N-phenylamide and N-pyridylamide derivatives, method of...

Details N-phenylamide and N-pyridylamide derivatives, method of... N-phenylamide and N-pyridylamide derivatives, method of...

2001-11-01

2003-01-21

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S337000, C514S336000, C546S015000, C546S279700, C546S281700, C546S309000

Reexamination Certificate

active

06509362

ABSTRACT:

The present invention relates to new N-phenylamide and N-pyridylamide derivatives, to the methods of preparing these compounds, to the pharmaceutical compositions containing them and to their use as medicaments especially in the treatment of hyperlipidaemia and atherosclerosis.
It is known that lipid deposits, especially cholesterol deposits in blood vessels are responsible for the formation of atheroma plaques which are the cause of a variety of cardiovascular diseases; more precisely, atheroma is a form of atherosclerosis characterized by an excessive accumulation of lipids, in particular of cholesterol esters, in the wall of the vessels; it has recently been found that an enzyme, acyl Coenzyme A:Cholesteryl Acyl transferase (ACAT) is responsible for the esterification of cholesterol, and a correlation was found between the increase in the activity of this enzyme and the accumulation of cholesterol esters in the vascular wall; it is also known that dietary cholesterol is absorbed in free form and is then esterified by intestinal ACAT for release into the bloodstream in the form of VLDL (very low density lipids) and/or of chylomicrons.
While several ACAT inhibitors have been identified (see for example: EP 295 637, EP 415 413 or EP 497 201) the development of new ACAT inhibitors having improved therapeutic properties should be continued.
Attempts have been made to develop ACAT-inhibiting products capable of preventing intestinal absorption of dietary and bile cholesterol and of acting against the deposition of cholesterol esters in the wall of the vessels.
This search for ACAT inhibitors has led the inventors to develop a new family of N-phenylamide and N-pyridylamide derivatives and to find that these products manifest a potent vascular ACAT-inhibiting activity associated with an intense antihyperlipidaemic effect on various animal species.
These properties of the compounds of the invention make them particularly useful especially for the treatment of hyperlipidaemia and of atherosclerosis.
The compounds of the invention have, more precisely, the formula:
in which X is O, S or CH
2
;
R
1
and R
2
, which may be identical or different, are hydrogen, (C
1
-C
6
)alkyl or (C
3
-C
8
)cycloalkyl, or alternatively R
1
and R
2
, together with the carbon atom bearing them, form (C
3
-C
8
)cycloalkyl;
R
3
is a (C
6
-C
12
)aryl optionally substituted with one or more Y radicals, which may be identical or different; or a 5- to 7-membered heteroaryl comprising 1 to 3 endocyclic heteroatoms chosen from O, S and N which is optionally substituted with one or more Y radicals, which may be identical or different;
Y is halogen, a (C
1
-C
6
)alkyl optionally substituted with one or more halogens, a (C
1
-C
6
)alkoxy optionally substituted with one or more halogens, a (C
1
-C
6
)alkylthio optionally substituted with one or more halogens, (C
1
-C
7
)acylamino, (C
1
-C
3
)acyloxy, hydroxyl, nitro, cyano, amino, (C
1
-C
6
)alkylamino, di-(C
1
-C
6
)alkylamino, pyrrolidono, piperidino, morpholino, (C
1
-C
4
)alkylsulfonylamino, (C
2
-C
5
)alkoxycarbonyl, carboxyl, (C
2
-C
6
)alkylcarbonyl, carbamoyl, (C
2
-C
5
)alkylcarbamoyl, di-(C
2
-C
5
)alkylcarbamoyl or (C
1
-C
6
)alkylsulfonyl;
R
4
and R
5
, which may be identical or different, are a Y radical or alternatively a hydrogen atom;
Ar is one of the following groups A, B or C:
T
1
and T
2
, which may be identical or different, are halogen, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio or (C
1
-C
6
)alkyl;
T is a hydrogen atom or (C
1
-C
6
)alkyl;
T
3
and T
4
, which may be identical or different, are (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, (C
6
-C
12
)arylthio, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylcarbonyl, (C
6
-C
12
)arylcarbonyl or —(CH
2
)
p
—OR in which p is 1, 2, 3 or 4 and R is (C
2
-C
3
)alkyl,
R
6
and R
7
are each a hydrogen atom or alternatively
R
6
and R
7
together are a bond;
Z is either
(i) the divalent group —CHR
9
— in which R
9
is a hydrogen atom or (C
1
-C
6
)alkyl;
or (ii) the divalent group —CHR
10
—CHR
11
— in which R
10
and R
11
together form a bond such that Z is —CH═CH— or alternatively R
10
and R
11
, which may be identical or different, are as defined above for R
9
;
or (iii) the divalent group —CHR
12
—CHR
13
—CH
2
— in which R
12
and R
13
together form a bond such that Z is —CH═CH—CH
2
—, or alternatively R
12
and R
13
, which may be identical or different, are as defined above for R
9
, as well as their addition salts with a pharmaceutically acceptable acid or base.
The addition salts of these compounds with pharmaceutically acceptable acids or bases also form part of the invention. Examples of these salts are the salts formed from hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid and mandelic acid.
In some cases, the compounds of the invention have one or more chiral centres. It should be understood that each stereoisomer forms part of the invention.
(C
1
-C
6
)Alkyl is a linear or branched, saturated hydrocarbon radical of 1 to 6 carbon atoms. The (C
1
-C
6
)alkoxy group consequently is the alkyl-O— group and the (C
1
-C
6
)alkylthio group is the alkyl-S— group where alkyl is as defined above.
Moreover, (C
3
-C
8
)cycloalkyl is understood to mean a saturated mono- or bicyclic hydrocarbon radical comprising from 3 to 8 carbon atoms. Examples are cyclopropyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term (C
6
-C
12
)aryl is, moreover, a mono- or polycyclic aromatic group having 6 to 12 carbon atoms, such as phenyl, naphthyl or anthryl. Thus, (C
6
-C
12
)arylthio is the (C
6
-C
12
)-aryl-S— radical.
As a 5- to 7-membered heterocycle comprising 1 to 3 endocyclic heteroatoms chosen from O, S and N, there may be mentioned furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine.
The halogen atoms are chlorine, bromine, fluorine and iodine.
The term acyl is the alkylcarbonyl radical. Thus, (C
1
-C
7
)acylamino is (C
1
-C
7
)alkylcarbonylamino and (C
1
-C
3
)acyloxy is (C
1
-C
3
)alkylcarbonyloxy.
Among these compounds, there are 6 subgroups of preferred compounds.
A first subgroup consists of compounds of formula I in which Y is halogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy or trifluoromethyl.
A second subgroup comprises the compounds of formula I in which:
R
1
and R
2
, which may be identical or different, are hydrogen or alternatively R
1
and R
2
, together with the carbon atom bearing them, form (C
3
-C
8
)cycloalkyl;
R
3
is a (C
6
-C
12
)aryl optionally substituted with one or more Y radicals, which may be identical or different;
Y is halogen;
R
4
and R
5
are each a hydrogen atom;
Ar is one of the following groups A, B or C:
T
1
and T
2
, which may be identical or different, are (C
1
-C
6
)alkyl;
T is a hydrogen atom or (C
1
-C
6
)alkyl;
T
3
and T
4
, which may be identical or different, are (C
1
-C
6
)alkyl; (C
1
-C
6
)alkoxy or (C
1
-C
6
)alkylthio;
R
6
and R
7
are each a hydrogen atom or alternatively R
6
and R
7
together are a bond;
Z is either
(i) the divalent group —CHR
9
— in which R
9
is a hydrogen atom or (C
1
-C
6
)alkyl; or
(ii) the divalent group —CHR
10
—CHR
11
— in which R
10
and R
11
together form a bond such that Z is —CH═CH—, or alternatively R
10
and R
11
are each a hydrogen atom.
A third subgroup consists of the compounds of formula I in which Z is —CHR
12
—CHR
13
—CH
2
—, R
12
and R
13
being as defined above.
Among the compounds of the first, second and third subgroups defined above, those for which R
1
and R
2
are a hydrogen atom are more particularly preferred.
A fourth subgroup consists of the compounds of formula I in which X is O or S and R
1
and R
2
, together with the carbon atom bearing them, form a (C
3
-C
8
)cycloalkyl.
A fifth subgroup of preferred compounds comprises the compounds of formula I in which X is O or S and Z is —CH═CH— or alternatively —CH═CH—CH
2
.
In general, it is preferable that

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