ES2360584T3 - COMPOUNDS THAT MODULATE RECEPTORS OF PPAR TYPE AND THE USE OF THE SAME IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS. - Google Patents

Abstract

Compounds characterized in that they correspond to the following formula (I): in which: - R1 represents a radical of formula (a) or (b) below: The meaning of R5 is indicated below, - R2 represents a radical of formula (CH2) m-NR6-CQ- (NH) nR7; Q, R6, R7, having m and the meanings given below, - R3 and R4, which may be the same or different, represent a hydrogen atom, a halogen atom, a linear or cyclic alkyl radical of 1 to 12 atoms carbon which may be interrupted with oxygen, fluorine or nitrogen atoms, a hydroxyl radical, an alkoxy radical containing from 1 to 7 carbon atoms, a polyether radical, an aralkyl radical or an aryloxy radical; - R5 represents a hydroxyl radical, an OR8 radical or a hydroxylamine radical; R8 being defined below, - R6 represents an alkyl radical containing from 1 to 4 carbon atoms; - R7 represents an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical; - R8 represents an alkyl, aryl or aralkyl radical; - m and n can take the values of 0 or 1; - Q represent an oxygen or sulfur atom; - Ar1 and Ar2 can be identical or different and represent an aromatic radical of the formula: that, when it is an aryl radical, it can be mono or disubstituted with a halogen atom, a CF3 radical, an alkyl radical containing 1 to 12 atoms carbon, an alkoxy radical containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected with a group acetyl or benzoyl, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms; and that, when it is a heteroaryl radical, it is optionally substituted with at least one halogen, an alkyl containing from 1 to 12 carbon atoms, an alkoxy containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with the minus an alkyl containing 1 to 12 carbon atoms - A represents a sulfur or oxygen atom or an N-R9 radical; - R9 represents a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms; it being understood that when Ar1 or Ar2 is an aryl radical, then Ar2 or Ar1 is necessarily a heteroaryl radical and the optical and geometric isomers of said compound of formula (I).

Description

The invention relates, as new and useful industrial products, to a new class of compounds that are modulators of receptors of the type of Receptors Activated by Peroxisome Proliferators of the subtype  (PPAR). The invention also relates to a process for its preparation and its use in pharmaceutical compositions intended for use in human or veterinary medicine or, alternatively, in cosmetic compositions.

The activity of PPAR type receptors has undergone many studies. As a guide, the publication entitled "Differential Expression of Peroxisone Proliferator-Activated Receptor Subtypes During the Differentiation of Human Keratinocytes", Michel Rivier et al, J. Invest. Dermatol 111, 1998, pages 11161121, which lists a large number of bibliographic references related to PPAR type receptors. As a guide, the report entitled "The PPARs From orphan recipient to Drug Dicoveri", Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach and Brad R. Henke, J. Med. Chem., 2000, may also be mentioned. Vol. 43, p. 527-550.

PPAR receptors activate transcription by binding to DNA sequence elements, known as peroxisome proliferator response elements (PPRE), in the form of a heterodimer with X retinoid receptors (known as RXR).

Three subtypes of human PPAR have been identified and described: PPAR, PPAR and PPAR (or NUC1).

 PPAR is expressed primarily in the liver, while PPAR is ubiquitous.

 PPAR is the most widely studied of the three subtypes. All references suggest a critical role of PPAR in the regulation of adipocyte differentiation, where it is extremely expressed. It also has a key function in systemic lipid homeostasis.

In particular it has been described in patent application WO 96/33724 that PPAR selective compounds, such as a J2 or D2 prostaglandin, are possible active agents for the treatment of obesity and diabetes.

In addition, the requesting firm has described PPAR compounds and / or the use thereof in FR 2 773 075, which describes the use of PPAR activating compounds in the preparation of a pharmaceutical composition, the composition being intended for treatment. of skin disorders associated with an epidermal cell differentiation abnormality.

One of the objectives of the present invention is to propose a new class of PPAR modulating compounds that show very good specific affinity for PPAR.

Therefore, the present invention relates to compounds that correspond to the general formula (I) below:

image 1

in which: R1 represents a radical of formula (a) or (b) below:

image2

image 1

5

10

fifteen

twenty

25

30

R5 having the meanings given below,

-R2 represents a radical of formula (CH2) m-NR6-CQ- (NH) nR7; having Q, R6, R7, m and n the same meanings given below,

-R3 and R4, which may be the same or different, represent a hydrogen atom, a halogen atom, a linear or cyclic alkyl radical of 1 to 12 carbon atoms that may be interrupted with oxygen, fluorine or nitrogen atoms, a hydroxyl radical, an alkoxy radical containing 1 to 10 carbon atoms, a polyether radical, an aralkyl radical or an aryloxy radical;

-R5 represents a hydroxyl radical, an OR8 radical or a hydroxylamine radical; defining R8 then

-R6 represents a lower alkyl radical containing from 1 to 4 carbon atoms;

-R7 represents an alkyl radical containing from 1 to 12 carbon atoms, an alkyl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical;

-R8 represents an alkyl, aryl or aralkyl radical;

-m and n can take the values 0 or 1;

-Q represents an oxygen or sulfur atom;

-Ar1 and Ar2 can be identical or different and represent an aromatic radical of the formula:

image 1

which, when it is an aryl radical, may be mono or disubstituted with a halogen atom, a CF3 radical, an alkyl radical containing from 1 to 12 carbon atoms, an alkoxy radical containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms;

and that, when it is a heteroaryl radical, it is optionally substituted with at least one halogen, an alkyl containing from 1 to 12 carbon atoms, an alkoxy containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a benzoyl group, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group, or an imino function optionally protected with an acetyl or benzoyl group, or optionally substituted with the minus an alkyl containing 1 to 12 carbon atoms

-A represents a sulfur or oxygen atom or an N-R9 radical;

-R9 represents a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms;

It is understood that, when Ar1 or Ar2 is an aryl radical, then Ar2 or Ar1 is necessarily a heteroaryl radical, and the optical and geometric isomers of said compounds of formula (I), and also the salts thereof.

image3

In particular, when the compounds according to the invention are in the form of salts, they are salts of an alkali metal, in particular a sodium or potassium salt, or salts of alkaline earth metals or salts of organic amines, more particularly amino acids, such as arginine or lysine. In the case of compounds containing nitrogen heterocycles, the salts may be mineral or organic acids.

In accordance with the present invention, the term "hydroxyl radical" refers to a -OH radical.

The term "halogen atom" refers to a fluorine, chlorine or bromine atom.

According to the present invention, the term "alkyl radical containing 1 to 12 carbon atoms" refers to a radical, saturated or unsaturated, linear or cyclic, optionally substituted, hydrogenated or fluorinated containing 1 to 12 carbon atoms , which may be interrupted with a heteroatom, and alkyl radicals containing from 1 to 12 carbon atoms are preferably methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, hexyl, heptyl, octyl, decyl, cyclopentyl, cyclohexyl or methylenecyclopropyl radicals .

Alkyl radicals containing 1 to 4 carbon atoms will preferably be methyl, ethyl, n-propyl, i-propyl, c-propyl, methylcyclopropyl, n-butyl, i-butyl or t-butyl radicals.

The term "alkoxy radical containing from 1 to 7 carbon atoms" refers to a methoxy, ethoxy, isopropyloxy, methylcyclopropyloxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, benzyloxy, aryloxy or phenoxy radical, which may be optionally substituted with an alkyl radical containing from 1 to 12 carbon atoms or an alkyl radical containing from 1 to 5 carbon atoms.

The term "polyether radical" refers to a polyether radical containing from 1 to 6 carbon atoms interrupted with at least one oxygen atom, such as methoxymethoxy, ethoxymethoxy or methoxyethoxymethoxy radicals.

The term "aralkyl radical" refers to a benzyl, phenethyl or 2-naphthylmethyl radical, which may be mono or disubstituted with a halogen atom, a CF3 radical, an alkyl radical containing from 1 to 12 carbon atoms, a radical alkoxy containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected with an acetyl group

or benzoyl, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with an alkyl containing from 1 to 12 carbon atoms.

The term "aryl radical" refers to a phenyl, biphenyl, cinnamyl or naphthyl radical, which may be mono or disubstituted with a halogen atom, a CF3 radical, an alkyl radical containing 1 to 12 carbon atoms, a radical alkoxy containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected with an acetyl group

or benzoyl, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.

The term "heteroaryl radical" refers to an aryl radical interrupted with one or more heteroatoms, such as a pyridyl, furyl, thienyl, isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, quinazolinyl, benzothiadiazolyl, benzimidazolyl, quinoxalyl, indolyl or benzofuryl optionally substituted with at least one halogen, an alkyl containing from 1 to 12 carbon atoms, an alkoxy group containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a radical benzoyl, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing 1 to 12 atoms carbon

The term "heterocyclic radical" preferably refers to a morpholino, piperidino, piperazino, 2oxo-1-piperidyl or 2-oxo-1-pyrrolidinyl radical, optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms, a alkoxy containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group , or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.

Among the compounds of formula (I) above included within the context of the invention, special mention may be made of the following compounds alone or in the form of a mixture:

one.

 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} thiophene-2-yl) acrylic acid

2.

 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} thiophene-2-yl) propanoic acid

3.

 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} furan-2-yl) -acrylic acid

Four.

 3- (4- {5 - [(Methyloctanoylamino) methyl] thiophene-3-yl} -phenyl) acrylic acid

5.

 3- (4- {5 - [(Methyloctanoylamino) methyl] thiophene-3-yl} -phenyl) propanoic acid

6.

 3- {4- [6- (3-Heptyl-1-methylureido) pyrid-2-yl] phenyl} -propanoic acid

7.

 3- {6- [3- (3-Heptyl-1-methylureido) phenyl] pyrid-3-yl} -propanoic acid

8.

 2- [4- (2-Carboxyethyl) phenyl] -4- (3-heptyl-1-methylureido) pyridinium acetate

9.

 3- {5- [3- (3-pentyl-1-methylureido) phenyl] pyrimidin-2-yl} acrylic acid

10.

 3- {5- [3- (3-pentyl-1-methylureido) phenyl] pyrimidin-2-yl} propanoic acid

eleven.

 2- [2-Butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-pentylureido) pyridinium hydrochloride

12.

 2- [2-Butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-heptylureido) pyridinium hydrochloride

13.

 2- [4- (2-Carboxyethyl) -2-ethoxyphenyl] -6- (3-heptyl-1-methylureido) pyridinium hydrochloride

14.

 3- (3-Butoxy-4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoic acid

fifteen.

 3- (3-Butoxy-4- (5 - {[(4-methoxybenzoyl) methylamino] -methylthiophene-3-yl) phenyl] propanoic acid

16.

 3- (3-Butoxy-4- (5 - {[(3-methoxybenzoyl) methylamino] -methyl} thiophene-3-yl) phenyl] propanoic acid

17.

 3- {5- [4- (3-Heptyl-1-methylureido) pyrid-2-yl] furan-2-yl} propanoic acid

18.

 3- [5- [3- (3-Heptyl-1-methylureido) phenyl] -4- (2,2,2-tri-fluoroethoxy) furan-2-yl] propanoic acid

19.

 3- (5- {3- [3- (3,5-Dimethoxyphenyl) -1-ethylureido] phenyl} -3-methylfuran-2-yl) propanoic acid

twenty.

 3- (5- {6- [3- (4-ethoxyphenyl) -1-ethylureido] pyrid-2-yl} -furan-2-yl) propanoic acid

twenty-one.

 3- (2-methyl-4- {6- [1-methyl-3- (4-methylpentyl) ureido] -pyrid-2-yl} phenyl) propanoic acid

22

 Methyl 3- {4- [6- (1-Ethyl-3-naphthalen-2-ylureido) pyrid-2-yl] -2-fluorophenyl} propanoate.

2. 3.

 3- (4- {6- [3- (4-Butoxyphenyl) -1-methylureido] pyrid-2-yl} phenyl) -N-hydroxypropionamide

24.

 3- {3-Cyclopropylmethoxy-4- [6- (1-methyl-3-pentylureido) -pyrid-2-yl] phenyl} propanoic acid

25.

 3- {4- [6- (1-ethyl-3-phenylthioureido) pyrid-2-yl] -3-propoxyphenyl} propanoic acid

26.

 3- {3-ethoxy-4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] -phenyl} propanoic acid

27.

 3- {4- [6- (3-Hexyl-1-methylureido) pyrid-2-yl] -3-isopropoxyphenyl} propanoic acid

28.

 3- [4- [6- (3-Heptyl-1-methylureido) pyrid-2-yl] -3- (4,4,4-trifluorobutoxy) phenyl] propanoic acid

29.

 3- {3- (2-Dimethylaminoethoxy) -4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} propanoic acid

30

 3- {3- (3-Hydroxypropoxy) -4- [6- (1-methyl-3-pentylureido) -pyrid-2-yl] phenyl} propanoic acid

31.

 3- {4- [6- (1-ethyl-3-phenylthioureido) pyrid-2-yl] -3-fluorophenyl} acrylic acid

32

 3- {4- [6- (3-Hexyl-1-methylureido) pyrid-2-yl] -3-trifluoromethylphenyl} propanoic acid

33.

 3- [6 '- (1-methyl-3-phenethylureido) [2,2'] bipyridinyl-5-yl] propanoic acid

3. 4.

 3- {2- [6- (3-Hexyl-1-methylureido) pyrid-2-yl] thiazol-4-yl} propanoic acid

35

 Ethyl 3- {2- [6- (3-Hexyl-1-methylureido) pyrid-2-yl] -thiazol-5-yl} propanoate

36.

 3- (3- {6- [1-methyl-3- (6-methylheptyl) ureido] pyrid-2-yl} isoxazol-5-yl) propanoic acid

37.

 3- {4- [2- (3-Heptyl-1-methylureido) pyrimidin-4-yl] phenyl} -propanoic acid

38.

 3- {3-Cyclopropylmethoxy-4- [2- (3-heptyl-1-methylureido) -pyrimidin-4-yl] phenyl} propanoic acid

39.

 3- (4- {2- [1-ethyl-3- (4-propoxyphenyl) ureido] pyrimidin-4-yl} -3-fluorophenyl) propanoic acid

40

 3- {2-Fluoro-4- [2- (1-methyl-3-naphthalen-2-ylureido) -pyrid-4-yl] phenyl} -N-hydroxypropionamide 41.Acid 3- [2 '- (3- hexyl-1-methylthioureido) [2,4 '] bipyridinyl-5-yl] propanoic acid

image4

42. 3- {4- [2- (3-Hexyl-1-methylureido) pyrid-4-yl] -3-propoxyphenyl} propanoic acid 43. 3- (3-benzyloxy-4- {4- [1- methyl-3- (5-methylhexyl) ureido] -pyrid-2-yl} phenyl) propanoic acid

image5

44.

 3- {2- [4- (3-Hexyl-1-methylureido) pyrid-2-yl] thiazol-5-yl} acrylic acid

Four. Five.

 3- {5- [3- (3-Hexyl-1-methylureido) phenyl] pyrid-2-yl} -acrylic acid

46.

 3- {5- [5- (3-Heptyl-1-methylthioureido) thiophene-3-yl] -pyrid-2-yl} acrylic acid

47

 3- {4- [2- (3-Heptyl-1-methylureido) thiazol-4-yl] -3-propoxyphenyl} propanoic acid

48.

 3- (2-Fluoro-4- {5 - [(heptanoylmethylamino) methyl] thiophene-3-yl} phenyl) propanoic acid

49.

 3- (4- {5 - [(heptanoylmethylamino) methyl] thiophene-3-yl} -3-isobutoxyphenyl) acrylic acid 50. 3- (3- (2-cyclopentylethoxy) -4- {5 - [(methyloctanoylamino) -methyl] thiophene-3-yl} phenyl) propanoic acid

51.

 Methyl 3- (3-Isobutoxy-4- {5 - [(methylnonanoylamino) -methyl] thiophene-3-yl} phenyl) propanoate

52

 3- {6- [5 - ({ethyl- [2- (2-pentylphenyl) acetyl] amino} methyl) -thiophene-3-yl] pyrid-3-yl} propanoic acid

53.

 3- (4- {4 - [(methylnonanoylamino) methyl] thiazol-2-yl} -3-propoxyphenyl) propanoic acid

54

 3- (2-Chloro-4- {4 - [(methylnonanoylamino) methyl] thiophene-2-illphenyl) propanoic acid 55. 3- (2-Fluoro-4- {4 - [(methylnonanoylamino) methyl] thiophene-2 acid -yl} phenyl) acrylic

56.

 3- (4- {4 - [(heptanoylmethylamino) methyl] thiophene-2-yl} -1-methyl-1H-pyrrole-2-yl) propanoic acid

57.

 3- (4- {4 - [(heptanoylmethylamino) methyl] thiophene-2-yl} -furan-2-yl) propanoic acid

58.

 3- {5 '- [(heptanoylmethylamino) methyl] [3,3'] bitiophenyl-5-yl} propanoic acid

59.

 3- {5 '- [(Heptanoylmethylamino) methyl] -3-propyl- [2,3'] bitiophenyl-5-yl} phenyl propanoate

60

 3- (5- {5 - [(heptanoylmethylamino) methyl] thiophene-3-yl} -4-propylfuran-2-yl) acrylic acid

61.

 3- {3-Butoxy-4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

62

 3- (3-Benzyloxy-4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

63.

 3- {3-benzyloxy-4- [2- (3-heptyl-1-methylureido) pyrimidin-4-yl] phenyl} propanoic acid

64.

 3- {3-Butyloxy-4- [2- (3-heptyl-1-methylureido) pyrimidin-4-yl] phenyl} propanoic acid

65

 3- {3-Butoxy-4- [4- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

66.

 3- {3-benzyloxy-4- [4- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

67.

 3- {3-benzyloxy-4- [5- (3-heptyl-1-methylureido) pyrid-3-yl] phenyl} propanoic acid

68.

 3- {3-Butoxy-4- [5- (3-heptyl-1-methylureido) pyrid-3-yl] phenyl} propanoic acid

69.

 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} -4-propylthiophene-2-yl) propanoic acid

70.

 3- (3-Benzyloxy-4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl} propanoic acid

71.

 3- (4-Benzyl-5- {3 - [(hexanoylmethylamino) methyl] phenyl} -thiophene-2-yl) propanoic acid

72.

 3- {4cyclopropylmethyl-5- [3- (1-methyl-3-pentylureido) -phenyl] thiophene-2-yl} propanoic acid

73

 3- {5- [3- (1-methyl-3-pentylureido) -4-trifluoromethylphenyl] thiophene-2-yl} propanoic acid 74. 3- (5- {3- [3- (4-Butoxyphenyl) - 1-ethylureido] phenyl} -thiophene-2-yl) propanoic acid

75.

 3- {5- [3- (3-Heptyl-1-methylureido) -4-trifluoromethylphenyl] furan-2-yl} propanoic acid

76

 3- {2-Butoxy-4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} propanoic acid

77.

 3- {2- (4-Methoxybenzyloxy) -4- [6- (1-methyl-3-pentyl-ureido) pyrid-2-yl] phenyl} propanoic acid

78.

 3- {2- (3-Methoxybenzyloxy) -4- [6- (1-methyl-3-pentyl-ureido) pyrid-2-yl] phenyl} propanoic acid

79.

 3- [2-Cyclopropylmethoxy-4- (6- {3- [2- (4-methoxyphenyl) -ethyl] -1-methylureido} pyrid-2-yl) phenyl] propanoic acid

image6

In accordance with the present invention, the compounds of formula (I) that are more particularly preferred are those having at least one of the following characteristics:

-R3 is an alkoxy radical having 1 to 7 carbon atoms;

-R5 corresponds to a hydroxyl radical;

-the sequence - (CH2) m-NR6-CQ (NH) nR7 has m = 0, n = 1;

-Q is an oxygen atom;

-R7 represents an alkyl radical of 1 to 8 carbon atoms;

-At least Ar1 or Ar2 is a pyridine type group.

Also subject to the present invention are processes for preparing the compounds of formula (I), in particular according to the reaction schemes given in Figures 1, 2, 3 and 4.

Figure 1: The boronic acid or ester 2 can be obtained from compound 1 using conventional conditions, for example by reaction with tert-butyl lithium followed by an addition to trimethyl borate or reaction with pinacoldiborane in the presence of a palladium catalyst, by example diphenylphosphinoferrocene palladium dichloride. Compound 1 can also be directly coupled with an isocyanate, a thioisocyanate or an acyl chloride (in this case n = 0) under conventional conditions to give compound 3.

The boronic acid or ester 4 can be obtained from compound 3 using conventional conditions, for example, by reaction with tert-butyl lithium followed by an addition to trimethyl borate, or reaction with pinacoldiborane in the presence of a palladium catalyst, by example, diphenylphosphoferrocene palladium dichloride.

Compounds 5 can also be purchased commercially or can be sintered from the corresponding aldehyde thereof using a Wittig reaction.

A Suzuki-type palladium coupling between boronate 4 or 2 and compound 5 (chosen from an aryl bromide, iodide, chloride or triflate) allows compounds having the aryl-aryl sequence 7 or 9, respectively, to be obtained.

A Suzuki-type palladium coupling between boronate 4 or 2 and compound 6 (chosen from an aryl bromide, iodide, chloride or triflate) allows compounds having the aryl-aryl sequence 8 or 11 to be obtained, respectively. .

Compounds 10 and 12 can be obtained from Compounds 9 and 11 by deprotection under conventional conditions, for example by treatment with a strong acid, for example trifluoroacetic acid if P is a Boc group.

Compounds 10 and 12 can be coupled with isocyanates, thioisocyanates or acyl chlorides (in this case n = 0) under conventional conditions to give compounds 7 and 8, respectively.

Compounds 8 and 11 can be obtained by hydrogenation of compounds 7 and 9 under conventional hydrogenation conditions, for example: hydrogen catalyzed with palladium on carbon.

The acidic functions of compounds 13 and 14 can be obtained from compounds 7 and 8 respectively: by saponification if R8 is an alkyl chain, using a base, for example, sodium hydroxide.

Compound 14 can be obtained by hydrogenation of compound 13 under conventional hydrogenation conditions, for example: hydrogen catalyzed with palladium on carbon.

Compounds 15 and 16 can be obtained from esters 7 and 8, respectively, by treatment with hydroxylamine.

Figure 2: A coupling of Suzuki-type palladium between a commercially available arylboronic acid containing a formyl group and compounds 1 or 3 (chosen from an aryl bromide, iodide, chloride or triflate) allows compounds to be obtained. they have the aryl-aryl sequence 18 or 17, respectively.

Compound 18 can be coupled with isocyanates, thioisocyanates or acyl chlorides (in this case n = 1) under conventional conditions to give compound 17.

Compounds 7 and 9 can be obtained by a Wittig reaction starting from compounds 17 and 18, respectively, for example by the action of methyl triphenylphosphoranylideneacetate.

image7

Figure 3

A coupling of Suzuki-type palladium between the 4 or 2 boronic acids or esters and aryl dihalides chosen from bromides, iodides and chlorides allows compounds having the aryl-aryl sequence 19 or 20, respectively, to be obtained.

Compounds 7 and 9 can be obtained from compounds 19 and 20, respectively, by a coupling of Heck-type palladium with alkyl or aryl acrylates.

Figure 4

Boronates 21 and 22 can be obtained by treating compounds 5 and 6, respectively, with pinacoldiborane, in the presence of a palladium-based catalyst, for example diphenylphosphoferoferlocene palladium dichloride.

A coupling of Suzuki-type palladium between the compound and compounds 3 and 1 (chosen from an aryl bromide, iodide, chloride or triflate) allows compounds having the aryl-aryl sequence 7 and 9, respectively, to be obtained.

A Suzuki palladium coupling between compound 22 and compounds 3 and 1 (chosen from bromide, iodide, chloride or aryl triflate) allows compounds having the aryl-aryl sequence 8 and 11, respectively, to be obtained.

The compounds according to the invention show modulating properties on PPAR type receptors. This activity on the PPAR,  and  receptors is measured in a transactivation assay and quantified by the dissociation constant Kdapp (apparent), as described in example 6.

Preferred compounds of the present invention have a dissociation constant less than or equal to 5000 nM and advantageously less than or equal to 1000 nM.

Preferably, the compounds are modulators of specific PPAR type receptors, ie they have a ratio between the Kdapp for the PPAR AR and PPAR receptors, and the Kdapp for the PPAR receptors greater than

or equal to 10. Preferably, this ratio PPAR / PPAR or PPAR / PPAR is greater than or equal to 50 and more advantageously greater than or equal to 100.

An object of the present invention also relates, as medicaments, to the compounds of formula (I) as described above.

An object of the present invention is the use of compounds of formula (I) to prepare a composition for regulating and or renewing lipids of the metabolism in the skin.

The compounds according to the invention are also particularly suitable in the following fields of treatment:

1) for the treatment of dermatological conditions associated with a keratinization disorder related to differentiation and proliferation, in particular for the treatment of common acne, comedones, polymorphic acne, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acne such as acne solar, medicinal or labor,

2) for the treatment of other types of keratinization disorders, in particular ichthyosis, ichthyosiform conditions, Darier's disease, palmoplantar keratoderma, leukoplakia and leucoplachiform conditions and cutaneous or mucous (oral) lichen,

3) for the treatment of other dermatological conditions with an inflammatory immuno-allergic component, with or without cell proliferation disorder and in particular all forms of psoriasis, both cutaneous, mucosal or nail psoriasis and even psoriatic arthritis or alternatively cutaneous atopy such as eczema or respiratory atopy or gingival hypertrophy,

4) for the treatment of all dermal or epidermal proliferations, both benign and malignant, whether or not of viral origin, such as common warts, flat warts and epidermodisplasia verruciformis, oral or florid papillomatosis, T lymphoma and proliferations that can be induced by ultraviolet light, particularly in the case of basal and spinocellular cell epithelioma and also any precancerous dermal lesions such as keratoacauses,

5) for the treatment of other dermatological disorders such as immune dermatitidis, such as lupus erythematosus, vesicular immune diseases and collagen diseases, such as scleroderma,

6) in the treatment of dermatological or systemic ailments with an immune component,

7) in the treatment of dermal disorders due to exposure to UV radiation, and also to repair or combat skin aging, both light-induced or chronological aging or to reduce actinic keratosis and pigmentation of any pathology associated with chronological aging or actinic, such as xerosis,

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8) to combat sebaceous function disorders such as acne hyperseborrhea, simple seborrhea or seborrheic dermatitis,

9) to prevent or treat scarring disorders or to prevent or repair stretch marks,

10) in the treatment of pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation

or vitiligo,

11) in the treatment of ailments related to lipid metabolism, such as obesity, hyperlipidemia, non-insulin-dependent diabetes or syndrome X,

12) in the treatment of inflammatory ailments such as arthritis,

13) in the treatment or prevention of cancerous or precancerous conditions,

14) in the prevention of the treatment of alopecia of various origins, particularly alopecia produced by chemotherapy or radiation,

15) in the treatment of disorders related to the immune system such as asthma, type 1 sugar diabetes, multiple sclerosis or other selective immune system dysfunctions, or

16) in the treatment of ailments of the cardiovascular system, such as atherosclerosis or hypertension.

An object of the present invention is also a pharmaceutical or cosmetic composition comprising, in a physiologically acceptable medium, at least one compound of formula (I) as defined above.

The composition according to the invention can be administered enterally, parenterally, topically or ocularly. The pharmaceutical composition is preferably packaged in a manner that is suitable for topical application.

Through the enteral route, the composition, more particularly the pharmaceutical composition, may be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions or lipid polymeric vesicles or nanospheres or microspheres for allow prolonged release. Through the parenteral route, the composition may be in the form of solutions or suspensions for infusion or for injection.

The compounds according to the invention are generally administered at a daily dose of about 0.001mg / kg to 100mg / kg of body weight of 1 to 3 dosages.

The compounds are used systemically at a concentration generally between 0.001% and 10% by weight and preferably between 0.01% and 1% by weight with respect to the weight of the composition.

By the topical route, the pharmaceutical composition according to the invention is more particularly intended for the treatment of dermal and mucous membranes and may be in the form of ointments, creams, milks, balsamic ointments, powders, impregnated compresses, synthetic detergents, solutions , gels, sprays, foams, suspensions, bar lotions, shampoos or washing bases. They may also be in the form of lipid suspensions or polymeric vesicles or nanospheres or microspheres or polymeric patches and hydrogels to allow prolonged release. This topical route composition may be in anhydrous form, in aqueous form or in the form of an emulsion.

The compounds are used topically at a concentration generally between 0.001% and 10% by weight, preferably between 0.01% and 1% by weight with respect to the total weight of the composition.

The compounds of formula (I) according to the invention also find an application in the field of cosmetics, in particular in body and hair hygiene and more particularly to regulate and restore lipid metabolism in the skin.

Therefore, the cosmetic use of a composition comprising, in a physiologically acceptable substrate, at least one of the compounds of formula (I) for body or hair hygiene is also an object of the invention.

The cosmetic composition according to the invention included, in a cosmetically acceptable support, at least one compound of formula (I) or an optical or geometric isomer thereof or a salt thereof, may normally be in the form of a cream, a milk, a lotion, a gel lipid suspensions or polymeric vesicles or nanospheres or microspheres, impregnated gauze, solutions, sprays, foams, bars, soaps, shampoos or washing bases.

The concentration of the compound of formula (I) in the cosmetic composition is between 0.0001% and 2% by weight with respect to the total weight of the composition.

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Pharmaceutical and cosmetic compositions, as described above, may also contain inert or even pharmacodynamically active additives as regards pharmaceutical compositions or combinations of other additives and especially:

-

 wetting agents;

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 flavor enhancers;

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 preservatives such as esters of para-hydroxybenzoic acid;

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 stabilizers;

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 humidity regulators;

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 pH regulators;

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 osmotic pressure modifiers;

emulsifiers;

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 UV-A and UV-B filter agents;

-

 antioxidants, such as -tocopherol, butylhydroxyanisole or butylhydroxytoluene, superoxide dismutase, ubiquinol or certain metal chelating agents;

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 depigmenting agents such as hydroquinone, acelaic acid, caffeic acid or logical acid;

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 emollients;

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 moisturizers, for example glycerol, PEG 400, thiaminomorpholinone and derivatives thereof, or urea;

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 antiseborrhoeic or anti-acne agents, such as S-carboxymethylcysteine, S-benzylcysteamine, salts thereof or derivatives thereof or benzoyl peroxide;

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 antibiotics, for example erythromycin and its esters, neomycin, clindamycin and its esters and tetracyclines;

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 antifungal agents such as ketoconazole or polymethylene-4,5-isothiazolidones-3;

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 agents for stimulating hair growth, for example Minoxidil (3-oxide 2,4-diamine-6-piperidinopyrimidine) and its derivatives, Diazoxida (7-chloro-3 methyl-2, 4-benzothiadiacin 1,4-dioxida) and Phenytoin (5,4-diphenylImidazolidine-2,4-dione);

-

 non-steroidal anti-inflammatory agent;

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 carotenoids and especially -carotene;

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 antipsoriatic agents such as anthralin and its derivatives;

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 eicosa-5,8,11,14-tetranoic acid and eicosa-5,8,11-triionic acid and esters and amides thereof;

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 retinoids, that is RAR or RXR receptor ligands, which may be natural or synthetic;

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 corticosteroids or estrogens;

--hydroxy acids and -keto acids or derivatives thereof, such lactic acid, malic acid, citric acid, glycolic acid, mandelic acid, tartaric acid, glyceric acid or ascorbic acid also salts, amides or esters thereof or -hydroxy acids or derivatives thereof, such as salicylic acid and the salts, amides or esters thereof;

- ion channel blockers such as potassium channel blockers;

- or as an alternative, more particularly for pharmaceutical compositions, in combination with medicinal products that are known to interfere with the immune system (eg, cyclosporine, FK 506, glucocorticoids, monoclonal antibodies, cytokines or growth factors, etc.).

It is not necessary to indicate that a person skilled in the art will carefully select the optional compound (or compounds) to be added to these compositions so that the advantageous properties intrinsically associated with the present invention are not, or are not substantially, adversely affected by The considered addiction.

Another object of the invention relates to a cosmetic procedure for skin care, characterized

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because the composition comprises at least one compound of formula (I) as defined above that is applied to the skin. The regulation and / or restoration of lipid metabolism in the skin makes it possible to obtain a skin whose surface appearance is more beautiful.

Next, as an illustration and without limitation, various examples of the production of the active compounds of formula (I) according to the invention, and also the biological activity resulting from said compounds and various concrete formulations based on these compounds will be provided. .

Example 1: 3- (5- {3 - [(Methyloctanoylamino) methyl] -phenyl} thiophene-2-yl) acrylic acid

image 1

to. N-Methyloctanamide

25 g (0.37 mol) of methylamine hydrochloride are dissolved in 125 ml of dichloromethane and then 115 ml of triethylamine are added. At 0 ° C, 70 ml (0.41 mol) of octanoyl chloride are slowly added. The reaction mixture is stirred for 3 hours at room temperature. The mixture is filtered and then 100 ml of water is added to the filtrate. The organic phase is separated by decantation, dried over sodium sulfate and evaporated. 61 g of Nmethyloctanamide are obtained in quantitative yield.

b. N-Methyl-N- (3-bromobenzyl) octanamide

5 g (31.8 mmol) of N-methyl octanamnamide (1a) are added at 0 ° C to a suspension of 1.4 g (35 mmol) of sodium hydride (60% fat) in 60 ml of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at room temperature and then a solution of 8.9 g (35 mmol) of 3-bromobenzyl bromide in 15 ml of tetrahydrofuran is added. The mixture is stirred for 16 hours at room temperature. The reaction is stopped by adding 100 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel (75/25 heptane / ethyl acetate). 7.4 g of N-methyl-N- (3-bromobenzyl) octanamide are obtained. Yield = 71%.

C. Octanoylmethyl- [3- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) benzyl] amide

1.0 g (3.98 mmol, 1.3 equiv.) Of pinacoldiborane is added to a mixture of 1.0 g (3.06 mmol, 1 equiv.) Of Nmethyl-N- (3-bromobenzyl) octanamide and 900 mg (9.18 mmol, 3 equiv.) Of potassium acetate, in the presence of 111 mg (0.15 mmol, 5% by mol) of diphenylphosphineoferrocenopaladium dichloride (PdCl2dppf) in 10 ml of dimethylformamide. The mixture is stirred for 2 hours at 80 ° C. The reaction is stopped by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (80/20 heptane / ethyl acetate). 1.0 g of octanoylmethyl- [3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzyl] amide is obtained as an oil. Yield = 88%.

F. Methyl 3- (5-Bromothiophene-2-yl) acrylate

4.2 g (12.5 mmol, 1.2 equiv.) Of methyl triphenylphosphoranylideneacetate are added to a solution of 2.0 g (10.4 mmol, 1.0 equiv.) Of 5-bromothiophene-2-carbaldehyde in 15 ml of toluene. The reaction mixture is stirred for 1 hour at 80 ° C. The reaction is stopped by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (80/20 heptane / ethyl acetate). 2.1 g of methyl 3- (5-bromothiophene-2-yl) acrylate are obtained. Yield = 82%.

g. Methyl 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} -thiophene-2-yl) acrylate

200 mg (0.81 mmol, 1.0 equiv.) Of methyl 3- (5-bromothiophene-2-yl) acrylate and 334 mg (0.89 mmol, 1.1 equiv.) Of octanoylmethyl- [ 3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzyl] amide in 5 ml of a 5/1 mixture of dimethylformamide and a 2M solution of potassium phosphate. 93 mg (0.08 mmol, 10 mol%) of tetrakis (triphenylphosphine) palladium are added and then the reaction mixture is stirred for 2 hours at 80 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to chromatography on gel.

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silica (from 80/20 to 60/40 heptane / ethyl acetate). 220 mg of methyl 3- (5- {3 [(methyloctanoylamino) methyl] phenyl} thiophene-2-yl) acrylate are obtained. Yield = 65%.

h. 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} -thiophene-2-yl) acrylic acid

212 mg (5.3 mmol, 10 equiv.) Of sodium hydroxide are added to a solution of 220 mg (0.53 mmol, 1 equiv.) Of 3- (5- {3 - [(methyloctanoylamino) methyl] phenyl} -thiophene-2-yl) methyl acrylate in 4 ml of 9/1 tetrahydrofuran / methanol. The reaction mixture is stirred for two hours at room temperature. The reaction is stopped by adding 20 ml of water and 3 ml of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel (90/10 dichloromethane / methanol). The oil obtained is crystallized from pentane. 155 mg of 3- (5- {3 - [(methyloctanoylamino) methyl] phenyl} thiophene-2-yl) acrylic acid are obtained. Yield = 73%. m.p. = 102-104 ° C.

1 H NMR (CDCl 3, 400 MHz): 0.88 (m, 3 H); 1.31 (m, 8H); 1.72 (m, 2 H); 2.42 (m, 2 H); 2.98 and 3.00 (2s (rotamers), 3H); 4.60 and 4.66 (2s (rotamers), 2H); 6.24 and 6.26 (2d (rotamers), J = 15.6 Hz, 1H); 7.16-7.56 (m, 6H); 7.86 (2d (rotamers), J = 15.6 Hz, 1H).

Example 2: 3- (5- {3 - [(Methyloctanoylamino) methyl] -phenyl} thiophene-2-yl) propanoic acid

image 1

A solution of 80 mg (0.20 mmol, 1 equiv.) Of 3- (5- {3 - [(methyloctanoylamino) methyl] phenyl} thiophene-2-yl) acrylic acid (prepared as in 1 h) in 2 ml of Methanol is stirred for 2 hours at room temperature in the presence of 50 mg of 10% Pd / C in a hydrogen atmosphere. The palladium is removed by filtration and then the solvents are removed by evaporation. The residue is crystallized from pentane / dichloromethane. 71 mg of 3- (5- {3 [(methyloctanoylamino) methyl] phenyl} thiophene-2-yl) propanoic acid are obtained. Yield = 89%. m.p. = 67-68 ° C.

1 H NMR (CDCl 3, 400 MHz): 0.88 (m, 3 H); 1.28 (m, 8H); 1.70 (m, 2 H); 2.41 (m, 2 H); 2.78 (m, 2 H); 2.96 and 2.98 (2s (rotamers), 3H); 3.18 (m, 2H); 4.57 and 4.63 (2s (rotamers), 2H); 6.82 (m, 1 H); 7.05-7.14 (m, 2H); 7.28-7.48 (m, 3H).

Example 3: 3- (5- {3 - [(Methyloctanoylamino) methyl] -phenyl} furan-2-yl) acrylic acid

image 1

to. 3- (5-Bromofuran-2-yl) methyl acrylate

4.58 g (13.7 mmol, 1.2 equiv.) Of methyl triphenylphosphoranylidenacetate are added to a solution of 2.0 g (11.4 mmol, 1.0 equiv.) Of 5-bromofuran-2-carbaldehyde in 15 ml of toluene. The reaction mixture is stirred for 1 hour at 80 ° C. The reaction is stopped by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (80/20 heptane / ethyl acetate). 2.0 g of methyl 3- (5-bromofuran-2-yl) acrylate are obtained. Yield = 77%.

b. Methyl 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} -furan-2-yl) acrylate

278 mg (1.20 mmol, 1.5 equiv.) Of methyl 3- (5-bromofuran-2-yl) acrylate and 300 mg (0.80 mmol,

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Four. Five

1.0 equiv.) Octanoylmethyl- [3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzyl] amide (prepared as in 1e) in 5 ml of a mixture 5/1 dimethylformamide and a 2M solution of potassium phosphate. 46 mg (0.04 mmol, 5 mol%) of tetrakis (triphenylphosphine) palladium are added and then the reaction mixture is stirred for 2 hours at 80 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (from 80/20 to 60/40 heptane / ethyl acetate). 250 mg of methyl 3- (5- {3 [(methyloctanoylamino) methyl] phenyl} furan-2-yl) acrylate are obtained. Yield = 78%.

C. 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} furan-2-yl) acrylic acid

300 mg (7.5 mmol, 12 equiv.) Of sodium hydroxide are added to a solution of 250 mg (0.63 mmol, 1 equiv.) Of 3- (5- {3 - [(methyloctanoylamino) methyl] phenyl} furan-2-yl) acrylate in 4 ml of 9/1 tetrahydrofuran / methanol. The reaction mixture is stirred for two hours at room temperature. The reaction is stopped by adding 20 ml of water and 3 ml of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel (90/10 dichloromethane / methanol). The oil obtained is crystallized from pentane. 140 mg of 3- (5- {3 [(methyloctanoylamino) methyl] phenyl} furan-2-yl) acrylic are obtained. Yield = 58%. m.p. = 96-98 ° C.

1 H NMR (CDCl 3, 400 MHz): 0.88 (m, 3 H); 1.28 (m, 8H); 1.71 (m, 2H); 2.42 (m, 2 H); 2.98 and 3.00 (2s (rotamers), 3H); 4.61 and 4.67 (2s (rotamers), 2H); 6.43 (2d (rotamers), J = 15.6 Hz, 1H); 6.76 (m, 2H); 7.18 (2d (rotamers), J = 7.6 Hz, 1H); 7.37-7.69 (m, 4H).

Example 4: 3- (4- (5 - [(Methyloctanoylamino) methyl] thiophene-3-yl) phenyl) acrylic acid

image 1

to. Octanoyl (4-bromothiophene-2-ylmethyl) methylamide

880 mg (13 mmol, 5 equiv.) Of methylamine hydrochloride and 500 mg (2.61 mmol, 1 equiv.) Of 4-bromothiophene-2-carbaldehyde are dissolved in 5 ml of methanol in the presence of 2 g of anhydrous magnesium sulfate . The reaction mixture is stirred for 1 hour at room temperature. 327 mg (5.2 mmol, 2 equiv.) Of sodium cyanoborohydride are added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is stopped by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is dissolved in 4 ml of tetrahydrofuran in the presence of 0.5 ml of triethylamine. 0.45 ml (2.6 mmol, 1 equiv.) Of octanoyl chloride are added and then the reaction mixture is stirred for 0.5 hours at room temperature. The reaction is stopped by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (80/20 heptane / ethyl acetate). 300 mg of octanoyl (4-bromothiophene-2-ylmethyl) methylamide are obtained. Yield = 35%.

b. Ethyl 3- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] acrylate

1.1 g (4.3 mmol, 1.1 equiv.) Of pinacoldiborane are added to a mixture of 1.0 g (3.9 mmol, 1 equiv.) Of ethyl 4-bromocinnamate and 1.1 g (11, 7 mmol, 3 equiv.) Of potassium acetate in the presence of 142 mg (0.19 mmol, 5% by mol) of diphenylphosphineoferrocenopaladium dichloride (PdCl2dppf) in 10 ml of dimethylformamide. The mixture is stirred for 2 hours at 70 ° C. The reaction is stopped by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel (90/10 heptane / ethyl acetate). 1.15 g of ethyl 3- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] acrylate are obtained in the form of an oil. Yield = 98%.

C. Ethyl 3- (4- {5 - [(Methyloctanoylamino) methyl] thiophene-3-yl} phenyl) acrylate

300 mg (0.90 mmol, 1.0 equiv.) Of octanoyl (4-bromothiophene-2-ylmethyl) methylamide and 326 mg (1.08 mmol, 1.2 equiv.) Of 3- [4- ( 4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] ethyl acrylate in 4 ml of a 5/1 mixture of dimethylformamide and a 2M solution of potassium phosphate. 52 mg (0.04 mmol, 5 mol%) of tetrakis (triphenylphosphine) -palladium are added and the reaction mixture is then stirred for 2 hours at 80 ° C. The reaction stops

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adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (80/20 to 60/40 heptane / ethyl acetate). 250 mg of ethyl 3- (4- {5 - [(methyloctanoylamino) methyl] thiophene-3yl} phenyl) acrylate are obtained. Yield = 65%.

d. 3- (4- {5 - [(Methyloctanoylamino) methyl] thiophene-3-yl} phenyl) acrylic acid

230 mg (5.8 mmol, 10 equiv.) Of sodium hydroxide are added to a solution of 250 mg (0.58 mmol, 1 equiv.) Of 3- (4- {5 - [(methyloctanoylamino) methyl] thiophene) 3-yl} phenyl) ethyl acrylate in 4 ml of 9/1 tetrahydrofuran / methanol. The reaction mixture is stirred for 2 hours at room temperature. The reaction is stopped by adding 20 ml of water and 3 ml of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel (90/10 dichloromethane / methanol). The oil obtained is crystallized from pentane. 80 mg of 3- (4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) acrylic acid are obtained. Yield = 35%. m.p. = 175 ° C.

1 H NMR (CDCl 3, 400 MHz): 0.88 (m, 3 H); 1.33 (m, 8H); 1.70 (m, 2 H); 2.38 and 2.48 (2t (rotamers), J = 7.6 Hz, 2H); 3.05 and 3.06 (2s (rotamers), 3H); 4.71 and 4.76 (2s (rotamers), 2H); 6.47 and 6.49 (2d (rotamers), J = 15.9 Hz, 1H); 6.76 (m, 2H); 7.28 (m, 1 H); 7.44 (m, 1 H); 7.60 (m, 4 H); 7.80 (2d (rotamers), J = 15.9 Hz, 1H).

Example 5: 3- (4- {5 - [(Methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoic acid

image 1

to. Ethyl 3- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] propanoate

A solution of 8 g (26.4 mmol) of ethyl 3- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] ethyl acrylate in 30 ml of methanol it is stirred for one hour at room temperature in the presence of 400 mg of 10% palladium on carbon in a hydrogen atmosphere. The catalyst is removed by filtration and the solvents are then removed by evaporation. 7.8 g of ethyl 3- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] propanoate are obtained. Yield = 96%.

b. Ethyl 3- (4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoate

430 mg (1.29 mmol, 1 equiv.) Of octanoyl (4-bromothiophene-2-ylmethyl) methylamide and 470 mg (1.55 mmol, 1.2 equiv.) Of 3- [4- (4, 4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] propanoate in 4 ml of a 6/1 mixture of dimethylformamide and a 2M solution of potassium phosphate. 15 mg (0.064 mmol, 5% by mol) of palladium acetate and 45 mg (0.129 mmol, 10% by mol) of dicyclohexyl-2-biphenylphosphine are added. The mixture is stirred for 2 hours at 90 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to silica gel chromatography (from 80/20 to 70/30 heptane / ethyl acetate). 245 mg of ethyl 3- (4- {5 [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoate are obtained. Yield = 44%.

C. 3- (4- {5 - [(Methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoic acid

100 mg (2.5 mmol, 4 equiv.) Of sodium hydroxide are added to a solution of 245 mg (0.57 mmol, 1 equiv.) Of 3- (4- {5 - [(methyloctanoylamino) methyl] thiophene) 3-yl} phenyl) ethyl propanoate in 4 ml of 9/1 tetrahydrofuran / methanol. The reaction mixture is stirred for two hours at room temperature. The reaction is stopped by adding 20 ml of water and 3 ml of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel (90/10 dichloromethane / methanol). The oil obtained is crystallized from pentane. 85 mg of 3- (4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoic acid are obtained. Yield = 37%.

1 H NMR (CDCl 3, 400 MHz): 0.89 (m, 3 H); 1.32 (m, 8H); 1.70 (m, 2 H); 2.37 and 2.48 (2t (rotamers), J = 7.2 Hz, 2H); 2.71 (t, 2H, J = 7.6 Hz); 2.99 (m, 2H); 3.02 (s, 3 H); 4.74 and 4.69 (2s (rotamers), 2H); 7.18-7.34 (m, 4H); 7, 50 (d, J = 3.2 Hz, 2H).

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Example 6: 3- {4- [6- (3-Heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

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to. Tert-Butyl (6-Bromopyrid-2-yl) Carbamate

62 g (284 mmol) of di-tert-butyl dicarbonate diluted in 200 ml of dichloromethane are added dropwise to a solution of 49.2 g (284 mmol) of 2-amino-6-bromopyridine, 43.4 ml (312 mmol) of triethylamine and 3.5 g (28.4 mmol) of 4-dimethylaminopyridine in 400 ml of dichloromethane. The reaction mixture is stirred at room temperature for 18 hours. After the addition of water and extraction with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a silica column eluting with a 95/5 mixture of heptane / ethyl acetate. 39 g (50%) of tert-butyl (6-bromopyrid-2-yl) carbamate are obtained as a white solid.

b. Tert-Butyl 6-Bromopyrid-2-yl-N-methylcarbamate

To a solution of 39 g (14.3 mmol) of tert-butyl (6-bromopyrid-2-yl) carbamate in 400 ml of dimethylformamide is added in portions 6.9 g (17.2 mmol) of sodium hydride 60% in oil. After stirring for 20 minutes at room temperature, 17.8 ml (28.6 mmol) of methyl iodide are added dropwise. The reaction medium is stirred at room temperature for 18 hours, collected in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated.

C. Ethyl 3- {4- [6- (tert-butoxycarbonylmethylamino) pyrid-2-yl] phenyl} acrylate

1.25 g (4.13 mmol, 1.2 equiv.) Of 3- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] acrylate are dissolved of ethyl and 1.0 g (3.48 mmol, 1 equiv.) of tert-butyl (6-bromopyrid-2-yl) -methylcarbamate in 15 ml of a 6/1 mixture of dimethylformamide and a 2 M solution of potassium phosphate. 200 mg (0.173 mmol, 5 mol%) of tetrakis (triphenylphosphine) palladium are added. The mixture is stirred for 3 hours at 90 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (80/20 to 70/30 heptane / ethyl acetate). 850 mg of ethyl 3- {4- [6- (tert-butoxycarbonylmethylamino) pyrid-2-yl] phenyl} acrylate are obtained. Yield = 64%.

d. Ethyl 3- {4- [6- (3-Heptyl-1-methylureido) pyrid-2-yl] phenyl} acrylate

300 mg (0.78 mmol) of ethyl 3- {4- [6- (tert-butoxycarbonylmethylamino) pyrid-2-yl] phenyl} ethyl acrylate are dissolved in 5 ml of dichloromethane. 2 ml of trifluoroacetic acid are added. The reaction mixture is stirred for 3 hours at room temperature. The reaction is stopped by adding 30 ml of a saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the oil obtained is dissolved in 5 ml of dichloromethane in the presence of 1 ml of triethylamine. 630 µl (3.9 mmol, 5 equiv.) Of heptyl isocyanate are added together with 100 mg of dimethylaminopyridine. The reaction mixture is stirred for 16 hours at reflux. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to silica gel chromatography (from 80/20 to 70/30 heptane / ethyl acetate). 170 mg of ethyl 3- {4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} acrylate are obtained. Yield = 51%.

and. 3- {4- [6- (3-Heptyl-1-methylureido) pyrid-2-yl] phenyl} -propanoic acid

170 mg (0.4 mmol) of ethyl 3- {4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} acrylate are dissolved in 5 ml of methanol. 50 mg of 10% palladium on carbon are added. The reaction mixture is stirred for 3 hours at room temperature under a hydrogen atmosphere. The catalyst is removed by filtration, then the solvents are removed by evaporation and the oil obtained is used directly in the next reaction. 170 mg of sodium hydroxide are added to the solution of ethyl 3- {4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoate in 5 ml of 9/1 tetrahydrofuran / methanol . The reaction mixture is stirred for two hours at room temperature. The reaction is

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Stop adding 20 ml of water and 3 ml of acetic acid and then extract with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (7/3 to 1/1 heptane / EtOAc). 110 mg of 3- {4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid are obtained. Yield = 69% in two stages. m.p. = 108 ° C.

1 H NMR (CDCl 3, 400 MHz): 0.87 (t, J = 7.0 Hz, 3H); 1.20-1.36 (m, 8H); 1.61 (m, 2 H); 2.76 (t, J = 7.7 Hz, 2H); 3.06 (t, 2H, J = 7.7 Hz) 3.38 (c, J = 5.5 Hz, 2H); 3.47 (s, 3 H); 6.94 (d, J = 8.4 Hz, 1H); 7.35 (m, 3 H); 7.76 (t, J = 7.8 Hz, 1H); 7.81 (d, J = 8.0 Hz, 2H); 10.48 (s, 1 H).

Example 7: 3- {6- [3- (3-Heptyl-1-methylureido) phenyl] -pyrid-2-yl} propanoic acid

image 1

to. Tert-Butyl (3-Bromophenyl) Carbamate

To a mixture of 94 g (549 mmol) of 3-bromoaniline and 1 l of dichloromethane are added portionwise, at room temperature, 120 g (549 mmol) of di-tert-butyl dicarbonate. After stirring for 18 hours, the reaction medium is poured into ice-water and then extracted with dichloromethane. The organic phase is removed by separation by decanting the phases, dried over magnesium sulfate and evaporated. 138 g of tert-butyl (3-bromophenyl) carbamate are obtained in 98% yield.

b. Tert-Butyl (3-Bromophenyl) -N-methylcarbamate

To a solution of 114 g (447 mmol) of tert-butyl (3-bromophenyl) carbamate in 800 ml of DMF are added in portions 19 g (475 mmol) of sodium hydride (60% in oil) and the medium The reaction is stirred until the gas evolution ceases. 29.3 ml (470 mmol) of methyl iodide are added dropwise and stirring continues for 18 hours. The reaction medium is poured into ice-water and extracted with ethyl acetate. The organic phase is removed by separation by decanting the phases, dried over magnesium sulfate and evaporated. 115 g of tert-butyl (3-bromophenyl) N-methylcarbamate are obtained in 95% yield.

C. (3-Bromophenyl) methylamine

5 ml of trifluoromethanesulfonic acid are added to a solution of 3.6 g (12.7 mmol) of tert-butyl (3-bromophenyl) -methylcarbamate in 15 ml of dichloromethane. The reaction medium is stirred for 1 hour at room temperature (RT). The reaction is stopped by adding 50 ml of a saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel, eluting with 1/1 heptane / ethyl acetate. 2.14 g of oil are obtained. 90% yield.

d. N-methyl-3-aminophenylboronic acid

37.6 g (202 mmol, 1 equiv.) Of (3-bromophenyl) methylamine (obtained as in 1c) are dissolved in 300 ml of tetrahydrofuran. The reaction mixture is cooled to -70 ° C and then 166 ml (242 mmol, 1.2 equiv.) Of 1.5 M methyl lithium are slowly added, while maintaining at -70 ° C. The reaction mixture is stirred for 1 hour at -70 ° C. 306 ml (444 mmol, 2.2 equiv.) Of 1.46 M tert-butyllithium are added, while maintaining the temperature at -70 ° C. The reaction mixture is stirred for 45 minutes at -70 ° C. 103.5 ml (808 mmol, 4 equiv.) Of trimethyl borate are added at 65 ° C and then the reaction mixture is heated to room temperature. The reaction is stopped by adding 1 L of 1 N hydrochloric acid. The pH is adjusted to pH 5 and then the reaction medium is extracted with n-butanol. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (70/30 heptane / ethyl acetate). 11.3 g of N-methyl3-aminophenylboronic acid are obtained. Yield = 40%.

and. [3- (5-Bromopirid-2-yl) phenyl] methylamine

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2.2 g (9.5 mmol, 1.2 equiv.) Of 2,5-dibromopyridine are dissolved in 3 ml of an 8/2 mixture of dimethylformamide / 2M potassium phosphate. 1.2 g (7, 9 mmol, 1 equiv.) Of N-methyl-3-aminophenylboronic acid with 456 mg (0.39 mmol, 5% by mol) of tetrakis (triphenylphosphine) palladium. The mixture is stirred for 3 hours at 90 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is subjected to chromatography on silica gel (from 80/20 to 70/30 heptane / ethyl acetate). 1.07 g of [3- (5-bromopyrid-2-yl) phenyl] methylamine are obtained. Yield = 52%.

F. [3- (5-Bromopyrid-2-yl) phenyl} methyl-carbamate tert-butyl

1.07 g (4 mmol, 1 equiv.) Of [3- (5-bromopyrid-2-yl) phenyl] methylamine are dissolved in 10 ml of dichloromethane in the presence of 1 ml of triethylamine and 200 mg of dimethylaminopyridine. 1.7 g (8 mmol, 2 equiv.) Of tert-butyl dicarbonate are added and the reaction mixture is stirred overnight at 40 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (70/30 heptane / ethyl acetate). 1.18 g of tert-butyl [3- (5-bromopyrid-2-yl) phenyl} methylcarbamate are obtained. Yield = 81%.

g. 3- {6- [3- (tert-Butoxycarbonylmethylamino) -phenyl} pyrid-3-yl} ethyl acrylate

1.18 g of tert-butyl [3- (5-bromopyrid-2-yl) phenyl} methylcarbamate (3.25 mmol, 1 equiv.) Are dissolved in 10 ml of dimethylformamide and 1 ml of triethylamine. 110 mg (0.48 mmol, 15%) of palladium acetate and 296 mg (0.96 mmol, 30%) of o-tolylphosphine are added, together with 1 ml of ethyl acrylate. The reaction mixture is stirred overnight at 80 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (70/30 heptane / ethyl acetate). 852 mg of ethyl 3- {6- [3- (tert-butoxycarbonylmethylamino) phenyl} pyrid-3-yl} acrylate are obtained. Yield = 68%.

h. Ethyl 3- [6- (3-Methylaminophenyl) pyrid-3-yl] propanoate

A solution of 852 mg (2.23 mmol) of ethyl 3- {6- [3- (tert-butoxycarbonylmethylamino) phenyl} pyrid-3-yl} acrylate in 10 ml of methanol is stirred for 4 hours at room temperature in presence of 100 mg of 10% palladium on carbon in a hydrogen atmosphere. The catalyst is removed by filtration and then the solvents are removed by evaporation. The oil obtained is dissolved in 15 ml of dichloromethane. 2 ml of trifluoroacetic acid are added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is stopped by adding 100 ml of a saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (70/30 heptane / ethyl acetate). 710 mg of ethyl 3- [6- (3-methylaminophenyl) pyrid-3-yl] propanoate are obtained. Yield = 68%.

i. Ethyl 3- {6- [3- (3-Heptyl-1-methylureido) phenyl] pyrid-3-yl} propanoate

572 µl (3.5 mmol, 2 equiv.) Of heptyl isocyanate are added to a solution of 500 mg (1.76 mmol, 1 equiv.) Of 3- [6- (3-methylaminophenyl) pyrid-3- Ethyl] ethyl propanoate in 10 ml of a 4/1 tetrahydrofuran / triethylamine mixture. The reaction mixture is stirred for 24 hours at 40 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (70/30 heptane / ethyl acetate). 488 mg of ethyl 3- {6- [3- (3-heptyl-1-methylureido) phenyl] pyrid-3-yl} propanoate are obtained. Yield = 65%.

j. 3- {6- [3- (3-Heptyl-1-methylureido) phenyl] pyrid-3-yl} propanoic acid

200 mg (5 mmol, 4 equiv.) Of sodium hydroxide are added to a solution of 488 mg (1.14 mmol, 1 equiv.) Of 3- {6- [3- (3-heptyl-1-methylureido) phenyl ] ethyl pyrid-3-yl} propanoate in 6 ml of 9/1 tetrahydrofuran / methanol. The reaction mixture is stirred for 3 hours at room temperature. The reaction is stopped by adding 20 ml of water and 3 ml of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (70/30 to 50/50 heptane / ethyl acetate). The oil obtained is crystallized from pentane. 442 mg of 3- {6- [3- (3-heptyl-1-methylureido) phenyl] pyrid-3-yl} propanoic acid are obtained. Yield = 94%. m.p. = 118 ° C.

1 H NMR (CDCl 3, 400 MHz): 0.85 (t, J = 6.8 Hz, 3H); 1.25 (m, 8H); 1.40 (m, 2 H); 2.74 (t, J = 7.4 Hz, 2H); 3.05 (t, J = 7.3 Hz, 2H); 3.17 (c, J = 6.0 Hz, 2H); 3.32 (s, 3 H); 4.42 (m, 1 H); 7.29 (m, 1 H); 7.52 (t, J = 8.0 Hz, 1H); 7.66 (m, 2H); 7.86 (m, 2H); 8.63 (m, 1 H).

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Example 8: 2- [4- (2-Carboxyethyl) phenyl] -4- (3-heptyl-1-methylureido) pyridinium acetate

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to. Tert-Butyl (2-Chloropyrid-4-yl) Carbamate

1.69 g (7.78 mmol, 1 equiv.) Of tert-butyl dicarbonate dissolved in 50 ml of dichloromethane, in the presence of 95 mg of dimethylaminopyridine, are added to a solution of 1 g (7.78 mmol, 1 equiv.) of 4-amino-2-chloropyridine in 30 ml of dichloromethane in the presence of 1.19 ml (1.19 mmol, 1.1 equiv.) of triethylamine. The reaction mixture is stirred overnight at room temperature. The reaction is stopped by adding 100 ml of water and then extracted with dichloromethane. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (70/30 to 50/50 heptane / ethyl acetate). The oil obtained is crystallized from pentane. 1.40 g of tert-butyl (2-chloropyrid-4-yl) carbamate are obtained. Yield = 80%.

b. Tert-Butyl (2-Chloropyrid-4-yl) methylcarbamate

A solution of 17.5 g (76.7 mmol, 1 equiv.) Dissolved in 100 ml of dimethylformamide is added to a suspension of 3.57 g (92 mmol, 1.2 equiv.) Of sodium hydride in 100 ml of dimethylformamide at 0 ° C. The reaction mixture is stirred for 30 minutes at room temperature. 9.26 ml (148 mmol, 2 equiv.) Of methyl iodide are added to the reaction mixture and then the reaction medium is stirred for 2 hours at room temperature. The reaction is stopped by adding 100 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation. 18 g of tert-butyl (2-chloropyrid-4-yl) methylcarbamate are obtained. Yield = 97%.

C. Ethyl 3- {4- [4- (tert-butoxycarbonylmethylamino) pyrid-2-yl] phenyl} propanoate

500 mg (2.06 mmol, 1 equiv.) Of tert-butyl (2-chloropyrid-4-yl) methylcarbamate and 750 mg (2.47 mmol, 1.2 equiv.) Of 3- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] ethyl propanoate (obtained as in 5a) in 10 ml of an 8/2 mixture of dimethylformamide / 2M potassium phosphate 23 mg (0.123 mmol, 5% by mol) of palladium acetate and 71 mg (0.24 mmol, 10% by mol) of dicyclohexyldiphenylphosphine are added. The mixture is stirred for 4 hours at 90 ° C. The reaction is stopped by adding 30 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to silica gel chromatography (from 80/20 to 70/30 heptane / ethyl acetate). 415 mg of ethyl 3- {4- [4- (tert-butoxycarbonylmethylamino) pyrid-2-yl] phenyl} propanoate are obtained. Yield = 52%.

d. Ethyl 3- [4- (4-Methylaminopyrid-2-yl) phenyl] propanoate

415 mg (1.08 mmol, 1 equiv.) Of ethyl 3- {4- [4- (tert-butoxycarbonylmethylamino) pyrid-2-yl] phenyl} propanoate are dissolved in 10 ml of dichloromethane. 3 ml of trifluoroacetic acid are added and the reaction mixture is stirred for 4 hours at room temperature. The reaction is stopped by adding 100 ml of a saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation. 270 mg of ethyl 3- [4- (4-methylaminopyrid-2-yl) phenyl] propanoate are obtained. Yield = 88%.

and. Ethyl 3- {4- [4- (3-Heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoate

270 mg (0.63 mmol, 1 equiv.) Of ethyl 3- [4- (4-methylaminopyrid-2-yl) phenyl] propanoate are mixed with 0.6 ml (3.7 mmol, 6 equiv.) Of Heptyl isocyanate and then irradiated twice in a microwave machine for 30 minutes, while maintaining the constant temperature at 100 ° C. The reaction mixture is chromatographed on silica gel (90/10 heptane / ethyl acetate). 260 mg of ethyl 3- {4- [4- (3-heptyl-1-methylureido) pyrid-2yl] phenyl} propanoate are obtained. Yield = 64%.

F. 2- [4- (2-Carboxyethyl) phenyl] -4- (3-heptyl-1-methylureido) pyridinium acetate

100 mg (2.5 mmol, 4 equiv.) Of sodium hydroxide are added to a solution of 260 mg (0.61 mmol, 1 equiv.) Of

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Ethyl 3- {4- [4- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoate in 5 ml of 9/1 tetrahydrofuran / methanol. The reaction mixture is stirred for two hours at room temperature. The reaction is stopped by adding 20 ml of water and 3 ml of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is crystallized from pentane. 143 mg of 2- [4- (2-Carboxyethyl) phenyl) -4- (3-heptyl-1-methylureido) pyridinium acetate are obtained. Yield = 59%. m.p. = 71-73 ° C.

1 H NMR (CDCl 3, 400 MHz): 0.88 (t, J = 7.2 Hz, 3 H); 1.32 (m, 8H); 1.58 (m, 2 H); 2.11 (s, 3 H); 2.70 (t, J = 6.9 Hz, 2H); 3.00 (t, J = 6.9 Hz, 2H); 3.29 (c, J = 6.3 Hz, 2H); 3.38 (s, 3 H); 6.14 (m, 1 H); 7.12 (d, J = 5.6 Hz, 1H); 7.31 (d, J = 7.6 Hz, 2H); 7.51 (s, 1 H); 7.79 (d, J = 7.6 Hz, 2H); 8.43 (d, J = 5.5 Hz, 1H).

Example 9: 3- {5- [3- (1-methyl-3-pentylureido) phenyl] -pyrimidin-2-yl) acrylic acid

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to. 3- (N-methyl-N-tert-butoxycarbonyl) phenylboronic acid

18.5 ml (46.2 mmol, 1.3 equiv.) Of 2.5 M butyl lithium in hexane are added to a solution of 10 g (34.9 mmol, 1 equiv.) Of (3-bromophenyl) methylcarbamate of tert-butyl (obtained as in 7b) in 25 ml of tetrahydrofuran cooled to 78 ° C. The reaction mixture is stirred for 30 minutes at -78 ° C and then 10 ml (41.9 mmol, 1.2 equiv.) Of diisopropyl borate are added dropwise. The reaction mixture is stirred at -78 ° C for 2 hours. The reaction is stopped by adding 70 ml of 1 N hydrochloric acid at -10 ° C and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation. 9.17 g of 3- (Nmethyl-N-tert-butoxycarbonyl) phenylboronic acid are obtained in 100% crude yield.

b. [3- (2-Bromopyrimidin-5-yl) phenyl] methyl-carbamate tert-butyl

22 ml of 2M potassium carbonate (43.9 mmol, 2.5 equiv.) Are added dropwise to a solution of 3- (Nmethyl-N-tert-butoxycarbonyl) phenylboronic acid (5.3 g, 21.06 mmol, 1.2 equiv.) and 5-bromo-2-iodopyrimidine (5 g, 17.6 mmol, 1 equiv.) in 50 ml of diethyl ether. The reaction medium is degassed with nitrogen for 30 minutes and then tetrakis (triphenylphosphine) palladium (1.01 g, 0.88 mmol, 0.05 equiv.) Is added. The reaction mixture is stirred overnight at 100 ° C. The reaction is stopped by adding water and then extracted with ethyl acetate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel (90/10 heptane / ethyl acetate). 1.87 g of tert-butyl [3- (2-bromopyrimidin-5-yl) phenyl] methylcarbamate are obtained in the form of a beige solid with a yield of 30%.

C. Methyl 3- {5- [3- (tert-butoxycarbonylmethylamino) -phenyl] pyrimidin-2-yl} acrylate

0.25 ml (2.75 mmol, 2 equiv.) Of methyl acrylate, 9.3 mg (0.04 mmol, 0.3 equiv.) Of palladium acetate and 25 mg (0.08 mmol, are added. 0.06 equiv.) Of tri-ortho-tolylphosphine in a solution of 0.5 g (1.37 mmol, 1 equiv.) Of tert-butyl [3- (2-bromopyrimidin-5-yl) phenyl] methylcarbamate in 0 , 5 ml of dimethylformamide. The reaction mixture is heated at 80 ° C overnight. The reaction is stopped by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (95/5 heptane / ethyl acetate). 377.7 mg of methyl 3 {5- [3- (tert-butoxycarbonylmethylamino) -phenyl] pyrimidin-2-yl} acrylate are obtained as a beige solid. Yield = 75%.

d. Methyl 3- (3'-Methylaminobiphenyl-4-yl) acrylate

0.16 ml (2.04 mmol, 5 equiv.) Of trifluoroacetic acid is added to a solution 151 mg (0.4 mmol, 1 equiv.) Of 3- {5 '- [3- (tert-butoxycarbonylmethylamino) - Phenyl] pyrimidin-2-yl} methyl acrylate in 3 ml of dichloromethane. The reaction mixture is stirred for eight hours at room temperature. The reaction is stopped by adding an aqueous solution of ammonia and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is taken up in heptane. 71.6 mg of

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Methyl 3- (3'-methylaminobiphenyl-4-yl) acrylate as a yellow solid. Yield = 65%.

and. Methyl 3- {5- [3- (1-Methyl-3-pentylureido) phenyl] -pyrimidine-2-acrylate

22 µl (0.53 mmol, 1 equiv.) Of pentyl isocyanate are added dropwise to a solution of 71.6 mg (0.27 mmol, 1 equiv.) Of 3- [5- (3-methylaminophenyl) ) methyl pyrimidin-2-yl] acrylate and 22 µl of triethylamine in 2 ml of dichloromethane. The reaction mixture is stirred for 2 days at room temperature. The reaction is stopped by adding 10 ml of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on silica gel (70/30 heptane / ethyl acetate). 37.6 mg of methyl 3- {5- [3- (1-methyl-3-pentylureido) phenyl] pyrimidine-2-acrylate are obtained in the form of white crystals. Yield = 38%.

F. 3- {5- [3- (1-methyl-3-pentylureido) phenyl] pyrimidin-2-yl} acrylic acid

10 mg (242.5 mol, 2.5 equiv.) Of granules of sodium hydroxide are added to a solution of 37.6 mg (97 mol, 1 equiv.) Of 3- {5- [3- (1 -methyl-3-pentylureido) phenyl] pyrimidine-2-acrylate in 2 ml of tetrahydrofuran and 4 drops of water. The reaction mixture is stirred for 8 hours at room temperature. The reaction medium is concentrated, then diluted with 10 ml of water and washed with 10 ml of dichloromethane twice. The aqueous phase is acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is chromatographed on a preparative silica plate (95/5 / 0.5% dichloromethane / methanol / aqueous ammonia). 7.9 mg of 3- {5- [3- (1-methyl3-pentylureido) phenyl] pyrimidin-2-yl} acrylic acid are obtained in the form of beige crystals. Yield = 22%.

1 H NMR (CDCl 3, 400 MHz): 0.88 (t, J = 7 Hz, 3 H); 1.27 (m, 4 H); 1.42 (m, 2 H); 3.18 (c, J = 6.8 Hz, 2H); 3.37 (s, 3 H); 4.41 (t, J = 5.5 Hz, 1H); 6.67 (6, J = 16.2 Hz, 1H); 7.44 (d, J = 7.8 Hz, 1H); 7.58 (t, J = 7.8 Hz, 1H); 7.76 (d, J = 16.2 Hz, 1H); 8.42 (m, 2H); 8.99 (s, 2H).

EXAMPLE 10: 3- {5- [3- (1-methyl-3-pentylureido) phenyl] -pyrimidin-2-yl) propanoic acid

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to. Methyl 3- {5- [3- (tert-butoxycarbonylmethylamino) -phenyl] pyrimidin-2-yl} propanoate

30 mg of 10% Pd / C are added to a solution of 0.3 g (0.81 mmol, 1 equiv.) Of 3- {5- [3- (tert-butoxycarbonylmethylamino) phenyl] pyrimidin-2-yl } methyl acrylate (obtained as in 9c) in 3 ml of methanol, in a PARR pump. The reaction mixture is placed at a hydrogen pressure of 3 bar and then heated at 50 ° C for 12 hours. The reaction medium is cooled to room temperature, then degassed with nitrogen and filtered through Celite. After evaporating the solvents, the residue is chromatographed on silica gel (90/10 heptane / ethyl acetate). 118.2 mg of methyl 3- {5- [3- (tert-butoxycarbonylmethylamino) phenyl] pyrimidin-2-yl} propanoate are obtained as a colorless oil. Yield = 40%.

b. Methyl 3- [5- (3-Methylaminophenyl) pyrimidin-2-yl] propanoate

0.12 ml (1.6 mmol, 5 equiv.) Of trifluoroacetic acid is added to a solution of 118 mg (0.32 mmol, 1 equiv.) Of 3- {5- [3- (tert-butoxycarbonylmethylamino) - methyl phenyl] pyrimidin-2-yl} propanoate in 4 ml of dichloromethane. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by adding 20 ml of a 1 N sodium hydroxide solution and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is subjected to chromatography on silica gel (99/1 dichloromethane / methanol). 163 mg of methyl 3- [5- (3-methylaminophenyl) pyrimidin-2-yl] propanoate are obtained as a colorless oil. Yield = 99%.

C. Methyl 3- {5- [3- (1-Methyl-3-pentylureido) phenyl] -pyrimidin-2-yl} propanoate

133 mg (0.66 mmol, 1.1 equiv.) Of 4-nitrophenyl chloroformate are added to a solution, cooled to 0 ° C, of

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163 mg (0.6 mmol, 1 equiv.) Of 3- [5- (3-methylaminophenyl) pyrimidin-2-yl] propanoate and 0.1 ml (0.72 mmol, 1.2 equiv.) In 5 ml of dichloromethane. The reaction mixture is stirred for 12 hours at room temperature. The reaction is stopped by adding 20 ml of water, dried over sodium sulfate, filtered and the solvents removed by evaporation. The residue is taken up in 3 ml of dimethylformamide and then 69 I (0.6 mmol, 1 equiv.) Of N-amylamine is added. The reaction medium is heated at 80 ° C for 4 hours, then poured onto ice and extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, the solvents are concentrated and then the residue is chromatographed on silica gel (60/40 heptane / ethyl acetate).

111.9 mg of methyl 3- {5- [3- (1-methyl-3-pentylureido) phenyl] pyrimidin-2-yl} propanoate are obtained in the form of a yellow oil. Yield = 48%.

d. 3- {5- [3- (1-methyl-3-pentylureido) phenyl] pyrimidin-2-yl} propanoic acid

1.44 ml (1.45 mmol, 5 equiv.) Of lithium hydroxide are added to a solution of 111 mg (0.29 mmol, 1 equiv.) Of 3- {5- [3- (1-methyl- 3-pentylureido) -phenyl] pyrimidin-2-yl} methyl propanoate in 3 ml of tetrahydrofuran. The reaction mixture is stirred for four hours at room temperature. The reaction is stopped by adding 10 ml of water, washed with ether, then acidified with a 1 N solution of hydrochloric acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are removed by evaporation and then the residue is crystallized from ether. 66.7 mg of 3- {5- [3- (1-methyl-3-pentylureido) phenyl] pyrimidin-2-yl} propanoic acid are obtained in the form of white crystals. Yield = 48%.

1 H NMR (CDCl 3, 400 MHz): 0.84 (t, J = 7.0 Hz, 3 H); 1.25 (m, 4 H); 1.39 (m, 2 H); 2.78 (t, J = 7.3 Hz, 2H); 3.03 (t, J = 7.2, 2H); 3.17 (c, J = 7.2 Hz, 2H); 3.19 (s, 3 H); 4.41 (t, J = 5.4 Hz, 1H); 7.38 (m, 1 H); 7.55 (t, J = 8 Hz, 1H); 8.35 (m, 2H); 8.75 (s, 2H).

EXAMPLE 11: 2- [2-Butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-pentylureido) pyridinium hydrochloride

image 1

to. 6-Methylamino-2-bromopyridine

30 g (0.13 mol) of 2,6-dibromopyridine are added to a solution of 225 ml (2.39 mol) of methylamine in ethanol (33% by weight, Aldrich) previously cooled to 0 ° C. The reaction is heated at 80 ° C with stirring for 20 hours, in a glass system equipped with a pressure gauge. The reaction is controlled with TLC control. The reaction medium is cooled to 0 ° C and the whole is opened. The slightly brown solution obtained in this way is concentrated in vacuo to give a volume of 60 ml and then water (240 ml) is added followed by the addition of an aqueous solution of sodium carbonate (2 N, 240 ml). The beige precipitate that forms is filtered off, washed with water and dissolved in dichloromethane (200 ml). The solution is dried over magnesium sulfate and the solvent is removed by evaporation. The addition of heptane allows the precipitation of 17.5 g (74%) of 6-methylamino-2-bromopyridine in the form of a beige powder.

b. 1- (6-Bromopirid-2-yl) -1-methyl-3-pentylurea

2 g of 6-methylamino-2-bromopyridine are mixed with 3.0 ml of pentyl isocyanate. The mixture is heated for 12 hours at 100 ° C. The residue is chromatographed on silica (9/1 heptane / ethyl acetate). 1.8 g of 1- (6-bromopyrid-2-yl) -1-methyl-3-pentylurea are obtained. Yield = 56%.

C. Methyl 3-Butoxy-4-Iodobenzoate

21.5 ml (0.189 mol, 1.5 equiv.) Of 1-iodobutane are added to a solution of 35.03 g (0.126 mol, 1 equiv.) Of methyl 3-hydroxy-3-iodobenzoate in 350 ml of methyl ethyl ketone in the presence of 52.24 g (0.388 mol, 3 equiv.) of potassium carbonate. The reaction medium is heated at 85 ° C for 2 hours. The solid is filtered off and the solvent is removed by evaporation. The solid obtained is washed with heptane to give 41.78 g of methyl 3-butoxy-4-iodobenzoate as white crystals. Yield = 99%.

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d. (3-Butoxy-4-iodophenyl) methanol

8.17 g (0.375 mol, 3 equiv.) Of lithium borohydride are added to a solution of 41.78 g (0.125 mol, 1 equiv.) Of methyl 3-butoxy-4-iodobenzoate in 210 ml of tetrahydrofuran. The reaction medium is heated at 60 ° C for 2 hours and then carefully hydrolyzed with a saturated solution of ice-cold ammonium chloride. The reaction medium is neutralized with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic phases are washed with water and dried over magnesium sulfate. The solvent is removed by evaporation to give 38.31 g of (3-butoxy-4-iodophenyl) methanol as an off-white oil. Yield = 100%.

and. 3-butoxy-4-iodobenzaldehyde

89.5 g (0.875 mol, 7 equiv.) Of manganese dioxide are added to a solution of 38.30 g (0.125 mol, 1 equiv.) Of (3-butoxy-4-iodophenyl) methanol in 250 ml of dichloromethane . The reaction medium is stirred at room temperature for 18 hours and then filtered through silica gel. The solvent is removed by evaporation to give 29.61 g of 3-butoxy-4-iodobenzaldehyde as an orange oil. Yield = 78%.

F. (E) -3- (3-Butoxy-4-iodophenyl) methyl acrylate

65.08 g (0.195 mol, 2 equiv.) Of methyl (triphenylphosphoranylidene) acetate are added to a solution of 29.60 g (0.097 mol, 1 equiv.) Of 3-butoxy-4-iodobenzaldehyde in 360 ml of toluene . The reaction mixture is heated at reflux for 2 hours. The solvent is removed by evaporation and the oil obtained is subjected to chromatography on silica gel (50/50 heptane / dichloromethane). 30.47 g of methyl (E) -3- (3-butoxy-4-iodophenyl) acrylate are obtained as pale yellow crystals. Yield = 87%.

g. (E) -3- [3-Butoxy-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] methyl acrylate

2.0 g of methyl (E) -3- (3-butoxy-4-iodophenyl) acrylate are dissolved in 10 ml of dimethylformamide and 1.8 g of pinacoldiborane are added, together with 226 mg of diphenylphosphoferoferlocene palladium dichloride and 1 , 6 g of potassium acetate. The mixture is stirred for 3 hours at 90 ° C. The reaction is hydrolyzed and extracted with ethyl acetate. After evaporation of the solvents and chromatography on silica gel (eluent = 7/3 heptane / ethyl acetate), 1.10 g of (E) -3- [3-butoxy-4- (4 , 4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] methyl acrylate. Yield = 55%.

h. (E) -3- {3-Butoxy-4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} methyl acrylate

496 mg of (E) -3- [3-Butoxy-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) phenyl] methyl acrylate are dissolved in 5 ml of dimethylformamide and 1 ml of a 2 N solution of potassium phosphate. 350 mg of 1- (6-bromopyrid-2-yl) -1methyl-3-phenylurea are added, together with 5 mg of palladium acetate and 16 mg of dicyclohexylbiphenylphosphine. The mixture is stirred for 3 hours at 90 ° C and then hydrolyzed and extracted with ethyl acetate. After evaporation of the solvents and chromatography on silica gel (eluent = 7/3 heptane / ethyl acetate), 430 mg of (E) -3- {3-butoxy-4 [6- (1 methyl-3-pentylureido) methyl pyrid-2-yl] phenyl} acrylate. Yield = 82%.

i. Methyl 3- {3-Butoxy-4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} propionate

A solution of 430 mg of (E) -3- {3-butoxy-4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} methyl acrylate in 5 ml of methanol is stirred for 3 hours at room temperature in the presence of 100 mg of palladium on carbon, in an atmosphere of hydrogen. After removing the palladium by filtration and removing the solvents by evaporation, 370 mg of 3- {3-butoxy-4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} propionate are obtained of methyl Yield = 86%.

j. 2- [2-Butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-pentylureido) pyridinium hydrochloride

300 mg of sodium hydroxide are added to a solution of 370 mg of methyl 3- {3-butoxy-4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} propionate dissolved in 15 ml of a 8/2 tetrahydrofuran / methanol mixture. After stirring for 4 hours at room temperature, the reaction is stopped with water and acetic acid and then extracted with ethyl acetate. The solvents are removed by evaporation. The residual oil is chromatographed on silica gel (7/3 heptane / ethyl acetate). 5 ml of a solution of hydrogen chloride in ethyl acetate are added and the hydrochloride is precipitated by the addition of isopropyl ether. After filtering, 205 mg of 2- [2-butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-pentylureido) pyridinium hydrochloride are obtained. Yield = 53%.

1 H NMR (DMSO, 400 MHz): 0.80 (m, 3 H); 0.93 (m, 3 H); 1.24 (m, 4 H); 1.44 (m, 4 H); 1.74 (m, 2 H); 2.64 (m, 2 H); 2.92 (m, 2H); 3.39 (s, 3 H); 4.10 (m, 2 H); 6.98 (d, J = 8 Hz, 1H); 7.13 (s, 1 H); 7.24 (d, J = 8 Hz, 1H); 7.56 (m, 2H); 7.97 (m, 1 H); 9.70 (s, 1 H).

image22

EXAMPLE 12: 2- [2-Butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-heptylureido) pyridinium hydrochloride

image 1

to. (6-Bromopirid-2-yl) -1-methyl-3-heptylurea

5 2 g of 6-methylamino-2-brompyridine (prepared according to the procedure of Example 11, step a) are mixed with 3.0 ml of heptyl isocyanate. The mixture is heated for 12 hours at 100 ° C. The residue is chromatographed on silica gel (9/1 heptane / ethyl acetate). 2.45 g of 1- (6-bromopyrid-2-yl) -1-methyl-3-heptylurea are obtained. Yield = 71%.

b. 2- [2-Butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-heptylureido) pyridinium hydrochloride

10 300 mg of sodium hydroxide are added to a solution of 377 mg of methyl 3- {3-butoxy-4- [6- (1-methyl-3-heptylureido) pyrid-2-yl] phenyl} propionate (prepared according to the procedure of Example 11, steps cai, replacing 1- (6-bromopyrid-2-yl) -1-methyl-3-pentylurea with 1- (6-bromopyrid-2-yl) -1-methyl-3-heptylurea in step h) dissolved in 15 ml of an 8/2 tetrahydrofuran / methanol mixture. After stirring for 4 hours at room temperature, the reaction is stopped with water and acetic acid and then extracted with ethyl acetate. The solvents are

15 removed by evaporation. The residual oil is chromatographed on silica gel (7/3 heptane / ethyl acetate). 5 ml of a solution of hydrogen chloride in ethyl acetate are added, and the hydrochloride is precipitated by the addition of isopropyl ether. After filtration, 220 mg of 2- [2-butoxy-4- (2carboxyethyl) phenyl] -6- (1-methyl-3-heptylureido) pyridinium hydrochloride are obtained. Yield = 55%.

1 H NMR (DMSO, 400 MHz): 0.80 (m, 3 H); 0.88 (m, 3 H); 1.16 (m, 8H); 1.37 (m, 4 H); 1.67 (m, 2 H); 2.50 (m, 2 H); 2.85 (m,

20 2H); 3.16 (m, 2H); 3.33 (s, 3 H); 4.04 (m, 2H); 6.92 (d, J = 8 Hz, 1H); 7.07 (s, 1 H); 7.17 (d, J = 8 Hz, 1H); 7.50 (m, 2 H); 7.91 (m, 1 H); 9.70 (s, 1 H).

EXAMPLE 13: Hydrochloride 2- [4- (2-Carboxyethyl) -2-ethoxyphenyl] -6- (3-heptyl-1-methylureido) pyridinium

image 1

25 a. 3-Ethoxy-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzaldehyde

2.0 g of ethyl vanillin are dissolved in 10 ml of dichloromethane and then 3 ml of triethylamine are added. Slowly add 2.36 ml of triflic anhydride at 0 ° C. After stirring for 1 hour at 0 ° C, the reaction is hydrolyzed with a solution of sodium hydrogen carbonate and then extracted with ethyl acetate. After removing the solvents by evaporation, the oil obtained is dissolved in 20 ml of dimethylformamide and 3.96 g of

30 pinacoldiborane, together with 489 mg of diphenylphosphoferoferocene palladium dichloride and 3.53 g of potassium acetate. The mixture is stirred for 3 hours at 90 ° C. The reaction is hydrolyzed and then extracted with ethyl acetate. The solvents are removed by evaporation and the residue obtained is subjected to chromatography on silica gel (eluent = 7/3 heptane / ethyl acetate). 1.62 g of 3-ethoxy-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzaldehyde are obtained. Yield = 49%.

image23

b. Tert-Butyl 6- (2-Ethoxy-4-formylphenyl) pyrid-2-yl] methylcarbamate

1.62 g of 3-ethoxy-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzaldehyde are dissolved in 15 ml of dimethylformamide, 3 ml of a solution are added 2 M potassium phosphate and 2.52 g of tert-butyl (6-bromopyrid-2-yl) methyl carbamate are added, together with 64 mg of palladium acetate and 200 mg of dicyclohexylbiphenylphosphine. The mixture is stirred for 3 hours at 90 ° C. The reaction is hydrolyzed and then extracted with ethyl acetate. The solvents are removed by evaporation and the residue obtained is subjected to chromatography on silica gel (eluent = 7/3 heptane / ethyl acetate). 1.1 g of tert-butyl 6- (2-ethoxy-4-formylphenyl) pyrid-2-yl] methylcarbamate are obtained. Yield = 53%.

C. (E) -3- {4- [6- (tert-Butoxycarbonylmethylamino) -pyrid-2-yl] -3-ethoxyphenyl} methyl acrylate

1.1 g of 6- (2-ethoxy-4-formylphenyl) pyrid-2-yl] methylcarbamate tert-butyl are dissolved in 10 ml of toluene and then 1.55 g of methyl triphenylphosphoranylideneacetate are added. The reaction mixture is stirred for 1 hour at 90 ° C. After evaporation of the solvent, the residual oil obtained is subjected to chromatography on silica gel (8/2 heptane / ethyl acetate). 1.0 g of methyl (E) -3- {4- [6- (tert-butoxycarbonylmethylamino) pyrid-2-yl] -3ethoxyphenyl} acrylate are obtained. Yield = 78%.

d. Methyl 3- {4- [6- (tert-butoxycarbonylmethylamino) -pyrid-2-yl] -3-ethoxyphenyl} propionate

A solution of 1.0 g of methyl (E) -3- {4- [6- (tert-butoxycarbonylmethylamino) pyrid-2-yl] -3-ethoxyphenyl} acrylate in 10 ml of methanol is stirred for 3 hours at room temperature in the presence of 200 mg of 10% palladium on carbon in a hydrogen atmosphere. After filtration of the palladium and removal of the solvents by evaporation, 1.0 g of methyl 3- {4- [6- (tert-butoxycarbonylmethylamino) pyrid-2-yl] -3-ethoxyphenyl} propionate are obtained. Yield = 100%.

and. Methyl 3- [3-Ethoxy-4- (6-methylaminopyrid-2-yl) phenyl] propionate

1.0 g of methyl 3- {4- [6- (tert-butoxycarbonylmethylamino) pyrid-2-yl] -3-ethoxyphenyl} propionate is dissolved in 10 ml of dichloromethane and then 4 ml of trifluoroacetic acid are added . The mixture is stirred for 48 hours at room temperature. After hydrolysis of the reaction with a solution of sodium hydrogen carbonate and after extraction with ethyl acetate, the solvents are removed by evaporation. 615 mg of methyl 3- [3-ethoxy-4- (6-methylaminopyrid-2-yl) phenyl] propionate are obtained. Yield = 81%.

F. Methyl 3- {3-Ethoxy-4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propionate

615 mg of methyl 3- [3-ethoxy-4- (6-methylaminopyrid-2-yl) phenyl] propionate is mixed with 1.0 ml of heptyl isocyanate. After irradiation with microwave for one hour (T = 100 ° C), the mixture is chromatographed on silica gel (9/1 heptane / ethyl acetate). 735 mg of methyl 3- {3-ethoxy-4- [6- (3-heptyl-1-methylureido) pyrid2-yl] phenyl} propionate are obtained. Yield = 82%.

g. 2- [4- (2-Carboxyethyl) -2-ethoxyphenyl] -6- (3-heptyl-1-methylureido) pyridinium hydrochloride

500 mg of sodium hydroxide are added to a solution of 735 mg of methyl 3- {3-ethoxy-4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propionate dissolved in 15 ml of a 8/2 tetrahydrofuran / methanol mixture. After stirring for 4 hours at room temperature, the reaction is stopped with water and acetic acid and then extracted with ethyl acetate. The solvents are removed by evaporation. The residual oil is chromatographed on silica gel (7/3 heptane / ethyl acetate). 5 ml of a solution of hydrogen chloride in ethyl acetate are added to the chromatographed product and the hydrochloride is precipitated by the addition of isopropyl ether. After filtration, 441 mg of 2- [4- (2-carboxyethyl) -2-ethoxyphenyl] -6- (3-heptyl-1-methylureido) pyridinium hydrochloride are obtained. Yield = 57%.

1 H NMR (DMSO, 400 MHz): 0.85 (m, 3 H); 1.18 (m, 8H); 1.37 (m, 3 H); 1.48 (m, 2 H); 2.64 (m, 2 H); 2.92 (m, 2H); 3.25 (s, 3 H); 4.20 (m, 2 H); 6.98 (d, J = 8 Hz, 1H); 7.12 (s, 1 H); 7.25 (d, J = 8 Hz, 1H); 7.58 (d, J = 8 Hz, 2H); 7.99 (m, 1 H); 9.70 (s, 1 H).

image24

EXAMPLE 14: 3- (3-Butoxy-4- {5 - [(methyloctanoylamino) -methyl] thiophene-3-yl} phenyl) propanoic acid

image 1

to. (4-Bromothiophene-2-ylmethyl) methylamine

10.6 g of 4-bromothiophene-2-carbaldehyde are dissolved in 100 ml of acetonitrile and 11.8 g of methylamine hydrochloride and 6.28 g of sodium cyanoborohydride are added. The reaction mixture is stirred overnight at room temperature. The reaction is stopped with a 1 M solution of sodium hydroxide. After removing the solvents by evaporation, the residue is chromatographed on silica gel (7/3 heptane / ethyl acetate). 8.19 g of (4-bromothiophene-2-ylmethyl) methylamine are obtained. Yield = 79%.

b. Tert-Butyl (4-Bromothiophene-2-ylmethyl) methylcarbamate

8.18 g of (4-bromothiophene-2-ylmethyl) methylamine are dissolved in 80 ml of dichloromethane in the presence of 6.65 ml of triethylamine. At 0 ° C, a solution of 9.53 g of di-tert-butyl dicarbonate in 10 ml of dichloromethane is slowly added. The reaction mixture is stirred for 2 hours at room temperature. The reaction is stopped with water and then extracted with ethyl acetate. After removal of the solvents by evaporation, the residue is chromatographed on silica gel (7/3 heptane / ethyl acetate). 5.93 g of tert-butyl (4-bromothiophene-2-methyl) methylcarbamate are obtained. Yield = 49%.

C. tert-butyl methyl- [4- (4,4,5,5-tetramethyl [1,3,2] -dioxaborolan-2-yl) thiophene-2-ylmethyl] carbamate

5.92 g of tert-butyl (4-bromothiophene-2-ylmethyl) methylcarbamate are dissolved in 70 ml of dimethylformamide and 5.89 g of pinacoldiborane are added together with 776 mg of diphenylphosphoferoferlocene palladium dichloride and 5.59 g of acetate potassium The mixture is stirred for 3 hours at 90 ° C. The reaction is stopped with water and then extracted with ethyl acetate. The solvents are removed by evaporation. The residue is chromatographed on silica (eluent = 7/3 heptane / ethyl acetate). 4.57 g of tert-butyl methyl- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) thiophene-2-methyl] carbamate are obtained. Yield = 63%.

d. (E) -3- (3-Butoxy-4- {5 - [(tert-butoxycarbonyl-methylamino) methyl] thiophene-3-yl} phenyl) methyl acrylate

2.50 g of tert-butyl methyl- [4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) thiophene-2-ylmethyl] carbamate are dissolved in 27 ml of dimethylformamide and 5.5 ml of a 2M solution of potassium phosphate and 1.96 g of (E) -3- (3-butoxy-4-iodophenyl) methyl acrylate (prepared according to the procedure of Example 11, step f) are added , together with 12 mg of palladium acetate and 38 mg of dicyclohexylbiphenylphosphine. The mixture is stirred for 1 hour at 90 ° C. The reaction is stopped with water and then extracted with ethyl acetate. The solvents are removed by evaporation. The residue is chromatographed on silica (eluent = 7/3 heptane / ethyl acetate). 1.98 g of methyl (E) -3- (3-butoxy4- {5 - [(tert-butoxycarbonyl-methylamino) methyl] thiophene-3-yl} phenyl) acrylate are obtained. Yield = 79%.

and. (E) -3- (3-Butoxy-4- {5 - [(tert-butoxycarbonyl-methylamino) methyl] thiophene-3-yl} phenyl) propionate methyl

1.98 g of (E) -3- (3-butoxy-4- {5 - [(tert-butoxycarbonylmethylamino) methyl] thiophene-3-yl} phenyl) acrylate are dissolved in 20 ml of methanol and stirred for 12 hours at room temperature in the presence of 1.0 g of palladium on carbon in a hydrogen atmosphere. After removing the palladium by filtration and removing the solvents by evaporation, 1.37 g of (E) -3- (3-butoxy-4- {5 - [(tert-butoxycarbonyl-methylamino) methyl] thiophene) are obtained. Methyl 3-yl} phenyl) propionate. Yield = 69%.

F. Methyl 3- [3-Butoxy-4- (5-methylaminomethylthiophene-3-yl) phenyl] propionate

1.36 g of methyl (E) -3- (3-butoxy-4- {5 - [(tert-butoxycarbonylmethylamino) methyl] thiophene-3-yl} phenyl) propionate are dissolved in 15 ml of dichloromethane and then add 2.2 ml of trifluoroacetic acid. The mixture is stirred for 2 hours at room temperature. The reaction is then hydrolyzed with a solution of sodium hydrogen carbonate, then extracted with ethyl acetate and the solvents are removed by evaporation, 1.15 g of 3- [3-butoxy-4 (5-methylaminomethylthiophene-3-yl) are obtained ) methyl phenyl] propionate. Yield = 100%.

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10

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twenty

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35

40

g. Methyl 3- (3-butoxy-4- {5 - [(methyloctanoylamino) -methyl] thiophene-3-yl} phenyl) propionate

1.07 g of methyl 3- [3-butoxy-4- (5-methylaminomethylthiophene-3-yl) phenyl] propionate are dissolved in 20 ml of dichloromethane and 1.25 ml of triethylamine are added, together with 36 mg of dimethylaminopyridine. 318 mg of octanoyl chloride are added. The reaction mixture is stirred for 12 hours at room temperature. The reaction is then hydrolyzed with a solution of sodium hydrogen carbonate, then extracted with ethyl acetate and the solvents are removed by evaporation, a crude product is obtained, which is subjected to chromatography on silica gel (eluent = 7/3 of heptane / ethyl acetate). 432 mg of methyl 3- (3-butoxy-4- {5 - [(methyloctanoylamino) -methyl] thiophene-3yl} phenyl) propionate are obtained. Yield = 81%.

h. 3- (3-Butoxy-4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoic acid

350 mg of sodium hydroxide are added to a solution of 427 mg of methyl 3- (3-butoxy-4- {5 [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propionate dissolved in 10 ml of methanol. After stirring for 2 hours at 40 ° C, the reaction is hydrolyzed with a solution of hydrochloric acid and then extracted with ethyl acetate. The solvents are removed by evaporation. The residual oil is crystallized from a heptane / ethyl ether mixture.

318 mg of 3- (3-butoxy-4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoic acid are obtained. Yield = 77%.

1 H NMR (CDCl 3, 400 MHz): 0.85 (m, 3 H); 1.28 (m, 8H); 1.49 (m, 2 H); 1.60 (m, 2 H); 1.79 (m, 2 H); 2.33 and 2.48 (2m (rotamers), 2H); 2.65 (m, 2 H); 2.95 (m, 2H); 2.99 (s, 3H); 4.00 (m, 2 H); 4.65 and 4.72 (2s (rotamers), 2H); 6.80 (m, 2 H); 7.27 (m, 2H); 7.37 (m, 1 H); 7.49 (m, 1 H).

EXAMPLE 15: 3- [3-Butoxy-4- (5 - {[(4-methoxybenzoyl) -methylamino] methyl} thiophene-3-yl) phenyl] propanoic acid

image 1

a.3- [3-Butoxy-4- (5 - {[(4-methoxybenzoyl) -methylamino] methyl} thiophene-3-yl) phenyl] methyl propionate

1.07 g of methyl 3- [3-butoxy-4- (5-methylaminomethylthiophene-3-yl) phenyl] propionate (prepared according to the procedure of Example 14, steps aaf) are dissolved in 20 ml of dichloromethane and 1.25 ml of triethylamine are added, together with 36 mg of dimethylaminopyridine. 270 mg of 4-methoxybenzoyl chloride are added. The reaction mixture is stirred for 12 hours at room temperature. The reaction is stopped with a solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The solvents are removed by evaporation. The residue is chromatographed on silica (eluent = 7/3 heptane / ethyl acetate).

388 mg of methyl 3- [3-butoxy-4- (5 - {[(4-methoxybenzoyl) methylamino] methyl} thiophene-3-yl) phenyl] propionate are added. Yield = 71%.

b. 3- [3-Butoxy-4- (5 - {[(4-methoxybenzoyl) methylamino] -methyl} thiophene-3-yl) phenyl] propanoic acid

308 mg of sodium hydroxide was added to a solution of 382 mg of methyl 3- [3-butoxy-4- (5 - {[(4methoxybenzoyl) methylamino] methyl} thiophene-3-yl) phenyl] propionate dissolved in 10 ml of methanol After stirring for 2 hours at 40 ° C, the reaction is hydrolyzed with a solution of hydrochloric acid and then extracted with ethyl acetate. The solvents are removed by evaporation. The residual oil is crystallized from a heptane / ethyl ether mixture.

300 mg of 3- [3-butoxy-4- (5 - {[(4-methoxybenzoyl) methylamino] methyl} thiophene-3-yl) phenyl] propanoic acid are obtained. Yield = 81%.

1 H NMR (CDCl 3, 400 MHz): 0.95 (m, 3 H); 1.47 (m, 2 H); 1.79 (m, 2 H); 2.70 (m, 2 H); 2.96 (m, 2H); 3.09 (s, 3 H); 3.82 (s, 3 H); 4.00 (m, 2 H); 4.79 (s, 2H); 6.81 (m, 2H); 6.88 (m, 3 H); 7.24-7.52 (m, 4H).

image26

EXAMPLE 16: 3- [3-Butoxy-4- (5 - {[(3-methoxybenzoyl) -methylamino] methyl} thiophene-3-yl) phenyl] propanoic acid

image 1

to. Methyl 3- [3-Butoxy-4- (5 - {[(3-methoxybenzoyl) methyl-amino] methyl} thiophene-3-yl) phenyl] propionate

1.07 g of methyl 3- [3-butoxy-4- (5-methylaminomethylthiophene-3-yl) phenyl] propionate (prepared according to the procedure of Example 14, steps aaf) are dissolved in 20 ml of dichloromethane and 1.25 ml of triethylamine are added, together with 36 mg of dimethylaminopyridine. 270 mg of 3-methoxybenzoyl chloride are added. The reaction mixture is stirred for 12 hours at room temperature. The reaction is stopped with a solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The solvents are removed by evaporation. The residue is chromatographed on silica (eluent = 7/3 heptane / ethyl acetate).

380 mg of methyl 3- [3-butoxy-4- (5 - {[(3-methoxybenzoyl) methylamino] methyl} thiophene-3-yl) phenyl] propionate are obtained. Yield = 70%.

b. 3- [3-Butoxy-4- (5 - {[(3-methoxybenzoyl) methylamino] -methyl} thiophene-3-yl) phenyl] propanoic acid

302 mg of sodium hydroxide are added to a solution of 374 mg of 3- [3-butoxy-4- (5 - {[(3methoxybenzoyl) methylamino] methyl} thiophene-3-yl) phenyl] propionate dissolved in 10 ml of methanol After stirring for 2 hours at 40 ° C, the reaction is hydrolyzed with a solution of hydrochloric acid and then extracted with ethyl acetate. The solvents are removed by evaporation. The residual oil is crystallized from a heptane / ethyl ether mixture.

307 mg of 3- [3-butoxy-4- (5 - {[(3-methoxybenzoyl) methylamino] methyl} thiophene-3-yl) phenyl] propanoic acid are obtained. Yield = 84%.

1 H NMR (CDCl 3, 400 MHz): 0.95 (m, 3 H); 1.47 (m, 2 H); 1.79 (m, 2 H); 2.69 (m, 2 H); 2.96 (m, 2H); 3.10 (s, 3H); 3.81 (s, 3 H); 4.00 (m, 2 H); 4.62 and 4.88 (2s (rotamers), 2H); 6.81 (m, 2H); 6.96 (m, 3 H); 7.26-7.52 (m, 4H).

EXAMPLE 17 - PPAR TRANSACTIVATION TESTS BY TRANSITION CURVES

Activation of PPAR receptors with an agonist (activator) in HeLN cells leads to the expression of an indicator gene, luciferase, which, in the presence of a substrate, generates light. The modulation of PPAR receptors is measured by quantifying the luminescence produced after incubating the cells in the presence of a reference agonist. The ligands displace the agonist from their site. The activity is measured by quantifying the light produced. This measurement makes it possible to determine the modulating activity of the compounds according to the invention by determining the constant that represents the affinity of the molecule for the PPAR receptor. Since this value can fluctuate depending on the basal activity and the expression of the receptor, this is called apparent Kd (KdApp in nM).

To determine this constant, "transition curves" of the product to be tested against a reference agonist were performed on a 96-well plate: 10 concentrations of the test product plus 1 concentration 0 were placed in a line and 7 concentrations of the agonist plus one concentration 0 were arranged in a column. This represents 88 measuring points for 1 product and 1 receiver. The remaining 8 wells were used for repeatability controls.

In each well, the cells were contacted with a concentration of the test product and a concentration of the reference agonist, 2- (4- {2- [3- (2,4-difluorophenyl) -1-heptylureido] ethyl acid } phenylsulfanyl) -2-methylpropionic for PPAR, {2-methyl-4- [4-methyl-2- (4-trifluoromethylphenyl) thiazol-5-ylmethylsulfanyl] -phenoxy} acetic acid for PPAR and 5- {4- [2- (methylpyrid-2-ylamino) epoxy] benzyl} thiazolidine-2,4-dione for PPAR. Measurements were also taken for controls of total agonists with the same products.

The HeLN cell lines used are stable transfectants that contain plasmids ERE-Glob-LucSV-Neo (indicator gene) and PPAR (, , ) Gal-hPPAR. These cells were inoculated in 96-well plates at a rate of 10,000 cells per well in 100 µl of DMEM medium without phenol red and supplemented with 10% defatted calf serum. Then, the plates were incubated at 37 ° C and with 7% CO2 for 16 hours.

image27

The various dilutions of the test products and the reference ligand were added at a rate of 5 µl per well. The plates were then incubated for 18 hours at 37 ° C and with 7% CO2. The culture medium was removed by turning and a 1: 1 PBS / luciferin mixture was added to each well. After 5 minutes, the plates were read by the luminescence detector.

5 These transition curves make it possible to determine the CA50 values (concentration at which 50% activation is observed) of the reference ligand at various concentrations of the test product. These CA50 values were used to calculate the Schild regression graphically representing a straight line corresponding to the Schild equation (“quantification in receiver pharmacology” Terry P. Kenakin, Receptors and Channels, 2001, 7, 371-385) that allow get the Kd app values (in nM) that allows you to get the Kd app values (in nM).

10 Transactivation results:

Compounds

PPAR Kd app (nM) PPAR Kd app (nM) PPAR Kd app (nM)

Reference 1: 2- (4- {2- [3- (2,4-Difluorophenyl) 1-heptylureido] -ethyl} phenylsulfanyl) -2-methylpropanoic acid

200  n.a. n.a.

Reference 2: {2-methyl-4- [4-methyl-2- (4trifluoromethyl-phenyl) thiazol-5ylmethylsulfanyl] phenoxy} acetic acid

n.a. 10 n.a.

Reference 3: 5- {4- [2- (methylpyrid-2-ylamino) ethoxy] benzyl} thiazolidine-2,4-dione

n.a. n.a. 30

Compound of Example 1

n.a. n.a. 1000

Compound of Example 6

n.a. 4000 250

Compound of Example 2

n.a. n.a. 500

Compound of Example 7

n.a. n.a. 60

Compound of Example 8

n.a. n.a. 1000

Compound of Example 11

2000 n.a. 120

Compound of Example 12

4000 n.a. fifteen

Compound of Example 13

4000 8000 120

Compound of Example 14

n.a. n.a. 2

Compound of Example 15

n.a. n.a. 30

Compound of Example 16

n.a. n.a. 30

n.a. means not active

These results show the affinity of the compounds for PPAR and more particularly the specificity

of the affinity of the compounds of the invention for the PPAR subtype, compared to the affinity of the

compounds for the PPAR subtype or for the PPAR subtype.

15 EXAMPLE 18 - COMPOSITIONS

Various concrete formulations based on the compounds according to the invention are illustrated in this example.

image28

A - ORAL ROUTE

-Compound of Example 1 -Almidon -Dicalcium phosphate -Silica -Lactose-Talc -Magnesium stearate

-Compound of Example 5 -Glycerol-70% Sorbitol -Sodium Saccharinate -Metil for -hydroxybenzoate -Saporiferous-Purified water

-Compound of Example 2 -Pregelatinized starch -Microcrystalline cellulose

-Lactose-Magnesium Stearate

-Compound of Example 4 -Glycerol-70% Sorbitol -Sodium Saccharinate -Metil for -hydroxybenzoate -Saporiferous

-Purified water

B - TOPICAL ROUTE

-Compound of Example 6

(a) 0.2g tablet 0.001g 0,114g 0.020g 0.020g  0.030g 0.010g 0.005g

(b) Drinkable suspension in 5 ml ampoules 0.001g 0.500g 0.500g 0.010g 0.040g cs cs 5 ml

(c) 0.8g tablet 0.500g 0,100g 0,115g

 00,075g 0,010g

(d) Drinkable suspension in 10ml ampoules 0,200g 1,000g 1,000g 0,010g 0,080g cs

cs 10ml

(a) 0.020g ointment

image29

- Isopropyl myristate

81,700g

- Liquid petroleum jelly

9,100g

-Slice (“Aerosil 200” sold by Degussa)

9.180g

(b) Ointment

-Compound of Example 2

0,150g

-Compound of Example 4

0,150g

-Codex white liquid petroleum jelly

cs 100g

(c) Water cream in non-ionic oil

-Compound of Example 1

0,100g

-Mixing emulsifying lanolin alcohols, waxes and

39,900g

oils ("Eucerin anhydrous" marketed by BDF)

-Methyl para-hydroxybenzoate

0.075g

-Propyl para-hydroxybenzoate

0.075g

(c) Water cream in non-ionic oil

-Demineralized sterile water

cs 100g

(d) lotion

-Compound of Example 3

0,100g

-Polietilen Glycol (PEG 400)

69,900g

-95% ethanol

30,000g

(e) Hydrophobic ointment

-Compound of Example 5

0,300g

-isopropyl myristate

36,400g

- Silicone oil (“Rhodorsil 47 V 300” marketed by

36,400g

Rhone-Poulenc)

-Bee wax

13,600g

- Silicone oil (“Abil 300,000 cst”

cs 100g

marketed by Goldschmidt)

(f) Oil cream in non-ionic water

-Compound of Example 2

1,000g

-Cetyl alcohol

4,000g

-Glyceryl monostearate

2,500g

-PEG-50 stearate

2,500g

- Shea butter

9,200g

-Propylene glycol

2,000g

-Methyl para-hydroxybenzoate

0.075g

-Propyl para-hydroxybenzoate

0.075g

-Demineralized sterile water

100g

image30

Claims (100)

1. Compounds characterized in that they correspond to the following formula (I): image 1 in which: - R1 represents a radical of formula (a) or (b) below: image 1 The meaning of R5 is indicated below, - R2 represents a radical of formula (CH2) m-NR6-CQ- (NH) nR7; Q, R6, R7, having m and n the meanings given below, 10-R3 and R4, which may be the same or different, represent a hydrogen atom, a halogen atom, a linear or cyclic alkyl radical of 1 to 12 carbon atoms that may be interrupted with oxygen, fluorine or nitrogen atoms, a hydroxyl radical, an alkoxy radical containing from 1 to 7 carbon atoms, a polyether radical, an aralkyl radical or an aryloxy radical;

-

 R5 represents a hydroxyl radical, an OR8 radical or a hydroxylamine radical; R8 being defined below, 15-R6 represents an alkyl radical containing from 1 to 4 carbon atoms;

-

 R7 represents an alkyl radical containing from 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a heterocyclic radical;

-

 R8 represents an alkyl, aryl or aralkyl radical;

-

 m and n can take the values of 0 or 1; 20-Q represent an oxygen or sulfur atom;

- Ar1 and Ar2 may be identical or different and represent an aromatic radical of the formula: image 1 which, when it is an aryl radical, may be mono or disubstituted with a halogen atom, a CF3 radical, an alkyl radical containing from 1 to 12 carbon atoms, an alkoxy radical containing from 1 to 7 carbon atoms, a Nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a image2 hydroxyl radical optionally protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms; and that, when it is a heteroaryl radical, it is optionally substituted with at least one halogen, an alkyl containing from 1 to 12 carbon atoms, an alkoxy containing from 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with the minus an alkyl containing 1 to 12 carbon atoms

-

 A represents a sulfur or oxygen atom or an N-R9 radical;

-

 R9 represents a hydrogen atom or an alkyl radical containing from 1 to 12 carbon atoms;

it being understood that when Ar1 or Ar2 is an aryl radical, then Ar2 or Ar1 is necessarily a heteroaryl radical and the optical and geometric isomers of said compound of formula (I).

2.

Compounds according to claim 1, characterized in that they are in the form of salts of an alkali metal or alkaline earth metal, or an organic amine.

3.

Compounds according to any of claims 1 and 2, characterized in that the halogen atom is selected from fluorine, chlorine and bromine atoms.

Four.

Compounds according to any of claims 1 and 2, characterized in that the alkyl radical containing from 1 to 12 carbon atoms is selected from methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, hexyl, heptyl, octyl, decyl radicals , cyclopentyl, cyclohexyl and methylenecyclopropyl.

5.

Compounds according to any of claims 1 and 2, characterized in that the lower alkyl radical containing from 1 to 4 carbon atoms is selected from methyl, ethyl, n-propyl, i-propyl, cpropyl, methylcyclopropyl, n-butyl radicals , i-butyl and t-butyl.

6.

Compounds according to any of claims 1 and 2, characterized in that the alkoxy radical containing 1 to 7 carbon atoms is selected from methoxy, ethoxy, isopropyloxy, methylcyclopropyloxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy radicals , benzyloxy, aryloxy or phenoxy, which may be optionally substituted with an alkyl radical containing from 1 to 12 carbon atoms or an alkoxy radical containing from 1 to 5 carbon atoms.

7.

Compounds according to any of claims 1 and 2, characterized in that the polyether radical is selected from methoxymethoxy, ethoxymethoxy and methoxyethoxymethoxy radicals.

8.

Compounds according to any of claims 1 and 2, characterized in that the aralkyl radical is selected from benzyl, phenethyl or 2-naphthylmethyl radicals, which may be mono- or disubstituted with a halogen atom, a radical CF3 radical, an alkyl radical that contains from 1 to 12 carbon atoms, an alkoxy radical containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl radical optionally protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.

9.

Compounds according to any of claims 1 and 2, characterized in that the aryl radical is selected from phenyl, biphenyl, cinnamyl or naphthyl radicals, which may be mono or disubstituted with a halogen atom, a CF3 radical, an alkyl radical containing from 1 to 12 carbon atoms, an alkoxy radical containing from 1 to 7 carbon atoms, a nitro function, a polyether radical, an aryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, an optionally hydroxyl radical protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms.

10.

Compounds according to any of claims 1 and 2, characterized in that the heteroaryl radical is selected from the group consisting of a pyridyl, furyl, thienyl, isoxazolyl, oxadiazolyl, oxazolyl, isothiazolyl, quinazolinyl, benzothiadiazolyl, benzimidazolyl, quinoxalyl, indolyl radical or benzofuryl, optionally substituted with at least one halogen, an alkyl containing 1 to 12 carbon atoms, an alkoxy containing 1 to 7 carbon atoms, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical , a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl containing 1 at 12 carbon atoms.

eleven.

Compounds according to any of claims 1 and 2, characterized in that the heterocyclic radical is selected from a morpholino, piperidino, piperazino, 2-oxo-1-piperidyl or 2-oxo-1-pyrrolidinyl radical, optionally substituted with at least one alkyl containing from 1 to 12 carbon atoms, an alkoxy containing from 1 to 7 atoms

carbon, an aryl radical, a nitro function, a polyether radical, a heteroaryl radical, a benzoyl radical, an alkyl ester group, a carboxylic acid, a hydroxyl optionally protected with an acetyl or benzoyl group, or an amino function optionally protected with an acetyl or benzoyl group, or optionally substituted with at least one alkyl, containing 1 to 12 carbon atoms.

12.

Compounds according to claim 1, characterized in that they are taken, alone or in the form of mixtures, between the group consisting of:

one.

 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} thiophene-2-yl) acrylic acid

2.

 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} thiophene-2-yl) propanoic acid

3.

 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} furan-2-yl) -acrylic acid

Four.

 3- (4- {5 - [(Methyloctanoylamino) methyl] thiophene-3-yl} -phenyl) acrylic acid

5.

 3- (4- {5 - [(Methyloctanoylamino) methyl] thiophene-3-yl} -phenyl) propanoic acid

6.

 3- {4- [6- (3-Heptyl-1-methylureido) pyrid-2-yl] phenyl} -propanoic acid

7.

 3- {6- [3- (3-Heptyl-1-methylureido) phenyl] pyrid-3-yl} -propanoic acid

8.

 2- [4- (2-Carboxyethyl) phenyl] -4- (3-heptyl-1-methylureido) pyridinium acetate

9.

 3- {5- [3- (3-pentyl-1-methylureido) phenyl] pyrimidin-2-yl} acrylic acid

10.

 3- {5- [3- (3-pentyl-1-methylureido) phenyl] pyrimidin-2-yl} propanoic acid

eleven.

 2- [2-Butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-pentylureido) pyridinium hydrochloride

12.

 2- [2-Butoxy-4- (2-carboxyethyl) phenyl] -6- (1-methyl-3-heptylureido) pyridinium hydrochloride

13.

 2- [4- (2-Carboxyethyl) -2-ethoxyphenyl] -6- (3-heptyl-1-methylureido) pyridinium hydrochloride

14.

 3- (3-Butoxy-4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl) propanoic acid

fifteen.

 3- (3-Butoxy-4- (5 - {[(4-methoxybenzoyl) methylamino] -methylthiophene-3-yl) phenyl] propanoic acid

16.

 3- (3-Butoxy-4- (5 - {[(3-methoxybenzoyl) methylamino] -methyl} thiophene-3-yl) phenyl] propanoic acid

17.

 3- {5- [4- (3-Heptyl-1-methylureido) pyrid-2-yl] furan-2-yl} propanoic acid

18.

 3- [5- [3- (3-Heptyl-1-methylureido) phenyl] -4- (2,2,2-tri-fluoroethoxy) furan-2-yl] propanoic acid

19.

 3- (5- {3- [3- (3,5-Dimethoxyphenyl) -1-ethylureido] phenyl} -3-methylfuran-2-yl) propanoic acid

twenty.

 3- (5- {6- [3- (4-ethoxyphenyl) -1-ethylureido] pyrid-2-yl} -furan-2-yl) propanoic acid

twenty-one.

 3- (2-methyl-4- {6- [1-methyl-3- (4-methylpentyl) ureido] -pyrid-2-yl} phenyl) propanoic acid

22

 Methyl 3- {4- [6- (1-Ethyl-3-naphthalen-2-ylureido) pyrid-2-yl] -2-fluorophenyl} propanoate.

2. 3.

 3- (4- {6- [3- (4-Butoxyphenyl) -1-methylureido] pyrid-2-yl} phenyl) -N-hydroxypropionamide

24.

 3- {3-Cyclopropylmethoxy-4- [6- (1-methyl-3-pentylureido) -pyrid-2-yl] phenyl} propanoic acid

25.

 3- {4- [6- (1-ethyl-3-phenylthioureido) pyrid-2-yl] -3-propoxyphenyl} propanoic acid

26.

 3- {3-ethoxy-4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] -phenyl} propanoic acid

27.

 3- {4- [6- (3-Hexyl-1-methylureido) pyrid-2-yl] -3-isopropoxyphenyl} propanoic acid

28.

 3- [4- [6- (3-Heptyl-1-methylureido) pyrid-2-yl] -3- (4,4,4-trifluorobutoxy) phenyl] propanoic acid

29.

 3- {3- (2-Dimethylaminoethoxy) -4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} propanoic acid

30

 3- {3- (3-Hydroxypropoxy) -4- [6- (1-methyl-3-pentylureido) -pyrid-2-yl] phenyl} propanoic acid

31.

 3- {4- [6- (1-ethyl-3-phenylthioureido) pyrid-2-yl] -3-fluorophenyl} acrylic acid

32

 3- {4- [6- (3-Hexyl-1-methylureido) pyrid-2-yl] -3-trifluoromethylphenyl} propanoic acid

33.

 3- [6 '- (1-methyl-3-phenethylureido) [2,2'] bipyridinyl-5-yl] propanoic acid

3. 4.

 3- {2- [6- (3-Hexyl-1-methylureido) pyrid-2-yl] thiazol-4-yl} propanoic acid

35

 Ethyl 3- {2- [6- (3-Hexyl-1-methylureido) pyrid-2-yl] -thiazol-5-yl} propanoate

36.

 3- (3- {6- [1-methyl-3- (6-methylheptyl) ureido] pyrid-2-yl} isoxazol-5-yl) propanoic acid

37.

 3- {4- [2- (3-Heptyl-1-methylureido) pyrimidin-4-yl] phenyl} -propanoic acid

38.

 3- {3-Cyclopropylmethoxy-4- [2- (3-heptyl-1-methylureido) -pyrimidin-4-yl] phenyl} propanoic acid

39.

 3- (4- {2- [1-ethyl-3- (4-propoxyphenyl) ureido] pyrimidin-4-yl} -3-fluorophenyl) propanoic acid

40

 3- {2-Fluoro-4- [2- (1-methyl-3-naphthalen-2-ylureido) -pyrid-4-yl] phenyl} -N-hydroxypropionamide

41.

 3- [2 '- (3-Hexyl-1-methylthioureido) [2,4'] bipyridinyl-5-yl] propanoic acid

42

 3- {4- [2- (3-Hexyl-1-methylureido) pyrid-4-yl] -3-propoxyphenyl} propanoic acid

43

 3- (3-Benzyloxy-4- {4- [1-methyl-3- (5-methylhexyl) ureido] -pyrid-2-yl} phenyl) propanoic acid

44.

 3- {2- [4- (3-Hexyl-1-methylureido) pyrid-2-yl] thiazol-5-yl} acrylic acid

Four. Five.

 3- {5- [3- (3-Hexyl-1-methylureido) phenyl] pyrid-2-yl} -acrylic acid

46.

 3- {5- [5- (3-Heptyl-1-methylthioureido) thiophene-3-yl] -pyrid-2-yl} acrylic acid

47

 3- {4- [2- (3-Heptyl-1-methylureido) thiazol-4-yl] -3-propoxyphenyl} propanoic acid

48.

 3- (2-Fluoro-4- {5 - [(heptanoylmethylamino) methyl] thiophene-3-yl} phenyl) propanoic acid

49.

 3- (4- {5 - [(heptanoylmethylamino) methyl] thiophene-3-yl} -3-isobutoxyphenyl) acrylic acid 50. 3- (3- (2-cyclopentylethoxy) -4- {5 - [(methyloctanoylamino) -methyl] thiophene-3-yl} phenyl) propanoic acid

51.

 Methyl 3- (3-Isobutoxy-4- {5 - [(methylnonanoylamino) -methyl] thiophene-3-yl} phenyl) propanoate

52

 3- {6- [5 - ({ethyl- [2- (2-pentylphenyl) acetyl] amino} methyl) -thiophene-3-yl] pyrid-3-yl} propanoic acid

53.

 3- (4- {4 - [(methylnonanoylamino) methyl] thiazol-2-yl} -3-propoxyphenyl) propanoic acid

54

 3- (2-Chloro-4- {4 - [(methylnonanoylamino) methyl] thiophene-2-illphenyl) propanoic acid

55.

 3- (2-Fluoro-4- {4 - [(methylnonanoylamino) methyl] thiophene-2-yl} phenyl) acrylic acid

56.

 3- (4- {4 - [(heptanoylmethylamino) methyl] thiophene-2-yl} -1-methyl-1H-pyrrole-2-yl) propanoic acid

57.

 3- (4- {4 - [(heptanoylmethylamino) methyl] thiophene-2-yl} -furan-2-yl) propanoic acid

58.

 3- {5 '- [(heptanoylmethylamino) methyl] [3,3'] bitiophenyl-5-yl} propanoic acid

59.

 3- {5 '- [(Heptanoylmethylamino) methyl] -3-propyl- [2,3'] bitiophenyl-5-yl} phenyl propanoate

60

 3- (5- {5 - [(heptanoylmethylamino) methyl] thiophene-3-yl} -4-propylfuran-2-yl) acrylic acid

61.

 3- {3-Butoxy-4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

62

 3- (3-Benzyloxy-4- [6- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

63.

 3- {3-benzyloxy-4- [2- (3-heptyl-1-methylureido) pyrimidin-4-yl] phenyl} propanoic acid

64.

 3- {3-Butyloxy-4- [2- (3-heptyl-1-methylureido) pyrimidin-4-yl] phenyl} propanoic acid

65

 3- {3-Butoxy-4- [4- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

66.

 3- {3-benzyloxy-4- [4- (3-heptyl-1-methylureido) pyrid-2-yl] phenyl} propanoic acid

67.

 3- {3-benzyloxy-4- [5- (3-heptyl-1-methylureido) pyrid-3-yl] phenyl} propanoic acid

68.

 3- {3-Butoxy-4- [5- (3-heptyl-1-methylureido) pyrid-3-yl] phenyl} propanoic acid

69.

 3- (5- {3 - [(Methyloctanoylamino) methyl] phenyl} -4-propylthiophene-2-yl) propanoic acid

70.

 3- (3-Benzyloxy-4- {5 - [(methyloctanoylamino) methyl] thiophene-3-yl} phenyl} propanoic acid

71.

 3- (4-Benzyl-5- {3 - [(hexanoylmethylamino) methyl] phenyl} -thiophene-2-yl) propanoic acid

72.

 3- {4cyclopropylmethyl-5- [3- (1-methyl-3-pentylureido) -phenyl] thiophene-2-yl} propanoic acid

73

 3- {5- [3- (1-methyl-3-pentylureido) -4-trifluoromethylphenyl] thiophene-2-yl} propanoic acid

74.

 3- (5- {3- [3- (4-Butoxyphenyl) -1-ethylureido] phenyl} -thiophene-2-yl) propanoic acid

75.

 3- {5- [3- (3-Heptyl-1-methylureido) -4-trifluoromethylphenyl] furan-2-yl} propanoic acid

76

 3- {2-Butoxy-4- [6- (1-methyl-3-pentylureido) pyrid-2-yl] phenyl} propanoic acid

77.

 3- {2- (4-Methoxybenzyloxy) -4- [6- (1-methyl-3-pentyl-ureido) pyrid-2-yl] phenyl} propanoic acid

78.

 3- {2- (3-Methoxybenzyloxy) -4- [6- (1-methyl-3-pentyl-ureido) pyrid-2-yl] phenyl} propanoic acid

image3 image4 image5 79. 3- [2-Cyclopropylmethoxy-4- (6- {3- [2- (4-methoxyphenyl) -ethyl] -1-methylureido} pyrid-2-yl) phenyl] propanoic acid 13. Compounds according to claim 1 or 2, characterized in that they have at least one of the following characteristics:

-

 R3 is an alkoxy radical of 1 to 7 carbon atoms;

-

 R5 corresponds to a hydroxyl radical;

-

 the sequence - (CH2) m-NR6-CQ (NH) nR7 has m = 0, n = 1;

-

 Q is an oxygen atom;

-

 R7 represents an alkyl radical of 1 to 8 carbon atoms;

-

 at least Ar1 or Ar2 is a pyridine type group.

14. Compounds according to claim 13, characterized in that all have the following characteristics:

-

 R3 is an alkoxy radical of 1 to 7 carbon atoms;

-

 R5 corresponds to a hydroxyl radical;

-

 the sequence - (CH2) m-NR6-CQ (NH) nR7 has m = 0, n = 1;

-

 Q is an oxygen atom;

-

 R7 represents an alkyl radical of 1 to 8 carbon atoms;

-

 at least Ar1 or Ar2 is a pyridine type group.

fifteen.

Cosmetic composition, characterized in that, in a pharmaceutically acceptable carrier, it comprises at least one of the compounds defined in any one of claims 1 to 14.

16.

Composition according to claim 15, characterized in that the concentration of the compound (or compounds) according to one of claims 1 to 14 is between 0.0001% and 2% by weight in relation to the total weight of the composition .

17.

Cosmetic use of a composition as defined in any of claims 15 and 16 for body or hair hygiene.

18.

Compounds according to any of claims 1 to 14, as medicaments.

19.

The use of a compound according to any one of claims 1 to 14 in the preparation of a composition for the regulation and / or restoration of lipid metabolism in the skin.

twenty.

The use of a compound according to any one of claims 1 to 14 in the preparation of a composition for treating

-

 Dermatological conditions associated with a keratinization disorder related to differentiation and proliferation, in particular for the treatment of common acne, comedones, polymorphic acne, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acne such as solar, medicinal or occupational acne.

-

 ichthyosis, ichthyosiform conditions, Darier's disease, palmoplantar keratoderma, leukoplakia and leucoplachiform conditions and cutaneous or mucous lichen (oral),

-

 dermatological conditions with an inflammatory immuno-allergic component, with or without cell proliferation disorder and in particular cutaneous, mucosal or nail psoriasis, psoriatic arthritis, cutaneous atopy such as eczema

image6 or respiratory atopy or gingival hypertrophy,

-

 dermal or epidermal proliferations, benign or malignant, of viral or non-viral origin, in particular common warts, flat warts and epidermodisplasia verruciformis, oral or florid papillomatosis, T lymphoma

-

 proliferations that can be induced by ultraviolet light, in particular basal and spinocellular cell epithelioma

-

 precancerous dermal lesions, especially keratoacamptoms,

-

 immune dermatitidis, especially lupus erythematosus,

-

 vesicular immune diseases,

-

 collagen diseases, especially scleroderma,

-

 dermatological or systemic ailments with an immune component,

-

 dermal disorders due to exposure to UV radiation, skin aging, both light or chronological induced aging or keratosis and actinic pigmentations, or any pathology associated with chronological or actinic aging, especially xerosis,

-

 Sebaceous function disorders, especially acne hyperseborrhea or simple seborrhea,

-

 scarring or stretch marks

-

 pigmentation disorders, such as hyperpigmentation, melasma, hypopigmentation or vitiligo,

-

 ailments related to lipid metabolism, such as obesity, hyperlipidemia, non-insulin-dependent diabetes,

-

 inflammatory ailments such as arthritis,

-

 cancerous or precancerous conditions,

-

 alopecia of various origins, especially alopecia produced by chemotherapy or radiation,

-

 disorders related to the immune system, such as asthma, type 1 sugar diabetes, multiple sclerosis or other selective immune system dysfunctions,

-

 cardiovascular system ailments, such as atherosclerosis or hypertension.

twenty-one.

A pharmaceutical composition, characterized in that it comprises, on a physiologically acceptable substrate, at least one of the compounds as defined in any one of claims 1 to 14.

22

A composition according to claim 1, characterized in that the concentration of the compound (or compounds) according to one of claims 1 to 14 is between 0.001% and 10% by weight with respect to the total weight of the composition.

2. 3.

A composition according to claim 22, characterized in that the concentration of the compound (or compounds) according to one of claims 1 to 14 is between 0.01% and 1% by weight with respect to the total weight of the composition .