; —(CH 2 ) m —NQ 1 S(O) 2 NQ 1 Q 2 ; —(CH 2 ) m —NQ 1 S(O) 2 Q 2 ; —(CH 2 ) m —NQ 1 C(O)OQ 2 ; —(CH 2 ) m —NQ 1 C(O)NQ 1 Q 2 ; —(CH 2 ) m —NQ 1 Q 2 ; —(CH 2 ) m —NH—C(NHQ 3 )=NQ 4 ; —(CH 2 ) m —NH—CH═NQ 3 ; —(CH 2 ) m —C(NHQ 3 )=NQ 4 ; —(X)—(CH 2 ) p OQ 1 ; —(X)—(CH 2 ) n —CN; —(X)—(CH 2 ) p —OC(O)Q 1 ; —(X)—(CH 2 ) n —C(O)OQ 1 ; —(X)—(CH 2 ) p —OC(O)OQ 1 ; —(X)—(CH 2 ) p —OC(O)NQ 1 Q 2 ; —(X)—(CH 2 ) n —C(O)NQ 1 Q 2 ; —(X)—(CH 2 ) n —C(O)ONQ 1 Q 2 ; —(X)—(CH 2 ) n —C(O)NQ 1 OQ 2 ; —(X)—(CH 2 ) n —C(O)NQ 1 -NQ 1 Q 2 ; —(X)—(CH 2 ) p —NQ 1 C(O)Q 2 ; —(X)—(CH 2 ) p —NQ 1 S(O) 2 NQ 1 Q 2 ; —(X)—(CH 2 ) p —NQ 1 S(O) 2 Q 2 ; —(X)—(CH 2 ) p —NQ 1 C(O)OQ 2 ; —(X)—(CH 2 ) p —NQ 1 C(O)NQ 1 Q 2 ; —(X)—(CH 2 ) p —NQ 1 Q 2 ; —(X)—(CH 2 ) p —NH—C(NHQ 3 )=NQ 4 ; —(X)—(CH 2 ) p —NH—CH═NQ 3 ; —(X)—(CH 2 ) n —C(NHQ 3 )=NQ 4 ; —C(O)—(CH 2 ) n OQ 1 ; —C(O)—(CH 2 ) n —CN; —C(O)—(CH 2 ) n —OC(O)Q 1 ; —C(O)—(CH 2 ) n —C(O)OQ 1 ; —C(O)—(CH 2 ) n —OC(O)OQ 1 ; —C(O)—(CH 2 ) n —OC(O)NQ 1 Q 2 ; —C(O)—(CH 2 ) n —C(O)NQ 1 Q 2 ; —C(O)—(CH 2 ) n —C(O)ONQ 1 Q 2 ; —C(O)—(CH 2 ) n —C(O)NQ 1 OQ 2 ; —C(O)—(CH 2 ) n —C(O)NQ 1 -NQ 1 Q 2 ; —C(O)—(CH 2 ) n —NQ 1 C(O)Q 2 ; —C(O)—(CH 2 ) n -NQ 1 S(O) 2 NQ 1 Q 2 ; —C(O)—(CH 2 ) n -NQ 1 S(O) 2 Q 2 ; —C(O)—(CH 2 ) n —NQ 1 C(O)OQ 2 ; —C(O)—(CH 2 ) n -NQ 1 C(O)NQ 1 Q 2 ; —C(O)—(CH 2 ) n -NQ 1 Q 2 ; —C(O)—(CH 2 ) n —NH—C(NHQ 3 )=NQ 4 ; —C(O)—(CH 2 ) n —NH—CH═NQ 3 ; or —C(O)—(CH 2 ) n —C(NHQ 3 )=NQ 4 ; or

□T 1 , identical or different, independently represents an unsubstituted or substituted by one or more T 2 , —(CH 2 ) m -(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle); —(X)—(CH 2 ) m -(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle); (C 1 -C 3 )-alkyl; (C 1 -C 3 )-fluoroalkyl; —(X)—(C 1 -C 3 )-alkyl; —(X)—(C 1 -C 3 )-fluoroalkyl; —(CH 2 ) m —(C 3 -C 6 )-cycloalkyl; —(X)—(CH 2 ) m —(C 3 -C 6 )-cycloalkyl; —(CH 2 ) m —(C 3 -C 6 )-cyclofluoroalkyl; —(X)—(CH 2 ) m —(C 3 -C 6 )-cyclofluoroalkyl; —C(O)—(CH 2 ) m -(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle); —C(O)—(C 1 -C 3 )-alkyl; —C(O)—(C 1 -C 3 )-fluoroalkyl; —C(O)O—(C 1 -C 3 )-fluoroalkyl; —C(O)—(CH 2 ) m —(C 3 -C 6 )-cycloalkyl; —C(O)—(CH 2 ) m —(C 3 -C 6 )-cycloalkyl; —C(O)—(CH 2 ) m —(C 3 -C 6 )-cyclofluoroalkyl; or —C(O)—(CH 2 ) m —(C 3 -C 6 )-cyclofluoroalkyl;

T 2 , identical or different, independently represents —OH; —NH 2 ; or —CONH 2 ;

□Q 1 and Q 2 , identical or different, independently represent a hydrogen atom; —(CH 2 ) r —NHQ 3 ; —(CH 2 ) r —NH—C(NHQ 3 )=NQ 4 ; —(CH 2 ) r —NH—CH═NQ 3 ; (CH 2 ) n —C(NHQ 3 )=NQ 4 ; —(CH 2 ) r —OQ 3 ; —(CH 2 ) n —CONHQ 3 ; an unsubstituted or substituted by one or more T 2 , (C 1 -C 3 )-alkyl; (C 1 -C 3 )-fluoroalkyl; or a saturated, partially or totally unsaturated, or aromatic-(CH 2 ) m -(4-, 5- or 6-membered heterocycle comprising at least one nitrogen atom); or

□Q 1 , Q 2 , and the nitrogen atom to which they are bonded, form together an unsubstituted or substituted by one or more T 2 , saturated or partially unsaturated 4-, 5- or 6-membered heterocycle comprising 1, 2, or 3 heteroatoms;

Q 3 and Q 4 , identical or different, independently represent a hydrogen atom or (C 1 -C 3 )-alkyl;

m, identical or different, independently represents 0, 1, 2 or 3;

n, identical or different, independently represents 1, 2 or 3;

p, identical or different, independently represents 2 or 3;

r is 1, 2 or 3 when the (CH 2 ), is directly linked to a carbon atom or 2 or 3 otherwise; and

X, identical or different, independently represents O; S; S(O); S(O) 2 or N(Q 3 ); and

wherein:

any carbon atom present within a group selected from alkyl, cycloalkyl, fluoroalkyl, cyclofluoroalkyl and heterocycle can be oxidized to form a C═O group;

any sulphur atom present within a heterocycle can be oxidized to form a S═O group or a S(O) 2 group; and

any nitrogen atom present within a heterocycle or present within group wherein it is trisubstituted thus forming a tertiary amino group, can be further quaternized by a methyl group;

or a racemate, an enantiomer, a diastereoisomer, a geometric isomer or a pharmaceutically acceptable salt of the formula (I) compound, but excluding the following compounds:

2. The compound of claim 1 , wherein the compound of formula (I) is a compound of formula (I)

3. The compound of claim 1 , wherein the 5-membered heterocycle of R 1 further comprises one, two, or three additional heteroatoms selected from the group consisting of N, O, and S, wherein one or more of said additional N heteroatoms may be quaternized.

4. The compound of claim 1 , wherein:

□T 1 identical or different, independently represents a fluorine atom; ═O; —C(O)Q′; —(CH 2 ) m —S(O) 2 —NQ 1 Q 2 ; —(CH 2 ) m —C(═NOQ 1 )Q 3 ; —(CH 2 ) n OQ 1 ; —(CH 2 ) m —CN; —(CH 2 ) m —C(O)OQ 1 ; —(CH 2 ) m —C(O)NQ 1 Q 2 ; —(CH 2 ) m —C(O)NQ 1 OQ 2 ; —(CH 2 ) m —NQ 1 C(O)Q 2 ; or —(CH 2 ) m -NQ 1 Q 2 ; or

5. The compound of claim 1 , wherein R 1 is selected from the group consisting of:

wherein each of the foregoing R 1 cycles may be substituted by one or more T 1 .

6. The compound of claim 1 , wherein R 1 is selected from the group consisting of:

wherein each of the foregoing R 1 cycles may be substituted by one or more T 1 .

7. The compound of claim 1 , wherein R 2 represents —SO 3 H or —CF 2 COOH.

8. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8 further comprising at least one antibacterial compound, at least one β-lactam compound, or a combination thereof.

10. The pharmaceutical composition of claim 9 , wherein: the at least one antibacterial compound is selected from the group consisting of aminoglycosides, β-lactams, glycylcyclines, tetracyclines, quinolones, fluoroquinolones, glycopeptides, lipopeptides, macrolides, ketolides, lincosamides, streptogramins, oxazolidinones, polymyxins, and combinations thereof; and

the at least one β-lactam compound is selected from the group consisting of penicillin, cephalosporins, penems, carbapenems, monobactam, and combinations thereof.

11. A pharmaceutical composition comprising the compound of claim 1 and ceftazidime.

12. A kit comprising at least two different pharmaceutical compositions of claim 8 .

13. A kit comprising a first pharmaceutical composition that comprises the compound of claim 1 and a second pharmaceutical composition that comprises ceftazidime.

14. A method for treating a bacterial infection comprising administering to a person in need thereof a pharmaceutically effective amount of the compound of claim 1 .

15. The method of claim 14 , wherein the bacterial infection is caused by bacteria producing one or more β-lactamase, or by a gram-positive bacteria, or by gram-negative bacteria.

16. A method for treating a bacterial infection comprising administering to a person in need thereof a pharmaceutically effective amount of the pharmaceutical composition of claim 8 .

17. A method for treating a bacterial infection comprising administering to a person in need thereof pharmaceutically effective amounts of the first and second pharmaceutical compositions of the kit of claim 13 simultaneously or separately or sequentially.

18. A compound of formula

wherein:

Y is selected from the group consisting of a halogen, —B(OR) 2 , and SnR 3 , wherein R is an alkyl or the OR are linked together with the B to form a 5-membered cycle; and

PG, is a protective group selected from the group consisting allyl, benzyl, tertbutyldimethylsilyl (TBDMS), and tert-butoxycarbonyl (Boc).

19. A compound of formula

wherein:

□T 1 , identical or different, independently represents a fluorine atom; ═O; —C(O)Q 1 ; —(CH 2 ) m —S(O) 2 -NQ 1 Q 2 ; —(CH 2 ) m —C(═NOQ 1 )Q 3 ; —(X)—(CH 2 ) p —S(O) 2 NQ 1 Q 2 ; —C(O)—(CH 2 ) n —S(O) 2 NQ 1 Q 2 ; —(CH 2 ) m —O—(CH 2 ) p —O—(CH 2 ) p —NQ 1 Q 2 ; —(CH 2 ) m OQ 1 ; —(CH 2 ) m —CN; —(CH 2 ) m —OC(O)Q 1 ; —(CH 2 ) m —C(O)OQ 1 ; —(CH 2 ) m —OC(O)OQ 1 ; —(CH 2 ) m —OC(O)NQ 1 Q 2 ; —(CH 2 ) m —C(O)NQ 1 Q 2 ; —(CH 2 ) m —C(O)ONQ 1 Q 2 ; —(CH 2 ) m —C(O)NQ 1 Q 2 ; —(CH 2 ) m —C(O)NQ 1 -NQ 1 Q 2 ; —(CH 2 ) m —NQ 1 C(O)Q 2 ; —(CH 2 ) m —NQ 1 S(O) 2 NQ 1 Q 2 ; —(CH 2 ) m —NQ 1 S(O) 2 Q 2 ; —(CH 2 ) m -NQ 1 C(O)OQ 2 ; —(CH 2 ) m NQ 1 C(O)NQ 1 Q 2 ; —(CH 2 ) m NQ 1 Q 2 ; —(CH 2 ) m —NH—C(NHQ 3 )=NQ 4 ; —(CH 2 ) m NH—CH═NQ 3 ; —(CH 2 ) m —C(NHQ 3 )=NQ 4 ; —(X)—(CH 2 ) p OQ 1 ; —(X)—(CH 2 ) n —CN; —(X)—(CH 2 ) p —OC(O)Q 1 ; —(X)—(CH 2 ) n —C(O)OQ 1 ; —(X)—(CH 2 ) p —OC(O)OQ 1 ; —(X)—(CH 2 ) p —OC(O)NQ 1 Q 2 ; —(X)—(CH 2 ) n —C(O)NQ 1 Q 2 ; —(X)—(CH 2 ) n —C(O)ONQ 1 Q 2 ; —(X)—(CH 2 ) n —C(O)NQ 1 OQ 2 ; —(X)—(CH 2 ) n —C(O)NQ 1 NQ 2 ; —(X)—(CH 2 ) p -NQ 1 C(O)Q 2 ; —(X)—(CH 2 ) p —NQ 1 S(O) 2 NQ 1 Q 2 ; —(X)—(CH 2 ) p —NQ 1 S(O) 2 Q 2 ; —(X)—(CH 2 ) p —NQ 1 C(O)OQ 2 ; —(X)—(CH 2 ) p —NQ 1 C(O)NQ 1 Q 2 ; —(X)—(CH 2 ) p —NQ 1 Q 2 ; —(X)—(CH 2 ) p —NH—C(NHQ 3 )=NQ 4 ; —(X)—(CH 2 ) p —NH—CH═NQ 3 ; —(X)—(CH 2 ) n —C(NHQ 3 )=NQ 4 ; —C(O)—(CH 2 ) n OQ 1 ; —C(O)—(CH 2 ) n —CN; —C(O)—(CH 2 ) n —OC(O)Q 1 ; —C(O)—(CH 2 ) n —C(O)OQ 1 ; —C(O)—(CH 2 ) n —OC(O)OQ 1 ; —C(O)—(CH 2 ) n —OC(O)NQ 1 Q 2 ; —C(O)—(CH 2 ) n —C(O)NQ 1 Q 2 ; —C(O)—(CH 2 ) n —C(O)ONQ 1 Q 2 ; —C(O)—(CH 2 ) n —C(O)NQ 1 OQ 2 ; —C(O)—(CH 2 ) n —C(O)NQ 1 -NQ 1 Q 2 ; —C(O)—(CH 2 ) n —NQ 1 C(O)Q 2 ; —C(O)—(CH 2 ) n —NQ 1 S(O) 2 NQ 1 Q 2 ; —C(O)—(CH 2 ) n —NQ 1 S(O) 2 Q 2 ; —C(O)—(CH 2 ) n —NQ 1 C(O)OQ 2 ; —C(O)—(CH 2 ) n —NQ 1 C(O)NQ 1 Q 2 ; —C(O)—(CH 2 ) n —NQ 1 Q 2 ; —C(O)—(CH 2 ) n —NH—C(NHQ 3 )=NQ 4 ; —C(O)—(CH 2 ) n —NH—CH═NQ 3 ; or —C(O)—(CH 2 ) n —C(NHQ 3 )=NQ 4 ; or

□T 1 , identical or different, independently represents an unsubstituted or substituted by one or more T 2 , —(CH 2 ) m -(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle); —(X)—(CH 2 ) m -(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle); (C 1 -C 3 )-alkyl; (C 1 -C 3 )-fluoroalkyl; —(X)—(C 1 -C 3 )-alkyl; —(X)—(C 1 -C 3 )-fluoroalkyl; —(CH 2 ) m —(C 3 -C 6 )-cycloalkyl; —(X)—(CH 2 ) m (C 3 -C 6 )-cycloalkyl; —(CH 2 ) m (C 3 -C 6 )-cyclofluoroalkyl; —(X)—(CH 2 ) m (C 3 -C 6 )-cyclofluoroalkyl; —C(O)—(CH 2 ) m -(4-, 5- or 6-membered saturated, partially or totally unsaturated, or aromatic heterocycle); —C(O)—(C 1 -C 3 )-alkyl; —C(O)—(C 1 -C 3 )-fluoroalkyl; —C(O)O—(C 1 -C 3 )-fluoroalkyl; —C(O)—(CH 2 ) m (C 3 -C 6 )-cycloalkyl; —C(O)—(CH 2 ) m (C 3 -C 6 )-cycloalkyl; —C(O)—(CH 2 ) m (C 3 -C 6 )-cyclofluoroalkyl; or —C(O)—(CH 2 ) m (C 3 -C 6 )-cyclofluoroalkyl;

T 2 , identical or different, independently represents —OH; —NH 2 ; or —CONH 2 ;

□Q 1 and Q 2 , identical or different, independently represent a hydrogen atom; —(CH 2 ) r —NHQ 3 ; —(CH 2 ) r —NH—C(NHQ 3 )=NQ 4 ; —(CH 2 ) r —NH—CH═NQ 3 ; (CH 2 ) n —C(NHQ 3 )=NQ 4 ; —(CH 2 ) r —OQ 3 ; —(CH 2 ) n —CONHQ 3 ; an unsubstituted or substituted by one or more T 2 , (C 1 -C 3 )-alkyl; (C 1 -C 3 )-fluoroalkyl; or a saturated, partially or totally unsaturated, or aromatic-(CH 2 ) m (4-, 5- or 6-membered heterocycle comprising at least one nitrogen atom); or

Q 3 and Q 4 , identical or different, independently represent a hydrogen atom or (C 1 -C 3 )-alkyl;

m, identical or different, independently represents 0, 1, 2 or 3;

n, identical or different, independently represents 1, 2 or 3;

p, identical or different, independently represents 2 or 3;

r is 1, 2 or 3 when the (CH 2 ), is directly linked to a carbon atom or 2 or 3 otherwise; and

X, identical or different, independently represents O; S; S(O); S(O) 2 or N(Q 3 ); and

wherein:

any carbon atom present within a group selected from alkyl, cycloalkyl, fluoroalkyl, cyclofluoroalkyl and heterocycle can be oxidized to form a C═O group;

any sulphur atom present within a heterocycle can be oxidized to form a S═O group or a S(O) 2 group; and

any nitrogen atom present within a heterocycle or present within group wherein it is trisubstituted thus forming a tertiary amino group, can be further quaternized by a methyl group.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 27, 2019

From: BARBION, JULIEN; CARAVANO, AUDREY; CHASSET, SOPHIE; CHEVREUIL, FRANCIS; FAIVRE, FABIEN; LEBEL, REMI; LECOINTE, NICOLAS; LEDOUSSAL, BENOIT; LE-STRAT, FREDERIC; SIMON, CHRISTOPHE; OLIVEIRA, CHRYSTELLE; LE FRALLIEC, GERALDINE; BRIAS, JULIE; FARESCOUR, LAURENCE; VOMSCHEID, SOPHIE; RICHARD, SEBASTIEN

To: MUTABILIS

Reel/Frame 050180/0514 →

Priority Claims (1)

EP 16306261 · Sep 30, 2016 · regional

Continuity (1)

Related Publication 20190224210A1 · Jul 25, 2019