Novel heterocyclic compounds, their preparation and their use as medicaments, in particular as antibacterials and beta-lactamase inhibitors

• US 20040157826A1
• Filed: 12/04/2003
• Published: 08/12/2004
• Est. Priority Date: 12/06/2002
• Status: Active Grant

• Current Assignee: Entasis Therapeutics Inc (Innoviva, Inc.)
• Original Assignee: Aventis Pharma SA (Sanofi )
• Inventors: Rowlands, David Alan, Lampilas, Maxime, Musicki, Branislav, Klich, Michel
• Granted Patent: US 7,439,253 B2
• Time in Patent Office: Days
• US Class Current: 514/214.03
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: C07D 471/08 Bridged systems

Abstract

The invention relates to novel heterocyclic compounds of general formula (I), and their salts with a base or an acid:

The invention also relates to a method for preparing these compounds, and to their use as medicaments, in particular as antibacterials and β-lactamase inhibitors.

Claims

1. ) A compound of the general formula:

2. ) The compound as claimed in claim 1, wherein n is 1.

3. ) The compound as claimed in claim 1, wherein R₂ is a hydrogen atom.

4. ) The compound as claimed in claim 1, wherein R₃ and R₄ together form a substituted phenyl or a substituted heterocycle.

5. ) The compound as claimed in claim 4, wherein the substituted heterocycle is a substituted thienyl or a pyrazolyl substituted with one or more of the substituents therefor as defined in claim 1.

6. ) The compound as claimed in claim 1, wherein R₁ is selected from the group consisting of hydrogen, COOCH₃, COOC₂H₅, CONH₂, CONHCH₃ and CONHOCH₃.

7. ) The compound as claimed in claim 1, wherein B is —

NR₈—

(CH₂)_n″

in which n″

is 0.

8. ) The compound as claimed in claim 1, wherein R₈ is OY in which Y is selected from the group consisting of CH₂COOH, CH₂COOR, CHF—

COOH, CHF—

COOR, CF₂—

COOH, CF₂—

COOR, CN, CH₂CN, CH₂CONHOH, CH₂CONHCN, CH₂tetrazole, protected CH₂tetrazole, CH₂SO₃H, CH₂SO₂R, CH₂PO(OR)₂, CH₂PO(OR)(OH), CH₂PO(R)(OH) and CH₂PO(OH)₂ and OY₁ in which Y₁ is selected from the group consisting of SO₂R, SO₂NHCOR, SO₂NHCOOR, SO₂NHCONHR and SO₃H, R being as defined in claim 1.

9. ) The compound as claimed in claim 1, wherein R′

is selected from the group consisting of —

O—

CH₂—

CHOH—

CH₂OH, —

CH₂—

CH₂—

NH₂, —

CH₂—

COOC₂H₅, —

CH₂—

CH₂-phenyl, —

CH₂-phenyl, —

O—

CO—

NHphenyl, —

O—

CO—

NHC₂H₅, —

O—

SO₂—

CF₃, —

O—

(CH₂)₂—

O—

SO₃H, —

O—

(CH₂)₂—

O—

CH₃, —

CH₂—

COOH, —

O—

CH₂-(2,2-dimethyl-1,3-dioxolan-4-yl), —

CO—

NH₂, —

CO—

NH phenyl, —

CH₂—

(p-OCH₃ phenyl) and phenyl optionally substituted with a substituent selected from CH₃, C₂H₅, F and CF₃.

10. ) A compound of formula (I), as defined in claim 1, selected from the group consisting of:

the triethylammonium salt of 5,6-dihydro-6-oxo-N²-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-2,8(8H)-dicarboxamide,

the sodium salt of 4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-1-carboxamide,

the sodium salt of 1,4,5,8-tetrahydro-1-[(4-methoxyphenyl)methyl]-5-(sulfoxy)-6H-4,7-methanopyrazolo[3,4-e][1,3]diazepin-6-one,

the sodium salt of trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(sulfoxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,

the sodium salt of trans-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-2-[2-(trifluoromethyl)phenyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,

the sodium salt of trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,

the sodium salt of trans-8-(2,3-dihydroxypropoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide,

the sodium salt of ethyl trans-3-(4-fluorophenyl)-4,6,7,8-tetrahydro-6-oxo-7-(sulfoxy)-5,8-methano-5H-thieno[2,3-e][1,3]diazepine-4-carboxylate,

the sodium salt of trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxamide,

the sodium salt of 1,4,5,8-tetrahydro-1-phenyl-5-(sulfoxy)-6H-4,7-methanopyrazolo[3,4-e][1,3]diazepin-6-one,

the sodium salt of trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3] diazepine-8-carboxamide,

the triethylammonium salt of methyl trans-2,5,6,8-tetrahydro-6-oxo-2-(phenylmethyl)-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate,

the triethylammonium salt of methyl trans-4,5,6,8-tetrahydro-6-oxo-1-(2-phenylethyl)-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate,

the triethylammonium salt of ethyl trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-1-acetate,

the triethylammonium salt of ethyl trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-2(8H)-acetate,

the di(triethylammonium) salt of trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-sulfoxy-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-2(8H)acetic acid,

the pyridinium salt of methyl trans-1-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate,

the pyridinium salt of methyl trans-2-(aminocarbonyl)-2,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e]diazepine-8-carboxylate,

the sodium salt of methyl trans-2-(4-fluorophenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate,

the sodium salt of methyl trans-2(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate,

the sodium salt of ethyl trans-1,2,3,5-tetrahydro-3-oxo-9-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,

the sodium salt of trans-1,2,3,5-tetrahydro-N-methoxy-8-[(2-methoxyethoxy)methoxy]-3-oxo-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide,

the sodium salt of ethyl trans-1,2,3,5-tetrahydro-3-oxo-8-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,

the sodium salt of ethyl trans-8-[[(ethylamino)carbonyl]oxy]-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,

the sodium salt of ethyl trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[[trifluoromethyl)sulfonyl]oxy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,

the disodium salt of trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[2-(sulfoxy)ethoxy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide,

the sodium salt of trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide, and

the triethylammonium salt of methyl trans-2,5,6,8-tetrahydro-6-oxo-(2-phenylethyl)-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate.

11. A method for preparing a compound as claimed in claim 1, which comprises:

a) reacting a carbonylating agent, where appropriate in the presence of a base, with a compound of formula (II);

 

in which either;

a) R′

₁ is selected from the group consisting of H, CN, protected COOH, COOR₉, (CH₂)_n′

R′

₅, CONR₆R₇ and

R₉ is selected from the group consisting of alkyl containing from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms or with a pyridyl;

—

CH₂-alkenyl containing in total from 3 to 9 carbon atoms;

aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the nucleus of the aryl or aralkyl being optionally substituted with a substituent selected from the group consisting of NO₂, protected OH, protected NH₂, alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or more halogen atoms;

R′

₅ is selected from the group consisting of protected OH, CN, protected NH₂, CO—

NR₆R₇, protected COOH, COOR₉, and OR₉, R₉ being as defined above;

n′

, R₆ and R₇ are as defined in claim 1;

R₃ and R′

₄, together with the carbons to which they are attached, form a phenyl or a 5- or 6-membered aromatic heterocycle containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with one or more R₁₀ groups, R₁₀ being selected from the group consisting of hydrogen;

alkyl containing from 1 to 6 carbon atoms substituted with one or more substituents selected from hydroxy, oxo, halogen and cyano;

alkenyl containing from 2 to 6 carbon atoms;

halo;

protected OH;

—

OR; and

OR″

;

R″

being as defined above;

—

(CH₂)_b-phenyl and —

(CH₂)_b-heterocycle, each of said phenyl and heterocycle being optionally substituted, as defined in claim 1;

or

b) R′

₄ represents a hydrogen atom or (CH₂)<sub>n′

1</sub> R′

₅, n′

₁ being 0, 1 or 2 and R′

₅ being as defined above,

and R′

₁ and R₃ together form an optionally substituted phenyl or heterocycle as defined above for R₃ and R′

₄;

and, in both cases a) and b),

R′

₂ is selected from the group consisting of hydrogen, halogen, R₉, S(O)_mR₉, OR₉, NHCOH, NHCOR₉, NHCOOR₉ and NHSO₂R₉, R₉ being as defined above and m being as defined in claim 1,

ZH is selected from the group consisting of HO—

(CH₂)_n″

—

HNR′

₈—

(CH₂)_n″

— and

HNR′

₈—

O—

, n″

being as defined in claim 1 and R′

₈ being selected from the group consisting of hydrogen, R₉, protected OH, OR₉, Y′

, OY′

, Y′

₁, OY′

₁, Y′

₂, OY′

₂, Y′

₃, O—

CH₂—

CH₂—

S(O)_m—

R″

, SiRaRbRc and OSiRaRbRc, each of Ra, Rb and Rc individually being a linear or branched alkyl containing from 1 to 6 carbon atoms or an aryl containing from 6 to 10 carbon atoms, R₉ and m being as defined above,

Y′

is selected from the group consisting of COH, COR₉, COOR₉, CONH₂, CONHR₉, CONHSO₂R₉, CH₂COOR₉, protected CH₂tetrazole, CH₂SO₂R₉, CH₂PO(OR₉)₂, protected CONHOH, protected CH₂COOH, protected CH₂CONHOH, protected CH₂SO₃, protected CH₂PO(OR)(OH), protected CH₂PO(R)(OH) and protected CH₂PO(OH)₂,

Y′

₁ is selected from the group consisting of SO₂R₉, SO₂NHCOH, SO₂NHCOR₉, SO₂NHCOOR₉, SO₂NHCONH₂, SO₂NHCONHR₉ and protected SO₃H,

Y′

₂ is selected from the group consisting of PO(OR₉)₂, protected PO(OH)₂, protected PO(OH)(OR) and protected PO(OH)(R),

Y′

₃ is selected from the group consisting of protected tetrazole, tetrazole substituted with R₉, protected squarate, protected NHtetrazole, protected NR₉tetrazole, protected NH, NR₉tetrazole substituted with R₉, NHSO₂R₉ and NSO₂R₉, R₉ being as defined above,

and n is as defined in claim 1;

in order to obtain an intermediate compound of formula (III);

 

in which;

R′

₁, R′

₂, R₃, R′

₄ and n have the same meanings as above and either X₁ is hydrogen and X₂ is —

Z—

CO—

X₃, X₃ representing the residue of the carbonylating agent, or X₂ is —

ZH and X₁ is CO—

X₃, X₃ being as defined above; and

b) cyclizing said intermediate in the presence of a base; and

c) where appropriate, step a) is preceded and/or step b) is followed by one or more of the following reactions, in an appropriate order;

protection of the reactive functional groups;

deprotection of the reactive functional groups;

esterification;

saponification;

sulfation;

phosphatization;

amidation;

acylation;

sulfonylation;

alkylation;

formation of a urea group;

reduction of carboxylic acids;

reduction of ketones and aldehydes to alcohols;

salification;

ion exchange;

resolution or separation of diastereoisomers;

oxidation of sulfide to sulfoxide and/or sulfone;

oxidation of aldehyde to acid;

oxidation of alcohol to ketone;

halogenation or dehalogenation;

carbamoylation;

carboxylation;

introduction of an azido group;

reduction of an azido to amine;

reactions of coupling of aromatic or heteroaromatic halides or triflates or of heterocyclic nitrogens with aryl- or heteroarylboronic acids;

reactions of coupling of aromatic or heteroaromatic halides or triflates with stannyl-containing reagents;

hydrogenation of double bonds;

dihydroxylation of double bonds;

cyanidation.

12. ) The method as claimed in claim 11, wherein the carbonylating agent is selected from the group consisting of phosgene, diphosgene, triphosgene, aryl, aralkyl, alkyl and alkenyl chloroformates, alkyl dicarbonates, carbonyldiimidazole and mixtures thereof.

13. ) The method as claimed in claim 11, wherein the carbonylation reaction occurs in the presence of a base.

14. ) The method as claimed in claim 11, wherein, in step b), the base is selected from the group consisting of amines, hydrides, alcoholates, amides and carbonates of alkali or alkaline earth metals.

15. ) The method as claimed in claim 14, wherein the base is an amine.

16. ) The method as claimed in claim 11, wherein the compound of formula (II) in which ZH is selected from HO—

(CH₂)_n″

—

, HNR′

₈—

(CH₂)_n″

—

in which n″

is 0, and HNR′

₈—

O—

, R′

₈ being as defined in claim 11, is obtained by a method wherein a compound of formula (IV);

17. ) The method as claimed in claim 11, wherein the compound of formula (II) in which ZH is NHR′

₈—

(CH₂)_n″

—

in which n″

is 0 is obtained by a method in which a compound of formula (IV) as defined above is treated with a compound of formula H₂NR′

₈, in order to obtain a compound of formula (VII);

18. A method of treating a bacterial infection comprising administering to a mammal in need thereof an antibacterially effective amount of a compound as defined in claim 1, or a salt thereof with a pharmaceutically acceptable acid or base.

19. A method of treating a bacterial infection comprising administering to a mammal in need thereof an antibacterially effective amount of a compound as defined in claim 10, or a salt thereof with a pharmaceutically acceptable acid or base.

20. A pharmaceutical composition containing, as an active ingredient, at least one compound as claimed in claim 1.

21. A pharmaceutical composition containing, as an active ingredient, at least one compound as claimed in claim 10.

22. A pharmaceutical composition containing, as an active ingredient, at least one β

-lactamase inhibiting medicament as defined in claim 1 and at least one β

-lactam medicament.

23. A pharmaceutical composition containing, as an active ingredient, at least one β

-lactamase inhibiting medicament as defined in claim 10 and at least one β

-lactam medicament.

24. A compound of general formula (III) or one of its salts with an acid:

25. A compound of claim 24 wherein said salt is a hydrochloride or trifluoroacetate.

26. A compound of general formula (III) or one of its salts with an acid:

27. A compound of claim 26 wherein said salt is a hydrochloride or trifluoroacetate.

28. A compound of formula (II) or one of its salts with an acid:

29. A compound of claim 28 wherein said salt is a hydrochloride or trifluoroacetate.

30. A compound of formula (II) or one of its salts with an acid:

31. A compound of claim 30 wherein said salt is a hydrochloride or trifluoroacetate.

32. A compound of formulae (IV), (V) or (VI) or one of its salts with an acid:

33. A compound of claim 32 wherein said salt is a hydrochloride or trifluoroacetate.

34. A compound selected from the compounds of formulae (IV), (V) and (VI) or one of its salts with an acid, in which R′

₁ is as defined in claim 11 and all the other values are as defined in claim 16.

35. A compound of claim 34 wherein said salt is a hydrochloride or trifluoroacetate.

36. A compound selected from the compounds of formulae (VII), (VIII) and (VIII′

) or one of its salts with an acid;

37. A compound of claim 36 wherein said salt is a hydrochloride or trifluoroacetate.

38. The compound of formulae (VII) and (VIII) or one of its salts with an acid, in which R′

₁ is as defined in claim 11 and all the other values are as defined in claim 17.

39. A compound of claim 38 wherein said salt is a hydrochloride or trifluoroacetate.

40. A method of treating a bacterial infection comprising administering to a mammal in need thereof a bata lactamase inhibiting effective amount of a compound as defined in claim 1, or a salt thereof with a pharmaceutically acceptable acid or base together with an antibacterially effective amount of a beta lactam medicament.

41. A method of treating a bacterial infection comprising administering to a mammal in need thereof a bata lactamase inhibiting effective amount of a compound as defined in claim 10, or a salt thereof with a pharmaceutically acceptable acid or base together with an antibacterially effective amount of a beta lactam medicament.