# US 7,745,462 B2 · Quinoline-2-one derivatives for the treatment of airways diseases

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- Number: US 7,745,462 B2
- Document ID: US7745462B2
- Status: Granted
- Kind: B2
- Application number: 10/552,023
- Filed: 2004-04-02
- Published: 2007-03-22
- Granted: 2010-06-29
- Earliest claimed: 2003-04-04
- Assignees: Novartis AG
- Inventors: Robin Alec Fairhurst; David Andrew Sandham; David Beattie; Ian Bruce; Bernard Cuenoud; Reamonn Madden; Neil John Press; Roger John Taylor; Katharine Louise Turner; Simon James Watson
- Web page: https://patentgrep.com/patent/US7745462B2

## CPC

- C07D 215/227: only one oxygen atom which is attached in position 2
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula I in free or salt form, wherein —C—Y—, R1 and R2 are G have the meanings as indicated in the specification, are useful for treating conditions that are prevented or alleviated by activation of the β2-adrenoreceptor. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

## Claims

### Claim 1

A compound of formula I:
in free or salt form, where
R1 is hydroxy and R2 is hydrogen;
G is a group having the formula Ib:
C˜C denotes C═C or CH—CH;
R7 and R8 are both hydrogen;
R9 and R10 are independently selected from the group consisting of hydrogen and C1-C10 alkyl, or R9 and R10 together form a C3-C10 cycloalkyl or C3-C10 cycloalkenyl, and in either case wherein R9 and R10 are optionally substituted by C1-C10 alkyl; and
R11 is a C3-C15 carbocyclic group or C1-C10 alkyl substituted by a C3-C15 carbocyclic group.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein:
R1 is hydroxy and R2 is hydrogen;
C˜C denotes C═C or CH—CH;
R7 and R8 are both hydrogen;
R9 and R10 are independently selected from the group consisting of hydrogen or C1-C4 alkyl, or
R9 and R10 together form a C3-C6 cycloalkyl or C3-C6 cycloalkenyl, and in either case wherein R9 and R10 are optionally substituted by C1-C4 alkyl; and
R11 is a C3-C10 carbocyclic or C1-C10 alkyl substituted by a C3-C10 carbocyclic group.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein R11 is a C3-C6 cycloalkyl.

### Claim 4 (depends on 2)

The compound according to claim 2, wherein R11 is a C1-C10 alkyl substituted by an unsaturated C5-8 carbocyclic group.

### Claim 5 (depends on 1)

The compound according to claim 1 that is:
5-[R-2-(1S,2S-2-Cyclohexylcyclopentylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one;
5-[R-2-(1R,2R-2-cyclohexylcyclopentylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one;
5-[R-2-(1R,2R-bicyclopentyl-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one; or
5-[R-2-(1R,2R-2-Benzylcyclopentylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable carrier.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a therapeutically effective amount of another drug substance selected from the group consisting of an anti-inflammatory, a bronchodilator, an antihistamine, an immunosuppressive and an anti-tussive.

### Claim 9 (depends on 1)

A method of treating a patient with obstructive or inflammatory airways disease by administering a therapeutically effective amount of at least one compound according to claim 1.

### Claim 10 (depends on 1)

A process for the preparation of a compound of claim 1 in free or salt form comprising:
(A) reacting a compound of formula II:
or a protected form thereof wherein R1 and R2 are as defined in claim 1, with a compound of formula III:
H2N-G III
where G is a group of formula Ib:
or a protected form thereof wherein R7, R8, R9, R10 and R11 are as defined in claim 1; and
(B) recovering the resultant compound of formula I in free or salt form.

### Claim 11 (depends on 1)

A process for the preparation of a compound of claim 1 in free or salt form comprising:
(A) reducing a compound of formula IV:
or a protected form thereof wherein R1, R2 and G are as defined in claim 1, to convert the indicated keto group into —CH(OH); and
(B) recovering the resultant compound of formula I in free or salt form.

### Claim 12 (depends on 9)

The method of claim 9 wherein the obstructive or inflammatory airways disease is asthma, adult/acute respiratory distress syndrome, chronic obstructive pulmonary or airways disease, chronic bronchitis or dyspnea associated therewith, emphysema, exacerbation of airways hyperreactivity consequent to other drug therapy, bronchitis or pneumoconiosis.