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US 2013/0296555 A1Published application
Beta-lactamase inhibitors
AssigneeCubist Pharmaceuticals, Inc.
InventorsYu Gui Gu, Yong He, Ning Yin, Dylan C. Alexander, Jason B. Cross, Robert Busch, Roland E. Dolle, Chester A. Metcalf, III
Life of this patent
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Abstract
Aryl substituted diazabicyclooctanes (DBO) compounds that inhibit β-lactamases of class A, class C or class D and potentiate β-lactam antibiotics are disclosed. In particular, this disclosure provides DBO compounds that, when used in the disclosed Synergy MIC Assay with a β-lactam antibiotic at a fixed concentration have an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains.
Claims6
A compound of Formula I or a pharmaceutically-acceptable salt thereof, wherein the compound of Formula I, when used in the Synergy MIC Assay of Example 23 with an antibiotic selected from ceftolozane or ceftazidime at a fixed concentration of 4 μg/mL, has an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains from Table X.
- wherein
- Z is a five-membered heteroaryl ring containing from one to four hetero atoms selected from N, O or S;
- R is selected
- from
- and
- R1 is selected from:
- a. hydrogen,
- b. cyano,
- c. (C1-C3)-unsubstituted alkyl,
- d. (C1-C3)-alkyl substituted with at least one substituent selected from hydroxyl,
- wherein each of R2, R3 and R4 is independently selected from hydrogen, (C1-C3)-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl,
- e.
- wherein R5 is selected from H or aminoalkyl,
- f.
- g. amino,
- h. (C1-C3)alkylamino, or
- i. a 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from O and N, or NX, wherein X is H,
- provided that the compound of Formula (I) is not a compound wherein:
- (1) Z is imidazol-2-yl, R1* is hydrogen and R* is OSO3H;
- (2) Z is 1,2,4-triazol-5-yl, R1* is methyl and R* is OSO3H;
- (3) Z is 5-oxo-1,3,4-oxadiazol-2-yl, R1* is hydrogen or piperidin-4-yl, and R* is OSO3H;
- (4) Z is 1,2,3-triazol-4-yl, R1* is methyl and R* is OSO3H;
- (5) Z is pyrazol-3-yl, R1* is hydrogen or methyl, and R* is OSO3H;
- or
- (6) Z is oxazol-2-yl, R1* is hydrogen and R* is OSO3H;
- wherein
- Table X is:
- TABLE X
- GenBank
- Accession
- Species
- Number
- β-
- Origin
- of β-
- Lactamase
- Name & SEQ. ID of
- β-
- of β-
- Lactamase
- Expressing
- plasmids producing
- Lactamase
- Lactamase
- Gene
- Strain
- β-Lactamase
- Class
- Gene
- Sequence
- KPC-2
- pBR-CBST-KPC-2
- A
- K.
- EU784136
- SEQ ID 6
- pneumoniae
- CTX-M-15
- pBR-CBST-CTX-M-15
- A
- K.
- JF775516
- SEQ ID 7
- pneumoniae
- SHV-12
- pBR-CBST-SHV-12
- A
- K.
- AY008838
- SEQ ID 8
- pneumoniae
- P99 AmpC
- pBR-CBST-P99 AMPC
- C
- E.
- XO7274
- SEQ ID 9
- cloacea
- OXA-15
- pBR-CBST-OXA-15
- D
- P.
- PAU63835
- SEQ ID 10
- aeruginosa
82 more elements
A compound of Formula (I) or a pharmaceutically acceptable salt thereof that has a inhibition kinetics of at least 250 mM1s1 according to the assay described in Example 24:
- wherein
- Z is a five-membered heteroaryl ring containing from one to four hetero atoms selected from N, O or S;
- R is selected
- from
- and
- R1 is selected from:
- a. hydrogen,
- b. cyano,
- c. (C1-C3)-unsubstituted alkyl,
- d. (C1-C3)-alkyl substituted with at least one substituent selected from hydroxyl,
- wherein each of R2, R3 and R4 is independently selected from hydrogen, (C1-C3)-alkyl, aminoalkyl, aminocycloalkyl, or hydroxyalkyl,
- e.
- wherein R5 is selected from H or aminoalkyl,
- f.
- g. amino,
- h. (C1-C3)alkylamino, or
- i. a 4-6 membered heterocyclyl containing 1-2 heteroatoms selected from O and N, or NX, wherein X is H,
- provided that the compound of Formula (I) is not a compound wherein:
- (1) Z is imidazol-2-yl, R1* is hydrogen and R* is OSO3H;
- (2) Z is 1,2,4-triazol-5-yl, R1* is methyl and R* is OSO3H;
- (3) Z is 5-oxo-1,3,4-oxadiazol-2-yl, R1* is hydrogen or piperidin-4-yl, and R* is OSO3H;
- (4) Z is 1,2,3-triazol-4-yl, R1* is methyl and R* is OSO3H;
- (5) Z is pyrazol-3-yl, R1* is hydrogen or methyl, and R* is OSO3H;
- or
- (6) Z is oxazol-2-yl, R1* is hydrogen and R* is OSO3H;
- wherein
- Table X is:
- TABLE X
- GenBank
- Accession
- Species
- Number
- β-
- Origin
- of β-
- Lactamase
- Name & SEQ. ID of
- β-
- of β-
- Lactamase
- Expressing
- plasmids producing
- Lactamase
- Lactamase
- Gene
- Strain
- β-Lactamase
- Class
- Gene
- Sequence
- KPC-2
- pBR-CBST-KPC-2
- A
- K.
- EU784136
- SEQ ID 6
- pneumoniae
- CTX-M-15
- pBR-CBST-CTX-M-15
- A
- K.
- JF775516
- SEQ ID 7
- pneumoniae
- SHV-12
- pBR-CBST-SHV-12
- A
- K.
- AY008838
- SEQ ID 8
- pneumoniae
- P99 AmpC
- pBR-CBST-P99 AMPC
- C
- E.
- XO7274
- SEQ ID 9
- cloacea
- OXA-15
- pBR-CBST-OXA-15
- D
- P.
- PAU63835
- SEQ ID 10
- aeruginosa
82 more elements
A compound of Formula (AI) or a pharmaceutically acceptable salt thereof:
- wherein
- Z is a five-membered heteroaryl ring containing from one to four hetero atoms selected from N, O or S;
- R* is selected from
- and
- R1* is selected from:
- a. hydrogen;
- b.
- wherein R2* is selected from
- R2* is selected from
- R3* is selected from hydrogen, (C1-C3)-alkyl, aminoalkyl, aminocycloalkyl, hydroxyalkyl,
- each of R4*, R5*, R6*and R7* is independently selected from hydrogen or (C1-C6)-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R4*, R5*, R6*and R7* is hydrogen,
- n is selected from 1, 2, 3 and 4, and
- m is selected from 1, 2 and 3;
- c.
- wherein R8* is selected from NH2,
- wherein each of R4*, R5*, R6*and R7* is as described previously and each of R9, R10 and R11 is independently selected from hydrogen or (C1-C6)-alkyl, provided that at least one of R9, R10, and R11 is hydrogen;
- d. amino;
- e.
- wherein Z is selected from CR12R13 or NR14,
- each of R12 and R13 is independently selected from H, NH2 and
- wherein each of R4*, R5*, R6*and R7* is as described previously,
- alternatively, R12 and R13 together with the carbon to which they are attached, form a cycloalkyl or heterocyclyl ring containing 4-6 ring members,
- R14 is selected from H and
- wherein each of R15, R16 and R17 is independently selected from hydrogen, (C1-C6)-alkyl, aminoalkyl, aminocycloalkyl, and hydroxyalkyl, provided that at least one of R15, R16 and R17 is hydrogen,
- R18 is selected from NH2 and
- wherein each of R4*, R5*, R6*and leis as described previously,
- each of p* and q* is independently selected from 0, 1, 2 and 3,
- T is selected from NH and O
- t is selected from 0, 1, 2, 3, and 4, and
- each of r and y is independently selected from 0 and 1;
- f.
- wherein R19 is selected from NH2 and
- wherein each of R4*, R5*, R6*and R7* is as described previously,
- R20 is selected from amino and hydroxyl, and
- w is selected from 0 and 1;
- g.
- h.
- wherein each of R4*, R5*, R6*and R7* is as described previously;
- i.
- wherein R21 is selected from NH2, —NH(C1-C3)-alkyl and
- wherein each of R4*, R5*, R6*and R7* is as described previously,
- s is selected from 0 and 1, and
- v is selected from 0, 1, 2, and 3;
- j.
- k.
- wherein M is selected from NR22, CR23R24 and O,
- wherein R22 is H or
- wherein each of R15, R16 and R17 is as described previously,
- each of R23 and R24 is independently selected from H, NH2 and
- wherein each of R4*, R5*, R6*and R7* is as described previously, and
- u is selected from 0, 1 and 2;
- l.
- m.
- n.
- o. (C1-C3)-unsubstituted alkyl;
- and
- p.
- provided that the compound of Formula (A-I) is not a compound wherein:
- (1) Z is imidazol-2-yl, R1* is hydrogen and R* is OSO3H;
- (2) Z is 1,2,4-triazol-5-yl, R1* is methyl and R* is OSO3H;
- (3) Z is 5-oxo-1,3,4-oxadiazol-2-yl, R1* is hydrogen or piperidin-4-yl, and R* is OSO3H;
- (4) Z is 1,2,3-triazol-4-yl, R1* is methyl and R* is OSO3H;
- (5) Z is pyrazol-3-yl, R1* is hydrogen or methyl, and R* is OSO3H;
- or
- (6) Z is oxazol-2-yl, R1* is hydrogen and R* is OSO3H.
62 more elements
Dependencies are inferred from the claim text.