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

• US 7,439,253 B2
• Filed: 12/04/2003
• Issued: 10/21/2008
• Est. Priority Date: 12/06/2002
• Status: Expired due to Fees

• Current Assignee: Entasis Therapeutics Inc (Innoviva, Inc.)
• Original Assignee: Novexel
• Inventors: Rowlands, David Alan, Musicki, Branislav, Klich, Michel, Lampilas, Maxime
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US10/727,911
• Publication Number:
  US 20040157826A1
• Time in Patent Office: 1,783 Days
• Field of Search: 514/292, 514/293, 546/82, 546/83, 546/84
• US Class Current: 514/292
• 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 formula:

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

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

4. The compound as claimed in claim 1, wherein R₃ and R₄ together form a substituted phenyl or a substituted heterocycle, wherein the substituted heterocycle is a substituted thienyl or a pyrazolyl substituted with one or more of the substituents therefore as defined in claim 1.

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

6. The compound as claimed in claim 1, wherein R₈ is selected from OY and OY₁, where 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 or Y₁ is selected from the group consisting of SO₂R, SO₂NHCOR, SO₂NHCOOR, SO₂NHCONHR and SO₃H, R being as defined in claim 1.

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

is selected from consisting of —

O—

CH₂—

CHOH—

CH₂OH, —

CH₂—

CH₂—

NH₂, —

CH₂—

COOC₂H₅, —

CH₂—

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.

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

the triethylammonium salt of 5,6dihydro-6-N²-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4e][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 1,4,5,8Tetrahydro-1[(4-methoxyphenyl)methyl]-5-(sulfoxy)-6H-4,7methanopyrazolo[3,4-e]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-(methoxycarbonal)-6oxo-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-thienol[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.

9. 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);

10. The method as claimed in claim 9, 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.

11. The method as claimed in claim 9, wherein the carbonylation reaction occurs in the presence of a base.

12. The method as claimed in claim 9, 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.

13. The method as claimed in claim 12, wherein the base is an amine.

14. The method as claimed in claim 9, wherein the compound of formula (II) in which ZH is HNR′

₈—

(CH₂)_n″

—

in which n″

is 0, R′

₈ being as defined in claim 9, is obtained by a method wherein a compound of formula (IV);

15. The method as claimed in claim 9, 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);

16. 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.

17. 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 8, or a salt thereof with a pharmaceutically acceptable acid or base.

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

19. A pharmaceutical composition containing, as an active ingredient, at least one compound as claimed in claim 8.

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

-lactam medicament selected from the group consisting of amoxicillin, ampicillin, azlocillin, mezlocillin, aralcillin, hetacillin, bacamricillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, mecillinam, pivmecillinam, methicillin, ciclacillin, talamricillin, asroxicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, pivamricillin, cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cerhacetril, cefotiam, cefotaxime, cefsulodin, ceforerazone, cefmenoxime, cefmetazole, cephaloglvcin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefburerazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, imipenem, meropenem, biarenem, panirenem, aztreonam, carumonam, and their salts.

21. A pharmaceutical composition containing, as an active ingredient, at least one compound as defined in claim 8 and at least one β

-lactam medicament selected from the group consisting of amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, mecillinam, pivmecillinam, methicillin, ciclacillin, talampicillin, aspoxicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, pivampicillin, cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetril, cefotiam, cefotaxime, cefsulodin, cefoperazone, cefmenoxime, cefmetazole, cerhaloglvcin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefriramide, cefbuperazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam, cefpmizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, imipenem, meropenem, biapenem, panipenem, aztreonam, carumonam. and their salts.

22. A method of treating a bacterial infection comprising administering to a mammal in need thereof an effective amount of a compound as defined in claim 1, or a salt thereof with a pharmaceutically acceptable acid or base and an antibacterially effective amount of a beta-lactam medicament agent selected from the group consisting of amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, mecillinam, pivmecillinam, methicillin, ciclacillin, talampicillin, aspoxicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, pivampicillin, cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetril, cefotiam, cefotaxime, cefsulodin, cefoperazone, cefmenoxime, cefmetazole, cephaloglvcin, cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefrodoxime axetil, cefpodoxime proxetil. cefteram pivoxil, cefetamet rivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, imipenem, meropenem, biapenem, panipenem, aztreonam, carumonam, and their salts.

23. A method of treating a bacterial infection comprising administering to a mammal in need thereof an effective amount of a compound as defined in claim 8, or a salt thereof with a pharmaceutically acceptable acid or base and an antibacterially effective amount of a beta-lactam medicament agent selected from the group consisting of amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin, sulbenicillin, ticarcillin, piperacillin, mecillinam pivmecillinam, methicillin, ciclacillin, talampicillin, aspoxicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, pivampicillin, cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetril, cefotiam, cefotaxime, cefsulodin, ceforerazone, cefmenoxime, cefmetazole, cephaloglvcin, cefonicid, cefodizime, cefrirome, ceftazidime, ceftriaxone, cefpiramide, cefburerazone, cefozopran, cefepim, cefoselis, cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefrodoxime axetil, cefrodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, imirenem, meropenem, biarenem, panipenem, aztreonam, carumonam, and their salts.