SPIRO ANTIBIOTIC DERIVATIVES

• US 20090270375A1
• Filed: 08/29/2007
• Published: 10/29/2009
• Est. Priority Date: 08/30/2006
• Status: Active Grant

• Current Assignee: Actelion Pharmaceuticals Limited (Johnson & Johnson)
• Original Assignee: Actelion Pharmaceuticals Limited (Johnson & Johnson)
• Inventors: Hubschwerlen, Christian, Zumbrunn-Acklin, Cornelia, Surivet, Jean-Philippe
• Granted Patent: US 7,999,115 B2
• Time in Patent Office: Days
• US Class Current: 514/224.200
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 498/10 Spiro-condensed systems

Abstract

The invention relates to compounds of formula (I) wherein R¹ represents H, alkyl, alkoxy, cyano or halogen; one of U and X represents CH or N and the other represents CH, or, in the case of U, may also represent CR^a and, in the case of X, may also represent CR^b; R^a represents halogen; R^b represents halogen or alkoxy; B represents N, D represents CH₂ and A represents CH(OH)CH₂ or CH₂CH₂, or B represents CH, D represents CH₂ or O and A represents OCH₂, CH₂CH(OH), CH(OH)CH₂, CH(OH)CH(OH), CH═CH, CH₂CH₂ Or NHCO, or also B represents C(OH), D represents CH₂ and A represents OCH₂, CH₂CH(OH), CH(OH)CH₂, CH(OH)CH(OH), CH═CH, CH₂CH₂ Or NHCO; R² represents H, alkyl, alkenyl, hydroxyalkyl or alkoxycarbonylalkyl; and E represents naphthyl or a binuclear heterocyclic group; and to salts of such compounds. These compounds are useful as antimicrobial agents.

Claims

1. A compound of formula (I)

wherein

R¹ represents H, alkyl, alkoxy, cyano or halogen;

one of U and X represents CH or N and the other represents CH, or, in the case of U, may also represent CR^a and, in the case of X, may also represent CR^b;

R^a represents halogen;

R^b represents halogen or alkoxy;

B represents N, D represents CH₂ and A represents CH(OH)CH₂ or CH₂CH₂, or

B represents CH, D represents CH₂ or O and A represents OCH₂, CH₂CH(OH), CH(OH)CH₂, CH(OH)CH(OH), CH═

CH, CH₂CH₂ or NHCO, or also

B represents C(OH), D represents CH₂ and A represents OCH₂, CH₂CH(OH), CH(OH)CH₂, CH(OH)CH(OH), CH═

CH, CH₂CH₂ or NHCO;

R² represents H, alkyl, alkenyl, hydroxyalkyl or alkoxycarbonylalkyl; and

E represents naphthyl or a binuclear heterocyclic group;

or a salt of the compound.

2. The compound of formula (I) according to claim 1, wherein R¹ represents (C₁-C₃)alkyl, (C₁-C₃)alkoxy or cyano;

or a salt of the compound.

3. The compound of formula (I) according to claim 1, wherein R¹ represents methoxy;

or a salt of the compound.

4. The compound of formula (I) according to claim 1, wherein both U and X represent CH or U represents N and X represents CH;

or a salt of the compound.

5. The compound of formula (I) according to claim 1, wherein E represents a binuclear heterocyclic group of the formula

wherein

Y is CH or N, and

the ring P is one of the following

in which Q is O or S;

or a salt of the compound.

6. The compound of formula (I) according to claim 1, wherein R² represents H or alkenyl;

or a salt of the compound.

7. The compound of formula I according to claim 1, wherein the compound is:

(5R,6R,8S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-6-hydroxymethyl-1,7-dioxa-3-aza-spiro[4.5]decan-2-one;

(5R,6R,8S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-6-hydroxymethyl-1,7-dioxa-3-aza-spiro[4.5]decan-2-one;

cis-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-(6-methoxy-quinolin-4-yloxymethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;

cis-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-(6-methoxy-[1,5]naphthyridin-4-yloxymethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;

3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

6-{8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]thiazin-3-one;

6-{8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]thiazin-3-one;

(5R,6R)-6-allyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5R,6R)-6-allyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5R,6S)-6-allyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5R6S)-6-allyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5S,6R)-6-allyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5S,6R)-6-allyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5S,6S)-6-allyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5S,6S)-6-allyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5R,6R)-{3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-6-yl}-acetic acid methyl ester;

(5R,6R)-{3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-6-yl}-acetic acid methyl ester;

(5R,6S)-{3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-6-yl}-acetic acid methyl ester;

(5R,6S)-{3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-6-yl}-acetic acid methyl ester;

(5S,6R)-{3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-6-yl}-acetic acid methyl ester;

(5S,6R)-{3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-6-yl}-acetic acid methyl ester;

(5S,6S)-{3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-6-yl}-acetic acid methyl ester;

(5S,6S)-{3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-2-oxo-1-oxa-3,8-diaza-spiro[4.5]dec-6-yl}-acetic acid methyl ester;

(5R,6R)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-(2-hydroxy-ethyl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5R,6R)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-(2-hydroxy-ethyl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5R,6S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-(2-hydroxy-ethyl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5R,6S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-(2-hydroxy-ethyl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5S,6R)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-(2-hydroxy-ethyl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5S,6R)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-(2-hydroxy-ethyl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5S,6S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-(2-hydroxy-ethyl)-8-[(2R)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

(5S,6S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-6-(2-hydroxy-ethyl)-8-[(2S)-2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-1-oxa-3,8-diaza-spiro[4.5]decan-2-one;

cis-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-1-oxa-3-aza-spiro[4.5]decane-8-carboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;

trans-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-1-oxa-3-aza-spiro[4.5]decane-8-carboxylic acid (6-methoxy-[1,5]naphthyridin-4-yl)-amide;

cis-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-hydroxy-8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;

trans-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-hydroxy-8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;

cis-6-{8-hydroxy-8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-2-oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]thiazin-3-one;

trans-6-{8-hydroxy-8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-2-oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]thiazin-3-one;

cis-6-{8-hydroxy-8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-2-oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]oxazin-3-one;

trans-6-{8-hydroxy-8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-2-oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]oxazin-3-one;

cis-6-{8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-2-oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]oxazin-3-one;

trans-6-{8-[2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethyl]-2-oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]oxazin-3-one;

cis-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(E)-2-(6-methoxy-quinolin-4-yl)-vinyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;

trans-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-[(E)-2-(6-methoxy-quinolin-4-yl)-vinyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;

cis-6-{8-[(E)-2-(6-methoxy-quinolin-4-yl)-vinyl]-2-oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]thiazin-3-one;

trans-6-{8-[(E)-2-(6-methoxy-quinolin-4-yl)-vinyl]-2-oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl}-4H-benzo[1,4]thiazin-3-one;

cis-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-8-(6-methoxy-quinazolin-4-yloxymethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;

or a salt of the compound.

8. A medicament comprising the compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt of the compound, and at least one therapeutically inert excipient.

10. A method for treating bacterial infection comprising administering the compound of formula (I) as defined claim 1, or a pharmaceutically acceptable salt of the compound to a patient in need thereof thereof.

11. The method of claim 10, wherein the bacterial infection is an infection from S. aureus, S. peumoniae, or M. catarrhalis.