Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-04
2003-04-15
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S342000, C514S365000, C514S626000, C514S646000, C544S333000, C544S335000, C546S264000, C546S269700, C546S334000, C546S336000, C548S203000, C564S194000, C564S203000
Reexamination Certificate
active
06548523
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for the preparation of certain biaryl derivatives.
BACKGROUND OF THE INVENTION
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 a typical 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 antiatherosclerotic agents, and as being useful in the treatment of glaucoma.
A UK patent application filed on Jun. 13, 1998 as GB 9812709.5 (and corresponding International patent application WO99/65877), discloses compounds of Formula (I) and pharmaceutically acceptable derivatives thereof:
wherein R
1
is an aryl, 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, 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, form a fused 5 or 6 membered ring optionally containing one or two nitrogen, oxygen, or sulfur atoms; and
Y is N or CH.
SUMMARY OF THE INVENTION
Briefly, in one aspect, the present invention provides a process for the preparation of a compound of Formula (IA) or a pharmaceutically acceptable salt thereof:
wherein R
1
is an aryl, 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, 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;
R
3
is 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
C
1-6
alkyl; and
Y is N or CH
comprising the step of preparing a diamide of Formula (II) or a pharmaceutically acceptable salt thereof:
wherein R
1
is an aryl, 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, 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;
R
3
is CO
2
R
7
where R
7
is C
1-6
alkyl;
R
4
and R
5
are independently hydrogen, C
1-6
alkyl, —CO
2
C
1-6
alkyl; and
Y is N or CH.
In an alternative aspect, the invention provides a process for the preparation of a compound of Formula (IA):
wherein R
1
is an aryl, 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, 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;
R
3
is 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
C
1-6
alkyl; and
Y is N or CH, or a pharmaceutically acceptable salt thereof, comprising reduction of a compound of Formula (II):
wherein R
1
is an aryl, 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, 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;
R
3
is CO
2
R
7
where R
7
is C
1-6
alkyl;
R
4
and R
5
are independently hydrogen, C
1-6
alkyl, —CO
2
C
1-6
alkyl; and
Y is N or CH, or a pharmaceutically acceptable salt thereof, and optionally the step of hydrolysis of the resulting ester group R
7
in Formula (IA) to produce a compound of Formula (IA) wherein R
7
is H.
In another aspect, the present invention provides a compound of Formula (II), wherein R
1
is an aryl, 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, 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;
R
3
is CO
2
R
7
where R
7
is C
1-6
alkyl;
R
4
and R
5
are independently hydrogen, C
1-6
alkyl, —CO
2
C
1-6
alkyl; and
Y is N or CH, or a pharmaceutically acceptable salt thereof.
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.
As used herein, the term “aryl” means monocyclic or bicyclic aromatic carbocyclic groups such as phenyl and naphthyl.
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, 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
is 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, R
3
is bonded to the carbon atom meta to the bonded phenyl ring. In a compound of Formula (IA), R
3
is preferably CO
2
H. In a compound of Formula (II), R
3
is preferably CO
2
CH
3
.
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, or compounds of the processes, of the invention include those in which each variable is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those where each variable is selected from the more preferred or most preferred groups for each variable.
Reagents for the transformation of a compound of Formula (II) to a compound of Formula (I) include any suitable reagent for the reduction of amide carbonyl bonds, e.g. borane-ether, borane-sulfide, borane-amine complexes and also conditions which form borane in situ (for example, sodium borohydride and iodine or sulfuric acid). Suitable solvents include hydrocarbons, e.g. toluene or ethers, e.g. tetrahydrofuran. The reaction may be conveniently carried out on a solid substrate, such as a bead or standard substrate used in solid-phase synthesis. For example, a compound of Formula (II) may be attached to the solid substrate through the group R
3
, i.e. —CO
2
-solid substrate.
In order to form a compound of Formula (IA) wherein R
7
is hydrogen, the step of reduction of a compound of Formula (II) should be followed by hydrolysis of the resulting ester group R
7
.
A compound of Formula (II) may be prepared by reaction of a compound of Formula (III) with a compound of Formula (IV)
using any suitable method for forming an amide link, e.g. suitable coupling agents include diimides, e.g. diisopropylcarbodiimide, dicyclohexylcarbodiimide, or carbonyl diimidazole, hydroxytriazoles and equivalents, or chloroformates, whilst suitable solvents include esters, e.g. ethyl acetate, et
Lawrence Ronnie Maxwell
Millar Alan
Davis Zinna Northington
Fix Amy H.
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