Propionic acid derivatives

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C548S235000

Reexamination Certificate

active

06750236

ABSTRACT:

The present invention relates to novel potent PPAR-alpha-activating compounds for treating, for example, coronary heart disease, and to their preparation.
In spite of many successful therapies, coronary heart disease (CHD) remains a serious public health problem. Treatment with statins, which inhibit HMG-CoA reductase, successfully lowers both LDL cholesterol plasma concentrations and the mortality of patients at risk; however, convincing treatment strategies for the therapy of patients having an unfavourable HDL/LDL cholesterol ratio or hypertriglyceridaemia are still not available to date.
Currently, fibrates are the only therapy option for patients of these risk groups. They act as weak agonists of the peroxisome-proliferator-activated receptor (PPAR)-alpha (
Nature
1990, 347, 645-50). A disadvantage of the fibrates which have hitherto been approved is that their interaction with the receptor is only weak, requiring high daily doses and causing considerable side-effects.
WO 00/23407 describes PPAR modulators for treating obesity, atherosclerosis and/or diabetes.
It was an object of the present invention to provide novel compounds which can be used as PPAR-alpha modulators.
It has now been found that this object is achieved by compounds of the general formula (I)
in which
A represents a bond or represents a —CH
2
— or —CH
2
CH
2
— group,
X represents O, S or CH
2
,
R
1
, R
2
and R
3
are identical or different and independently of one another each represents hydrogen, (C
1
-C
6
)-alkyl, (C
3
-C
7
)-cycloalkyl, hydroxyl, (C
1
-C
6
)-alkoxy, (C
6
-C
10
)-aryloxy, halogen, trifluoromethyl, trifluoromethoxy, (C
1
-C
6
)-alkylaminosulphonyl, nitro or cyano,
or
R
1
and R
2
are attached to two adjacent carbon atoms and together with these form a fused cyclohexane or benzene ring, the latter optionally being substituted by a (C
1
-C
4
)-alkylsulphonylmethyl group,
and
R
3
is as defined above,
R
4
represents hydrogen or (C
1
-C
4
)-alkyl,
R
5
and R
6
represent hydrogen or together with the carbon atom to which they are attached form a carbonyl group,
R
7
represents hydrogen, (C
1
-C
6
)-alkyl, phenyl or benzyl, where the aromatic radicals mentioned for their part may in each case be mono- to trisubstituted by identical or different substituents from the group consisting of (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, hydroxyl and halogen,
R
8
represents hydrogen, (C
6
-C
10
)-aryl or represents (C
1
-C
4
)-alkyl which for its part may be substituted by hydroxyl, trifluoromethoxy, (C
1
-C
4
)-alkoxy or phenoxy, which for their part are optionally mono- or disubstituted by trifluoromethyl, or by (C
6
-C
10
)-aryl or 5- or 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S, where all aryl and hetaroaryl rings mentioned may for their part in each case be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino,
R
9
and R
10
are identical or different and independently of one another each represents hydrogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, trifluoromethyl, trifluoromethoxy or halogen,
R
11
and R
12
are identical or different and independently of one another each represents hydrogen or (C
1
-C
6
)-alkyl or together with the carbon atom to which they are attached form a (C
4
-C
7
)-cycloalkyl ring,
and
R
13
represents hydrogen or represents a group which can hydrolysed and degraded to the corresponding carboxylic acid,
and their pharmaceutically acceptable salts, hydrates and solvates,
which have pharmacological action and can be used as medicaments or for preparing medicament formulations.
In the context of the invention, a hydrolysable group in the definition of R
13
is a group which, in particular in the body, leads to a conversion of the —C(O)OR
13
grouping into the corresponding carboxylic acid (R
13
=hydrogen). Such groups are, by way of example and by way of preference: benzyl, (C
1
-C
6
)-alkyl or (C
3
-C
8
)-cycloalkyl which are in each case optionally mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, amino, (C
1
-C
6
)-alkoxy, carboxyl, (C
1
-C
6
)-alkoxycarbonyl, (C
1
-C
6
)-alkoxycarbonylamino and (C
1
-C
6
)-alkanoyloxy, and in particular (C
1
-C
4
)-alkyl which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of halogen, hydroxyl, amino, (C
1
-C
4
)-alkoxy, carboxyl, (C
1
-C
4
)-alkoxycarbonyl, (C
1
-C
4
)-alkoxycarbonylamino and (C
1
-C
4
)-alkanoyloxy.
In the context of the invention, (C
1
-C
6
)-alkyl and (C
1
-C
4
)-alkyl represent a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, respectively. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methyl, ethyl, n-propyl, isopropyl and tert-butyl.
In the context of the invention, (C
6
-C
10
)-aryl represents an aromatic radical having 6 to 10 carbon atoms. A preferred example is the aryl radical phenyl.
In the context of the invention, (C
3
-C
8
)-cycloalkyl and (C
4
-C
7
)-cycloalkyl represent a cycloalkyl group having 3 to 8 and 4 to 7 carbon atoms, respectively. The following radicals may be mentioned by way of example and by way of preference: cyclobutyl, cyclopentyl and cyclohexyl.
In the context of the invention, (C
1
-C
6
)-alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
In the context of the invention, (C
6
-C
10
)-aryloxy represents an aromatic radical having 6 to 10 carbon atoms which is attached via an oxygen atom. A preferred example is the aryloxy radical phenoxy.
In the context of the invention, (C
1
-C
6
)-alkoxycarbonyl represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms which is attached via a carbonyl group. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
In the context of the invention, (C
1
-C
6
)-alkoxycarbonylamino represents an amino group having a straight-chain or branched alkoxycarbonyl substituent which has 1 to 6 carbon atoms in the alkoxy radical and is attached via the carbonyl group. Preference is given to an alkoxycarbonylamino radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and tert-butoxycarbonylamino.
In the context of the invention, (C
1
-C
6
)-alkanoyloxy represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms which carries a doubly attached oxygen atom in the 1-position and is attached in the 1-position via a further oxygen atom. The following radicals may be mentioned by way of example and by way of preference: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.
In the context of the invention, (C
1
-C
6
)-alkylamninosulphonyl represents an amino group which is attached via a sulphonyl group and has a straight-chain or branched alkyl substituent having 1 to 6 carbon atoms. Preference is given to an alkylaminosulphonyl radical having 1 to 4 carbon atoms. The following radicals may be mentioned by way of example and by way of preference: methylaminosulphonyl, ethylaminosulphonyl, n-propylaminosulphonyl, isopropylaminosulphonyl and tert-butylaminosulphonyl.
In the context of the invention, halogen represents fluorine, chlorine, bromine and iodine.

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