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HK1157745B - Ppar agonist compounds and preparation and uses thereof for treating diabetes and/or dyslipidemia - Google Patents

Ppar agonist compounds and preparation and uses thereof for treating diabetes and/or dyslipidemia Download PDF

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Publication number
HK1157745B
HK1157745B HK11107457.8A HK11107457A HK1157745B HK 1157745 B HK1157745 B HK 1157745B HK 11107457 A HK11107457 A HK 11107457A HK 1157745 B HK1157745 B HK 1157745B
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Hong Kong
Prior art keywords
methyl
methoxy
amino
phenyl
radical
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HK11107457.8A
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German (de)
French (fr)
Chinese (zh)
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HK1157745A (en
Inventor
Christophe Masson
Karine Caumont-Bertrand
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Genfit
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Description

The present invention relates to compounds of therapeutic interest, particularly for the treatment of diabetes and/or dyslipidemia, and to pharmaceutical formulations containing such compounds.
Diabetes and dyslipidemia (high plasma LDL and triglyceride cholesterol, low HDL cholesterol, etc.) are among the clearly identified cardiovascular risk factors that predispose an individual to developing cardiovascular disease (The Atlas of Heart Disease and Stroke, edited by Mackay J and Mensah M, published by the World Health Organization, 2004). These risk factors are in addition to lifestyle risk factors such as smoking, physical inactivity and unbalanced diets. A synergistic effect exists between these different factors: the concomitant presence of several dyslipidemia leads to a dramatic worsening of cardiovascular risk and therefore a significant global risk (outbreak) for cardiovascular disease. The prevalence of diabetes in the developed countries is estimated to increase from 7.6% in 2005 to 7.6% in 2010, according to The Business Insights Market Outlook. The prevalence of diabetes in the developed countries is now estimated to be 7.6% (June 2010).
According to the International Atherosclerosis Society, cardiovascular disease is the leading cause of death in industrialized countries and is becoming increasingly common in developing countries. These diseases include coronary heart disease, cerebral ischemia and peripheral artery disease. These data justify the adoption of vigorous measures to significantly reduce cardiovascular morbidity and mortality.
Among the different nuclear receptors that can be therapeutic targets (Hansen MK and ConnollyTM, 2008), the involvement of Peroxysome Proliferator-Activated Receptors (PPARs) in this type of disease is now very well established (Blaschke F et al., 2006; Gilde AJ et al., 2006; Gervois P et al., 2007). The PPAR family includes three isoforms, designated α, γ and δ (also called β), each encoded by a different gene. These receptors, which are part of the nuclear receptor and transcription factor superfamily, play a major role in regulating lipid and carbohydrate metabolism.
PPARα controls lipid (hepatic and muscle) metabolism and glucose homeostasis, and influences intracellular lipid and sugar metabolism by direct control of transcription of genes coding for proteins involved in lipid homeostasis. PPARα also exerts anti-inflammatory and anti-proliferative effects and prevents pro-atherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol outflow (Lefebvre P and al., 2006). PPARα is a key regulator of adipogyny. It is also involved in lipid metabolism, in homogenous insulin, in glucose resistance, and in the control of proliferation of cholesterol in cells (Lazaro, 2005). PPARα is involved in the formation of lipid and glycogen levels, in the control of neuroblasts, in the metabolism of fat and fat cells, in the metabolism of neurotransmitters, in the metabolism of insulin, in the metabolism of glucose and in the control of blood sugar levels (Lazaro, 2005).
These multiple properties make PPARs therapeutic targets of interest for the treatment of diabetes and dyslipidemia, and for the prevention of cardiovascular disease. PPAR ligands are already known, some are marketed and prescribed in the treatment of some of the previously mentioned conditions, and their toxicology has been studied (Peraza M et al., 2006). PPARα activators, such as fibrates (fénofibrate, bézafibrate, ciprofibrate, gemfibro), which are used clinically to treat dyslipidemia by increasing plasma HDL (High Density Liptontein) levels and lowering triglycerides (Digital al. 2001 and WO.049 and other compounds, such as thiazolidin, are also used in the treatment of some types of diabetes.
The purpose of the invention is to propose new PPAR agonist compounds (PPARα and/or PPARγ and/or PPARδ), in particular those which are suitable for the therapeutic and/or prophylactic treatment of diabetes, dyslipidemia, insulin resistance, conditions associated with metabolic syndrome, atherosclerosis, obesity, hypertension and/or inflammatory diseases. These PPAR agonist compounds may also be particularly effective in reducing cardiovascular risk and preventing cardiovascular diseases, in particular those related to lipid and/or carbohydrate metabolism disorders.
These and other objectives are achieved by the following compounds of General Formula (I): - What? in which, G is: a -ORa, -SRa; or a -NRaRb radical; Ra being chosen from an alkyl radical of 1 to 6 carbon atoms or an alkenyl radical of 2 to 6 carbon atoms, a cycle of 3 to 14 atoms, a phenyl radical, a phenylalkyl radical of an alkyl part having 1 to 3 carbon atoms;Rb being chosen from a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms or an alkenyl radical of 2 to 6 carbon atoms, a cycle of 3 to 14 atoms,a phenyl radical, or a phenylalkyl radical with an alkyl part having 1 to 3 carbon atoms;Ra and Rb together with the nitrogen atom to which they are bound may form a heterocycle of 3 to 8 atoms;R1 and R2, whether or not identical, are a hydrogen atom or an alkyl radical of 1 to 6 carbon atoms or an alkenyl radical of 2 to 6 carbon atoms;R1 and R2 together with the carbon atom to which they are bound may form a carbocycle of 3 to 6 carbon atoms;Y1 is:an oxygen or sulphur atom,or a group -NR-, where R has the same definition as Rb;Y2 represents: one oxygen or sulphur atom, or one radical -CR5R6-; with R5 and R6, identical or different, chosen from one hydrogen or halogen atom, one alkyl radical of 1 to 6 carbon atoms or one alkyl or alkynyl radical of 2 to 6 carbon atoms, a cycle of 3 to 6 atoms, a phenylalkyl radical of part alkyl having 1 to 3 carbon atoms,X1, X2, X3 independently representing one hydrogen or halogen atom, one alkyl radical of 1 to 6 carbon atoms or an alkynyl radical of 2 to 6 carbon atoms,Err1:Expecting ',' delimiter: line 1 column 541 (char 540)Err1:Expecting ',' delimiter: line 1 column 120 (char 119)Err1:Expecting ',' delimiter: line 1 column 49 (char 48)
For the purposes of this invention, the following definitions are applicable: The term alkyl, alkyl or alkynyl radicals of n carbon atoms means, according to the invention, hydrocarbon radicals, linear, saturated or unsaturated, branched or unbranched, consisting of n carbon atoms in total (carbon atoms of the main chain and carbon atoms of the branches), comprising 1 to 12 carbon atoms and, more particularly, 1 to 6 carbon atoms. This definition also includes alkyl, alkyl or alkynyl radicals substituted by one or more halogen atoms.by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiobutyl, dry-butyl, pentyl, neopentyl, n-hexyl or cyclohexyl, preferably. by an alkyl radical having 7 to 12 carbon atoms, preferably by an octyl, decyl or dodecyl radical. by an alkenyl radical having 1 to 6 carbon atoms, preferably by hydrocarbon radicals with at least one double bond between two carbon atoms, of the type -CH=CH-, e.g. ethyl, propyl-1-ethyl, propyl-2-ethyl, butyl-1-ethyl, butyl-2-ethyl, triple-butyl, pent-1-ethyl, pent-2-ethyl, 3-methyl-2-ethyl-ethyl. by an alkylyl radical of at least 6 carbon atoms, preferably by a double bond between two hydrocarbon atoms,A halogen atom is a fluorine, chlorine, bromine, or iodine atom.The term cycle of n atoms is used to describe monocyclic or polycyclic radicals whose cyclic part is made up of n atoms in total (in this case, n = 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) and preferably comprises 3 to 7 carbon atoms.It may also be a heterocycle; in which case at least one of the atoms of the cyclic body is a heteroatom, such as nitrogen, oxygen or sulphur. This definition of cycles according to the invention, including phenyl, includes in particular cycles substituted by one or more halogen atoms (and/or by one or more hydroxyl, thiol, cyano, nitro functions, and/or by one or more alkyl, alkynyl, alkyloxy, alkylthio radicals having 1 to 6 carbon atoms, and/or by one or more phenyl or phenyl radical having 1 to 3 carbon atoms, the phenyl radicals themselves being the perfluoroalkyls (alkyls, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogens, halogFor example: saturated carbocycles such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, or cycloheptyl; unsaturated aromatic or partially aromatic carbocycles such as cyclobutadiene, benzene (or benzene group), pentalene, heptalene, naphthalene, or anthracycline; among aromatic carbocycles, the unsaturated phenyl or naphthalene group is particularly preferred; saturated or unsaturated carbocycles such as morphine, pyrroxide, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxyethane, 2-pyrroxide, 2-pyrroxide, 2-pyrroxide, 2-pyrroxine, 2-pyrroxide,The terms alkyloxy and alkylthio refer respectively to an alkyl chain linked to the rest of the molecule via an oxygen atom (ether bond) or an alkyl chain linked to the rest of the molecule via a sulfur atom (thioether bond). alkyloxy can be used to refer to the definition set out above. Examples include oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoxy, oncoEthylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tertio-butylthio, dry-butylthio or hexylthio.The term phenylalkyl refers to an alkyl-type radical substituted by a phenyl group, the alkyl radical being as defined above.This definition includes in particular those phenylalkyl radicals whose phenyl group is substituted by one or more halogen atoms and/or by one or more alkyl-type radicals of 1 to 6 carbon atoms or alkyl-type radicals of 2 to 6 carbon atoms, possibly themselves halogenated.The term biobox radical refers to compounds that are chemically equivalent to a carboxylic radical (i.e. can substitute a carboxylic radical without significantly changing the overall biological activity of the carboxylic radical), i.e. without significantly changing the chemical activity of the carboxylic radical.Biosteroid groups are generally used to improve the efficiency, selectivity, stability, or pharmacokinetics of molecules. Many carboxyl radical bioisosteric groups are known and widely described in the literature (Burger A, 1991; Lima LM and Barreiro EJ, 2005).
The R-alkyl radical of triazole may be an alkyl radical as defined above. The term functions derived from the carboxylic acid function refers to hydrolysis-sensitive functions (especially enzymatic hydrolysis) known to the art world as precursors to the carboxylic acid function. These functions are widely used to modify the pharmacokinetic properties of carboxylated active molecules. These include esters, thioesters, amides and thioamides.
In general, the invention relates to compounds which satisfy the General Formula (I) as defined above, in which, preferably: is chosen from the radicals methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tertio-butyloxy, dry-butyloxy, n-pentyloxy, cyclopentyloxy, n-hexyloxy, cyclohexyloxy, phenoxy, methylamine, dimethylamine, ethyllamine, diethylamine, n-propylamine, dipropylamine, isopropylamine, diisopropylamine, n-butylamine, dibutylamine, tertio-butylamine, tertio-butylamine, n-hexylamine, dipropylamine, piproxylamine, aniline, pyroxylamine, methylbutylamine, n-propylamine, isopropylamine, isopropylamine, isopropylamine, isopropylamine, xylamine, n-butylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xylamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xlamine, xn-hexylamine, dihexylamine, piperidine, pyrolidine, aniline, methylthyl, ethylthyl, n-propylthyl, isopropylthyl, n-butylthyl, tertio-butylthyl, dry-butylthyl, n-pentylthyl, cyclopentylthyl, n-hexylthyl, cyclohexylthyl, thiophenol, phenyl, benzyl, benzyl, 2-methylphenyle, 3-methylphenyle, 4-methylphenyle, 2-methylhoxyphenyle, 3-methylhoxyphenyle, 4-methylhydroxyphenyle, 2-fluoromethyl, 3-fluoromethylfluoromethylfluoromethylfluoromethyl, 4-fluoromethylfluoromethylfluoromethyl, 2-fluoromethylfluoromethylfluoromethyl, 2-fluoromethylfluoromethylfluoromethyl, 2-fluoromethylfluoromethylfluoromethyl, 2-fluoromethylfluoromethylfluoromethyl, 3-fluoromethylfluoromethylfluoromethylfluoromethyl, 2-fluoromethylfluoromethylfluoromethylfluoromethyl, 3-fluoromethylfluoromethylfluoromethylfluoromethyl, 3-fluoromethylfluoromethylfluoromethylfluoromethyl, 4-fluoromethylfluoromethylfluoromethyl, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 6, 2, 6, 2, 6, 2, 6, 2, 2, 2, 2, 3, 4, 6, 2, 2, 2, 2, 2, 2, 2, 3, 4, 2, 2, 2, 2, 2, 3, 2, 2, 2, 3, 2, 2, 3, 2, 2, 3, 2, 3, 2, 2, 3, 2, 3, 2, 3, 2, 2, 3, 2, 3, 4, 2, 2, 3, 4, 2, 2, 2, 3, 4, 2, 2, 3, 4, 2, 2, 3, 4, 6, 2, 2, 2, 2, 3, 2, 3, 2, 2, 3, 2, 3, 2, 3, 4, 2, 2, 2, 3, 2, 2, 3, 2, 3, 4, 2, 2, 3, 4, 2, 2, 3, 4, 2, 2, 3, 4, 2, 2, 3, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 5, 6, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2,Fluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tertio-butyl, dry-butyl, cyclobutyl, pentyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl; R1 and R2 may also form together with the carbon atom to which they are bound a cyclopropyl, cyclobutyl, cyclopentyl or cyclopentyl-type cycle; cyclopentyl and/or cyclopentyl and/or cyclopentyl and/or cyclopentyl and/or cyclopentyl and/or cyclopentyl and/or cyclopentyl; R3 and R4 may be chosen independently from the hydrogen atom; the i, bromo, chloropentyl, fluoropentyl, cyclopentyl, methyle, ethyl, n-propyl, isopentyl, n-propyl, cyclopentyl, isopentyl, phenyle, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, cyclopentyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl, tributyl,Cyclopentyl, or cyclohexyl; and/orY1 can be chosen from an oxygen, sulphur or selenium atom, or a -NR in which case R can be chosen from the hydrogen atom, methyl radicals, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tertiobutyl, sec-butyl, pentyl, neopentyl, n-hexyl, phenylethyl, benzyl, phenylethyl, 2-methylphenyl, 3-methylphenyl, 4-thenylethylphenyl, 2-methylhexyphenyl, 3-methylhexyphenyl, 4-methylhexyfluorod, 4-methylhexyfluorethylene, 2-methylhexyfluorethylene, 2-methylhexyfluorethylene, 2-methylhexyfluorethylene, 2-methylhexyfluorethylene, 2-methylhexyfluorethylene, 3-methylhexyfluorethylene, 4-methylhexyfluorethylene, 4-methylhexybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxybromoxyor -CR5R6 in which case R5 and R6 may be independently selected from the hydrogen atom, the iodine, bromine, chlorine, fluorine, methyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tertio-butyl, dry-butyl, cyclobutyl, pentyl, neopentyl, cyclopentyl, n-hexyl, phyllohexyl, ethyl, benzyl, pyrenylethyl, 2-methyl, 3-methyl, 4-methyl, 4-methyl, 2-methyl, 3-methyl, 3-methyl, 3-methyl, 3-methyl, 3-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 2-methyl, 4-methyl, 4-methyl, 4-methyl, 2-methyl, 2-methyl, 4-methyl, 4-methyl, 2-methyl, 3-methyl, 4-methyl, 4-methyl, 3-methyl, 4-methyl, 4-methyl, 3-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 4, 4-methyl, 4-methyl, 4-methyl, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2, 4-methyl, 2,isopropylamine, diisopropylamine, n-butylamine, dibutylamine, tertio-butylamine, n-hexylamine, dihexylamine, piperidine, pyrolidine, aniline, methylthione, ethylthione, n-propylthione, isopropylthione, n-butylthione, tertio-butylthione, sec-butylthione, n-pentylthione, cyclopentylthione, n-hexylthione, cyclohexylthione, and thiophilol; also R5 and R6 together with the carbon atom to which they are bound can form a cyclopropyl, cyclopentylbutylamide, cyclohexyl or cyclohexyl radical; and a radical (Westerbutyl) is a functional group of isophil, or a cyclopentyl, or a radical (Westerbutyl) is a functional group, namely the propyl, isophthiol, or propyl carboxylic acid.
Err1:Expecting ',' delimiter: line 1 column 657 (char 656)R2, R3, R4 independently designate a hydrogen atom or a methyl, ethyl, propyl, butyl, isopropyl or tertiobutyl radical; and/or X3, R1 and R2 simultaneously designate hydrogen atoms; and/or X1 and/or X2 designate a cycle of 5 to 14, preferably 5 to 10, atoms, not substituted or substituted by a -CF3 grouping, and more preferably a phenyl, furanyl or naphenyl radical, not substituted or substituted by a -CF3 grouping; and/or RaG designates a -Ra or -Ra radical, with Ra selected from an alkyl radical of 1 to 6 carbons, a cyclohexyl or a phenyl radical; then GRa or a phenyl radical, then designates a -RN radical,Ra and Rb together forming, with the nitrogen atom to which they are bound, a 3- to 8-atom heterocycle (including a piperidinyl radical); and/orG means an -ORa radical with Ra chosen from a methyl, ethyl, propyl, butyl, isopropyl or tertiobutyl radical.
A first particular aspect of the invention concerns compounds of General Formula (I) in which Y1 denotes an oxygen or sulphur atom and Y2 simultaneously denotes an oxygen atom, a sulphur atom or a group -CR5R6 in which R5 and R6, identical or different, are chosen from a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, an alkyl radical or alkynyl radical of 2 to 6 carbon atoms, and a cycle of 3 to 6 atoms, the cycle being preferably phenyl.
A second peculiarity of the invention concerns compounds of General Formula (I) in which Y1 denotes an amino group -NH. According to this second peculiarity of the invention, Y2 preferably represents an oxygen atom, a sulphur atom or a radical -CR5R6-, in which R5 and R6, identical or different, are chosen from a hydrogen atom, an alkyl radical of 1 to 6 carbon atoms, an alkyl radical or alkynyl radical of 2 to 6 carbon atoms, and a cycle of 3 to 6 atoms, the cycle being preferably phenyl.
Depending on this first or second particular aspect of the invention, X1 preferably denotes an unsubstituted phenyl radical or a phenyl radical substituted by a -CF3 group, the -CF3 group being preferably in para of the pyridinyl radical, and/or G preferably denotes a -OCH3 or -OCCH3 group. More specifically, X1 advantageously denotes a phenyl radical substituted by a -CF3 group in para of the pyridinyl radical, G a -OCH3 group, and X2 a hydrogen atom. According to a variant of the first embodiment of this invention, X1 simultaneously denotes an unsubstituted phenyl radical, G a -OCCH3 group, and X2 denotes a particular aspect of the R2 or R3 hydrogen radical.
A third particular aspect of the invention concerns compounds of General Formula (I) which are are identified and grouped on the basis of structural characteristics as defined in Figures 7g, 7h and 7i; and/or represent activities as set out in Examples 8 to 12, and more specifically in Table 8-1 and Figures 8 to 12.
These results show how General Formula (I) compounds with specific groups of superior and unexpected properties met the pharmacological criteria cited in the literature for these types of compounds, by measuring different parameters such as the activating properties of human PPARs in vitro and in cell models, and the anti-diabetic or lipid-lowering character in vivo in mouse models. These results show how General Formula (I) compounds with specific groups of superior and unexpected properties compared to the previous state-of-the-art documents mentioning related groups of compounds, such as WO 03/084916, WO 08/1533, WO 05/041959, WO 08/066356, EP 1266888, and E 200966.334, according to which the properties of PPARs were confirmed in vivo for example in Table 12 (see Figure 12), and in Table 12 (see Figure 12), and in vitro for example in Table 12 (see Figure 7 and Figure 12), wherein which the active groups of PPARs were evaluated in vitro for example in Table 12 and Table 12 (see Figure 7 and Figure 11), and in Table 7 for example in vitro for example in Table 12 and Table 8 (see Figure 7 and Figure 11), wherein which the active groups of PPARs were confirmed in vitro for example in Table 12 and Table 8 and Table 8 (see Figure 7 and Figure 11 and Figure 12).
The compounds of the invention are preferably selected from: - What?
Cpd 1 : acide 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-2-méthyl-propanoïque
Cpd 2 : acide 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)éthanoïque
Cpd 3 : acide 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)propanoïque
Cpd 4 : acide 2-(4-(((2-méthoxy-6-phénylpyridin-3yl)méthyl)amino)phénoxy) éthanoïque
Cpd 5 : acide 2-(4-(((2-méthoxy-6-phénylpyridin-3yl)méthyl)amino)phénoxy) propanoïque
Cpd 6 : acide 2-(4-((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-2-méthyl-propanoïque
Cpd 7 : acide 2-(4-(((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy) éthanoïque
Cpd 8 : acide 2-(4-((2-tertio-butytoxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy) éthanoïque
Cpd 9 : acide 2-(4-(((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy)-2-méthyl-propanoïque
Cpd 10 : acide 2-(4-(((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy)-propanoïque
Cpd 11 : acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénylthio)-2-méthyl-propanoïque
Cpd 12 : acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy)-2-méthyl-propanoïque
Cpd 13 : acide 2-(3-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy)-2-méthyl-propanoïque
Cpd 14 : acide 2-(3-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy) éthanoïque
Cpd 15 : acide 2-(4-((2-hexyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)éthanoïque
Cpd 16 : acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénylthio)-éthanoïque
Cpd 17 : acide 2-(4-((2-hexyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-2-méthyl-propanoïque
Cpd 18 : acide 2-(4-((2-cyclohexyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)éthanoïque
Cpd 19 : acide 3-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phényl) propanoïque
Cpd 20 : acide 2-(4-((6-phényl-2-(pipéridin-1-yl)pyridin-3-yl)méthoxy)phénoxy)-éthanoïque
Cpd 21 : acide 2-(4-((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthoxy)-phénoxy)-2-méthylpropanoïque
Cpd 22 : acide 2-(4-(((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthyl)amino) -phénylthio)-2-méthylpropanoïque
Cpd 23 : acide 2-(4-(((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthyl)amino) -phénylthio)éthanoïque
Cpd 24 : acide 2-(4-((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthoxy)-phénoxy)éthanoïque
Cpd 25 : acide 2-(4-((2-phénylthio-6-(phényl)pyridin-3-yl)méthoxy)phénoxy)éthanoïque
Cpd 26 : acide 2-(4-(((2-méthoxy-5-phénylpyridin-3-yl)méthyl)amino)phénylthio) éthanoïque
Cpd 27 : acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénylthio)-2,2-difluoroéthanoïque
Cpd 28 : acide 2-(4-(((2-méthoxy-5,6-diphénylpyridin-3-yl)méthyl)amino)phénylthio)-éthanoïque
Cpd 29 : acide 2-(4-(((2-méthoxy-5-bromo-6-phénylpyridin-3-yl)méthyl)amino) phénylthio)-éthanoïque
Cpd 30 : acide 2-(4-(((2-méthoxy-6-furylpyridin-3-yl)méthyl)amino)phénylthio)-éthanoïque
Cpd 31 : acide 3-(4-(((2-méthoxy-6-furylpyridin-3-yl)méthyl)amino)phényl)propanoïque
Cpd 32 : acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénylthio)-2-phényl-éthanoïque
Cpd 33 : acide 3-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)(méthyl)amino)phényl)-propanoïque
Cpd 34 : acide 3-(4-(1-((2-méthoxy-6-phénylpyridin-3-yl)propyl)amino)phényl)-propanoïque
Cpd 35 : acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)-2,6-diméthyl-phénoxy)éthanoïque
Cpd 36 : acide 3-(4-(((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthyl)amino) -phényl)-propanoïque
Cpd 37 : acide 3-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylthio)phényl)propanoïque
Cpd 38 : acide 3-(4-(((2-(éthylthio)-6-phénylpyridin-3-yl)méthyl)amino)phényl)-propanoïque
Cpd 39 : acide 3-(4-(((2-méthoxy-6-(parabiphényl)pyridin-3-yl)méthyl)amino)phényl)-propanoïque
Cpd 40 : acide 3-(4-(((2-méthoxy-6-(3-(trifluorométhyl)phényl)pyridin-3-yl)méthyl)amino)-phényl)propanoïque
Cpd 41 : acide 3-(4-(((2-méthoxy-5-phénylpyridin-3-yl)méthyl)amino)phényl)-propanoïque
Cpd 42 : acide 3-(4-((2(-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phényl)-3-phényl-propanoïque
Cpd 43 : acide 3-(2-méthoxy-4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)-phényl)-propanoïque
Cpd 44 : acide 3-(3-méthoxy-4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)-phényl)-propanoïque
Cpd 45 : acide 3-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phényl)butanoïque
Cpd 46 : acide 3-(4-(((2-méthoxy-5-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthyl)amino)phényl)propanoïque
Cpd 47 : acide 3-(4-(((2-méthoxy-5-(3-(trifluorométhyl)phényl)pyridin-3-yl)méthyl)amino) -phényl)propanoïque
Cpd 48 : acide 3-(4-(((2,6-diméthoxy-5-phénylpyridin-3-yl)méthyl)amino)phényl)-propanoïque
Cpd 49 : acide 3-(4-(((5-(4-chlorophényl)-2-méthoxypyridin-3-yl)méthyl)amino)phényl)-propanoïque
Cpd 50 : acide 3-(4-(((2-méthoxy-5-(naphthalèn-2-yl)pyridin-3-yl)méthyl)amino)phényl)-propanoïque
Cpd 51 : acide 3-(4-(((2-éthoxy-6-phénylpyridin-3-yl)méthyl)amino)phényl)propanoïque
Cpd 52 : acide 3-(4-((2-méthoxy-5-phénylpyridin-3-yl)méthoxy)phényl)hex-4-ynoïque
Cpd 53 : acide 3-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phényl)hex-4-ynoïque
Cpd 54 : acide 3-(4-(((2-isopropyloxy-6-phénylpyridin-3-yl)méthyl)amino)phényl)-propanoïque.
Although the compounds of the invention may be generated and purified by processes and with compounds already known to the art and as described in the literature, the invention concerns the processes of preparation of the compounds of General Formula (I).
According to a first variant of the preparation process (Figures 7a, 7b and 7c), the compounds of General Formula (I) can be obtained by a series of reactions consisting of reacting intermediates of the phenol, thiophenol, or aniline type according to the invention with one of the pyridine 3-carboxaldehyde or ketone type according to the invention.
According to a second variation of the preparation process (Figures 7d, 7e and 7f), the compounds of General Formula (I) can be obtained by a series of reactions consisting of reacting intermediates of the phenol, thiophenol, or aniline type according to the invention with one of the intermediates of the 3-hydroxymethyl, 3-halomethyl or 3-arylsulfonyl methyl-pyridine type according to the invention.
Err1:Expecting ',' delimiter: line 1 column 713 (char 712)
The functional groups that may be present in the reaction intermediates used in the processes can be protected either permanently or temporarily by protective groups that ensure a univocal synthesis of the expected compounds.The protective and deprotective reactions are performed using techniques well known to the art or as described in the literature, such as in the book Greene's Protective Groups in Organic Synthesis (4th edition, 2007; edited by Wuts PG and Greene TW; published by John Wiley and Sons).
The compounds of the invention may contain one or more asymmetrical centers. The invention includes stereoisomers (diastereoisomers, enantiomers), pure or in mixtures, as well as racemic mixtures and geometric isomers, or tautomers. When an enantiomerically pure (or enriched) mixture is desired, it may be obtained either by purification of the final product or chiral intermediates, or by asymmetrical synthesis using methods known to the trade (e.g., using chiral reactants and catalysts). Some pure compounds of the invention may have different stable tautomers and tautomers as well as their compounds included in the invention. The techniques for characterizing and obtaining a steroisomeric mixture or a chiral intermediate, such as R&D, are described in the book Chlorellate, and the techniques for this are described in the book R&D, R&D, and Chemical Mixtures and Chemical Mixtures by Mihang R&D.
The compounds of General Formula (I) may exist as bases or salts of addition to acids. These salts may be prepared, selected and used according to techniques well known to the art or as described in the literature such as in the book Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002 ed. by PH Stahl and Wermuth GH ; published by VHCA Switzerland and Wiley-VCH Germany). In particular, this invention concerns the pharmaceutically acceptable salts of the compounds of the invention. Generally, this term refers to salts or non-toxic salts obtained from acids or bases, whether organic or inorganic.
These salts can be obtained during the final purification step of the compound of the invention or by incorporating salt into the already purified compound. These salts can be prepared with pharmaceutically acceptable acids but salts of other acids useful for purification or isolation of compounds of General Formula (I) are also part of the invention. In particular, when the compounds of the invention are in the form of a salt, it is a salt of an alkaline metal, in particular, a salt of sodium or potassium, or a salt of an alkaline-earth metal, in particular magnesium or calcium, or a salt with an organic amine, in particular, with an amino acid such as lysine or calcinarine.
In particular, the W group as described above may have an acidic character. The corresponding salts are chosen from metal salts (e.g. aluminium, zinc, chromium), alkaline salts (e.g. lithium, sodium, potassium) or alkaline earth salts (e.g. calcium, magnesium). These may be for example organic salts such as ammonium derivatives and non-toxic amines: ammonium, quaternary ammonium (e.g. tetraethylammonium, tetraethylammonium), alkylamines (e.g. methylamine, dimethylamine, trimethylamine, triethylamine, basilamine, etc.), hydroxyl amines (e.g. 2-hydroxyalamine, 2-hydroxyalamine, 2-hydroxylamine, 2-hydroxylamine, 2-hydroxylamine, quinethylamine, quinethylamine, quinethylamine, quinethylamine, quinethylamine, quinethylamine, quinethylamine, quinethylamine, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinamide, quinam, quinam, quinam, quinam, quinam, quinam, quinol, quinam, quinam, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol, quinol
The pyridine nucleus, the G and/or Y1 groups as described above may have a basic character. The corresponding salts are chosen advantageously from mineral acids (hydrochloric, bromic, sulfuric, boric, nitric, phosphoric, etc.) or organic acids (e.g. carboxylic or sulfonic acids such as formic, acetic, methylsulfonic, propionic, tolueneulfonic, valeric, oleic, succinic, palmitic, stearic, lactic, lauric, oxalic, citric, maloccol, tartaric, glycolic, etc.) or salts obtained from amino acids of a character such as glutamic acid.
Some compounds of the invention may be isolated as zwitterions and each of these forms is included in the invention as well as their mixtures. Some compounds of the invention and their salts may be stable in several solid forms. This invention includes all solid forms of the compounds of the invention including amorphous, polymorphous, mono- and poly-crystalline forms.
Compounds of General Formula (I) may exist in free form or in solvated form, i.e. as combinations or combinations with one or more molecules of a solvent, e.g. with pharmaceutically acceptable solvents such as water (hydrates) or ethanol. This specification also discloses prodrugs of compounds of the invention which, after administration to a subject, are transformed into compounds as described in the invention or into their metabolites which exhibit therapeutic activities comparable to those of compounds of the invention.
The compounds of the invention marked with one or more isotopes are also included in the invention: these compounds are structurally identical but differ in that at least one atom of the structure is replaced by an isotope (radioactive or not). Examples of isotopes that may be included in the structure of the compounds of the invention may be selected from hydrogen, carbon, nitrogen, oxygen, sulfur such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S respectively. The radioactive isotopes 3H and 14C are particularly preferred because they are easy to prepare and detect in in vivo bioavailability studies of substances.
The present invention also relates to compounds as described above as medicinal products, and in particular relates to the use of a compound of the invention in the manufacture of a medicinal product for the therapeutic and/or prophylactic treatment of diabetes, dyslipidemia, insulin resistance, conditions associated with metabolic syndrome, atherosclerosis, and cardiovascular disease (including those associated with impaired lipid and/or carbohydrate metabolism), obesity, hypertension and/or inflammatory disease.
The present invention also concerns a pharmaceutical composition comprising, in a pharmaceutically acceptable medium, at least one compound as described above, possibly in combination with one or more other therapeutic and/or cosmetic active ingredients. It is an advantageous pharmaceutical composition for the therapeutic and/or prophylactic treatment of diabetes, dyslipidemia, insulin resistance, conditions associated with metabolic syndrome, atherosclerosis, cardiovascular disease, obesity, hypertension, inflammatory diseases, etc. The inflammatory conditions are particularly relevant to lipidemia. It is a preferred pharmaceutical composition for the treatment of lipidemia and the risk of developing diabetes mellitus, such as type 2 diabetes mellitus (AJ/GAR, 2006), and for the treatment of lipidemia and lipidemia with reduced glycemic activity and reduced risk of cardiovascular disease (Figure 2, FIG, 2006).
This description refers to a nutritional composition containing at least one of the compounds described above.
In the context of the present invention and in general, pharmaceutically acceptable carrier means substances such as excipients, vehicles, adjuvants, tampons which are conventionally used in combination with the active substance (s) for the preparation of a medicinal product.
Another object of the invention is the use of at least one compound as described above for the preparation of pharmaceutical formulations for the therapeutic and/or prophylactic treatment of various pathologies, including those related to metabolic disorders including diabetes (especially type 2 diabetes), dyslipidemia, insulin resistance, pathologies associated with X syndrome, metabolic, atherosclerosis, cardiovascular diseases, obesity, hypertension, inflammatory diseases.
For example, the compounds of the invention, such as insulin-secreting compounds and PPAR activators currently marketed for the treatment of metabolic diseases, may be advantageously administered in combination with one or more other therapeutic and/or cosmetic agents, marketed or in development, such as: Anti-diabetics: insulin secretions (such as sulphonylureas and glinoids ...), alpha-glucosidase inhibitors, PPARγ agonists (such as thiazolidinediones ...), mixed PPARα/ PPARγ agonists, pan-PPARs (compounds that simultaneously activate all 3 PPAR isoforms), biguanides, inhibitors of Dipeptidyl Peptidase IV, agonists of Glucose-like Peptide-1 (such as exenatide), alpha-glucosidase inhibitors,including insulin and insulin analogues; lipid-lowering and/ or cholesterol-lowering molecules: fibrates (such as fenofibrate and gemfibrozil), hydroxylmethylglutaryl coenzyme A reductase inhibitors (such as statins), cholesterol absorption inhibitors (such as ezetimibe and phytosterols), cholesterol ester transfer protein inhibitors, acyl-CoA:Cholesterol O-Acyl Transferase (ACAT) inhibitors, Microsomal Triglyceride Transfer Protein inhibitors, bile acids, E vitamins, polypeptides, acids of the acetylated type 3, and nicotinamide and acetylated type 3 inhibitors; and acetylated fat (including captocin), acetylated acids and nicotinamide (including captocin),The main risks associated with the use of this medicine are: - the use of anti-platelet agents (such as aspirin and clopidogrel); - anti-obesity agents: sibutramine, lipases inhibitors (orlistat), PPARδ agonists and antagonists, CB1 cannabinoid receptor antagonists, dopamine agonists, serotonin receptor agonists, beta beta reuptake inhibitors, NPK agonists, MCK agonists, Melanin agonists,- orexin antagonists, phosphodiesterase inhibitors, 11-β-hydroxy steroid dehydrogenase inhibitors, dipeptidyl peptidase IV inhibitors, histamine H3 antagonists (or reverse agonists), Ciliary Neurotrophic Factor derivatives, growth hormone secretagogue receptor agonists, ghrelin modulators, diacylglycerol acyltransferase inhibitors; anti-inflammatory agents: corticosteroids (such as prednisone and probrocortisone), non-steroidal anti-inflammatory agents (derived from cellulose, aryl group, phenylalanine, or dioxamide); anti-oxidants used in the treatment of heart failure or stroke; or anti-coagulants such as thiazolamines or thioxifenoxides (used in the treatment of CO2 inhibition agents, such as thiazolamines or rococoxib).Angiotensin converting enzyme inhibitors, digitalis, beta-blockers, phosphodiesterase inhibitors; agents used to treat coronary heart failure: beta-blockers, calcium channel blockers, NO donors, amiodarone,anti-asthmatics: bronchodilators (beta 2 receptor agonists), corticosteroids, chromoglycates, leukocyte receptor antagonists; corticosteroids used to treat skin conditions such as psoriasis and dermatitis; vasodilators and/ or anti-seizure agents.
This specification also describes a method of therapeutic and/or prophylactic treatment of diabetes, dyslipidemia, insulin resistance, pathologies associated with metabolic syndrome, atherosclerosis, cardiovascular disease (including those related to lipid and/or carbohydrate metabolism disorders), obesity, hypertension and/or inflammatory diseases, including administration to a subject, particularly a human, of an effective amount of a compound or a pharmaceutical composition as defined above.
The term treatment refers to curative, symptomatic, and/or prophylactic treatment. The compounds of the invention can thus be used in subjects (especially humans) with a declared disease. The compounds of the invention can also be used to delay or slow the progression or prevent further progression of the disease, thus improving the condition of the subjects. The compounds of the invention can finally be administered to people who are not ill, but who could normally develop the disease or who have a significant risk of developing the disease.
According to another aspect of the invention, the compound of General Formula (I), or one of its salts of addition to a pharmaceutically acceptable acid or one of its solvates or hydrates and another therapeutic agent may be administered simultaneously (in a single pharmaceutical form), separately (with the administration of both compounds at the same time but each in a separate pharmaceutical form) or over time (with the administration, at different times, of both compounds, usually for a period not exceeding 24 hours).
The pharmaceutical compositions of the invention include one or more excipients or vehicles, which are pharmaceutically acceptable. Examples include saline, physiological, isotonic, buffered, etc. solutions, which are compatible with a pharmaceutical use and known to the trade. The compositions may contain one or more agents or vehicles chosen from the dispersing agents, solubilisers, stabilizers, preservatives, emulsifiers, antioxidants, emollients, moisturizers, moisturizers, moisturizers, for flavor enhancement, to regulate hydration or pH, etc.Gelatin, lactose, certain vegetable or animal oils, acacia, dextrose, sucrose, gelatine, agar, stearic acid, liposomes, etc. The formulations may be in the form of suspensions for injection, gels, oils, tablets, suppositories, powders, capsules, capsules, aerosols, etc., possibly by means of galenic forms or devices providing for prolonged and/or delayed release. For this type of formulations, an agent such as cellulose, carbonates or starches is used advantageously. For example, a form of a drug for a compound according to the invention may include the following: mannitol, sodium ammonium, sodium croscarnitol, corn starch,Hydroxypropyl methyl cellulose, magnesium stearate
The compounds or compositions of the invention may be administered in various ways and in different forms. For example, they may be administered systemically, orally, parenterally, topically, ocularly, rectally, perlingually, by inhalation or injection, e.g. intravenously, intramuscularly, subcutaneously, transdermally, intravenously, etc. For injections, the compounds are usually packaged as liquid suspensions, which may be injected by means of syringes or infusions. Orally, the composition may be in the form of tablets, capsules, drops, syrups, suspensions, powders, lipid granules, emulsions, nano- or nano-shaped solutions or suspensions for controlled perfusion or as a parenteral or molecular solution.
Of course, the professional will take care to select the compound (s) to be added to these compositions in such a way that the beneficial properties inherent in the present invention are not or substantially not altered by the intended addition, as also explained in the literature, e.g. in the book Pharmaceutical Dosage Forms and Drug Delivery (2007; edited by Mahato R; published by CRC Press).
It is understood that the rate and/or dose injected may be adjusted by the practitioner according to the patient's sex, age and weight, pathology, mode of administration, or possibly associated treatments. Typically, the compounds are administered in doses ranging from 1 μg to 2 g per administration, preferably 0.1 mg to 1 g per administration. The doses may be daily or even repeated several times per day as appropriate.
The following abbreviations are used:
Err1:Expecting ',' delimiter: line 1 column 602 (char 601)
The Commission has already made a number of recommendations.
The statistical analyses of the various pharmacological experiments consist of a Student test (t-test) and the results are expressed in relation to the control group as the value of the p parameter: p< 0.05 (noted *); p< 0.01 (noted **); p< 0.001 (noted ***).
The legend of the figures
Figure 1- General scheme for the synthesis of compounds according to the invention. Except for specific compounds that are shown in Examples 1 through 7, the intermediates generated in Example 2 (Figure 2) were used to synthesize the intermediates in Example 3 (Figure 3) which were then used to synthesize the intermediates in Example 5 (Figure 5). The intermediates in Example 6 (Figure 6) were generated separately. As described in Example 7 (Figure 7), the compounds of the invention were synthesized using either the intermediates in Example 4 and Example 6 or the intermediates in Example 5 and Example 6.Figure 2- Intermediates of the 2-oxo-1,2-dihydropyridine type 2-1, 2-2 and 2-5 to 2-7 (Figure 2a); 2-3 (Figure 2b); 2-4 (Figure 2c). These intermediates can be classified according to their groups X1, X2 and X3 (Figure 2d).Figure 3-Alkoxy, alkylthio-, alkylamino-, halo-pyridine-type intermediates 3-1 to 3-4, 3-7, 3-9, 3-12, 3-13, 3-15, 3-16, 3-24 and 3-25 (Figure 3a); 3-10, 3-11, 3-17, 3-18, 3-19 to 3-23 (Figure 3b); 3-5, 3-6, 3-8 and 3-14 (Figure 3c). These intermediates can be classified according to their groups X1,X2 and X3 (Figures 3d and 3e).Figure 4- Intermediates of the 3-hydroxymethyl, 3-halomethyl and 3-arylsulfonyl methylpyridine type 4-1 to 4-10, 4-12, 4-13, 4.14, 4-17 to 4-23 (Figure 4a); 4-15 (Figure 4b); 4-11 (Figure 4c)); 4-16 (Figure 4d). These intermediates can be classified according to their groups X1, X2 and X3 (Figures 4e and 4f).Figure 5- Intermediates of the pyridine 3-carboxaldehyde and ketone type Reaction diagram for the synthesis of the intermediates in Example 5: Ex.5-1, 5-3, 5-4, 5-6 to 5-18 (Figure 5a); 5-2 (Figure 5b) ; 5-5 (Figure 5c).X2 and X3 (Figures 5d and 5e).Figure 6- Intermediates such as phenol, thiophenol and aniline Reaction diagram for the synthesis of the intermediates in Example 6 : Ex.6-1 to 6-6, 6-11 to 6-13, and 6-20 (Figure 6a); 6-10, 6-14, 6-16 to 6-19 (Figure 6b); 6-7 to 6-9 (Figure 6c); 6-15 (Figure 6d)); 6-21 to 6-24 (Figure 6e). These intermediates may be classified according to their groupings Y1 and Y2 (Figure 6f and 6g).Figure 7- Composites according to the invention Reaction diagram for the synthesis of compounds according to the invention: Cpd 4, Cpd 8-12, Cpd 16, Cpd 19, Cpd 22, Cpd 23, Cpd 26-32,Cpd 35, Cpd 36, Cpd 38-51, and Cpd 54 (Figure 7a) ; Cpd 13 and Cpd 14 (Figure 7b) ; Cpd 34 (Figure 7c) ; Cpd 2, Cpd 6, Cpd 7, Cpd 15, Cpd 17, Cpd 18, Cpd 20, Cpd 21, Cpd 24, Cpd 25, Cpd 52, Cpd 53 (Figure 7d) ; Cpd 1, Cpd 3, Cpd 5, Cpd 33 (Figure 7e) ; Cpd 37 (Figure 7f). The compounds of the invention may be classified according to their groups X1, X2, X3, Y1 and Y2 (Figures 7g, 7h, and 7i). The effect of Cpd 24 was evaluated in vivo in db/db mice.Plasma glucose (Figure 8a), insulin (Figure 8b), and HOMA (Figure 8c) levels were measured after 8 days of treatment with Cpd 24 administered at 30 mpk in mice. The difference measured reflects the effect of Cpd 24 on insulin resistance parameters. A decrease in HOMA, calculated from these plasma parameters, is also reflective of an improvement in insulin sensitivity. Blood glucose was measured in mice treated with Cpd 24, administered at 30 mpk for 9 days, and in mice treated with Cpd 24, administered at 30 mpk for 9 days.The corrective action of Cpd 24 on insulin resistance results in an improvement in glucose tolerance. The levels are compared with those obtained in control animals (untreated).Figure 9- Hypolipemic and HDL-cholesterol synthesis stimulating properties of the compounds according to the invention Plasma total cholesterol (Figure 9a) and HDL cholesterol (Figure 9b) levels were measured in ApoE2/E2 dyslipidemic mice after 7 days of oral Cpd 2 or Cpd 4 therapy.These parameters are compared with those obtained in control animals (untreated): the difference measured shows the lipid-lowering effect of the compounds of the invention. The effect of Cpd 2 and Cpd 4 was also assessed in the hepatic tissue of mouse ApoE2/E2 by measuring the expression of genes involved in lipid and/or carbohydrate metabolism such as ACO (Figure 9c), PDK4 (Figure 9d) and Apo CIII (Figure 9e).The higher the factor, the more gene expression-activating the compound is. The final result is represented as the average of the induction values in each experimental group.Figure 10-Hypolypaemic properties of the compounds according to the invention Plasma levels of total cholesterol (Figure 10a) and free fatty acids (Figure 10b) were measured in E2/E2 dyslipidemic mice after 7 days of oral treatment with Cpd 19, administered at 100 mpk. These parameters are compared with those obtained with control animals (untreated): the difference measured is indicative of the lipid-lowering effect of the compounds of the invention.Figure 11- PPARδ activating properties of compounds according to the invention The stimulatory effects of lipid, carbohydrate metabolism and energy expenditure in skeletal muscle of the compounds of the invention have been evaluated by measuring the expression of PDK4 (Figure 11a), CPT1b (Figure 11b), and UCP2 (Figure 11c) in mouse myocytes treated for 24 hours with Cpd 7 or Cpd 24 at different concentrations (0.1, 1, 10μM and 0.2, 2 and 20μM respectively). The expression of these genes in this cell type is a direct consequence of the activation of PPARδ by the compounds of the invention.The expression levels presented are normalised with respect to the expression level of the reference gene 36B4.Figure 12- PPARγ activating properties of the compounds according to the invention The adipogenesis stimulating effects of Cpd 19, Cpd 24 and Cpd 36 were assessed by measurement of TG accumulation (Figures 12a and 12c) and adiponectin secretion (Figures 12b and 12d) in an in vitro model of mouse pre-adipocytes.The levels were compared with those measured in untreated cells: the higher the TG and Adiponectin concentrations, the more adipogenous the compounds and therefore activate PPARγ. The activity of the compounds of the invention is also compared with the effects of a reference molecule agonist of PPARγ (rosiglitazone). The higher the triglyceride accumulation and adiponectin secretion, the more the compound of the invention is therefore activating PPARγ and stimulating metabolism in adipocytic cells.
Examples Example 1 General protocols
The compounds of the invention are prepared according to the general methods and general synthesis protocols SA to SY below. The compounds of the invention and the corresponding reactive intermediates have been characterized at the structural level by RMN 1H (300MHz; CDCl3, CDCl3+D2O, or DMSO-d6, the latter conditions in particular for the compounds of the invention; δ in ppm).
The following shall be recorded:
The adequate ketone (Acetophenone for Ex. 2-1; 4-trifluoroacetophenone for Ex. 2-2; 2-phenylacetophenone for Ex. 2-3; 2-acetylfurane for Ex. 2-5; para-acetylbiphenyl for Ex. 2-6; 3-trifluoromethylacetophenone 2.7) is solubilised in N,N-dimethylformamide dimethyl acetal (1.2 to 1.5 equ). The medium is maintained under reflux agitation. The estimated reaction time is between 24 and 48 hours. Satisfactory results were obtained in 24 hours: Protocol SB.
The prop-2-en-1-one from the previous step (see Examples 2-1, 2-2, 2-5, 2-6, and 2-7) is soluble in methanol (0.3 to 1.5 mol/L). The medium is maintained under reflux agitation. The estimated reaction time varies from 18 to 48 hours.
Protocol SC:
The methyl ester from the previous step (see Examples 2-1, 2-2, 2-5, 2-6, 2-7) is solubilised in toluene (0.15 to 0.5 mol/L) and acetic acid (1 to 1.5 eq.) is added. The mixture is kept under reflux agitation. The estimated reaction time varies from 12 to 48 hours. Satisfactory results were obtained in 18 hours.
This is SD protocol:
The aminopropenone of the previous step, cyanoacetamide (1.1 μl) and methanol (2 μl) are soluble in N,N-dimethylformamide (0.3 mol/L). This solution is added to a suspension of NaH (2 μl) in N,N-dimethylformamide (3 μl). The solution is agitated at 95 °C for 18 hours.
Protocol SE: the following
The pyridinone from the previous step (Ex. 3-9 for Ex. 3-10; Ex. 3-19 for Ex. 3-20) and N-bromosuccinimide (1 to 1.1 equ) are solublelized in N,N-dimethylformamide (0.1 to 0.4 mol/L). The reaction medium is maintained under reflux agitation. For an efficiency of at least 30-80%, the estimated reaction time is between 4 and 16 hours. Satisfactory results were obtained in 4 hours. After return to room temperature, the precipitate formed is exsorted and washed with water and/or heptane.
Protocol SF:
2-oxo-1,2-dihydropyridine (Ex. 2-1 for Ex. 3-1 to 3-4, 3-24, 3-25 ; Ex. 2-2 for Ex. 3-7 ; Ex. 2-4 for Ex. 3-12 ; Ex. 2-5 for Ex. 3-13 ; Ex. 2-6 for Ex. 3-15; Ex. 2-7 for Ex. 3-16 ; 3-18 ; 2-hydroxynicotinic acid for Ex. 3-9) is solublelized in toluene (0.06 to 0.4 mol/L) then silver oxide (1 to 1.2 eq.) and the halogen derivative (e.g. 1 to 1.2 eq. ; methyl iodide for Ex. 3-12, 3-15, 3-16, 3-19, 5-5; 3-15; 2-hydroxynicotinic acid for Ex. 3-16 ; Ex. 2-hydroxynicotinic acid for Ex. 3-16 ; 3-18 ; 2-hydroxynicotinic acid for Ex. 3-9) is solublelized in toluene (0.06 to 0.4 mol/L) then silver oxide (1 to 1.2 eq.) and the halogen derivative (e.g. 1 to 1.2 eq. ; methyl iodide for Ex. 3-12, 3-12, 3-15, 3-16, 3-16, 3-16, 3-19, 3-19, 5-5; 5-5; 5-5; 2-hydroxycysteine iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide iodide i
SG protocol:
2-oxo-1,2-dihydropyridine (Ex. 2-1 for Ex. 3-5) is soluble in phosphoryl trichloride (10 equ) in the presence of a catalytic amount of N,N-dimethylformamide.
Protocol SH:
Halopyridine (Ex. 3-5 for Ex. 3-8, 3-14) is solubilised in acetonitrile (0.06 to 0.4 mol/L) and potassium carbonate (2 to 3 equ) is added. Thiol (e.g. 1.2 to 3 equ; thiophenol for Ex. 3-8; ethanethiol for Ex. 3-14) is added drop by drop and the whole is agitated at reflux. For an efficiency of at least 80%, the estimated reaction time varies between 18 and 48 hours.
Protocol SI: the following
The intermediate (0.15 mol/L; Ex. 3-1 for Ex. 3-11; Ex. 3-10 for Ex. 3-17, Ex. 3-18, Ex. 3-22, Ex. 3-23; Ex. 3-20 for 3-21), potassium carbonate (3 equ.) and water (11 equ.) are solublelized in N,N-dimethylformamide under inert atmosphere. Palladium acetate (0.1 equ.) is added, then the boronic acid solution (phenylboronic acid for Ex. 3-11 and 3-21); 4-trifluoroethylboronic acid is added for Ex. 3-17lu; 3-trifluoroethylboronic acid for Ex. 3-18l; 4-chloroethylboronic acid for Ex. 3-22l; NaOH in the ambient environment. The estimated reaction time is between 48 hours and 1 minute.
Protocol SJ:
The 2-alkoxy-1,2-dihydropyridine ester (Ex. 3-1 for Ex. 4-1; Ex. 3-2 for Ex. 4-2; Ex. 3-3 for Ex. 4-3; Ex. 3-4 for Ex. 4-4; Ex. 3-6 for Ex. 4-5; Ex. 3-7 for Ex. 4-6; Ex. 3-8 for Ex. 4-7; Ex. 3-11 for Ex. 4-8; Ex. 3-12 for Ex. 4-9; Ex. 3-13 for Ex. 4-10; Ex. 3-14 for Ex. 4-12; Ex. 3- for Ex. 4-5; Ex. 3-15 for Ex. 4-13; Ex. 3-16 for Ex. 4-14; Ex. 3-17 for Ex. 4-17; Ex. 3-18 for Ex. 4-18; Ex. 3-21 for Ex. 3-22 for Ex. 4-20; Ex. 3-21 for Ex. 4-24; Ex. 3-24 for Ex. 3-22; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; Ex. 3-25; 3-25; 3-25; 3-25; 3-25; 3-25; 3-25; 3-25; 3-25; 3-25; 3
The following shall be recorded:
The pyridine carboxaldehyde (Ex 5-1 for Ex 4-11) is solubilised in tetrahydrofuran (0.45 mol/L) and the solution is cooled to -78°C. A solution of ethylmagnesium bromide (3.4 μM) is added drop by drop.
Protocol SL:
Hydroxymethylpyridine (Ex 4-1 for Ex 4-15) and triethylamine (1.5 equ) are soluble in tetrahydrofuran (1 mol/L) and then paratoluene sulphonyl chloride (1.5 equ) is added.
This is SM protocol:
The hydroxymethylpyridine (Ex. 4-1 for Ex. 4-16) is solubilised in dichloromethane (0.2 mol/L) and then the solution is cooled to 0°C. Phosphorus tribromide (1 equ.) is added. The whole is kept agitated at 0°C. After 0.2 hours, the reaction medium is poured over the ice and then extracted with dichloromethane.
The following shall be recorded:
Hydroxymethylpyridine (Ex. 4-1 for Ex. 5-1; Ex. 4-6 for Ex. 5-3; Ex. 4-8 for Ex. 5-4; Ex. 4-9 for Ex. 5-6; Ex. 4-10 for Ex. 5-7; Ex. 4-11 for Ex. 5-8; Ex. 4-12 for Ex. 5-9; Ex. 4-13 for Ex. 5-10; Ex. 4-14 for Ex. 5-11; Ex. 4.17 for Ex. 5-12 for Ex. 4-18 for Ex. 5-13; Ex. 4-19 for Ex. 5-14; Ex. 4-20 for Ex. 5-15 for Ex. 4-21 for Ex. 5-16; Ex. 4-22 for Ex. 5-17 for Ex. 4-23 for Ex. 5-18) is then added to the soil in dichloromethane (0.06 to 0.5 L) and chloropyridinium chloride (CC 2); the reaction time is maintained at an approximate ambient temperature of between 2 and 48 hours; the reaction time is then estimated to vary from 2 to 2 hours.
The following shall be recorded:
The hydroxymethylpyridine (Ex. 4-2 for Ex. 5-2) is solubilised in dichloromethane (1.5 mol/L) and the solution is cooled to 0 °C. The Dess-Martin reagent (1.1 equ) is added drop by drop and the whole is kept agitated at 0 °C.
Protocol SP:
1,2-dihydropyridine-carbonitrile (Ex. 2-3 for Ex. 5-5) is dissolved in formic acid (1.1 mol/L) and Raney's Nickel (50%Wt) is added (1.5 eq.).
Protocol SQ:
The phenol (4-benzyloxyphenol for Ex. 6-1 to 6-5; 3-nitrophenol for Ex. 6-12, 6-13; 4-nitrophenol for Ex. 6-6, 6-11; 4-nitro-2,6-dimethylphenol for Ex. 6-20), thiophenol (4-aminothiophenol for Ex. 6-10, 6-14, 6-16 to 6-19), aniline (4-hydroxy-10-tertibutyloxycarbonylaniline for Ex. 6-7, 6-8, 6-9) or acid (2,6 dimethyloxynicotinic acid for Ex. 3-19) is dissolved in the appropriate solvent (0.2 to 1.2 mol/L) and then the halogen derivative or tosylate (1,2 to 3 mol/L; 6-1,2-fluoroethyl bromidate for Ex. 6-18; 6-1,6-methyloxybromid for Ex. 6-19, 6-3, 2-methyloxybromidate for Ex. 6-19, 6-3, 6-methyloxybromid for Ex. 6-19, 6-3, 6-methyloxybromid for Ex. 6-1, 6-methyloxybromid bromid for Ex. 6-1, 6-9, 6-methyloxybromid bromid for Ex. 6-3, 6-methybromid bromid bromid. 6-3, 6-9, 6-methybromid bromid bromid. 6-3, 6-methybromid. 6-3, 6-methybromid. 6-3, 6-methybromid bromid.6-2, 6-5, 6-11, 6-12, 6-16; tertiobutyl bromoacetate for Ex. 6-13, 6-14; ethyl bromoacetate for Ex. 6-4, 6-8, 6-17, 6-20; tertiobutyl bromoacetate for Ex. 6-6; 2-bromo-2-ethyl phenylacetate for Ex. 6-19) and potassium carbonate (2.5 to 6 equ) are added. The reaction medium is kept agitated at the appropriate temperature and, if necessary, at the reflux of acetrylonitrile, N,N-dimethylformamide, acetrylonitrile from a mixture of acetrylonitrile/N,N-dimethylamide (6%), in the presence of tetraethylammonium (0,3 to 5 equ) or thiol, or in the presence of tetraethylammonium (0,3 to 5 equ) or thiol, or in the presence of halogenated acetylammonium (0,3 to 5 equ) or thiol, or in the presence of a mixture of acetrylonitrile, N,N,N,N,N,dimethylammonium or thiol.The estimated reaction time is between 0.1 and 48 hours and the reaction medium is cooled to room temperature.
Protocol SR:
The ester from the previous step is solubilised in the appropriate solvent (0.3 to 1.2 mol/L of methanol, ethanol, dichloromethane, or a mixture of methanol/dichloromethane 1/1 or 2/1) and then palladium on coal (10%Wt) is added in catalytic amounts. The assembly is placed under agitation, under hydrogen atmosphere at the appropriate pressure. The estimated reaction time varies from 4 to 120 hours of agitation at room temperature.
SS protocol:
The protected amine (propanoic acid 3- ((4-aminophenyl) for Ex. 6-15) is solubilised in ethanol (0.3 to 0.6 mol/L) and an ethanol solution of hydrochloric acid is added (2 equals).
Protocol ST:
The triethylphosphonacetate (0.5 mol,L) is added drop by drop to a sodium hydride suspension (1 equ) in tetrahydrofuran at 0°C. After a half hour's agitation at room temperature, the carbonyl derivative (1 equ; 4-nitrobenzophenone for Ex. 6-21; 4-nitroacetophenone for Ex. 6-24; 3-methoxy-4-nitrobaldenzdehyde for Ex. 6-23; 2-methoxy-4-nitrobenzaldehyde for Ex. 6-22) is added and the reaction medium is brought to reflux for 16 hours.
The following shall be recorded:
The ester of the previous step is solubilised in ethanol (0.03 to 1 mol/L) and then a 1 N or 2N (1 to 84 eq., preferably 2 to 20 eq.) sodium solution is added. The whole is kept agitated at room temperature. For an efficiency of at least 30-85% after purification by one of the alternatives shown in example 2, the estimated reaction time ranges from 1 to 96 hours. Satisfactory results were obtained in 16 hours.
Protocol SV:
The phenol (0.1 to 0.9 mol/L), triphenylphosphine (1.05 eq.) are soluble in tetrahydrofuran under inert atmosphere. The diisopropyl azodicarboxylate (1.05 eq.) and the alcohol solution in tetrahydrofuran (1.05 eq., 0.1 to 0.9 mol/L) are successively added drop by drop. The whole is kept agitated at room temperature. For efficiency of at least 30-80%, the estimated reaction time is between 16 and 72 hours. Satisfactory results have been obtained in 16 hours.
Protocol SW:
The precipitate is filtered, picked up in water (0.2 Umol) and treated with a 2N (3Eq.) soda solution for 0.5 hours. The set is acidified with a 1N citric acid solution, stirred, then filtered. For an efficiency of at least 30-80%, the estimated reaction time varies from 16 to 24 hours. Satisfactory results were obtained within 16 hours. The reaction medium can be treated with a potassium carbonate solution agitated for 0.5 hours (H=0.5-0.8-9%) by a 10% acidified potassium carbonate solution.
Protocol SX:
The aldehyde and aniline (1-1.5 μl) are soluble in dichloromethane (0.1-0.4 mo/L) under inert atmosphere. The reaction medium is kept agitated at room temperature for 1 hour. Sodium triacetetoxyborohydride (1.2-1.5 μl) is added in portions, and then the whole is kept agitated at room temperature. When the required aniline is available in its hydrochloride form, it is first re-released by basic treatment. For a cleaning efficiency of at least 40-85% depending on the alternatives in example 2, the estimated reaction time varies between 2.5 and 72 hours.
Protocol SY:
The ketone and aniline (1.2 μl) are soluble in toluene (0.03 mo/L), in the presence of paratoluene sulfonic acid (1 μl) and molecular sieve 3Å, in a Dean-Stark assembly. The reaction medium is kept agitated at 110 °C for 16 hours. After cooling the insoluble are filtered and the filtrate is concentrated under reduced pressure. The evaporation residue is taken up into dichloromethane.
The resulting raw materials can be purified according to one or more of the general PA to PE purification protocols. To this end, the usual preliminary steps are hydrolysis (with or without dilution, e.g. by ethyl acetate) or washing (neutral, acid or base, e.g. by water), of a saturated solution of sodium chloride, a 1N citric acid solution, a saturated solution of ammonium chloride, a 10% solution of potassium carbonate, a 1N solution of sodium hydroxide, then extraction from the reaction medium by means of a solvent (diethyl ether or dichloromethane, e.g. insoluble methane), e.g. by means of organic solvents (e.g. sulphite), and the elimination of insoluble solvents (e.g. sulphite) may be appropriate (e.g. by means of pressure reduction, e.g. magnesium sulphite), and the elimination of organic solvents (e.g. insoluble solvents) and/or solvents (e.g.g. sulphite) may be beneficial for the reaction.
In the case of the PA protocol, flash chromatography on silica gel (40-63μm) was performed with different elution conditions (movable phase), as summarized in Table 1-1. - What?
dichlorométhane/méthanol ou (9/1 à 98/2) Etp. 1 pour Ex. 2-5, 4-1, 4-7, 5-5 ; Cpd 33 ;
Etp. 2 pour Cpd 1, Cpd 8, Cpd 10, Cpd 11, Cpd 15, Cpd 21, Cpd 22, Cpd 24, Cpd 28, Cpd 29, Cpd 32-36, Cpd 38-48, Cpd 50, Cpd 51, Cpd 53, Cpd 54
Etp. 3 pour 2-7,
dichlorométhane/ cyclohexane (8/2) Etp. 2 pour 5-5
dichlorométhane/acétate d'éthyle ou cyclohexane/acétate d'éthyle (95/5 ou 98/2) Etp. 1 pour Ex. 3-3, 3-4, 3-12, 5-1, 5-12, 5-13, 5-15, 5-175-6, 5-18, et 6-5 ; Cpd 3, Cpd 6, Cpd 7, Cpd 13-18, Cpd 32, Cpd 34, Cpd 36, Cpd 38, Cpd 42, Cpd 43, Cpd 46-48
Etp. 2 pour Cpd 15
dichlorométhane/acétate d'éthyle ou cyclohexane /acétate d'éthyle (9/1 ou 85/15) Etp. 1 pour Ex. 2-3 , 3-2, 3-5, 3-7, 3-8, 3-11, 3-13, 3-14, 3.22, 3-23, 3-24, 4-5, 4-9, 4-11, 4-21, 5-2, 5-4, 5-7, 5-8, 5-9, 5-14, 5-16, 6-1, 6-3, 6-4, 6-12, 6-14, 6-18, 6-22; Cpd 1, Cpd 2, Cpd 4, Cpd 5, Cpd 8, Cpd 9, Cpd 10, Cpd 11, Cpd 12, Cpd 16, Cpd 19-26, Cpd 30, Cpd 31, Cpd 39, Cpd 40, Cpd 41, Cpd 44, Cpd 45, Cpd 49-54
Etp. 2 pour Ex. 6-3, 6-12
dichlorométhane/ acétate d'éthyle ou cyclohexane /acétate d'éthyle (7/3, 8/2, ou 6/4) Etp. 1 pour Ex. 3-1, 3-9, 3-15, 3-16, 3-19, 3-25, 4-2, 4-6, 4-10, 4-12, 4-13, 4.14, 4-15, 4-19, 5-3, 5-10, 5-11, 6-10, 6-11, 6-13, 6-16, 6-17, 6-19, 6-21, 6-23, 6-24 ; Cpd 27, Cpd 28, Cpd 29, Cpd 35 ;
Etp. 2 pour Ex. 6-5 6-21, 6-24
In the case of the PB protocol, silica gel chromatography is performed by a preparatory HPLC (lichrospher, Merck; RP18 12μm 100A, column : 25*250 mm; Step 2 for Cpd 5, Cpd 13, Cpd 14, Cpd 17, Cpd 18, Cpd 20, Cpd 23, Cpd 52; Step 1 for Cpd 37).
In the case of the PC protocol, precipitation is carried out in a mixture of solvents which are chosen from the solvents common to the tradesmen, such as dichloromethane, heptane, cyclohexane, toluene, e.g. dichloromethane/heptane 4/6 (Etp. 1 for Ex. 2-1, 2-2, 2-6; Etp. 2 for Cpd 12, Cpd 16, Cpd 19, Cpd 22, Cpd 27, Cpd 30, Cpd 31, Cpd 49; Etp. 3 for Cpd 46, Cpd 47, Cpd 48, Cpd 51, Cpd 53), dichloromethane/toluene 4/6 (Etp. 2 for Ex. 2-5), or dichloromethane/cyclohexane 4/6 (Etp. 54 for Cpd 45, Cpd 3/6).
In the case of the PD protocol, the (re) crystallization is carried out in a solvent chosen from the solvents common to the tradesmen such as isopropanol (Etp. 2 for Cpd 9), ethanol (Etp. 2 for Ex. 2-1, Cpd 25), acetone (Etp. 2 for Ex. 2-2), methanol (Etp. 2 for Ex. 2-6, Cpd 3, Cpd 6, Cpd 7), petroleum ether (Etp. 1 for Ex. 6-2, 6-13), dichloromethane, heptane (Etp. 1 for Ex. 6-11, 6-20), cyclohexane (etp. 1 for Ex. 6-6, 6-7, 6-9), or mixtures with e.g. heptane or dichloromethane (Etp. 24, Cpd 15, Cpd 28, Cpd 42, Cpd 29, Cpd 23, Cpd 24, Cpd 24, Cpd 24, Cpd 24, Cpd 24, Cpd 24, Cp24, Cp24, Cp24, Cp24, Cp24, Cp25, Cp25, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, Cp28, C
In the case of the PE protocol, the precipitating product is filtered at the end of the reaction. The estimated reaction time varies between 12 and 24 hours. After the reaction medium has been cooled to 0°C, the hydrolysis or acid hydrolysis of the reaction medium (Ep. 3 for Ex. 2-1, 2.2, 2-5 to 2-7, Ep. 3 for Ex. 2-3, 2-4; Cpd 2, Cpd 4, Cpd 26 ;p. 1 for Ex. 3-20) or a sequence of basic hydrolysis/filtration/crushing of the cake in acidic medium (e.g. in ethanol); Ep. 2 for Ex. 6-7, 6-8, 6-9; Etp. 1 for Ex. 6-15) is performed.
Example 2 - Synthesis of intermediates of the 2-oxo-1,2-dihydropyridine type according to the invention
The synthesis of these intermediates (Figure 2) requires 2 or 3 steps as summarized in Table 2-1: - What?
1 : Préparation du 3-diméthylamino-1-phénylprop-2-én-1-one (Protocole SA et PC) Rendement : 92%. Aspect : solide jaune.
2 : Préparation du 2-carbamoyl-5-diméthylamino-5-phénylpentan-2,4-diènoate de méthyle (Protocole SB et PD) Rendement : 63%
3 : Obtention du 2-oxo-6-phényl-1,2-dihydropyridine-3-carboxylate de méthyle (Protocole SC et PE) Rendement : 66%. Aspect : solide jaune.
1 : Préparation du 3-diméthylamino-1-(4-trifluorométhylphényl)prop-2-én-1-one(Protocole SA et PC) Rendement : 81%. Aspect : solide jaune.
2 : Préparation du 2-carbamoyl-5-diméthylamino-5-(4-trifluorométhylphényl)pentan-2,4-dienoate de méthyle (Protocole SB et PD) Rendement : 37%. Aspect : solide jaune.
3 : Obtention du 2-oxo-6-(4-(trifluorométhyl)phényl)-1,2-dihydropyridine-3-carboxylate de méthyle (Protocole SC et PE) Rendement : 38%. Aspect : solide jaune.
1 : Préparation du 1,2-diphénylprop-2-én-1-one (Protocole SA et PE) Rendement : 68%. Aspect : solide jaune.
2 : Obtention du 2-oxo-5,6-diphényl-1,2-dihydropyridine-3-carbonitrile (Protocole SD et PE) Rendement : 73%. Aspect : solide blanc.
5-bromo-2-oxo-6-phényl-1,2-dihydropyridine-3-carboxylate de méthyle (Protocole SE et PE) Rendement : 37%. Aspect : solide blanc.
1 : Préparation 3-diméthylamino-1-furyl-prop-2-én-1-one (Protocole SA et PA) Rendement : 69%. Aspect : solide jaune.
2 : Préparation du 2-carbamoyl-5-diméthylamino-5-furyl-pentan-2,4-dienoate de méthyle (Protocole SB et PC) Rendement : 24%. Aspect : solide jaune.
3 : Obtention du 6-furyl-2-oxo-1,2-dihydropyridine-3-carboxylate de méthyle (Protocole SC et PE) Rendement : 47%. Aspect : solide jaune.
1 : Préparation du 3-diméthylamino-1-parabiphénylprop-2-én-1-one (Protocole SA et PC) Rendement : 40%. Aspect : solide jaune.
2 : Préparation du 2-carbamoyl-5-diméthylamino-5-(parabiphényl) pentan-2,4-dienoate de méthyle (Protocole SB et PD) Rendement : 43%. Aspect : solide jaune.
3 :Obtention du 2-oxo-6-parabiphényl-1,2-dihydropyridine-3-carboxylate de méthyle. (Protocole SC et PE) Rendement : 59%. Aspect : solide jaune.
1 : Préparation du 3-diméthylamino-1-(3-trifluorométhylphényl)prop-2-én-1-one (Protocole SA et PA) Rendement : 53%. Aspect : huile marron.
2 : Préparation du 2-carbamoyl-5-diméthylamino-5-(3-trifluorométhylphényl)-pentan-2,4-dienoate de méthyle (Protocole SB et PA) Rendement : 23%. Aspect : solide jaune.
3: Obtention du 2-oxo-6-(4-(trifluorométhyl)phényl)-1,2-dihydropyridine-3-carboxylate de méthyle (Protocole SC et PE) Rendement : 58%. Aspect : solide beige.
Example 3: Synthesis of intermediates of the alkoxy, alkylthio, alkylamino, halo-pyridine types according to the invention
The synthesis of the intermediates in Figure 3a is summarized in Table 3-1. - What?
2-méthoxy-6-phényl-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 73%. Aspect : huile incolore.
2-tertiobutoxy-6-phényl-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 56%. Aspect : solide blanc.
2-hexyloxy-6-phényl-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 80%. Aspect : huile incolore.
2-cyclohexyloxy-6-phényl-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 12%. Aspect : huile incolore.
2-méthoxy-6-(4-(trifluorométhyl)phényl)-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 67%. Aspect : solide blanc.
2-méthoxy-pyridine-3-carboxylate de méthyle (Protocole SE et PA) Rendement : 38%. Aspect : huile incolore.
5-bromo-2-méthoxy-6-phényl-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 48%. Aspect : solide blanc.
2-méthoxy-6-furyl-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 70%. Aspect : solide blanc.
2-méthoxy-6-(parabiphényl)-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Aspect : solide blanc.
2-méthoxy-6-(3-(trifluorométhyl)phényl)-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 30%. Aspect : solide blanc
2-éthoxy-6-phényl-pyridine-3-carboxylase de méthyle (Protocole SF et PA) Rendement : 86%. Aspect : solide blanc.
2-isopropoxy-6-phényl-pyridine-3-carboxylate de méthyle (Protocole SF et PA) Rendement : 74%. Aspect :huile incolore.
The introduction of groups at position 5 and, in particular, groups of the aryl or alkyl type, can be achieved by Suzuki-type coupling between the suitably selected boronic acid precursor and the appropriate 5-halopyridine.
5-bromo-2-méthoxy-pyridine-3-carboxylate de méthyle (Protocole SE et PE) Rendement : 33%. Aspect : solide gris.
2-méthoxy-5-phényl-pyridine-3-carboxylate de méthyle (Protocole SI et PA) Rendement : 71%. Aspect : huile incolore.
2-méthoxy-5-(4-(trifluorométhyl)phényl)-pyridine-3-carboxylate de méthyle (Protocole SI et PA) Rendement : 21%. Aspect : solide blanc.
2-méthoxy-5-(3-(trifluorométhyl)phényl)-pyridine-3-carboxylate de méthyle (Protocole SI et PA) Rendement : 30%. Aspect : solide blanc.
2,6-diméthoxy-pyridine-3-carboxylate de méthyle (Protocole SQ et PA) Rendement : 69%. Aspect : solide blanc.
5-bromo-2,6-diméthoxy-pyridine-3-carboxylate de méthyle (Protocole SE et PE) Rendement : 81%. Aspect : solide blanc.
5-phényl-2,6-diméthoxy-pyridine-3-carboxylase de méthyle (Protocole SI et PA) Rendement : 76%. Aspect : solide blanc.
5-(4-chlorophényl)-2-méthoxy-pyridine-3-carboxylate de méthyle (Protocole SI et PA) Rendement : 97%. Aspect : solide blanc.
5-(naphthalèn-2-yl)-2-méthoxy-pyridine-3-carboxylate de méthyle (Protocole SI et PA) Rendement : 84%. Aspect : solide blanc.
Intermediates substituted at position 2 by alkylthio, alkylamino groups are available from the corresponding 2-halo-pyridine intermediates 3-6, 3-8 and 3-14 have been prepared from 2-chloropyridine 3-5 (Figure 3c), as summarized in Table 3-3. - What?
2-chloro-6-phényl-pyridine-3-carboxylate de méthyle (Protocole SG et PA) Rendement : 83%. Aspect : solide blanc.
2-(piperidin-1-yl)-6-phényl-pyridine-3-carboxylate de méthyle (l'intermédiaire 3-5 est solubilisé dans de la pipéridine (0,1 mol/L) et l'ensemble est maintenu sous agitation à reflux pendant 16 heures ; Protocole PA) Rendement : 95%. Aspect : huile jaune.
2-phénylthio-6-phényl-pyridine-3-carboxylate de méthyle ( Protocole SH et PA) Rendement : quantitatif. Aspect : huile incolore.
2-éthylthio-6-phényl-pyridine-3-carboxylate de méthyle ( Protocole SH et PA) Rendement : 90%. Aspect : solide beige.
Example 4: Synthesis of intermediates of the type 3-hydroxymethyl, 3-halomethyl and 3-arylsultonyl methyl pyridine according to the invention
The synthesis of the Intermediates in Figure 4a is summarized in Table 4-1. - What?
(2-méthoxy-6-phénylpyridin-3-yl)méthanol (Protocole SJ et PA) Rendement : 96%. Aspect : solide jaune.
(2-tertiobutoxy-6-phénylpyridin-3-yl)méthanol (Protocole SJ et PA)
(2-hexyloxy-6-phénylpyridin-3-yl)méthanol (Protocole SJ) Rendement : quantitatif. Aspect : solide blanc.
(2-cyclohexyloxy-6-phénylpyridin-3-yl)méthanol (Protocole SJ) Rendement : 88%. Aspect : huile transparente.
(6-phényl-2-(pipéridin-1-yl)pyridin-3-yl)méthanol (Protocole SJ et PA) Rendement : 46%. Aspect : solide blanc.
(2-méthoxy-6-(4-(trifluoro méthyl)phényl)pyridin-3-yl) méthanol (Protocole SJ et PA) Rendement : 93%. Aspect : solide blanc.
(6-phényl-2-(phénylthio)pyridin-3-yl) méthanol (Protocole SJ et PA) Rendement : 39%. Aspect : solide blanc.
(2-méthoxy-5-phénylpyridin-3-yl)méthanol (Protocole SJ) Rendement : quantitatif. Aspect : solide blanc.
(5-bromo-2-méthoxy-6-phénylpyridin-3-yl)méthanol (Protocole SJ et PA) Rendement : 50%. Aspect : solide blanc.
(2-méthoxy-6-furylpyridin-3-yl)méthanol (Protocole SJ et PA) Rendement : 78%. Aspect : solide blanc.
(2-(éthylthio)-6-phénylpyridin-3-yl)méthanol (Protocole SJ et PA) Rendement : 75%. Aspect : huile jaune.
(2-méthoxy-6 (parabiphényl) pyridin-3-yl)méthanol (Protocole SJ et PA)
(2-méthoxy-6-(3-(trifluorométhyl)phényl)pyridin-3-yl)méthanol (Protocole SJ et PA) Rendement : 85%. Aspect : solide blanc.
(2-méthoxy-5-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthanol (Protocole SJ) Rendement : quantitatif. Aspect : solide blanc.
(2-méthoxy-5-(3-(trifluorométhyl)phényl)pyridin-3-yl)méthanol (Protocole SJ) Rendement : 77%. Aspect : solide blanc.
(2,6-diméthoxy-5-phénylpyridin-3-yl)méthanol (Protocole SJ et PA) Rendement : 77%. Aspect : solide blanc.
(5-(4-chlorophényl)-2-méthoxypyridin-3-yl)méthanol (Protocole SJ) Rendement: 84%. Aspect : huile incolore.
(2-méthoxy-5-(naphthalen-2-yl)pyridin-3-yl)méthanol (Protocole SJ et PA) Rendement : 75%. Aspect : solide blanc.
(2-éthoxy-6-phénylpyridin-3-yl)méthanol (Protocole SJ) Rendement : 91%. Aspect : solide blanc.
(2-isopropoxy-6-phénylpyridin-3-yl)méthanol (Protocole SJ)
The synthesis of the intermediates in Figures 4b, 4c and 4d is summarized in Table 4-2
1-(2-méthoxy-6-phénylpyridin-3-yl)propan-1-ol (Protocole SK et PA) Rendement : 66%. Aspect : solide beige
(2-méthoxy-6-phénylpyridin-3-yl)méthyl-4-méthylbenzènesulfonate (Protocole SL et PA) Rendement : 31%. Aspect : huile jaune.
3-(bromométhyl)-2-méthoxy-6-phénylpyridine (Protocole SM) Rendement : 91%. Aspect : solide blanc.
Example 5 - Synthesis of intermediates of the pyridine 3-carboxaldehyde and ketone types according to the invention
The synthesis of the Intermediates of Figures 5a is summarized in Table 5-1. - What?
2-méthoxy-6-phényl-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 63%. Aspect : solide blanc.
2-méthoxy-6-(4-(trifluorométhyl)phényl)-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 94%. Aspect : solide blanc.
2-méthoxy-5-phényl-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 63%. Aspect : solide blanc.
5-bromo-2-méthoxy-6-phénylpyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 63%. Aspect : solide blanc.
2-méthoxy-6-furyl-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 86%. Aspect : solide jaune.
1-(2-méthoxy-6-phénylpyridin-3-yl)propan-1-one (Protocole SN et PA) Rendement : 92%. Aspect : solide blanc.
2-éthylthio-6-phényl-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 86%. Aspect : huile jaune.
2-méthoxy-6-(parabiphényl)-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 79%. Aspect : solide blanc.
2-méthoxy-6-(3-(trifluorométhyl)phényl)-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 68%. Aspect : solide blanc
2-méthoxy-5-(4-(trifluorométhyl)phényl)-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 70%. Aspect : solide blanc
2-méthoxy-5-(3-(trifluorométhyl)phényl)-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 58%. Aspect : solide blanc.
2,6-diméthoxy-5-phényl-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 93%. Aspect : solide blanc.
2-méthoxy-5-(4-chlorophényl)-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 58%. Aspect : solide blanc.
2-méthoxy-5-(naphthalen-2-yl)-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 75%. Aspect : solide blanc.
2-éthoxy-6-phényl-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 87%. Aspect : solide blanc.
2-isopropoxy-6-phényl-pyridine-3-carboxaldéhyde (Protocole SN et PA) Rendement : 77%. Aspect : huile incolore.
The synthesis of the Intermediates in Figures 5b and 5c is summarized in Table 5-2.
2-tertiobutoxy-6-phényl-pyridine-3-carboxaldéhyde (Protocole SO et PA) Rendement : 83%. Aspect : solide blanc.
Etape 1 : Préparation du 5,6-diphényl-2-oxo-pyridine-3-carboxaldéhyde (Protocole SP et PA) Rendement : 59%. Aspect : solide jaune.
Etape 2 : Obtention du 2-méthoxy-5,6-diphényl-pyridine-3-carboxaldéhyde (Protocole SF et PA) Rendement : 16%. Aspect : solide blanc.
Example 6 : Synthesis of intermediates such as phenol, thiophenol, aniline
The synthesis of the Intermediates in Figures 6a, 6c, and 6e requires 2 steps and is summarized in Table 6-1. - What?
Etape 1 : Préparation du 2-(4-(benzyloxy)phénoxy)-2-méthylpropanoate d'éthyle (Protocole SQ et PA) Rendement : 70%. Aspect : huile incolor.
Etape 2 : Obtention du 2-(4-hydroxyphénoxy)-2-méthylpropanoate d'éthyle (Protocole SR) Rendement : 94%. Aspect : solide rose.
Etape 1 : Préparation du 2-(4-(benzyloxy)phénoxy)éthanoate de tertiobutyle (Protocole SQ) Rendement : quantitatif. Aspect : huile incolore.
Etape 2 : Obtention du 2-(4-hydroxyphénoxy)éthanoate de tertiobutyle (Protocole SR et PD)
Etape 1 : Préparation du 2-(4-(benzyloxy)phénoxy)propanoate d'éthyle (Protocole SQ et PA) Rendement : 92%. Aspect : huile incolore.
Etape 2 : Obtention du 2-(4-hydroxyphénoxy)propanoate d'éthyle (Protocole SR et PA) Rendement : 86%. Aspect : huile jaune.
Etape 1 : Préparation du 2-(4-(benzyloxy)phénoxy)éthanoate d'éthyle (Protocole SQ et PA) Rendement : 80%. Aspect : solide blanc.
Etape 2 : Obtention du 2-(4-hydroxyphénoxy) éthanoate d'éthyle (Protocole SR) Rendement : 95%. Aspect : solide blanc.
Etape 1 : Préparation du 2-(4-(benzyloxy)phénoxy)2-méthylpropanoate de tertiobutyle (Protocole SQ et PA) Rendement : 71%. Aspect : solide blanc.
Etape 2 : Obtention du 2-(4-hydroxyphénoxy)-2-méthylpropanoate de tertiobutyle (Protocole SR et PA) Rendement : 64%. Aspect : solide blanc.
Etape 1 : Préparation du 2-(4-nitrophénoxy)éthanoate de tertiobutyle (Protocole SQ et PD) Rendement : 60%. Aspect : solide ocre.
Etape 2 : Obtention du 2-(4-aminophénoxy)éthanoate de tertiobutyle (Protocole SR)
Etape 1 : Préparation du 2-(4-(tertiobutylcarbonylamino)phénox y)propanoate d'éthyle (Protocole SQ et PD) Rendement : 80%. Aspect : solide blanc.
Etape 2 : Obtention du chlorhydrate de 2-(4-aminophénoxy)propanoate d'éthyle (Protocole SS et PE) Rendement : 99%. Aspect : solide blanc.
Etape 1 : Préparation du 2-(4-(tertiobutylcarbonylamino)phénox y)éthanoate d'éthyle (Protocole SQ) Rendement : quantitatif. Aspect : solide blanc.
Etape 2 : Obtention du chlorhydrate de 2-(4-aminophénoxy)éthanoate d'éthyle (Protocole SS et PE) Rendement : 86%. Aspect : solide rose
Etape 1 : Préparation du 2-(4-(tertiobutylcarbonylamino)phénox y)-2-méthyl-propanoate d'éthyle (Protocole SQ et PD) Rendement : 95%. Aspect : huile incolore.
Etape 2 : Obtention du chlorhydrate de 2-(4-aminophénoxy)-2-méthylpropanoate d'éthyle (Protocole SS et PE) Rendement : 89%. Aspect : solide blanc.
Etape 1 : Préparation du 2-(4-nitrophénoxy)-2-méthylpropanoate de tertiobutyle (Protocole SQ et PA) Rendement : 65%. Aspect : solide jaune
Etape 2 : Obtention du 2-(4-aminophénoxy)-2-méthylpropanoate de tertiobutyle (Protocole SR et PD) Rendement : 91%. Aspect : solide marron.
Etape 1 : Préparation du 2-(3-nitrophénoxy)-2-méthylpropanoate de tertiobutyle (Protocole SQ et PA) Rendement : 11%. Aspect : solide vert.
Etape 2 : Obtention du 2-(3-aminophénoxy)-2-méthylpropanoate de tertiobutyle (Protocole SR et PD) Rendement : 37%. Aspect : solide vert.
Etape 1 : Préparation du 2-(3-nitrophénoxy)éthanoate de tertiobutyle (Protocole SQ et PC) Rendement : 96%. Aspect : solide rouge-orangé.
Etape 2 : Obtention du 2-(3-aminophénoxy)éthanoate de tertiobutyle (Protocole SR et PA) Rendement : 72%. Aspect : huile rose/rouge.
Etape 1 : Préparation du 2-(4-nitro-2,6-diméthylphénoxy)éthanoate d'éthyle (Protocole SQ et PD) Rendement : 99%. Aspect : solide jaune.
Etape 2 : Obtention du 2-(4-amino-2,6-diméthylphénoxy)éthanoate d'éthyle (Protocole SR) Rendement : quantitatif. Aspect : huile incolore.
Etape 1 : Préparation du 3-(4-nitrophényl)-3-phénylacrylate d'éthyle (Protocole ST et PD) Rendement : 57%. Aspect : huile jaune.
Etape 2 : Obtention du 3-(4-aminophényl)-3-phénylpropanoate d'éthyle (Protocole SR) Rendement : 53%. Aspect : huile incolore.
Etape 1 : Préparation du 3-(2-méthoxy-4-nitrophényl)acrylate d'éthyle (Protocole ST et PA) Rendement : 20%. Aspect : solide jaune.
Etape 2 : Obtention du 3-(4-amino-2-méthoxyphényl)propanoate d'éthyle (Protocole SR) Rendement : 64%. Aspect : huile incolore.
Etape 1 : Préparation du 3-(3-méthoxy-4-nitrophényl)acrylate d'éthyle (Protocole ST et PA) Rendement : 43%. Aspect : solide jaune.
Etape 2 : Obtention du 3-(4-amino-3-méthoxyphényl)propanoate d'éthyle (Protocole SR) Rendement : 99%. Aspect : huile incolore.
Etape 1 : Préparation du 3-(4-nitrophenyl)but-2-ènoate d'éthyle (Protocole SQ et PD) Rendement : 84%. Aspect : solide jaune.
Etape 2: Obtention du 3-(4-aminophényl)butanoate d'éthyle (Protocole SR) Rendement : 59%. Aspect : huile incolore
The synthesis of the Intermediates in Figures 6b and 6d requires a single step and is summarized in Table 6-2. - What?
2-(4-aminophénylthio)-2-méthylpropanoate d'éthyle (Protocole SQ et PA)
2-(4-aminophénylthio)acétate de tertiobutyle (Protocole SQ et PA) Rendement : 28%. Aspect : huile jaune.
chlorhydrate de 3-(4-aminophényl)propanoate d'éthyle (Protocole SS et PE) Rendement : 86%. Aspect : solide blanc.
2-(4-aminophénylthio)-2-méthylpropanoate de tertiobutyle (Protocole SQ et PA) Rendement : 79%. Aspect : solide blanc.
2-((4 amino)phénylthio) éthanoate d'éthyle (Protocole SQ et PA)
2-(4-aminophénylthio)-2,2-difluoroacétate d'éthyle (Protocole SQ et PA) Rendement : 29%. Aspect : huile incolore
2-(4-aminophénylthio)-2-phényléthanoate d'éthyle (Protocole SQ et PA) Rendement : 37%. Aspect : huile jaune.
In the first step (preparation of 5-(4-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione), a solution of 4-hydroxybenzaldehyde in water (1 mol/L) is brought to 75°C. Meldrum acid (1.05 equ.) is added in portions, then the reaction medium is left to agitate at 75°C for 2 hours. The reaction medium is cooled and agitated for 2 hours at 0°C. The precipitation is tested, the solid is washed with ice water and poured: (a) 90% (Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd; Hd;In the second step (production of 5-(1-(4-hydroxyphenyl) but-2-ynyl)-2,2-dimethyl-1,3-dioxane-4,6-dione), a solution of the previous intermediate in tetrahydrofuran (0.5 mol/L) is added under inert atmosphere, drop by drop (0.25 h), to a solution of 1-propylmagnesium bromide in tetrahydrofuran (0.5 mol/L, 2 eq.). After 0.25 h agitation at room temperature, the reaction medium is diluted by an aqueous solution of ammonium chloride (0.6 N, 3 eq.), extracted by cyclohexane, acidified (pH2) by sodium bisulfate. The evaporation residue is used without any other form of purification (aspect: 98%; yield: 1.64 H; volume: 1.82 H; volume: 1.64 H; volume: 1.32 H; volume: 1.64 H; volume: 1.64 H; volume: 1.32 H; volume: 1.64 H; volume: 1.32 H); volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.64 H; volume: 1.The number of samples is calculated by multiplying the number of samples by the number of samples of samples taken.
Example 7: Synthesis of compounds according to the invention
The synthesis of the compounds according to the invention in Figures 7a requires 2 or 3 steps and is summarized in Table 7-1. - What?
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phénoxy)éthanoate de tertiobutyle (Ex. 5-1 et Ex. 6-6 avec Protocole SX et PA) Rendement : quantitatif. Aspect : huile jaune
2: Obtention du acide 2-(4-(((2-méthoxy-6-phénylpyridin-3yl)méthyl)amino)phénoxy) éthanoïque (Protocole SW et PE) Rendement: 81%. Aspect: solide blanc
1 : Préparation du 2-(4-((2-tertiobutoxy-6-phénylpyridin-3-yl)méthylamino)-phénoxy)éthanoate d'éthyle (Ex. 5-2 et Ex. 6-8 avec Protocole SX et PA) Rendement : 51%. Aspect : solide blanc
2 : Obtention du acide 2-(4-((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy) éthanoïque (Procole SU et PA) Rendement : 63%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-tertiobutoxy-6-phénylpyridin-3-yl)méthylamino)-phénoxy)-2-méthyl-propanoate d'éthyle (Ex. 5-2 et Ex. 6-9 avec Protocole SX et PA) Rendement : 79%. Aspect : huile orange.
2 : Obtention du acide 2-(4-(((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy)-2-méthyl-propanoïque (Protocole SU et PD)
1 : Préparation du 2-(4-((2-tertiobutoxy-6-phénylpyridin-3-yl)méthylamino)-phénoxy)propanoate d'éthyle (Ex. 5-2 et Ex. 6-7 avec Protocole SX et PA) Rendement : 52%. Aspect : huile jaune.
2 : Obtention du acide 2-(4-(((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy)-propanoïque (Protocole SU et PA)
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phénylthio)-2-méthyl-propanoate d'éthyle (Ex. 5-1 et Ex. 6-10 avec Protocole SX et PA)
2 : Obtention du acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl) méthyl)amino)phénylthio)-2-méthyl-propanoïque (Protocole SU et PA) Rendement : 57%. Aspect : solide beige
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)phénoxy)-2-méthyl-propanoate de tertiobutyle (Ex. 5-1 et Ex. 6-11 avec Protocole SX et PA) Rendement : 71%. Aspect : huile jaune.
2 : Obtention du acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy)-2-méthyl-propanoïque (Protocole SW et PC) Rendement : 70%. Aspect : solide blanc
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phénylthio)éthanoate de tertiobutyle (Ex. 5-1 et Ex. 6-14 avec Protocole SX et PA) Rendement : 99%. Aspect : huile jaune.
2 : Obtention du acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénylthio)-éthanoïque (Protocole SW et PC) Rendement : 64%. Aspect : solide blanc
1 : Préparation du 3-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phényl)propanoate d'éthyle (Ex. 5-1 et Ex. 6-15 avec Protocole SX et PA) Rendement : 53%. Aspect : huile jaune.
2 : Obtention du acide 3-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phényl) propanoïque (Protocole SU et PC) Rendement : 73%. Aspect : solide jaune.
1 : Préparation du 2-(4-((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthylamino)phénylthio)-2-méthylpropanoate de tertiobutyle (Ex. 5-3 et Ex. 6-16 avec Protocole SX et PA) Rendement : 92%; Aspect : huile jaune;
2 : Obtention du acide 2-(4-(((2-méthoxy-6-(4-(trifluorométhyl) phényl)pyridin-3-yl)méthyl)amino) - phénylthio)-2-méthylpropanoïque (Protocole SW et PB) Rendement : 55%; Aspect : solide jaune.
1 : Préparation du 2-(4-((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthylamino)phénylthio)éthanoate de tertiobutyle (Ex. 5-3 et Ex. 6-14 avec Protocole SX et PA) Rendement : 96%. Aspect : huile jaune orange.
2 : Obtention du acide 2-(4-(((2-méthoxy-6-(4-(trifluorométhyl) phényl)pyridin-3-yl)méthyl)amino) - phénylthio)éthanoïque (Protocole SW et PB) Rendement : 21%. Aspect : solide jaune.
1 : Préparation du 2-(4-((2-méthoxy-5-phénylpyridin-3-yl)méthylamino)-phénylthio)éthanoate d'éthyle (Ex. 5-4 et Ex. 6-17 avec Protocole SX et PA) Rendement: 73%. Aspect : huile jaune
2 : Obtention du acide 2-(4-(((2-méthoxy-5-phénylpyridin-3-yl)méthyl)amino)phénylthio) éthanoïque (Protocole SU et PE) Rendement : 66%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phénylthio)-2-2-difluoroéthanoate d'éthyle (Ex. 5-1 et Ex. 6-18 avec Protocole SX et PA) Rendement : 88%. Aspect : huile jaune.
2 : Obtention du acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl) méthyl)amino)phénylthio)-2,2-difluoro - éthanoïque (Protocole SU et PC) Rendement : 36%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-méthoxy-5-6-diphénylpyridin-3-yl)méthylamino)-phénylthio) éthanoate d'éthyle (Ex. 5-5 et Ex. 6-17 avec Protocole SX et PA)
2 : Obtention du acide 2-(4-(((2-méthoxy-5,6-diphénylpyridin-3-yl)méthyl)amino)phénylthio)-éthanoïque (Protocole SU et PA) 3 : Protocole PC Rendement : 6,56%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-méthoxy-5-6-diphénylpyridin-3-yl) méthyl amino)-phénylthio)éthanoate d'éthyle (Ex. 5-6 et Ex. 6-17 avec Protocole SX et PA) Rendement : 58%. Aspect : huile incolore.
2 : Obtention du acide 2-(4-(((2-méthoxy-5-bromo-6-phénylpyridin-3-yl)méthyl)amino) phénylthio)-éthanoïque (Protocole SU et PA) 3 : Protocole PC
1 : Préparation du 2-(4-((2-méthoxy-6-furylpyridin-3-yl)méthylamino)-phénylthio)éthanoate d'éthyle (Ex. 5-è et Ex. 6-17 avec Protocole SX et PA)
2 : Obtention du acide 2-(4-(((2-méthoxy-6-furylpyridin-3-yl)méthyl)amino)phénylthio)-éthanoïque (Protocole SU et PC)
1 : Préparation du 3-(4-((2-méthoxy-6-furylpyridin-3-yl)méthylamino)-phényl)propanoate d'éthyle (Ex. 5-6 et Ex. 6-15 avec Protocole SX et PA) Rendement : 68%. Aspect : huile jaune.
2 : Obtention du acide 3-(4-(((2-méthoxy-6-furylpyridin-3-yl)méthyl)amino)phényl)propanoïque (Protocole SU et PC)
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phénylthio)-2-phényléthanoate d'éthyle (Ex. 5-1 et Ex. 6-19 avec Protocole SX et PA) Rendement : 75%. Aspect : huile jaune.
2 : Obtention du acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl) méthyl)amino)phénylthio)-2-phényl-éthanoïque (Protocole SU et PA) Rendement : 58%. Aspect : solide blanc.
RMN 1H : 4,03 (s, 3H); 4,21 (d, 2H, J=5,6Hz); 4,71 (s, 1H); 6,43-6,48 (m, 3H); 7,07 (d, 2H, J=8,8Hz); 7,25-7,59 (m, 10H); 8,07 (d, 2H, J=7,0Hz).
3 : Protocole PC
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-2,6-diméthyl-phénoxy)éthanoate d'éthyle (Ex. 5-1 et Ex. 6-20 avec Protocole SX et PA) Rendement : 96%. Aspect : huile jaune.
RMN 1H (300MHz, CDCl3, d en ppm) : 1,33 (t, 3H, J=7,0Hz); 2,23 (s, 6H); 4,11 (s, 3H); 4,26-4,34 (m, 6H); 6,31 (s, 2H); 7,32 (d, 1H, J=7,6Hz); 7,38-7,48 (m, 3H); 7,61 (d, 1H, J=7,6Hz); 8,03-8,07 (d, 2H, J=7,0Hz).
2: Obtention du acide 2-(4-(((2-méthoxy-6-phénylpyridin-3-yl) méthyl)amino)-2,6-diméthyl-phénoxy) éthanoïque (Protocole SU et PA) Rendement : 6%. Aspect : solide blanc.
1 : Préparation du 3-(4-((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthylamino)phényl)propanoate d'éthyle (Ex. 5-3 et Ex. 6-15 avec Protocole SX et PA) Rendement : 43%. Aspect : huile orange.
2: Obtention du acide 3-(4-(((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthyl)amino) -phényl)-propanoïque (Protocole SU et PA) Rendement : 58%. Aspect : solide blanc.
1 : Préparation du 3-(4-((2-(éthyfthio)-6-phénylpyridin-3-yl)méthylamino)-phényl)propanoate d'éthyle (Ex. 5-9 et Ex. 6-15 avec Protocole SX et PA)
2 : Obtention du acide 3-(4-(((2-(éthylthio)-6-phénylpyridin-3-yl)méthyl)amino)phényl)-propanoïque (Protocole SU et PA) Rendement : 40%. Aspect : solide beige.
1 : Préparation du 3-(4-((2-méthoxy-6-(parabiphényl)pyridin-3-yl)méthyl-amino)phényl)-propanoate d'éthyle (Ex. 5-10 et Ex. 6-15 avec Protocole SX et PA) Rendement : 84%. Aspect : huile jaune.
2 : Obtention du acide 3-(4-(((2-méthoxy-6-(parabiphényl)pyridin-3-yl)méthyl)amino)phényl)-propanoïque (Protocole SU et PA) Rendement : 60%. Aspect : solide beige.
1 : Préparation du 3-(4-((2-méthoxy-6-(3-(trifluorométhyl)phényl)pyridin-3-yl)méthylamino)phényl)propanoate d'éthyle (Ex. 5-11 et Ex. 6-15 avec Protocole SX et PA) Rendement : 86%. Aspect : huile jaune .
2 : Obtention du acide 3-(4-(((2-méthoxy-6-(3-(trifluorométhyl)phényl)pyridin-3-yl)méthyl)amino)-phényl)propanoïque (Protocole SU et PA) Rendement : 53%. Aspect : solide beige.
Rendement : 72%. Aspect : huile incolore.
1 : Préparation du 3-(4-((2-méthoxy-5-phénylpyridin-3-yl)méthylamino)-phényl)propanoate d'éthyle (Ex. 5-4 et Ex. 6-15 avec Protocole SX et PA)
2: Obtention du acide 3-(4-(((2-méthoxy-5-phénylpyridin-3-yl)méthyl)amino)phényl)-propanoïque (Protocole SU et PA) Rendement : 57%. Aspect : solide blanc
1 : Préparation du 3-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phényl)-3-phénylpropanoate d'éthyle (Ex. 5-1 et Ex. 6-14 avec Protocole SX et PA) Rendement : 75%. Aspect : huile incolore.
2 : Obtention du acide 3-(4-((2(-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phényl)-3-phényl-propanoïque (Protocole SU et PA) 3 : Protocole PC Rendement : 36%. Aspect : solide blanc.
1 : Préparation du 3-(2-méthoxy-4-((2-méthoxy-6-phénylpyridin-3-yl)méthyl-amino)phényl)propanoate d'éthyle (Ex. 5-1 et Ex. 6-22 avec Protocole SX et PA) Rendement : 57%. Aspect : huile jaune.
2 : Obtention du acide 3-(2-méthoxy-4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)-phényl)-propanoïque (Protocole SU et PA) 3 : Protocole PC Rendement : 44%. Aspect : solide jaunâtre.
1 : Préparation du 3-(3-méthoxy-4-((2-méthoxy-6-phénylpyridin-3-yl)méthyl-amino)phényl)propanoate d'éthyle (Ex. 5-1 et Ex. 6-23 avec Protocole SX et PA) Rendement : 51%. Aspect : huile jaune.
2 : Obtention du acide 3-(3-méthoxy-4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)-phényl)-propanoïque (Protocole SU et PA) 3 : Protocole PC Rendement : 46%. Aspect : solide blanc.
1 : Préparation du 3-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phényl)butanoate d'éthyle (Ex. 5-1 et Ex. 6-24 avec Protocole SX et PA) Rendement : 56%. Aspect : huile jaune ;
2 : Obtention du acide 3-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phényl)butanoïque (Protocole SU et PA) 3 : Protocole PC Rendement : 52%; Aspect : solide blanc.
1 : Préparation du 3-(4-((2-méthoxy-5-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthylamino)phényl)propanoate d'éthyle (Ex. 5-12 et Ex. 6-15 avec Protocole SX et PA)
2 : Obtention du acide 3-(4-(((2-méthoxy-5-(4-(trifluorométhyl) phényl)pyridin-3-yl)méthyl) amino) phényl)propanoïque (Protocole SU et PA) 3 : Protocole PC Rendement : 44%. Aspect : solide blanc.
1 : Préparation du 3-(4-((2-méthoxy-5-(3-(trifluorométhyl)phényl)pyridin-3-yl)méthylamino)-phényl)propanoate d'éthyle (Ex. 5-13 et Ex. 6-15 avec Protocole SX et PA) Rendement : 65%. Aspect : huile jaune.
2 : Obtention du acide 3-(4-(((2-méthoxy-5-(3-(trifluorométhyl) phényl) pyridin-3-yl)méthyl)amino) -phényl) propanoïque (Protocole SU et PA) 3 : Protocole PC Rendement : 52%. Aspect : solide blanc.
1 : Préparation du 3-(4-((2,6-diméthoxy-5-phénylpyridin-3-yl)méthylamino)-phényl)propanoate d'éthyle (Ex. 5-14 et Ex. 6-15 avec Protocole SX et PA) Rendement : 48%. Aspect : huile incolore.
2 : Obtention du acide 3-(4-(((2,6-diméthoxy-5-phénylpyridin-3-yl)méthyl)amino)phényl)-propanoïque (Protocole SU et PA) 3 : Protocole PC
1 : Préparation du 3-(4-((5-(4-chlorophényl)-2-méthoxypyridin-3-yl)méthyl-amino)phényl)propanoate d'éthyle (Ex. 5-15 et Ex. 6-15 avec Protocole SX et PA) Rendement : 68%. Aspect : huile incolore.
2 : Obtention du acide 3-(4-(((5-(4-chlorophényl)-2-méthoxypyridin-3-yl)méthyl)amino)phényl)-propanoïque (Protocole SU et PC) Rendement : 32%. Aspect : solide blanc.
1 : Préparation du 3-(4-((2-méthoxy-5-(naphthalen-2-yl)pyridin-3-yl)méthyl-amino)phényl)propanoate d'éthyle (Ex. 5-16 et Ex. 6-15 avec Protocole SX et PA) Rendement : 80%. Aspect : huile incolore.
2 : Obtention du acide 3-(4-(((2-méthoxy-5-(naphthalèn-2-yl)pyridin-3-yl)méthyl) amino)phényl)-propanoïque (Protocole SU et PC)
1 : Préparation du 3-(4-((2-éthoxy-6-phénylpyridin-3-yl) méthylamino)-phényl)propanoate d'éthyle (Ex. 5-17 et Ex. 6-15 avec Protocole SX et PA) Rendement 49%. Aspect : huile incolore.
2 : Obtention du acide 3-(4-(((2-éthoxy-6-phénylpyridin-3-yl)méthyl)amino)phényl)propanoïq ue (Protocole SU et PA)
3 : Protocole PC
1 : Préparation du 3-(4-((2-isopropoxy-6-phénylpyridin-3-yl)méthylamino)-phényl) propanoate d'éthyle (Ex. 5-18 et Ex. 6-15 avec Protocole SX et PA) Rendement : 65% . Aspect : huile incolore .
2 : Obtention du acide 3-(4-(((2-isopropyloxy-6-phénylpyridin-3-yl)méthyl)amino)phényl)-propanoïque (Protocole SU et PA)
3 : Protocole PC
The synthesis of the compounds of the invention in Figures 7b and 7c requires 2 steps and is summarized in Table 7-2. - What?
1 : Préparation du 2-(3-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phénoxy)-2-méthyl-propanoate de tertiobutyle (Ex. 5-1 et Ex. 6-12 avec Protocole SX et PA) Rendement : 49%. Aspect : huile jaune.
2: Obtention du acide 2-(3-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy)-2-méthyl-propanoïque (Protocole SU et PB) Rendement : 33%. Aspect : solide blanc.
1 : Préparation du 2-(3-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phénoxy)éthanoate de tertiobutyle (Ex. 5-1 et Ex. 6-13 avec Protocole SX et PA) Rendement : 80%. Aspect : huile jaune.
2: Obtention du acide 2-(3-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)amino)phénoxy) éthanoïque (Protocole SU et PB) Rendement : 60%. Aspect : solide blanc.
1 : Préparation du 3-(4-(1-(2-méthoxy-6-phénylpyridin-3-yl)propylamino)-phényl)propanoate d'éthyle (Ex. 5-8 et Ex. 6-15 avec Protocole SY et PA) Rendement : 14%. Aspect : huile jaune
2 : Obtention du acide 3-(4-(1-((2-méthoxy-6-phénylpyridin-3-yl)propyl)amino)phényl)-propanoïque (Protocole SU et PB) Rendement : 58%. Aspect : solide blanc.
The synthesis of the compounds according to the invention in Figures 7d requires 2 or 3 steps and is summarized in Table 7-3. - What?
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-éthanoate de tertiobutyle (Ex. 4-1 et Ex. 6-2 avec Protocole SV et PA) Rendement : 54%. Aspect : solide blanc.
2 : Obtention du acide 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)éthanoïque (Protocole SW et PE) Rendement : 83%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-tertiobutoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-2-méthyl-propanoate d'éthyle (Ex. 4-2 et Ex. 6-1 avec Protocole SV et PA) Rendement : 33%. Aspect : huile jaune.
2 : Obtention du acide 2-(4-((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-2-méthyl-propanoïque (Protocole SU et PD) Rendement : 67%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-tertiobutoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)éthanoate d'éthyle (Ex. 4-2 et Ex. 6-4 avec Protocole SV et PA) Rendement : 80%. Aspect : solide blanc.
2 : Obtention du acide 2-(4-(((2-tertio-butyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy) éthanoïque (Protocole SU et PD) Rendement : 33%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-hexyloxy-6-phénylpyridin-3-yl)méthoxy)-phénoxy)éthanoate de tertiobutyle (Ex. 4-3 et Ex. 6-2 avec Protocole SV et PA) Rendement : 39%. Aspect : huile jaune.
2 : Obtention du acide 2-(4-((2-hexyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)éthanoïque (Protocole SW et PA) 3 : Protocole PC Rendement : 31%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-hexyloxy-6-phénylpyridin-3-yl)méthoxy)-phénoxy)-2-méthyl-propanoate de tertiobutyle (Ex. 4-3 et Ex. 6-5 avec Protocole SV et PA)
2: Obtention du acide 2-(4-((2-hexyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-2-méthyl-propanoïque (Protocole SW et PB) Rendement : 26% ; Aspect : solide blanc.
1 : Préparation du 2-(4-((2-cyclohexyloxy-6-phénylpyridin-3-yl)méthoxy)-phénoxy)éthanoate de tertiobutyle (Ex. 4-4 et Ex. 6-2 avec Protocole SV et PA)
2 : Obtention du acide 2-(4-((2-cyclohexyloxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)éthanoïque (Protocole SW et PB)
1 : Préparation du 2-(4-((6-phényl-2-(pipéridin-1-yl)pyridin-3-yl)méthoxy)-phénoxy)éthanoate d'éthyle (Ex. 4-5 et Ex. 6-4 avec Protocole SV et PA) Rendement : 60%. Aspect : solide blanc.
2: Obtention du acide 2-(4-((6-phényl-2-(pipéridin-1-yl)pyridin-3-yl)méthoxy)phénoxy)-éthanoïque (Protocole SU et PB)
1 : Préparation du 2-(4-((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthoxy)-phénoxy)-2-méthyl propanoate de tertiobutyle (Ex. 4-6 et Ex. 6-5 avec Protocole SV et PA) Rendement : 47%; Aspect : solide blanc.
2 : Obtention du acide 2-(4-((2-méthoxy-6-(4-(trifluorométhyl) phényl) pyridin-3-yl)méthoxy)-phénoxy)-2-méthylpropanoïque (Protocole SW et PA)
3 : Protocole PC
1 : Préparation du 2-(4-((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthoxy)phénoxy)éthanoate de tertiobutyle (Ex. 4-6 et Ex. 6-2 avec Protocole SV et PA) Rendement : 53%. Aspect : solide blanc.
2: Obtention du acide 2-(4-((2-méthoxy-6-(4-(trifluorométhyl)phényl)pyridin-3-yl)méthoxy)-phénoxy)éthanoïque (Protocole SW et PA) Rendement : 12%. Aspect : solide blanc.
3 : Protocole PC
1 : Préparation du 2-(4-((2-phénylthio-6-(phényl)pyridin-3-yl)méthoxy)-phénoxy)éthanoate d'éthyle (Ex. 4-7 et Ex. 6-4 avec Protocole SV et PA) Rendement : 27%. Aspect : solide blanc.
2: Obtention du acide 2-(4-((2-phénylthio-6-(phényl)pyridin-3-yl)méthoxy)phénoxy)éthanoïque (Protocole SU et PD) Rendement : 71%; Aspect : solide blanc
1 : Préparation du 3-(4-((2-méthoxy-5-phénylpyridin-3-yl)méthoxy)phényl)-hex-4-ynoate d'éthyle (Ex. 4-8 et Ex. 6-25 avec Protocole SV et PA) Rendement : 18% ; Aspect : huile jaune.
2: Obtention du acide 3-(4-((2-méthoxy-5-phénylpyridin-3-yl)méthoxy) ph ényl)hex-4-ynoïque (Protocole SU et PB) Rendement : 26%. Aspect : solide blanc.
1 : Préparation du 3-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phényl)-hex-4-ynoate d'éthyle (Ex. 4-1 et Ex. 6-25 avec Protocole SV et PA) Rendement : 36% . Aspect : huile incolore.
2: Obtention du acide 3-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phényl)hex-4-ynoïque (Protocole SU et PA) 3 : Protocole PC Rendement : 42%. Aspect : solide blanc.
The synthesis of the compounds of the invention in Figures 7e and 7f requires 1 or 2 steps and is summarized in Table 7-4. - What?
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-2-méthyl-propanoate d'éthyle (Ex. 4-15 et Ex. 6-1 avec Protocole SQ et PA) Rendement : 47%. Aspect : huile incolore.
2: Obtention du acide 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-2-méthyl-propanoïque (Protocole SU et PA) Rendement : 20%. Aspect : solide blanc.
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)-propanoate d'éthyle (Ex. 4-15 et Ex. 6-3 avec Protocole SQ et PA) Rendement : quantitatif. Aspect : solide blanc.
2: Obtention du acide 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthoxy)phénoxy)propanoïque (Protocole SU et PD) Rendement : 29% . Aspect : solide blanc.
1 : Préparation du 2-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylamino)-phénoxy)propanoate d'éthyle, (Ex. 4-16 et Ex. 6-7 avec Protocole SQ et PA) Rendement : 20%. Aspect : huile jaune.
2: Obtention du acide 2-(4-(((2-méthoxy-6-phénylpyridin-3yl)méthyl)amino)phénoxy) propanoïque (Protocole SU et PB) Rendement : 52%. Aspect : solide jaune.
1 : Préparation du 3-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)(méthyl)-amino)phényl)propanoate d'éthyle) (Cpd 19 avec Protocole SQ et PA) Rendement : 39%. Aspect : huile jaune.
2: Obtention du acide 3-(4-(((2-méthoxy-6-phénylpyridin-3-yl)méthyl)(méthyl)amino)phényl)-propanoïque (Protocole SU et PA) Rendement : 37%. Aspect : solide blanc
Obtention du acide 3-(4-((2-méthoxy-6-phénylpyridin-3-yl)méthylthio)phényl)propanoïque (Ex. 4-16 et d'acide 3-(4-mercaptophényl)propanoïque avec Protocole SQ et PB) Rendement : 9%. Aspect : solide blanc.
Example 8: PPAR activating properties of compounds of the invention The principle
PPAR activation is assessed in vitro on a monkey kidney fibroblast line (COS-7) by measuring the transcriptional activity of chimeras consisting of the DNA binding domain of yeast transcription factor Gal4 and the ligand binding domain of different human PPARs (hPPARs).
The Protocol (a) Cell culture
COS-7 cells are derived from ATCC and are grown in DMEM medium supplemented with 10% (vol/vol) of fetal calf serum, 1% of penicillin/streptomycin (Biochrom, AG), 1% of amino acids (Gibco) and 1% of sodium pyruvate (Gibco).
(b) Description of plasmids used in transfection
The plasmids Gal4(RE)_TkpGL3, pGal4-hPPARα, pGal4-hPPARγ, pGal4-hPPARδ and pGal4-φ have been described in the literature (Raspe E et al., 1999).The pGal4-hPPARα, pGal4-hPPARγ and pGal4-hPPARδ constructs were obtained by cloning in the pGal4-φ vector of DNA fragments amplified by PCR corresponding to the DEF domains (structural elements of the promoter of PPARs: ligand binding domain D=, EF= and AF2 binding site) of the human PPARα, PPARγ and PPARδ nuclear receptors.
(c) Transfection
The adhering COS-7 cells are transfected with 40 μg of DNA per 225 cm2 flask, with a pGal4-hPPAR/Gal4(RE)_TkpGL3 ratio of 1/10, in the presence of 10% fetal calf serum. The cells are then detached and seeded in the absence of serum in 384-well plates (2x104 cells/well) and then incubated for 4 hours at 37°C. The compounds are then diluted in a 96-well plate and transferred to the 384-well plate. Activation with the test compounds is carried out for an additional 24 hours at 37°C in the presence of 1% synthetic Ultroserum (Biosecan). These last 2 steps are automated using a 200-step GenesisTM (Laser A) experiment. The determination of cell activity is provided by the HTS (Permanent) and the Lyserase (Laser A) are recommended by the Elkin-Lyserase (Laser A) laboratory.
Results and Conclusion
The inventors have thus demonstrated a significant dose-dependent increase in luciferase activity in cells transfected with pGal4-hPPAR plasmids and treated with the compounds of the invention. The experimental data are summarized in Table 8-1 below, which shows for each compound the maximum activation values (TOP %) and EC50 values measured for each PPAR isoform. The maximum activation values are expressed as percentages of the maximum activations obtained with reference agonists: fenophenic acid for PPARα, rosiglitazone for PPARγ and 2-methyl-methyl-methyl-4-methyl-2-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-methyl-115 (GW15-methyl-methyl-methyl-methyl-1) (515). - What?
2 48,29 0,143 39,15 12,4 108,56 2,00
3 68,71 0,432 43,64 3,24 113,83 1,20
4 66,66 1,47 70,47 17,7 114,90 8,67
5 67,52 0,389 57,27 3,72 70,97 6,17
6 30,27 5,43 17,28 11,8 70,72 0,489
7 28,85 39,6 20,65 46,8 96,49 0,550
8 21,94 7,92 13,36 12,2 72,39 2,11
9 33,72 4,50 23,87 6,09 74,16 0,464
10 53,23 6,06 25,65 10,5 96,74 0,754
11 86,19 0,022 54,51 2,45 85,67 3,00
12 78,06 0,195 44,92 2,64 84,16 2,36
13 61,87 1,43 24,15 6,93 96,12 3,22
14 58,41 33,3 53,67 24,3 102,80 16,2
15 78,15 3,24 46,58 12,3 96,55 1,52
16 78,03 0,510 70,03 5,18 85,15 3,37
17 66,84 0,009 75,61 0,583 99,60 0,992
18 35,30 10,7 26,08 14,2 97,12 3,97
19 67,98 2,37 86,95 1,29 95,12 3,13
20 34,19 14,3 42,98 30,2 87,68 5,26
21 70,17 ND 51,48 1,43 99,96 0,276
22 75,94 ND 88,88 1,05 102,03 1,15
23 65,27 0,044 75,58 2,84 85,44 0,501
24 76,78 0,371 65,74 4,49 94,08 0,784
25 53,90 6,96 38,34 8,29 71,03 6,38
26 66,97 20,9 208,15 44,1 137,99 31,1
27 99,78 3,64 98,68 10,6 72,87 41,1
28 55,37 1,74 45,03 11,3 49,14 25,2
29 59,30 3,85 57,71 8,43 85,61 10,11
30 38,70 12,1 7,28 ND 1,13 ND
31 49,52 2,49 62,35 3,36 86,72 16,3
32 70,40 1,48 66,62 2,51 3,59 22,8
33 49,93 4,55 64,95 12,4 74,46 10,5
34 67,58 1,42 80,40 2,33 107,79 0,526
35 26,15 0,647 38,80 6,18 13,16 1,54
36 77,98 0,304 123,27 1,52 93,88 0,595
37 65,47 9,95 98,51 9,17 94,71 12,7
38 36,24 10,8 45,37 7,60 64,54 6,78
39 52,19 0,175 100,29 1,94 95,28 1,39
40 66,70 0,165 87,25 0,955 107,35 0,080
41 35,90 7,36 72,14 27,2 107,40 17,0
42 16,53 5,66 65,78 4,36 86,55 3,04
43 44,93 1,44 85,61 0,402 77,90 1,51
44 55,48 0,929 72,21 2,64 80,64 2,38
45 43,20 6,43 79,38 2,39 97,34 3,36
46 60,00 0,622 69,37 1,94 107,16 0,028
47 58,64 1,90 84,98 1,08 79,17 1,91
48 35,92 26,4 58,17 9,57 68,11 16,7
49 51,13 3,62 73,20 4,04 122,96 0,408
50 46,76 0,771 63,71 1,92 103,28 0,77
51 50,50 1,29 70,94 2,23 93,12 1,93
52 34,31 13,7 54,80 2,76 16,07 19,8
53 48,64 5,14 77,95 1,01 9,86 10,3
54 34,51 7,97 42,17 4,85 92,14 3,20
The activities measured differ according to the test compound and there is also more or less selectivity between the compounds according to the invention with respect to the different hPPAR isoforms: Some compounds of the invention are selective for a subtype of PPAR. This is the case for example for Cpd 11 which shows high selectivity for hPPARα; the latter activates hPPARγ and hPPARδ with EC50s more than 100 times higher than that measured on hPPARα. Similarly, Cpd 7 appears to be selective for hPPARδ. Other compounds of the invention are simultaneously activators of two or three subtypes of PPAR. This is the case for Cpd19 and Cpd 1 which activates hPPARα, hPPARγ, hPPARδ and hPPARau with comparable EC50s. The compound 1 of the invention was also composed for its agonist properties. As shown in Table 19, the results for Cpd 8 and PPAR-1 are not comparable to the other isoforms, and are obtained by a different test method compared to the previous one, the results of which are not comparable.
The results show that, in general, the compounds of the invention bind and activate hPPARα, hPPARγ, and/or hPPARδ receptors significantly.
EXAMPLE 9 Anti-diabetic properties of compounds according to the invention The principle
The purpose of this study is to evaluate in vivo the anti-diabetic properties of the compounds of the invention in db/db mice (Berger J et al., 1996). The anti-diabetic effect of the compounds is assessed by measuring blood glucose and insulin after 8 days of treatment. In diabetic animals (as in humans), administration of glucose results in a significant increase in plasma insulin levels. This induced hyperinsulinemia causes a decrease in blood glucose which is delayed in insulin-resistant animals, as for example in db/db mice. The corrective action of the compounds on insulin resistance should result in an improvement in glucose tolerance.
The Protocol (a) Treatment of animals
The test compound was suspended in carboxymethylcellulose (Sigma C4888) and administered by intragastric infusion, taken once daily at the selected dose for 9 days. After acclimatization, the mice were weighed and grouped into groups of 8 animals selected so that the distribution of their body weight and fasting blood glucose levels determined for the first time before the experiment were uniform. The test compound was suspended in carboxymethylcellulose (Sigma C4888) and administered by intragastric infusion, taken once daily at the selected dose. The animals were given free access to water and food (standard regimen) and were housed in volatile compounds under a constant ventilation regime for 12 hours in light/darkness at a constant temperature of 20 ± 3°C. The animals were administered by a continuous dose of insulin and plasma glucose at a constant concentration of 20 ± 3°C. The animals were recorded with a standard dose of insulin and blood glucose at a constant dose of 8 ± 3°C.
After 9 days, the animals were deprived of food for 16 hours before the glucose tolerance test was performed, which consisted of a single administration of glucose after fasting (orally administered at a dose of 1 g/kg) and blood samples were then taken over time to study the evolution of plasma glucose.
(b) Measurement of plasma insulin levels
The insulin is then applied to the mouse, and the mouse insulin is then applied to the mouse. The mouse insulin is then applied to the mouse insulin, and the mouse insulin is then applied to the mouse insulin. The mouse insulin is then applied to the mouse insulin. The mouse insulin is then applied to the mouse insulin.
(c) Measurement of blood glucose
The glucose was measured by enzymatic dosing (bioMérieux-Lyon-France) as recommended by the supplier.
Results and Conclusion
This study aims to evaluate in vivo the anti-diabetic properties of a compound of the invention (Cpd 24) by measuring blood glucose and insulinemia after 8 days of oral treatment with the compound of the invention Unexpectedly, the experimental data obtained show that Cpd 24, administered at 30mpk for 8 days, improves the overall glycemic and insulin profile of diabetic animals. These results also result in a decrease in the HOMA index, calculated from these plasma parameters, which reflects an improvement in insulin sensitivity (Figures 8a, 8b and 8c).
In normal animals and diabetic animals (as in humans), administration of glucose results in a significant increase in plasma insulin levels. This induced hyperinsulinemia causes a decrease in blood sugar which is delayed in insulin resistant animals. The glucose tolerance test also shows a marked decrease in insulin resistance in animals treated for 9 days with Cpd 24 (Figures 8d and 8e).
The compounds of the invention have anti-diabetic properties by lowering plasma glucose and insulin levels. The compounds of the invention also improve insulin sensitivity. These in vivo results demonstrate the therapeutic potential of the compounds of the invention for major diseases such as type 2 diabetes.
EXAMPLE 10 - Lipid-lowering and cholesterol-stimulating properties of the compounds of the invention The principle
The lipid-lowering properties of the compounds of the invention were evaluated in vivo by plasma lipid dosing and analysis of gene expression of PPAR target genes in the liver following oral treatment of a dyslipidemic mouse with the compounds of the invention.
The mouse model used is the mouse type ApoE2/E2, a mouse transgenic for the human apolipoprotein E E2 isoform (Sullivan PM et al., 1998). In humans, this apolipoprotein, which is low- and very-low-density lipoproteins (LDL-VLDL), is present in three isoforms E2, E3 and E4. The E2 form has a mutation on an amino acid at position 158, which significantly weakens the affinity of this protein for the receptor for LDL. The clearance of VLDL is therefore almost zero. This results in accumulation of low-density lipoproteins and so-called type III hyperlipidemia (high triglycerides and michoesterol).
PPARα regulates the expression of genes involved in lipid transport (apolipoproteins such as Apo AI, Apo AII and Apo CIII, membrane transporters such as FAT) or lipid catabolism (ACO, CPT-I or CPT-II, fatty acid β-oxidation enzymes). Thus, treatment with PPARα activators results in decreased circulating triglyceride levels in humans and rodents.
The agonist properties of PPARα previously measured in vitro must be translated to the liver by modification of the level of expression of the target genes directly under the control of the PPARα receptor: the genes studied in these experiments are those coding for ACO (a key enzyme in the mechanism of β-oxidation of fatty acids), PDK-4 (an enzyme of carbohydrate metabolism) and Apo CIII (apolipoprotein involved in lipid metabolism).
The Protocol (a) Treatment of animals
Transgenic Apo E2/E2 mice were kept under a 12h/12h light/dark cycle at a constant temperature of 20 ± 3°C. After acclimation for one week, the mice were weighed and grouped into groups of 6 animals selected so that the distribution of their body weight and plasma lipid levels first determined before the experiment were uniform. The test compounds were then suspended in carboxymethylcellulose (Sigma C4888) and administered at the selected dose by intragastric pre-feeding, once daily for 7 days at the desired dose. The animals were given free access to water and food. At the end of the experiment, the animals were subjected to a rapid anaesthetic and were stored in a plasma sample at 20 °C. Samples were taken immediately after the experiment and stored in a 4 minute + 4 minute + 3 minute + 3 minute + 4 minute + 4 minute + 4 minute + 4 minute + 4 minute. Samples were analyzed and stored at a temperature of 3000 °C.
(b) Measurement of plasma lipids
Plasma lipid concentrations (total cholesterol, HDL cholesterol, and free fatty acids) were measured by enzymatic dosing (bioMérieux-Lyon-France) as recommended by the supplier.
(c) Analysis of gene expression by quantitative RT-PCR
The total RNA was extracted from liver fragments using the NucleoSpin® 96 RNA kit (Macherey Nagel, Hoerdt, France) according to the manufacturer's instructions and 1 μg of total RNA (quantified using the Ribogreen RNA quantification kit (Molecular Probes)) was then reversed into complementary DNA by a 1-hour reaction at 37°C in a total volume of 20 μl containing 1X buffer (Sigma), 1.5 mM of DTT, 0.18 mM of dNTPs (Promega), 200 ng of pdN6 (Amersham), 30U of RNase inhibitor (LVLV) and 1 μl of MM-RT (Sigma).
Quantitative PCR experiments were performed using the MyiQ Single-Color Real-Time PCR Detection System (Biorad, Marnes-la-Coquette, France) and were performed using the iQ SYBR Green Supermix kit as recommended by the supplier, in 96-well plates, on 5 μl of diluted reverse transcription reactions, with a hybridization temperature of 55°C. Specific pairs of initiators of the studied genes were used: The following is the list of the types of products which are to be considered for the purposes of the calculation of the amount of the premium:
The amount of fluorescence emitted is directly proportional to the amount of complementary DNA present at the start of the reaction and amplified during PCR. For each target studied, a range is produced by successive dilutions of a pool of a few μl of different reverse transcription reactions. The relative expression levels of each target are thus determined using the efficiency curves obtained with the range points.
The expression levels of the genes of interest were then normalized against the expression level of the reference gene 36B4 (whose specific priming is: sensory priming: 5'-CATGCTCAACATCTCCCCTCTCC-3' (SEQ ID NO: 11) and antisense priming: 5'-GGGAAGGTTAATCCGTCTCCACAG -3' (SEQ ID NO: 12).
The induction factor, i.e. the ratio of the relative signal (induced by the compound of the invention) to the mean of the relative values of the control group, was then calculated for each sample. The higher this factor, the more the compound has a gene expression activating character.
Results and Conclusion (a) Measurement of plasma lipids
Total cholesterol levels were decreased after 7 days of treatment with compounds 2 and 4 (administered at 10 and 100 mpk; Figure 9a) and with compound 19 at 100 mpk (Figure 10a).Also, treatment with Cpd 2 or Cpd 4 resulted in dose-dependent increases in plasma HDL cholesterol (Figure 9b).Treatment with Cpd 19, at 100 mpk, also resulted in decreases in plasma free fatty acid levels (Figure 10b).
(b) Analysis of gene expression by quantitative RT-PCR
Cpd 2 and Cpd 4 induce hepatic overexpression of the genes coding for ACO and PDK-4, and significant inhibition of hepatic expression of the gene coding for ApoCIII ((Figures 9c, 9d, and 9c).
The compounds of the invention have lipid-lowering properties by lowering plasma cholesterol and free fatty acids. The compounds of the invention also have the property of increasing the beneficial fraction of HDL-cholesterol. In addition, the compounds of the invention are regulators of gene expression for enzymes heavily involved in lipid and carbohydrate metabolism. These results, obtained in vivo, demonstrate the therapeutic potential of the compounds of the invention for major pathologies such as dyslipidemia.
Example 11: PPARδ activating properties of compounds according to the invention by measurement of PPARδ target gene expression in myocytes The principle
The agonist properties of PPARδ previously measured in vitro have been assessed by measuring in mouse myocytes the expression of genes involved in lipid, carbohydrate metabolism and energy expenditure (PDK4, CPT1b, UCP2). The regulation of the expression of these genes in this cell type is a direct consequence of activation by the compounds of the invention of PPARδ. The higher the expression of the genes, the more the compound of the invention is a stimulator of metabolism in muscle cells (Dressel U et al., 2003).
The Protocol (a) Differentiation of C2C12 cells into myocytes
The C2C12 mouse cells (ECACC origin) are cultured in DMEM medium (Gibco ; 41965-039) with 1% L-glutamine (Gibco ; 25030), 1% penicillin/streptomycin (VWR; BWSTL0022/100) and 10% decomposed foetal calf serum (SVF. Gibco ; 10270-106) added to the medium.
The cells are seeded in 24-well plates with a density of 50 x 103 cells/well. At the confluence, the medium is replaced by a differentiation medium (base culture medium with 2% horse serum (Gibco; 26050-088)) and the culture is continued at 37°C and 5% CO2 for 7 days to allow the differentiation of myoblasts into myocytes.
(b) Treatment
After 6 days of differentiation, the cells are placed in a deprivation medium (serum-free base culture medium) for 6 hours. The cells are then treated with the compounds of the invention in the deprivation medium. The compounds of the invention were tested at doses of 0.1, 1, 10μM and 0.2, 2 and 20 μM respectively. The compounds of the invention were dissolved in dimethyl sulfoxide (DMSO, Sigma ; D5879). The cells are treated for 24 hours at 37°C, 5% CO2.
(c) RNA extraction, reverse transcription and quantitative PCR.
These processes were performed on the cells essentially as described in Example 10 (point (c) of the Protocols).
The following pairs of specific genes were used: The following information is provided for the purpose of the calculation of the value of the input data:
Results and Conclusion
In mouse myocytes in vitro, the compounds of the invention such as Cpd 7 and Cpd 24 have significant stimulatory effects on the expression of genes involved in carbohydrate, lipid metabolism and thermoregulation, and known to be regulated by PPARδ agonists such as PDK4, CPT1b and UCP2 (Figures 11a, 11b and 11c).
The experimental data presented show that the compounds of the invention have a metabolic action in mouse myocytes by activation of PPARδ.
Example 12: PPARγ activating properties of compounds of the invention The principle
The functional effect of PPARγ activation is evaluated in vitro on a 3T3-L1 pre-adipocytes cell line (Thompson GM et al., 2004) by measuring intracellular triglyceride concentration and culture medium-secreted adiponectin concentration after 9 days of treatment with the compounds of the invention, similar to that of PPARγ agonists such as thiazolidinediones (Kallen CB and Lazar MA, 1996), which demonstrated the functional properties of these compounds in vitro.
The Protocol
The 3T3-L1 cells (Mus musculus embryo fibroblasts, ATCC; CL-173) were cultured in DMEM medium (4.5 g/L glucose, Gibco 41965) supplemented with 10% Fetal Calf Serum (Gibco ; 10270), 1% L-glutamine (Gibco ; 25030), 100 units/mL penicillin + 100 μg/mL streptomycin (VWR ; BWSTL0022/100) until confluence (37°C, 5% CO2). At confluence, the cells were then rinsed in PBS (Phosphate Buffered Saline solution) according to culture medium and DMEM glucose was replaced with 4.5 g/L (10Gibco ; 25030), 1% L-glutamine, 100 μmL (100 μmL); 100 μmL and 100 μmL streptomycin (BWSTL0022/100) according to culture medium.
After 2 days of incubation, the cells were washed with PBS and the differentiation medium was replaced with 4.5 g/L DMEM glucose supplemented with 10% SVF, 1% L-glutamine, 100 units/mL penicillin and 100 μg/mL streptomycin, 0.4 μM insulin, and the compounds of the invention in order to complete cell differentiation and obtain adicytes. The medium was changed every 2 days until complete differentiation. After 9 days of culture, treatment was stopped by removing the culture medium that had been stored for the dosage of secreted adiponectin. The cells were then washed 2 times and placed in PBS for intracellular periphosphate membrane analysis. The triglyceride content was evaluated immediately.
Intracellular triglyceride quantification was performed with the Triglyceride Enzyme Kit PAP1000 (bioMérieux ; 61238) as recommended by the supplier.
Results and Conclusion
Experimental data show that Cpd 19, Cpd 24 and Cpd 36 in vitro dose-dependently stimulate the accumulation of triglycerides in adipocytes and adiponectin secretion. These results therefore show an in vitro PPARγ activating capacity of the compounds of the invention, which is reflected in the stimulation of adipogenesis in the 3T3-L1 mouse pre-adipocytes cell model.
The Bible is a book of wisdom.
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Claims (15)

  1. A compound of general formula: in which, G represents:
    - a radical -ORa, -SRa, or
    - a radical -NRaRb,
    Ra being selected from an alkyl radical with 1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms, a ring with 3 to 14 atoms, a phenyl radical, a phenylalkyl radical with the alkyl moiety having 1 to 3 carbon atoms; Rb being selected from a hydrogen atom, an alkyl radical with 1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms, a ring with 3 to 14 atoms, a phenyl radical, or a phenylalkyl radical with the alkyl moiety having 1 to 3 carbon atoms; Ra and Rb can form, together and with the nitrogen atom to which they are bound, a heterocycle with 3 to 8 atoms. R1 and R2, which may be identical or different, represent a hydrogen atom or an alkyl radical with 1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms; R1 and R2 can form, together and with the carbon atom to which they are bound, a carbocycle with 3 to 6 carbon atoms; Y1 represents:
    - a oxygen atom or sulfur atom, or
    - a group -NR-, in which R has the same definition as Rb;
    Y2 represents:
    - a oxygen atom or sulfur atom, or
    - a radical -CR5R6-; with R5 and R6, which may be identical or different, selected from a hydrogen atom or halogen atom, an alkyl radical with 1 to 6 carbon atoms or an alkenyl or alkynyl radical with 2 to 6 carbon atoms, a ring with 3 to 6 atoms, a phenyl radical, a phenylalkyl radical with the alkyl moiety having 1 to 3 carbon atoms;
    X1, X2, X3 represent independently a hydrogen atom or halogen atom, an alkyl radical with 1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms, a group -OR'a, - SR'a, -NR'aR'b, a ring with 5 to 14 atoms, or a phenylalkyl radical with the alkyl moiety having 1 to 3 carbon atoms, with at least one of the groups X1, X2 and X3 different from a hydrogen atom and from a halogen atom;
    R'a and R'b, which may be identical or different, having the same definitions as Ra and Rb;
    X4 and X5 represent independently a hydrogen atom or halogen atom, an alkyl radical with 1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms, a group -OR"a, - SR"a or -NR"aR"b, a ring with 3 to 14 atoms, a phenyl radical, or a phenylalkyl radical with the alkyl moiety having 1 to 3 carbon atoms; R"a and R"b, which may be identical or different, having the same definitions as Ra and Rb; R3 and R4, which may be identical or different, represent a hydrogen atom or halogen atom, an alkyl radical with 1 to 6 carbon atoms or alkenyl radical with 2 to 6 carbon atoms, a ring with 3 to 14 atoms, a phenyl radical, or a phenylalkyl radical with the alkyl moiety having 1 to 3 carbon atoms; W represents:
    - a carboxyl radical -COOH; or
    - a function derived from the carboxylic acid function, selected from
    - COOR"'a, -COSR"'a, -CONR"'aR"'b, -CSNR"'aR"'b, -CONH2; or
    - a bioisosteric group of the carboxyl radical, selected from:
    - an acylsulfonamide radical (-CONHSO2R"'a);
    - a hydrazide radical (-CONHNR"'aR"'b);
    - a radical selected from the thiazolidinedione, oxazolidinedione, tetrazole, oxadiazolone, triazolone, triazole, 3-alkyltriazole, or imidazolidinedione rings;
    R"'a and R"'b, which may be identical or different, having the same definitions as Ra and Rb.
  2. The compound as claimed in claim 1, characterized in that Y2 is positioned para or meta of Y1.
  3. The compound as claimed in claim 1 or 2, characterized in that:
    - X3 denotes a hydrogen atom, and/or
    - X4 and X5 denote independently a hydrogen atom, an alkyl radical having 1 to 6 carbon atoms, a group -OR"a or -SR"a; R"a being an alkyl radical having 1 to 6 carbon atoms.
  4. The compound as claimed in one of claims 1 to 3, characterized in that R1, R2, R3, R4 denote independently a hydrogen atom or a methyl, ethyl, propyl, butyl, isopropyl or tert-butyl radical.
  5. The compound as claimed in one of claims 1 to 4, characterized in that X3, R1 and R2 denote hydrogen atoms.
  6. The compound as claimed in one of claims 1 to 5, characterized in that X1 and/or X2 denote a ring with 5 to 10 atoms, unsubstituted or substituted with a -CF3 group.
  7. The compound as claimed in one of claims 1 to 6, characterized in that G denotes
    - a radical -ORa or -SRa, with Ra selected from alkyl radical having 1 to 6 carbon atoms, a cyclohexyl or a phenyl radical; or
    - a radical -NRaRb, Ra and Rb forming together, and with the nitrogen atom to which they are bound, a heterocycle with 3 to 8 atoms.
  8. The compound as claimed in one of claims 1 to 6, characterized in that G denotes a radical -ORa with Ra selected from a methyl, ethyl, propyl, butyl, isopropyl or tert-butyl radical.
  9. The compound as claimed in claim 7 or 8, characterized in that:
    - X2 and X3 denote simultaneously a hydrogen atom; or
    - X3 and X1 denote simultaneously a hydrogen atom.
  10. The compound as claimed in one of claims 1 to 9, characterized in that Y1 denotes an oxygen or sulfur atom, and simultaneously Y2 denotes an oxygen atom, a sulfur atom, or a group -CR5R6.
  11. The compound as claimed in one of claims 1 to 9, characterized in that Y1 denotes a group -NR and simultaneously Y2 denotes an oxygen atom, a sulfur atom or a group - CR5R6.
  12. The compound as claimed in claim 10 or 11, characterized in that X1 denotes an unsubstituted phenyl radical or a phenyl radical substituted with a group -CF3, said group -CF3 being preferably in para of the pyridinyl radical, and/or G denotes a group -OCH3 or -OC(CH3)3.
  13. The compound as claimed in one of claims 1 to 12, characterized in that it is selected from: Cpd 1: 2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoic acid Cpd 2: 2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic acid Cpd 3: 2-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenoxy)propanoic acid Cpd 4: 2-(4-(((2-methoxy-6-phenylpyridin-3yl)methyl)amino)phenoxy)ethanoic acid Cpd 5: 2-(4-(((2-methoxy-6-phenylpyridin-3yl)methyl)amino)phenoxy)propanoic acid Cpd 6: 2-(4-((2-tert-butyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoic acid Cpd 7: 2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic acid Cpd 8: 2-(4-((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino) phenoxy)ethanoic acid Cpd 9: 2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoic acid Cpd 10: 2-(4-(((2-tert-butyloxy-6-phenylpyridin-3-yl)methyl)amino) phenoxy)-propanoic acid Cpd 11: 2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2-methyl-propanoic acid Cpd 12: 2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoic acid Cpd 13: 2-(3-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)-2-methyl-propanoic acid Cpd 14: 2-(3-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenoxy)ethanoic acid Cpd 15: 2-(4-((2-hexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic acid Cpd 16: 2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-ethanoic acid Cpd 17: 2-(4-((2-hexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)-2-methyl-propanoic acid Cpd 18: 2-(4-((2-cyclohexyloxy-6-phenylpyridin-3-yl)methoxy)phenoxy)ethanoic acid Cpd 19: 3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic acid Cpd 20: 2-(4-((6-phenyl-2-(piperidin-1-yl)pyridin-3-yl)methoxy)phenoxy)-ethanoic acid Cpd 21: 2-(4-((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methoxy) - phenoxy)-2-methylpropanoic acid Cpd 22: 2-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl) amino)-phenylthio)-2-methylpropanoic acid Cpd 23: 2-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl) amino)-phenylthio)ethanoic acid Cpd 24: 2-(4-((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methoxy) - phenoxy)ethanoic acid Cpd 25: 2-(4-((2-phenylthio-6-(phenyl)pyridin-3-yl)methoxy)phenoxy)ethanoic acid Cpd 26: 2-(4-(((2-methoxy-5-phenylpyridin-3-yl)methyl)amino)phenylthio)-ethanoic acid Cpd 27: 2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2,2-difluoroethanoic acid Cpd 28: 2-(4-(((2-methoxy-5,6-diphenylpyridin-3-yl)methyl)amino)phenylthio)-ethanoic acid Cpd 29: 2-(4-(((2-methoxy-5-bromo-6-phenylpyridin-3-yl)methyl)amino)-phenylthio)-ethanoic acid Cpd 30: 2-(4-(((2-methoxy-6-furylpyridin-3-yl)methyl)amino)phenylthio)ethanoic acid Cpd 31: 3-(4-(((2-methoxy-6-furylpyridin-3-yl)methyl)amino)phenyl)propanoic acid Cpd 32: 2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenylthio)-2-phenyl-ethanoic acid Cpd 33: 3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)(methyl)amino)phenyl)-propanoic acid Cpd 34: 3-(4-(1-((2-methoxy-6-phenylpyridin-3-yl)propyl)amino)phenyl)propanoic acid Cpd 35: 2-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-2,6-dimethyl-phenoxy)ethanoic acid Cpd 36: 3-(4-(((2-methoxy-6-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl) amino)-phenyl)-propanoic acid Cpd 37: 3-(4-((2-methoxy-6-phenylpyridin-3-yl)methylthio)phenyl) propanoic acid Cpd 38: 3-(4-(((2-(ethylthio)-6-phenylpyridin-3-yl)methyl)amino)phenyl)-propanoic acid Cpd 39: 3-(4-(((2-methoxy-6-(parabiphenyl)pyridin-3-yl)methyl)amino)phenyl)-propanoic acid Cpd 40: 3-(4-(((2-methoxy-6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-amino)-phenyl)propanoic acid Cpd 41: 3-(4-(((2-methoxy-5-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic acid Cpd 42: 3-(4-((2(-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)-3-phenyl-propanoic acid Cpd 43: 3-(2-methoxy-4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-phenyl)-propanoic acid Cpd 44: 3-(3-methoxy-4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)-phenyl)-propanoic acid Cpd 45: 3-(4-(((2-methoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)butanoic acid Cpd 46: 3-(4-(((2-methoxy-5-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-amino)phenyl)propanoic acid Cpd 47: 3-(4-(((2-methoxy-5-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)-amino)-phenyl)propanoic acid Cpd 48: 3-(4-(((2,6-dimethoxy-5-phenylpyridin-3-yl)methyl)amino)phenyl)-propanoic acid Cpd 49: 3-(4-(((5-(4-chlorophenyl)-2-methoxypyridin-3-yl)methyl)amino)phenyl)-propanoic acid Cpd 50: 3-(4-(((2-methoxy-5-(naphthalen-2-yl)pyridin-3-yl)methyl)amino)phenyl)-propanoic acid Cpd 51: 3-(4-(((2-ethoxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)propanoic acid Cpd 52: 3-(4-((2-methoxy-5-phenylpyridin-3-yl)methoxy)phenyl)hex-4-ynoic acid Cpd 53: 3-(4-((2-methoxy-6-phenylpyridin-3-yl)methoxy)phenyl)hex-4-ynoic acid Cpd 54: 3-(4-(((2-isopropyloxy-6-phenylpyridin-3-yl)methyl)amino)phenyl)-propanoic acid.
  14. A pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, at least one compound as defined in one of claims 1 to 13, optionally in combination with one or more other therapeutic and/or cosmetic active substances.
  15. The pharmaceutical composition as claimed in claim 14 for the therapeutic, curative and/or prophylactic treatment of diabetes, dyslipidaemias, insulin resistance, pathologies associated with metabolic syndrome, atherosclerosis, cardiovascular diseases, obesity, hypertension and/or inflammatory diseases.
HK11107457.8A 2008-05-26 2009-05-26 Ppar agonist compounds and preparation and uses thereof for treating diabetes and/or dyslipidemia HK1157745B (en)

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Application Number Priority Date Filing Date Title
FR0853415 2008-05-26

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HK1157745A HK1157745A (en) 2012-07-06
HK1157745B true HK1157745B (en) 2014-02-28

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