Therapeutic biaryl derivatives

Details Therapeutic biaryl derivatives Therapeutic biaryl derivatives

2000-12-13

2001-06-26

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S344000, C514S356000, C514S524000, C514S539000, C514S564000, C546S322000, C546S321000, C546S286000, C546S326000, C548S252000, C558S422000, C549S462000, C560S042000, C562S451000

Reexamination Certificate

active

06251925

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a new class of chemical compounds and to their use in medicine. In particular, the invention relates to biaryl derivatives, methods for their preparation, pharmaceutical compositions containing them, and their use as agonists at atypical beta-adrenoceptors (also known as beta-3-adrenoceptors).
BACKGROUND OF THE INVENTION
Atypical beta-adrenoceptors belong to the family of adrenoceptors which mediate the physiological actions of the hormones adrenaline and noradrenaiine. Such receptors have been described for example by J R S Arch et. al.,
Nature,
309, 163-165 (1984); C Wilson et. al.,
Eur. J. Pharrnacol.,
100, 309-319 (1984); L J Emorine et. al.,
Science,
245, 1118-1121 (1989); and A. Bianchetti et. al. Br.
J. Pharmacol.,
100, 831-839 (1990).
Phenethanolamine derivatives having activity at atypical beta-adrenoceptors are disclosed in, for example, European Patent Applications EP-A-0455006 and EP-A-0543662.
Sub-types of the adrenoceptors, &agr;
1
-, &agr;
2
-, &bgr;
1
-, &bgr;
2
- and &bgr;
3
-(atypical) can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents which stimulate or block these receptors (but not &bgr;
3
) are widely used in clinical medicine. More recently, emphasis has been placed upon specific receptor selectivity in order to reduce side effects caused, in part, by interactions with other receptors.
Atypical beta-adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract. Atypical beta-adrenoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents. Compounds having atypical beta-adrenoceptor agonist activity have also been described as being useful in the treatment of hyperglycaemia, as animal growth promoters, as blood platelet aggregation inhibitors, as positive inotropic agents and as antiatheroscierotic agents, and as being useful in the treatment of glaucoma.
SUMMARY OF THE INVENTION
Briefly, in one aspect, the invention therefore provides compounds of Formula (I) and pharmaceutically derivatives thereof:
wherein
R
1
is a phenyl, naphthyl, pyridyl, thiazolyl, phenoxymethyl, or pyrimidyl group, optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C
1-6
alkoxy, C
1-6
alkyl, nitro, cyano, hydroxymethyl, trifluoromethyl, —NR
6
R
6
, and —NHSO
2
R
6
, where each R
6
is independently hydrogen or C
1-4
alkyl;
R
2
is hydrogen or C
1-6
alkyl;
X is oxygen, sulfur, —NH, or —NC
1-4
alkyl;
R
3
is cyano, tetrazol-5-yl, or —CO
2
R
7
where R
7
is hydrogen or C
1-6
alkyl;
R
4
and R
5
are independently hydrogen, C
1-6
alkyl, —CO
2
H, —CO
2
C
1-6
alkyl, cyano, tetrazol-5-yl, halogen, trifluoromethyl, or C
1-6
alkoxy, or, when R
4
and R
5
are bonded to adjacent carbon atoms, R
4
and R
5
may, together with the carbon atoms to which they are bonded, forrn a fused 5 or 6 membered ring optionally containing one or two nitrogen, oxygen, or sulfur atoms; and
Y is N or CH.
The compounds of the present invention are of use in medical therapy. Preferably the compounds of this invention are agonists for human beta-3 adrenoceptor (“&bgr;
3
”). More preferably, the compounds of this invention are selective agonists for &bgr;
3
.
In another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the invention, or a pharmaceutically acceptable derivative thereof, and one or more pharmaceutically acceptable carriers.
In another aspect, the present invention provides a method for the prevention or treatment of clinical conditions or diseases susceptible to amelioration by administration of an atypical beta-adrenoceptor agonist, comprising administration of an effective amount of a compound or composition of this invention, or a pharmaceutically acceptbale derivative thereof.
In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of conditions or diseases susceptible to amelioration by administration of an atypical beta-adrenoceptor agonist.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the terms ‘alkyl’ and “alkoxy” mean a straight or branched alkyl group or alkoxy group respectively, containing the indicated number of carbon atoms. For example, C
1-6
alkyl means a straight or branched alkyl containing at least 1 and at most 6 carbon atoms.
Preferably, R
1
is phenoxymethyl or phenyl optionally substituted by one, two or three substituents selected from halogen, hydroxy, C
1-6
alkoxy, C
1-6
alkyl, nitro, cyano, hydroxymethyl and trifluoromethyl. More preferably, R
1
is phenoxymethyl or phenyl substituted by a chlorine, fluorine or bromine atom or a methyl or trifluoromethyl group, which atom or group is preferably located in the meta position. Most preferably R
1
represents phenyl substituted by a chlorine atom located in the meta position.
Preferably, R
2
is hydrogen or methyl. Most preferably R
2
is hydrogen,
Preferably, X is —NH or —NCH
3
. Most preferably, X is —NH.
Preferably, R
3
is —CO
2
H. Preferably, R
3
is bonded to the carbon atom meta or para to the bonded phenyl ring, more preferably the meta position.
Preferably, R
4
and R
5
are independently hydrogen, methyl, trifluoromethyl, —CO
2
H or, where R
4
and R
5
are bonded to adjacent carbon atoms, R
4
and R
5
, together with the carbon atoms to which they are bonded, form a fused dihydrofuran ring. More preferably, R
4
and R
5
are independently hydrogen, methyl, or trifluoromethyl. Preferably, at least one of R
4
and R
5
is hydrogen. Most preferably, both R
4
and R
5
are hydrogen.
Preferably Y is CH.
Particularly preferred compounds of the invention include those in which each variable in Formula (I) is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those where each variable in Formula (I) is selected from the more preferred or most preferred groups for each variable.
It will be appreciated that the above compounds of Formula (I) may contain optically active centers. The individual, isolated isomers and mixtures thereof, including racemates, are all within the scope of the present invention. Typically, where R
2
is C
1-6
alkyl, mixtures of diastereomers of compounds of Formula (I) may be obtained, which are enriched with greater than or equal to 80% by weight of one diastereomer. Particularly preferred compounds of Formula (I) are those wherein the asymmetric carbon atoms in the —CH(OH)— group and the —CH(R
2
)— group are both in the (R)-configuration.
Suitable compounds of Formula (I) of the invention include:
(R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester;
(R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-2,4-dicarboxylic acid dimethyl ester;
(R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-2-methyl-5-carboxylic acid methyl ester;
(R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3,4-dicarboxylic acid dimethyl ester;
(R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-chloro-4-carboxylic acid methyl ester;
(R)-3′-[[2-[[2-(3,5-dichlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester;
(R)-3′-[[2-[[2-(3,5-dichlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-biphenyl]-3-carboxylic acid;
(R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyet

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