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NZ751016B2 - Beta-lactamase inhibitor compounds - Google Patents

Beta-lactamase inhibitor compounds

Info

Publication number
NZ751016B2
NZ751016B2 NZ751016A NZ75101617A NZ751016B2 NZ 751016 B2 NZ751016 B2 NZ 751016B2 NZ 751016 A NZ751016 A NZ 751016A NZ 75101617 A NZ75101617 A NZ 75101617A NZ 751016 B2 NZ751016 B2 NZ 751016B2
Authority
NZ
New Zealand
Prior art keywords
alkyl
alkoxy
pharmaceutically acceptable
compound
heteroaryl
Prior art date
Application number
NZ751016A
Other versions
NZ751016A (en
Inventor
Gregory S Basarab
Prevoir Janelle Comita
Reville Thomas Francois Durand
Lise Gauthier
Bill Moss
Donnell John O
Jan Romero
Ruben Tommasi
Jeroen Cunera Verheijen
Frank Wu
Original Assignee
Entasis Therapeutics Limited
Filing date
Publication date
Application filed by Entasis Therapeutics Limited filed Critical Entasis Therapeutics Limited
Priority claimed from PCT/US2017/051692 external-priority patent/WO2018053215A1/en
Publication of NZ751016A publication Critical patent/NZ751016A/en
Publication of NZ751016B2 publication Critical patent/NZ751016B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C07F7/0892—Compounds with a Si-O-N linkage
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts are useful in combination with beta- lactam antibiotics, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3, R4, R5and R6are described herein.

Claims (20)

WE CLAIM:
1. A compound according to a (I): or a pharmaceutically acceptable salt thereof; wherein: R1 is –C(O)NR7R8, -CN, phenyl, a 5-6 membered heteroaryl, -C(O)NR’NR’C(O)R9, R’OR10, or a C1-C6 alkyl group, wherein the alkyl group is substituted with one to three groups selected from halo, C1-C3 alkoxy, -OH, -CN, – NR7R8, -NR7COR9, a 5-6 membered heteroaryl and a 5-7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently substituted with 1- 3 groups selected from halo, -OH, C1-C3 alkoxy, -CN, –NR7R8, and -CONR7R8; R2 and R3 are independently selected from hydrogen, halo, C1-C3 alkyl, and C3-C6 cycloalkyl; R4 and R5 are independently selected from hydrogen, halo, -CN, -CO2R9, C1-C3 alkyl, and C1-C3 haloalkyl; R6 is hydrogen, C1-C12 alkyl, C1-C4 alkyl-C1-C3 alkoxy-(NR’C1-C6 alkyl)-C1-C3 , C1-C4 alkyl-C1-C3 alkoxy-C1-C3 alkoxy, C2-C12 alkenyl, C3-C10 cycloalkyl, a 5-6 membered aryl and a 5-7 membered heterocyclyl, wherein the alkyl, alkenyl, lkyl, heteroaryl and heterocyclyl are optionally and independently substituted with 1-6 groups selected from a carboxyl, halo, C1-C6 alkoxy, C1-C6 alkyl and phenyl; each R7 and R8 are independently en, C1-C3 alkyl, C1-C3 , phenyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, or 5-6 ed heteroaryl, wherein the alkyl, alkoxy, phenyl, lkyl, heterocyclyl or heteroaryl represented by R7 or R8 is optionally and independently substituted with 1-6 groups selected from a 5-6 membered heterocyclyl optionally substituted with one or two –F atoms, yl or –CO(OC1-6 alkyl), 5-6 membered heteroaryl, -CN, -OH, C1-C3 alkyl optionally substituted with –NH2 or –OH, C1-C3 haloalkyl, C1-C3 koxy, C1-C3 alkoxy -NHCO(C1-C3alkyl), -NHCO(C1- C3alkoxy), -S(O)2NR’R’’, -NHS(O)2NR’R’’, -NHS(O)2(C1-C3alkyl), -NR’R’’, and -C(O)NR’R’’; each R9 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C1-C6 alkoxy; each R10 is a C1-C3 alkyl optionally substituted with 1-6 groups selected from a 5-6 membered heterocyclyl optionally substituted with one or two –F atoms, carboxyl or –CO(OC1-6 alkyl), a C3-C6 cycloalkyl, a 5-6 membered heteroaryl, -CN, -OH, -NHCO(C1-C3 alkyl), -NHCO(C1-C3 alkoxy), -S(O)2NR’R’’, -NHS(O)2NR’R’’, -NHS(O)2(C1-C3 alkyl), - NR’R’’, or -C(O)NR’R’’; and each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’’ are taken together with the nitrogen to which they are attached to form a 5-6 membered heterocyclyl; ed that at least one of R2 and R3 is other than hydrogen.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is C1- C12 alkyl, C1-C4 C1-C3 alkoxy-(NR’C1-C6 alkyl)-C1-C3 alkoxy, C1-C4 alkyl-C1-C3 - C1-C3 alkoxy, C2-C12 alkenyl, C3-C10 lkyl, a 5-6 ed heteroaryl and a 5-7 membered heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl and heterocyclyl are optionally and independently substituted with 1-6 groups selected from a carboxyl, halo, C1-C6 alkoxy, C1- C6 alkyl and phenyl.
3. The compound of claim 1 or 2, according to formula (III): or a pharmaceutically acceptable salt f.
4. The nd according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R3 is C1-C3 alkyl.
5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R3 is methyl.
6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R1 is –C(O)NR7R8.
7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are both hydrogen.
8. The compound of claim 3, ing to formula (V): or a pharmaceutically acceptable salt thereof.
9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R6 is C1-C12 alkyl.
10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are independently H, methyl or fluoro.
11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein one of R4 and R5 is hydrogen, and the other is fluoro.
12. The compound according to claim 10 or a ceutically able salt thereof, n R4 is fluoro and R5 is en.
13. The compound of Claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof.
14. The compound of Claim 1, wherein the nd is of the formula: or a pharmaceutically acceptable salt thereof.
15. 15 A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-14, and at least one pharmaceutically acceptable carrier, diluent or excipient.
16. Use of the compound according to any one of Claims 1-14, or a pharmaceutically acceptable salt thereof, in combination with a beta-lactam otic in the manufacture of a medicament in treating a bacterial infection.
17. The use of claim 16, wherein said beta-lactam antibiotic is cefpodoxime proxetil.
18. The use of claim 16 or 17, wherein the ial infection is selected from the group consisting of complicated urinary tract infection, uncomplicated urinary tract infection, kidney infection, lower respiratory tract infection, hospital-acquired bacterial pneumonia (HAP), pneumonia, acute bacterial prostatitis, acute bacterial skin and soft tissue infection, sepsis, intraabdominal infection, and diabetic foot ion.
19. A process for forming a compound of the a VI: (VI); or a salt thereof, wherein R1 is –C(O)NR7R8, –C(O)OR7, –CH2OR7, -CN, phenyl, a 5-6 ed heteroaryl, - C(O)NR’NR’C(O)R9, R’OR10, or a C1-C6 alkyl group, wherein the alkyl group is substituted with one to three groups selected from halo, C1-C3 alkoxy, -OH, -CN, – NR7R8, -NR7COR9, a 5-6 membered heteroaryl and a 5-7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently substituted with 1- 3 groups selected from halo, -OH, C1-C3 alkoxy, -CN, -NR7R8, and -CONR7R8; R2 and R3 are each independently selected from hydrogen, halo, C1-C3 alkyl, and C3-C6 cycloalkyl, provided that at least one of R2 and R3 is other than en; each R7 and R8 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the alkyl, , phenyl, cycloalkyl, heterocyclyl or heteroaryl ented by R7 or R8 is optionally and independently substituted with 1-6 groups ed from a 5-6 membered heterocyclyl optionally substituted with one or two –F atoms, carboxyl or –CO(OC1-6 , 5-6 membered heteroaryl, -CN, -OH, C1-C3 alkyl optionally substituted with –NH2 or –OH, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy C1-C3alkyl), -NHCO(C1- C3alkoxy), -S(O)2NR’R’’, -NHS(O)2NR’R’’, -NHS(O)2(C1-C3alkyl), -NR’R’’, and -C(O)NR’R’’; each R9 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C1-C6 alkoxy; each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’’ are taken together with the nitrogen to which they are attached to form a 5-6 membered heterocyclyl; PG and PG’ are each independently an amine protecting group; the process comprising reacting a compound of the formula XI: (XI); or a salt thereof, with PG’NHOH in the presence of an oxidant to form the nd of the Formula VI.
20. A process for forming a nd of the formula VI: (VI); or a salt thereof, wherein R1 is –C(O)NR7R8, –C(O)OR7, –CH2OR7, -CN, , a 5-6 membered heteroaryl, - C(O)NR’NR’C(O)R9, R’OR10, or a C1-C6 alkyl group, n the alkyl group is substituted with one to three groups selected from halo, C1-C3 alkoxy, -OH, -CN, – NR7R8, -NR7COR9, a 5-6 membered heteroaryl and a 5-7 membered heterocyclyl, and wherein the phenyl and heteroaryl represented by R1 are optionally and independently substituted with 1- 3 groups selected from halo, -OH, C1-C3 alkoxy, -CN, -NR7R8, and -CONR7R8; R2 and R3 are each independently selected from hydrogen, halo, C1-C3 alkyl, and C3-C6 cycloalkyl, provided that at least one of R2 and R3 is other than hydrogen; each R7 and R8 are independently hydrogen, C1-C3 alkyl, C1-C3 alkoxy, phenyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered aryl, wherein the alkyl, alkoxy, phenyl, cycloalkyl, heterocyclyl or heteroaryl represented by R7 or R8 is optionally and independently tuted with 1-6 groups selected from a 5-6 membered heterocyclyl ally substituted with one or two –F atoms, carboxyl or –CO(OC1-6 alkyl), 5-6 membered heteroaryl, -CN, -OH, C1-C3 alkyl optionally substituted with –NH2 or –OH, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 alkoxy -NHCO(C1-C3alkyl), C1- C3alkoxy), -S(O)2NR’R’’, -NHS(O)2NR’R’’, -NHS(O)2(C1-C3alkyl), -NR’R’’, and -C(O)NR’R’’; each R9 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy or C1-C6 alkoxy; each R’ and R’’ is independently hydrogen, methyl, ethyl or propyl; or R’ and R’’ are taken together with the nitrogen to which they are attached to form a 5-6 membered heterocyclyl; PG and PG’ are each ndently an amine protecting group; the process comprising reacting a compound of the formula XI: (XI); or a salt f, with PG’N=O to form the compound of the Formula VI.
NZ751016A 2017-09-15 Beta-lactamase inhibitor compounds NZ751016B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201662395464P 2016-09-16 2016-09-16
US201762456423P 2017-02-08 2017-02-08
PCT/US2017/051692 WO2018053215A1 (en) 2016-09-16 2017-09-15 Beta-lactamase inhibitor compounds

Publications (2)

Publication Number Publication Date
NZ751016A NZ751016A (en) 2025-02-28
NZ751016B2 true NZ751016B2 (en) 2025-06-04

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