# US 2010/0168245 A1 · Preparation of (r,r)-fenoterol and (r,r)-or (r,s)-fenoterol analogues and their use in treating congestive heart failure

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- Number: US 2010/0168245 A1
- Document ID: US20100168245A1
- Status: Published application
- Kind: A1
- Application number: 12/376,945
- Filed: 2007-08-10
- Published: 2010-07-01
- Earliest claimed: 2006-08-10
- Inventors: Irving W. Wainer; Weizhong Zhu; Khalid Chakir; Rui Ping Xiao; Darrell R. Abernethy; Farideh M. Beigi
- Web page: https://patentgrep.com/patent/US20100168245A1

## CPC

- C07C 215/60: the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This disclosure concerns the discovery of (R,R)- and (R,S)-fenoterol analogues which are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogues are provided. Also provided are pharmaceutical compositions including the disclosed (R,R)-fenoterol and fenoterol analogues, and methods of using such compounds and compositions for the treatment of cardiac disorders such as congestive heart failure and pulmonary disorders such as asthma or chronic obstructive pulmonary disease.

## Claims

### Claim 1

A compound having the formula:
wherein R1-R3 independently are hydrogen, acyl, alkoxy carbonyl or a combination thereof;
R4 is H or lower alkyl;
R5 is lower alkyl,
wherein Y1, Y2 and Y3 independently are hydrogen, lower —OR6 and —NR7R8;
wherein X and Y independently are selected from H, —OR6 and —NR7R8;
R6 is H or lower alkyl;
R7 and R8 independently are hydrogen, lower alkyl, alkoxy carbonyl, acyl or amino carbonyl; and
wherein the compound is optically active.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R4 is lower alkyl and R5 is
wherein X is H, —OR6 or —NR7R8;
R6 is lower alkyl; and
R7 and R8 independently are hydrogen or lower alkyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R4 is selected from methyl, ethyl, n-propyl, and isopropyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R4 is methyl.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R5 has the formula
wherein X is H, —OR6 or —NR7R8.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R6 is methyl.

### Claim 7 (depends on 6)

The compound of claim 6, wherein the compound is a (R,R)-compound.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R5 is one of

### Claim 9 (depends on 1)

The compound of claim 1 wherein R5 is

### Claim 10 (depends on 1)

The compound of claim 1, wherein R7 and R8 are hydrogen.

### Claim 11 (depends on 4)

The compound of claim 4, wherein R5 has the formula

### Claim 12 (depends on 11)

The compound of claim 11, wherein R1-R3 are hydrogen.

### Claim 13 (depends on 11)

The compound of claim 11, wherein the compound is a (R,R)-compound.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the compound is a (R,S)-compound.

### Claim 15 (depends on 1, 2)

A pharmaceutical composition comprising the compound of claim 1 or claim 2 and at least one pharmaceutically acceptable carrier.

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15, wherein R4 is methyl.

### Claim 17 (depends on 16)

The pharmaceutical composition of claim 16, wherein R1-R3 are hydrogen.

### Claim 18 (depends on 16)

The pharmaceutical composition of claim 16, wherein R5 has the formula
wherein X is H, —OR6 or —NR7R8.

### Claim 19 (depends on 18)

The pharmaceutical composition of claim 18, wherein R6 is methyl.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19, wherein the compound is a (R,R)-compound.

### Claim 21 (depends on 18)

The pharmaceutical composition of claim 18, wherein R7 and R8 are hydrogen.

### Claim 22 (depends on 17)

The pharmaceutical composition of claim 17, wherein R5 has the formula

### Claim 23 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is a (R,R)-compound.

### Claim 24 (depends on 1)

A pharmaceutical composition, comprising a compound of claim 1, wherein the compound is a (R,S) compound.

### Claim 25 (depends on 2)

A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
administering a therapeutically effective amount of the compound of claim 2 to the subject with the pulmonary or cardiovascular disorder.

### Claim 26 (depends on 25)

The method of claim 25, wherein the disorder is a cardiovascular disorder.

### Claim 27 (depends on 26)

The method of claim 26, wherein the cardiovascular disorder is congestive heart failure.

### Claim 28 (depends on 25)

The method of claim 25, wherein the disorder is a pulmonary disorder.

### Claim 29 (depends on 28)

The method of claim 28, wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease.

### Claim 30 (depends on 11)

A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
administering a therapeutically effective amount of the compound of claim 11 to the subject with the pulmonary or cardiovascular disorder.

### Claim 31 (depends on 30)

The method of claim 30, wherein the disorder is a cardiovascular disorder.

### Claim 32 (depends on 30)

The method of claim 30, wherein the cardiovascular disorder is congestive heart failure.

### Claim 33 (depends on 30)

The method of claim 30, wherein the disorder is a pulmonary disorder.

### Claim 34 (depends on 33)

The method of claim 33, wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease.

### Claim 35 (depends on 12)

A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
administering a therapeutically effective amount of the compound of claim 12 to the subject with the pulmonary or cardiovascular disorder.

### Claim 36 (depends on 36)

The method of claim 36, wherein the disorder is a cardiovascular disorder.

### Claim 37 (depends on 36)

The method of claim 36, wherein the cardiovascular disorder is congestive heart failure.

### Claim 38 (depends on 35)

The method of claim 35, wherein the disorder is a pulmonary disorder.

### Claim 39 (depends on 38)

The method of claim 38, wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease.

### Claim 40 (depends on 15)

A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
administering a therapeutically effective amount of the pharmaceutical composition of claim 15 to the subject with the pulmonary or cardiovascular disorder.

### Claim 41 (depends on 40)

The method of claim 40, wherein the disorder is a cardiovascular disorder.

### Claim 42 (depends on 41)

The method of claim 41, wherein the cardiovascular disorder is congestive heart failure.

### Claim 43 (depends on 40)

The method of claim 40, wherein the disorder is a pulmonary disorder.

### Claim 44 (depends on 43)

The method of claim 43, wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease.

### Claim 45 (depends on 20)

A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
administering a therapeutically effective amount of the pharmaceutical composition of claim 20 to the subject with the pulmonary or cardiovascular disorder.

### Claim 46 (depends on 45)

The method of claim 45, wherein the disorder is a cardiovascular disorder.

### Claim 47 (depends on 44)

The method of claim 44, wherein the cardiovascular disorder is congestive heart failure.

### Claim 48 (depends on 45)

The method of claim 45, wherein the disorder is a pulmonary disorder.

### Claim 49 (depends on 48)

The method of claim 48, wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease.

### Claim 50 (depends on 21)

A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
administering a therapeutically effective amount of the pharmaceutical composition of claim 21 to the subject with the pulmonary or cardiovascular disorder.

### Claim 51 (depends on 50)

The method of claim 50, wherein the disorder is a cardiovascular disorder.

### Claim 52 (depends on 51)

The method of claim 51, wherein the cardiovascular disorder is congestive heart failure.

### Claim 53 (depends on 50)

The method of claim 50, wherein the disorder is a pulmonary disorder.

### Claim 54 (depends on 53)

The method of claim 53, wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease.

### Claim 55

A method for treating a cardiovascular disorder in a subject, comprising:
administering an effective amount of a substantially optically pure (R,R)-fenoterol to the subject with the cardiovascular disorder.

### Claim 56 (depends on 55)

The method of claim 55, wherein the cardiovascular disorder is congestive heart failure.