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    • 专利摘要:
    The present invention relates to compounds of formula (I) [Formula I] Wherein R 1 represents a radical of formula (a) or (b); Y represents a CH 2 radical or a sulfur atom; R 5 represents a hydroxy radical, alkoxy radical, NH-OH radical, or N (R 8 ) represents a (R 9 ) radical; R 6 represents an alkyl radical, OR 10 radical, SR 10 radical, or (CH 2 ) r -COR 11 radical). The compounds can be used in human or veterinary medicines (in dermatology, as well as in the fields of diseases related to cardiovascular diseases, immune diseases and / or lipid metabolism), or in pharmaceutical compositions or PPARγ receptor activation in cosmetic compositions. Useful as a zero.
    公开号:KR20030051611A
    申请号:KR10-2003-7001815
    申请日:2001-08-03
    公开日:2003-06-25
    发明作者:베르나르동쟝-미셸；끌라리로렁스
    申请人:갈데르마 리써어치 앤드 디벨로프먼트,에스.엔.씨.；
    IPC主号:
    专利说明:

    Biphenyl derivatives, and their use as PPA-gamma receptor activators {BIPHENYL DERIVATIVES AND THEIR USE AS PPAR-GAMMA RECEPTOR ACTIVATORS}
    [1] The present invention relates to a novel family of biaromatic compounds, which are novel and useful industrial products, are activators of the peroxysomal proliferation activated receptor form (PPAR-γ) receptor of subtype γ. The present invention also relates to a process for its preparation and its use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
    [2] The subject of this study was the activity of PPAR type receptors. As a guide, the publication "Differential Expression of Peroxisome Proliferator-Activated Receptor Subtypes during the Differentiation of Human Keratinocytes", Michel Rivier et al., J. Invest. Dermatol 111, 1998, pp. 1116-1121. In addition, as a guide, the report ["The PPARs: From orphan receptors to Drug Discovery", Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach and Brad R. Henke, J. Med. Chem., 2000, Vol. 43, pp. 527 to 550 may be mentioned.
    [3] PPAR receptors activate transcription by binding to elements in the DNA sequence known as the peroxysome proliferation response element (PPRE) in the form of a heterodimer with the retinoid X receptor (known as RXR).
    [4] Three subtypes of human PPARs have been identified and described: PPARα, PPARγ and PPARδ (or NUC1).
    [5] PPARδ is everywhere, but PPARα is mainly expressed in the liver.
    [6] PPARγ is the most widely studied of the three subtypes. All references suggest that a significant role of PPARγ is in regulating the differentiation of fat cells, where it is expressed a lot. It also plays a critical role in systemic lipid homeostasis.
    [7] In particular, patent application WO 96/33724 describes PPARγ-selective compounds such as prostaglandin J2 or D2 as potential active agents for the treatment of obesity and diabetes.
    [8] In addition, Applicant has already described in patent application FR 98/02894 the use of PPARγ activator compounds as pharmaceutical compositions in the manufacture of pharmaceutical compositions intended to treat skin disorders associated with epidermal cell differentiation abnormalities.
    [9] One of the objects of the present invention is to propose a new family of PPARγ activator compounds.
    [10] The present invention therefore relates to the compounds corresponding to formula (I), to salts of compounds of formula (I) when R 1 comprises a carboxylic acid function, and also to the optical and geometric isomers of the compounds of formula (I) It is about:
    [11]
    [12] {In the meal,
    [13] R 1 represents a radical of the formula (a) or (b):
    [14]
    [15]
    [16] (Y, R 5 and R 6 have the following meanings),
    [17] R 2 and R 3 may be the same or different and have a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, a halogen atom, an -OR 7 radical, a polyether radical, a nitro radical, or one having 1 to 12 carbon atoms An amino radical which may be optionally substituted with (or more) alkyl radical (s),
    [18] (R 7 has the meaning below),
    [19] X represents the following structural linkages:
    [20] -(CH 2 ) m- (Z) n- (CO) p- (W) q-
    [21] (The structural connection can be read from left to right and vice versa)
    [22] (Z, W, m, n, p and q have the following meanings),
    [23] R 4 represents an alkyl radical having 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a 9-fluorenylmethyl radical,
    [24] Y represents a CH 2 radical or a sulfur atom,
    [25] R 5 represents a hydroxyl radical, an alkoxy radical having 1 to 6 carbon atoms, an NH-OH radical, or an N (R 8 ) (R 9 ) radical,
    [26] (R 8 and R 9 have the following meanings),
    [27] R 6 represents an alkyl radical having 1 to 12 carbon atoms, an OR 10 radical, an SR 10 radical or a (CH 2 ) r -COR 11 radical,
    [28] (r, R 10 and R 11 have the following meanings),
    [29] R 7 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, or an aralkyl radical,
    [30] Z represents an oxygen or sulfur atom or an NR 12 radical,
    [31] (R 12 has the following meaning),
    [32] W represents an oxygen or sulfur atom, an NR 13 radical, or a CH 2 radical,
    [33] (R 13 has the following meaning),
    [34] m, n, p and q can be the same or different and can take a value of 0 or 1 (where the sum m + n + p + q is 2 or more and p takes a value of 0, understand that n or q is 0),
    [35] R 8 represents a hydrogen atom or an alkyl radical having 1 to 12 carbon atoms,
    [36] R 9 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, or an aryl radical,
    [37] -r represents 0 or 1,
    [38] R 10 represents an alkyl radical having 1 to 12 carbon atoms, an aryl radical, or an aralkyl radical,
    [39] R 11 represents a hydroxyl radical, an OR 14 radical, or an N (R 15 ) (R 16 ) radical,
    [40] R 12 represents a hydrogen atom or an alkyl radical having 1 to 12 carbon atoms,
    [41] R 13 represents a hydrogen atom or an alkyl radical having 1 to 12 carbon atoms,
    [42] R 14 represents an alkyl radical having 1 to 12 carbon atoms, an aryl radical, or an aralkyl radical,
    [43] R 15 represents a hydrogen atom or an alkyl radical having 1 to 12 carbon atoms,
    [44] R 16 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, or a heteroalkyl radical.
    [45] When the compounds according to the invention are in the form of salts, they are preferably alkali metal or alkaline earth metal salts, or alternatively zinc salts or organic amine salts.
    [46] According to the invention, the expression "alkyl radicals having 1 to 12 carbon atoms" means radicals having 1 to 12 carbon atoms, preferably methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl or dodecyl radicals. do.
    [47] The term "polyether radical" means a polyether radical having 1 to 6 carbon atoms, such as methoxymethoxy, ethoxymethoxy, or methoxyethoxymethoxy radical, in which one or more oxygen atoms are involved.
    [48] The term "halogen atom" means a fluorine, chlorine, or bromine atom.
    [49] The expression "alkoxy radical having 1 to 6 carbon atoms" means a radical having 1 to 6 carbon atoms, such as a methoxy, ethoxy, isopropyloxy, tert-butoxy or hexyloxy radical.
    [50] The term “aryl radical” refers to a halogen atom, a CF 3 radical, an alkyl radical having 1 to 12 carbon atoms, an alkoxy radical having 1 to 6 carbon atoms, a nitro function, a polyether radical, a hydroxyl radical optionally protected with an acetyl or benzoyl group, or acetyl Or a phenyl radical which may be monosubstituted or disubstituted with an amino function optionally protected with a benzoyl group or optionally substituted with one or more alkyl of 1 to 12 carbon atoms.
    [51] The term "aralkyl radical" refers to a halogen optionally protected with a halogen atom, a CF 3 radical, an alkyl radical having 1 to 12 carbon atoms, a hydroxyl radical, an alkoxy radical having 1 to 6 carbon atoms, a nitro function, a polyether radical, an acetyl or benzoyl group. By benzyl or phenethyl radical, which may be monosubstituted or disubstituted with an oxyl radical, or an amino function optionally protected with acetyl or optionally substituted with one or more alkyl of 1 to 12 carbon atoms.
    [52] The term “heteroaryl radical” refers to one or more halogens, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 6 carbon atoms, nitro functionality, polyether radicals, hydroxyl optionally protected with acetyl or benzoyl groups, or optionally protected with acetyl or benzoyl groups. Or a pyridyl, furyl, thienyl or isoxazolyl radical optionally substituted with an amino function optionally substituted with one or more alkyl of 1 to 12 carbon atoms.
    [53] Among the compounds of the formula (I) which fall within the context of the present invention, mention may in particular be made (alone or as a mixture):
    [54] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [55] 5- {3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-ylmethyl} thiazolidine-2,4-dione
    [56] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] benzamide
    [57] Ethyl 3- {3 '-[(benzoylmethylamino) methyl] biphenyl-4-yl} -2-methylpropionate
    [58] 2-Methyl-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] -methyl} biphenyl-4-yl) propionic acid
    [59] N- [4 '-(2-carbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [60] N-methyl-N- [4 '-(2-phenylcarbamoylpropyl) biphenyl-3-ylmethyl] benzamide
    [61] N- [4 '-(2-hydroxycarbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [62] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-phenylurea
    [63] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -1-methyl-3-phenylurea
    [64] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamate
    [65] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylnonanamide
    [66] (S) -2-ethoxy-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [67] Monomethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [68] Dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [69] Methyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamate
    [70] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-ethylbenzamide
    [71] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-pentylbenzamide
    [72] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] ethylcarbamate
    [73] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] propylcarbamate
    [74] 9H-fluorene-9-ylmethyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamate
    [75] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2,2, N-trimethylpropionamide
    [76] N-octyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [77] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl-N-methyl] -3-phenylpropionamide
    [78] 2- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-N-phenylacetamide
    [79] N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-propylbenzamide
    [80] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] carbamate
    [81] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3,4-diethoxy-N-methylbenzamide
    [82] 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamic acid
    [83] N-benzyl-N-methyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [84] N-benzyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [85] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyldecanamide
    [86] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -2-phenylacetamide
    [87] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [88] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylheptanamide
    [89] N-hydroxy-2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamic acid
    [90] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-2-phenylacetamide
    [91] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-methoxy-N-methylbenzamide
    [92] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-methoxy-N-methylbenzamide
    [93] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3, N-dimethylbenzamide
    [94] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-4-propylbenzamide
    [95] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4, N-dimethylbenzamide
    [96] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylisoxazole-5-carboxamide
    [97] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-ethoxy N-methylbenzamide
    [98] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-fluoro-N-methylbenzamide
    [99] 4-dimethylamino-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [100] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylnicotinamide
    [101] 3,5-Dichloro-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [102] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylthiophene-2-carboxamide
    [103] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylhexaneamide
    [104] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2-methoxy-N-methylbenzamide
    [105] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylpyridine-2-carboxamide
    [106] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylfuran-2-carboxamide
    [107] 4-butoxy-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [108] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylthiophene-3-carboxamide
    [109] 4-{[4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamoyl} phenyl acetate
    [110] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-hydroxy-N-methylbenzamide
    [111] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2N-dimethylbenzamide
    [112] 2-butyl-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [113] 4-acetylamino-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [114] Hexyl N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylcarbamate
    [115] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-phenylurea
    [116] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2-phenylacetamide
    [117] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3-phenylurea
    [118] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-heptyl-1-methylurea
    [119] 4-monomethyl ester of 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4-ylmethyl} succinic acid
    [120] 2- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-ylmethyl} succinic acid
    [121] N- [4 '-(2,5-dioxopyrrolidin-3-ylmethyl) biphenyl-3-ylmethyl] -N-methylheptanamide
    [122] 3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-phenylcarbamate
    [123] 3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-heptylcarbamate
    [124] 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl phenylacetate
    [125] 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl nonanoate
    [126] 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl N-heptylcarbamate
    [127] 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl N-phenylcarbamate
    [128] N- [6-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [129] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -6-hydroxybiphenyl-3-ylmethyl] -N-methyloctanamide
    [130] N- [4-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [131] N- [4 "-(2,4-dioxothiazolidin-5-ylmethyl)-[1,1 '; 3', 1"] terphenyl-5'-ylmethyl] -N-methyloctanamide
    [132] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -2'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide
    [133] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -3'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide
    [134] (S) -2-ethoxy-3- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-yl} propionic acid
    [135] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-ethyl-3-phenylurea
    [136] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyldecanamide
    [137] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methylnonanamide
    [138] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2- (4-butoxyphenyl) acetamide
    [139] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2- (4-methoxyphenyl) acetamide
    [140] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2- (4-ethoxyphenyl) acetamide
    [141] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2- (4-hydroxyphenyl) acetamide
    [142] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3- (4-butoxyphenyl) urea
    [143] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3- (4-methoxyphenyl) urea
    [144] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3- (4-ethoxyphenyl) urea
    [145] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3- (4-hydroxyphenyl) urea
    [146] (S) -2-ethoxy-3- (3 '-{[methyl- (1- (4-butoxy) phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [147] (S) -2-ethoxy-3- (3 '-{[methyl- (1- (4-methoxy) phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [148] (S) -2-ethoxy-3- (3 '-{[methyl- (1- (4-ethoxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [149] (S) -2-ethoxy-3- (3 '-{[methyl- (1- (4-hydroxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [150] (S) -2-phenoxy-3- (3 '-{[methyl- (1- (4-butoxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [151] (S) -2-phenoxy-3- (3 '-{[methyl- (1- (4-methoxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [152] (S) -2-phenoxy-3- (3 '-{[methyl- (1- (4-ethoxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [153] (S) -2-phenoxy-3- (3 '-{[methyl- (1- (4-hydroxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [154] (S) -2-phenoxy-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [155] (S) -2-phenoxy-3- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-yl} propionic acid
    [156] 5- {3 '-[methyl- (2-oxo-2-phenylethyl) amino] biphenyl-4-ylmethyl} thiazolidine-2,4-dione
    [157] 5- [3 '-(methylphenethylamino) biphenyl-4-ylmethyl] thiazolidine-2,4-dione
    [158] Phenyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] methylcarbamate
    [159] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] methylcarbamate.
    [160] According to the invention, more particularly preferred compounds of formula (I) are those having one or more of the following characteristics:
    [161] R 1 represents a radical of formula (a) or a radical of formula (b), wherein R 5 represents a hydroxyl radical and R 6 represents an OR 10 radical,
    [162] -X represents a structural linkage selected from -CH 2 -N (R 12 ) -CO-, -NR 12- (CO) -NR 13 or NR 12- (CO) -CH 2- (where the Read to the right or vice versa).
    [163] The subject of the invention is also a process for the preparation of compounds of formula (I), in particular according to the schemes shown in FIGS. 1 and 2.
    [164] Derivatives of formula (Ia) (in FIG. 1) can be obtained from derivative (Ic) by hydrogenation in the presence of palladium-on-charcoal in charcoal in a solvent such as dioxane, ethyl acetate, DMF or ethanol have.
    [165] Derivatives of formula (Ia) (in FIG. 1) are also derived from thiazolidine-2,4-dione derivatives (6),
    [166] When Q represents-(CH 2 ) m -ZH, reaction with an acyl halide of the formula Cl-CO- (W) q -R 4 in the presence of a base such as triethylamine in a solvent such as THF or dichloromethane Or by reaction with an isocyanate of the formula O = C = NR 4 ;
    [167] When Q represents-(CH 2 ) m -COOH, the acid is in the presence of a tertiary amine (for example triethylamine or pyridine) in an anhydrous medium in an organic solvent, preferably THF or dichloromethane. By reacting the activated form of the functional moiety, for example acid chloride, with an amine, hydroxyl or thiol derivative of the formula HW-R 4 ,
    [168] Can be obtained.
    [169] Derivatives of formula (6) (in FIG. 1) can be obtained from the derivatives of formula (5) by hydrogenation in the presence of palladium on charcoal in a solvent such as dioxane, ethyl acetate, DMF or ethanol.
    [170] (FIG. 1) Compounds (5) and (Ic) are prepared from compounds (3) and (8), respectively, in the presence of 2,4-thiazoli in an alcoholic solvent such as ethanol or in toluene in piperidine acetate It can be obtained by reaction with dindione. Compounds (3) and (8), respectively, from halo derivatives (1) and (7), preferably iodo or bromo derivatives, by Suzuki form coupling reaction with boronic acid (2) Can be obtained. The reaction is carried out in the presence of a palladium catalyst, for example tetrakis (triphenylporpin) palladium, [N. Miyaura et al., Synthetic Communications (1981), 11 (7), 513-519.
    [171] The boron-based derivative (2) first protects the aldehyde function in the acetal form from the corresponding halo derivative (preferably iodo or bromo), then converts it to a lithium reactant, reacts with trimethyl borate and hydrolysis Can be obtained.
    [172] Derivatives of formula (Ib) (from FIG. 2) are carried out from aldehyde derivatives (9), following a Horne form reaction with a lithium or sodium derivative of phosphonate (10), followed by hydrogenation in the presence of charcoal palladium and acid Can be obtained by saponification of the ester.
    [173] Derivatives of formula (Id) (in FIG. 2) are described in [S. Doulut et al., J. Med. Chem. (1993), 36, 1369-1379, can be obtained by a series of reactions.
    [174] Derivatives of formula (Ie) (in FIG. 2) are described by [H. Shinkai et al., J. Med. Chem. (1998), 41, 1927-1933, which can be obtained by a series of reactions.
    [175] Derivatives of formula (If) (in FIG. 2) are described in [B. Hulin et al., J. Med. Chem. (1996), 39, 3987-3907, can be obtained by a series of reactions under the conditions described.
    [176] When R 1 contains an acid functional moiety, the compounds are prepared by protecting R 1 with a protecting group of alkyl, allyl, benzyl or tert-butyl type having 1 to 12 carbon atoms.
    [177] The transition to the glass form,
    [178] For alkyl protecting groups of 1 to 12 carbon atoms using sodium hydroxide or lithium hydroxide in an alcoholic solvent such as methanol or in THF;
    [179] For allyl-based protecting groups, using catalysts such as certain transition metal complexes in the presence of secondary amines such as morpholine;
    [180] In the case of benzyl-based protecting groups, by debenzylation in the presence of hydrogen using a catalyst such as palladium on charcoal;
    [181] for tert-butyl type protecting groups, trimethylsilyl iodide is used,
    [182] Can be performed.
    [183] The compounds according to the invention have activating properties on PPARγ type receptors.
    [184] According to the present invention, the expression "activator of PPARγ type receptor" is described in Kliewer et al., Nature, 358, 771-774, 1992, at a concentration of 1 μM in the transactivation test. By any compound that exhibits at least 20% of the percentage of PPARγ receptor activation calculated for SB 219994, a reference compound that confers 100% activation.
    [185] Preferably, the activator of the PPARγ type receptor exhibits a percentage of activation of at least 40%, advantageously at least 70%.
    [186] Preferably, the activator of the PPARγ type receptor is specific, i.e., the ratio of the percentage of PPARγ receptor activation to the percentage of PPARα receptor activation (calculated for Wy 14643, the reference compound conferring 100% activation of PPARα) is at least 3 to be. Preferably the ratio is at least 5, more advantageously at least 10.
    [187] The affinity of the PPAR derivative for the human PPARγ receptor was also determined in the binding test by binding competition of the reference agonist tritiated BRL 49,653. Adsorption techniques on hydroxyapatite gels have been used to separate receptor binding ligands from free ligands. Human PPARγ receptors were prepared from Sf9 insect cells infected with recombinant baculovirus. The result is expressed as a Kd value (nM) indicating the equilibrium dissociation constant obtained for each compound. The expression “PPARγ receptor ligand” means any compound according to the invention having a Kd value of less than 10,000 nM. Preferably, the compounds according to the invention have a Kd value of less than 1,000 nM, advantageously less than 100 nM.
    [188] The subject of the invention is also a compound of formula (I) as described above, as a pharmaceutical product.
    [189] The compounds according to the invention are particularly suitable for the following therapeutic fields:
    [190] 1) For the treatment of dermatological complications associated with keratin disorders related to differentiation and proliferation, in particular common acne, scrim, polymorphs, injectable acne, crystalline cystic acne, clot acne For the treatment of secondary acne, such as senile acne, and sunlight, drug or occupational acne,
    [191] 2) Treatment of other forms of keratin disorders, in particular sclerosis, sunburn symptoms, Darrier disease, palmar keratosis, leukoplakia and leukoplakiform symptoms, and skin or mucosal (oral) lichens for,
    [192] 3) other dermatological lesions with or without cell proliferative disorders, especially inflammatory allergic immune components, especially all types of psoriasis, whether skin, mucous or nail psoriasis, and even psoriatic arthrosis, or alternatives For the treatment of skin atopic, such as eczema, or respiratory atopic or gingival hypertrophy,
    [193] 4) all dermal or epidermal hyperplasia, such as common wart, squamous warts, and warty epidermal dysplasia, oral or florid papilloma, T lymphoma, whether benign or malignant or viral of origin. And proliferation that can be induced by ultraviolet light, especially in the case of basal and spine cell epithelial cells, and also for treating any precancerous skin lesions such as keratinocytes,
    [194] 5) to treat other dermatological disorders such as immune dermatitis such as erythematous lupus, bullous immune disease, and collagen diseases such as scleroderma,
    [195] 6) in the treatment of dermatological or systemic lesions with immunological components,
    [196] 7) in the treatment of skin disorders due to exposure to UV radiation, and also to restore or counteract aging of the skin, whether photoinduced or age aging, or actinic keratosis and pigmentation, or age or To alleviate any pathology associated with chemical aging, such as dryness,
    [197] 8) to combat sebaceous dysfunction, such as hyper seborrhea of acne, or simple seborrhea,
    [198] 9) to prevent or treat cicatrization disorders, or to prevent or recover stretch marks,
    [199] 10) in the treatment of pigmentation disorders such as hyperpigmentation, melanoma, hypopigmentation or vitiligo,
    [200] 11) in the treatment of lipid metabolic lesions such as obesity, hyperlipidemia, or non-insulin dependent diabetes mellitus,
    [201] 12) in the treatment of inflammatory lesions, such as arthritis,
    [202] 13) in the treatment or prevention of cancerous or precancerous symptoms,
    [203] 14) in the prevention or treatment of alopecia of various origins, in particular alopecia caused by chemotherapy or radiation,
    [204] 15) in the treatment of immune system disorders such as asthma, type I sugar diabete, multiple sclerosis, or other selective dysfunction of the immune system,
    [205] 16) in the treatment of cardiovascular lesions, such as atherosclerosis or hypertension.
    [206] Subject of the invention is also a pharmaceutical or cosmetic composition containing at least one compound of formula (I) as defined above in a physiologically acceptable medium.
    [207] The subject of the invention is also the use of a compound of formula (I) for the preparation of a composition for the treatment of the aforementioned lesions, in particular for the regulation and / or repair of skin lipid metabolism.
    [208] The composition according to the invention can be administered in the digestive tract, parenterally, topically or intraocularly. The pharmaceutical composition is preferably packaged in a form suitable for topical application.
    [209] Via the digestive tract route, the composition, more particularly the pharmaceutical composition, can be tablets, gel capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, or lipid or polymeric vesicles or nanospheres for controlled release. It may be in the form of (nanosphere) or microsphere (microsphere). Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection.
    [210] The compounds according to the invention are usually administered in one to three dosage intakes in a daily dosage of about 0.001 to 100 mg / kg body weight.
    [211] The compound is used systemically at a concentration of usually 0.001 to 10% by weight, preferably 0.01 to 1% by weight, based on the weight of the composition.
    [212] Via the topical route, the pharmaceutical compositions according to the invention are more particularly intended to treat skin and mucous membranes, which are ointments, creams, milks, salves, powders, impregnation pads, solutions, It may be in the form of a gel, spray, lotion or suspension. It may also be in the form of lipid or polymeric vesicles or nanospheres or microspheres or polymer patches and hydrogels for controlled release. This topical route composition may be in anhydrous form, in aqueous form, or in emulsion form.
    [213] The compound is used topically, usually at a concentration of 0.001 to 10% by weight, preferably 0.01 to 1% by weight relative to the total weight of the composition.
    [214] The compounds of formula (I) according to the invention are also applied in the cosmetic field, in particular in the body and hair hygiene, more particularly for the regulation and / or repair of skin lipid metabolism. Compared with previously known products, these compounds of formula (I) have the advantage of additionally having other advantageous properties, in particular anti-inflammatory or soothing properties, which make these compounds less irritating and better tolerated. .
    [215] Subject of the invention is also the cosmetic use of a composition containing at least one compound of formula (I) in a physiologically acceptable support for body or hair hygiene.
    [216] Cosmetic compositions according to the invention, which contain at least one compound of formula (I), or optical or geometric isomers thereof, or salts thereof in a cosmetically acceptable support, are typically creams, milks, lotions, gels, lipids or polymers. Vesicles or nanospheres or microspheres, soap or shampoo.
    [217] The concentration of the compound of formula (I) in the cosmetic composition is from 0.001 to 3% by weight relative to the total weight of the composition.
    [218] Of course, the compositions as described above may contain inert or even pharmacodynamical active additives, or combinations of these additives, in particular: wetting agents; Depigmentants such as hydroquinone, azelaic acid, caffeic acid, or kojic acid; Emollients; Humectants such as glycerol, PEG-400, thiamorpholinone and derivatives or ureas thereof; Anti-seborrhea or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, salts thereof, or derivatives thereof, or benzoyl peroxide; Antifungal agents such as ketoconazole or poly (4,5-methylene-3-isothiazolidone); Antibacterial agents, carotenoids and in particular β-carotene; Anti-psoriasis agents such as anthraline and derivatives thereof; Eicosa-5,8,11,14-tetraynoic acid and eicos-5-5,8,11-triinoic acid, and esters and amides thereof, and finally retinoids . The compounds of formula (I) may also be combined with vitamin D or derivatives thereof, corticosteroids, free radical scavengers, α-hydroxy or α-keto acids or derivatives thereof, or alternatively with ion channel blockers. have.
    [219] These compositions also contain flavor enhancers, preservatives such as para-hydroxybenzoic acid esters, stabilizers, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifiers, UV-A and UV-B blockers, and antioxidants such as α-tocopherol , Butylhydroxyanisole or butylhydroxytoluene.
    [220] Needless to say, one of ordinary skill in the art would be careful to select the optional compound (s) to be added to these compositions such that the advantageous properties essentially associated with the present invention are not adversely affected or substantially affected by the intended addition. will be.
    [221] The preparation of the active compounds of formula (I) according to the invention and also the results of the biological activity of such compounds, as well as several examples of various specific formulations based on these compounds, will be presented by way of explanation, which limits their properties. It is not.
    [222] Example 1
    [223] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [224] (a) tert-butyl (3-bromobenzyl) carbamate
    [225] 15 g (67 mmol) 3-bromobenzylamine hydrochloride, 9.4 mL (67 mmol) triethylamine and 150 mL dichloromethane were introduced into a round bottom flask under a stream of nitrogen. 15.5 mL (67 mmol) di-tert-butyl dicarbonate was added portionwise at room temperature and the mixture was stirred for 3 hours. The reaction medium was poured into ice water, extracted with dichloromethane, the organic phase was separated off after the phase settling occurred, dried over magnesium sulfate and evaporated. 19.3 g (100%) of the expected product were collected.
    [226] (b) tert-butyl (3-bromobenzyl) -N-methylcarbamate
    [227] 19.3 g (67 mmol) tert-butyl (3-bromobenzyl) carbamate and 200 mL of THF were introduced into a round bottom flask under a stream of nitrogen. 3 g (74 mmol) of sodium hydride (60% in oil) were added portionwise and the mixture was stirred until gas evolution ceased. Then 4.6 mL (74 mmol) methyl iodide was added and the mixture was stirred for 1 hour. The reaction medium is poured into ice water, extracted with ethyl acetate, and the organic phase is separated off after phase settling has occurred, dried over magnesium sulfate and evaporated. 20.4 g (100%) of the expected product were collected.
    [228] (c) (3-bromobenzyl) methylamine
    [229] 20.2 g (67 mmol) tert-butyl (3-bromobenzyl) -N-methylcarbamate were introduced into 100 mL dichloromethane in a round bottom flask under a stream of nitrogen and 26 mL (335 mmol) trifluoro Acetic acid was added. The reaction medium was stirred for 8 hours at room temperature and hydrolyzed with saturated potassium carbonate solution. The mixture was extracted with dichloromethane and the organic phase was separated off after phase settling occurred, washed with water, dried over magnesium sulfate and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (50/50). After evaporation of the solvent, 9 g (67%) of the expected product were collected.
    [230] (d) N- (3-bromobenzyl) -N-methylbenzamide
    [231] 9 g (45 mmol) of (3-bromobenzyl) methylamine, 90 mL of THF, and 6.9 mL (50 mmol) of triethylamine were introduced into a round bottom flask under a stream of nitrogen. 5.7 mL (50 mmol) benzoyl chloride was added dropwise and the mixture was stirred for 1 hour. The reaction medium is poured into water, extracted with dichloromethane and the organic phase is separated off after phase settling has occurred, washed with water, dried over magnesium sulfate and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of ethyl acetate and heptane (15/85). After evaporation of the solvent 13.7 g (64%) of the expected product was collected.
    [232] (e) N- (4'-formylbiphenyl-3-ylmethyl) -N-methylbenzamide
    [233] 8.8 g (29 mmol) of N- (3-bromobenzyl) -N-methylbenzamide, 8.7 g (58 mmol) of 4-formylbenzeneboronic acid and 125 mL of toluene were introduced into a three neck flask under argon. It was. 36 ml (72 mmol) aqueous potassium carbonate solution (2 M) was added dropwise, the reaction medium was degassed with argon and 1 g of tetrakis (triphenylphosphine) palladium (0) chloride was heated to 90 ° C for 24 hours. Was added. The reaction medium is poured into water, extracted with dichloromethane, the organic phase is separated off after phase settling has occurred, dried over magnesium sulphate and evaporated. The residue obtained was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (50/50). After evaporation of the solvent 7.2 g (75%) of the expected product was collected.
    [234] (f) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [235] 1.6 g (4.6 mmol) N- (4'-formylbiphenyl-3-ylmethyl) -N-methylbenzamide, 610 mg (4.6 mmol) 2,4-thiazolidinedione, 137 mg piperi Dean acetate and 60 ml of toluene were introduced into a round bottom flask under a stream of nitrogen. The mixture was refluxed for 5 hours and the water formed was separated using a Dean-Stark apparatus. The reaction medium was cooled and the precipitate formed was filtered and purified on a silica column with an elution mixture of heptane and ethyl acetate (70/30). After evaporation of the solvent 1.4 g (70%) of the expected product was collected.
    [236] (g) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [237] 1.4 g (3.3 mmol) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methylbenzamide, 30 ml of DMF, And 25 ml of ethyl acetate were introduced into a three neck flask. The reaction medium was degassed, 1.4 g of charcoal palladium (10%) were introduced and the mixture was hydrogenated at 60 ° C. under atmospheric pressure. The reaction medium was filtered and evaporated and the residue obtained was purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (99/1). 300 mg of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide having a melting point of 70-71 ° C. after evaporation of the solvent. (21%) was collected.
    [238] Example 2
    [239] 5- {3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-ylmethyl} thiazolidine-2,4-dione
    [240] (a) (3-bromobenzyl) methylpyrid-2-ylamine
    [241] 1.5 g (7.5 mmol) of (3-bromobenzyl) methylamine and 15 mL of 2-fluoropyridine were introduced into a round bottom flask under a stream of nitrogen. The reaction medium was refluxed for 8 hours, evaporated to dryness. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvent 1 g (50%) of the expected product was collected.
    [242] (b) 3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-carbaldehyde
    [243] In a similar manner as in Example 1 (e), 475 mg (1.7 mmol) of (3-bromobenzyl) methylpyrid-2-ylamine is reacted with 386 mg (2.6 mmol) of 4-formylbenzeneboronic acid This gave 310 mg (60%) of the expected product.
    [244] (c) 5- {3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-ylmethylene} thiazolidine-2,4-dione
    [245] In a similar manner as in Example 1 (f), 216 mg (1.85 mmol) of 610 mg (1.85 mmol) of 3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-carbaldehyde By reacting with 2,4-thiazolidinedione, 640 mg (81%) of the expected product were obtained.
    [246] (d) 5- {3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-ylmethyl} thiazolidine-2,4-dione
    [247] In a similar manner as in Example 1 (g), 310 mg (0.8 mmol) of 5- {3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-ylmethylene} thiazolidine- 5- {3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-ylmethyl} thiazolidine-2,4 having a melting point of 135 to 136 ° C. starting from 2,4-dione 80 mg (26%) of dione were obtained.
    [248] Example 3
    [249] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] benzamide
    [250] (a) N- (3-bromobenzyl) benzamide
    [251] In a similar manner as in Example 1 (d), 7 g (32 mmol) of 3-bromobenzylamine was reacted with 4 mL (35 mmol) of benzoyl chloride to give 9.1 g (100%) of the expected product. .
    [252] (b) N- (4'-formylbiphenyl-3-ylmethyl) benzamide
    [253] In a similar manner as in Example 1 (e), by reacting 2 g (6.9 mmol) of N- (3-bromobenzyl) benzamide with 1.6 g (10.3 mmol) of 4-formylbenzeneboronic acid, the expected product 1.4 g (65%) was obtained.
    [254] (c) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] benzamide
    [255] In a similar manner as in Example 1 (f), 1 g (3.2 mmol) of N- (4'-formylbiphenyl-3-ylmethyl) benzamide was added 370 mg (3.2 mmol) of 2,4-thiazoli By reacting with dindione, 1.2 g (93%) of the expected product were obtained.
    [256] (d) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] benzamide
    [257] In a similar manner as in Example 1 (g), 600 g (1.45 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] 200 mg (33%) of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] benzamide starting at benzamide and having a melting point of 225-226 ° C. ) Was obtained.
    [258] Example 4
    [259] Ethyl 3- {3 '-[(benzoylmethylamino) methyl] biphenyl-4-yl} -2-methylpropionate
    [260] (a) ethyl (E) -2-methyl-3- (3 '-{[(1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) acrylate
    [261] 440 mg (11 mmol) of sodium hydride (80% in oil) and 10 ml of THF were introduced into a three neck flask under a stream of nitrogen. A solution of 2.2 ml of triethyl 2-phosphonopropionate in 10 ml THF was added dropwise followed by 3 g (9.1 mmol) of N- (4'-formylbiphenyl-3-ylmethyl) -N-methylbenz A solution of amide (prepared in Example 1 (e)) was added dropwise and the mixture was stirred for 3 hours at room temperature. The reaction medium is poured into water, extracted with dichloromethane, the organic phase is separated off after phase settling has occurred, dried over magnesium sulphate and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvent, 3 g (80%) of ethyl (E) -2-methyl-3- (3 '-{[(1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) acrylate Collected in form.
    [262] (b) ethyl 3- {3 '-[(benzoylmethylamino) methyl] biphenyl-4-yl} -2-methylpropionate
    [263] 2.2 g (5.3 mmol) of ethyl (E) -2-methyl-3- (3 '-{[(1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) acrylate and 100 ml of ethyl acetate Was introduced into a three neck flask. The reaction medium was degassed, 450 mg of charcoal palladium (10%) were added and the mixture was hydrogenated at atmospheric pressure for 2 hours. The reaction medium was filtered and evaporated and the residue obtained was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvent, 1.45 g (64%) of ethyl 3- {3 '-[(benzoylmethylamino) methyl] biphenyl-4-yl} -2-methylpropionate was collected in oil form.
    [264] Example 5
    [265] 2-Methyl-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [266] 1.25 g (3 mmol) ethyl 3- {3 '-[(benzoylmethylamino) methyl] biphenyl-4-yl} -2-methylpropionate, 3 ml sodium hydride (10 N), 32 ml THF and 2 ml of methanol were introduced into a round bottom flask. The reaction medium was refluxed for 8 hours, poured into water, acidified to pH 4 with 1N hydrochloric acid, extracted with dichloromethane, the organic phase was separated off after phase precipitation had occurred, dried over magnesium sulfate and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (60/40). 900 mg (90%) of 2-methyl-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid having a melting point of 60 to 61 ° C was obtained.
    [267] Example 6
    [268] N- [4 '-(2-carbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [269] (a) 3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionyl chloride
    [270] 1.6 g (4.1 mmol) of 2-methyl-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid was added to 390 μl (4.5 μl of oxalyl chloride in dichloromethane. mmol), and 1.7 g (100%) of 3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionyl chloride was obtained after evaporation.
    [271] (b) N- [4 '-(2-carbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [272] A solution of 1.7 g (4.1 mmol) of 3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionyl chloride in 5 mL of THF was reacted with 10 mL of aqueous ammonia. After purification by chromatography on a silica column, 200 mg of N- [4 '-(2-carbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide having a melting point of 47-48 ° C. 32%) was obtained.
    [273] Example 7
    [274] N-methyl-N- [4 '-(2-phenylcarbamoylpropyl) biphenyl-3-ylmethyl] benzamide
    [275] A solution of 637 mg (1.6 mmol) of 3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionyl chloride in 5 ml of THF was diluted with 250 μl of triethylamine ( Purification by chromatography on a silica column by reaction with 146 μl (1.6 mmol) of benzylamine in the presence of 1.8 mmol), followed by N-methyl-N- [4 ′-(2-phenylcarba) having a melting point of 68-69 ° C. 370 mg (50%) of barmoylpropyl) biphenyl-3-ylmethyl] benzamide were obtained.
    [276] Example 8
    [277] N- [4 '-(2-hydroxycarbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [278] A solution of 669 mg (1.65 mmol) of 3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionyl chloride in 6 mL of THF was diluted with 250 μl of triethylamine ( On the silica column by reacting with 243 mg (1.65 mmol) O- (tert-butyldimethylsilyl) hydroxylamine in the presence of 1.8 mmol) and then deprotecting with 530 μl of tetrabutylammonium fluoride solution (1N in THF). After purification by chromatography, 350 mg (42%) of N- [4 '-(2-hydroxycarbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide having a melting point of 65-66 ° C. Was obtained.
    [279] Example 9
    [280] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-phenylurea
    [281] (a) 1- (4'-bromobiphenyl-3-ylmethyl) -3-phenylurea
    [282] 2.9 g (14.5 mmol) of 3-bromobenzylamine and 90 mL of dichloromethane were introduced into a round bottom flask and 1.73 mL (16 mmol) of phenyl isocyanate was added dropwise. The reaction medium was stirred for 8 hours at room temperature, poured into water, extracted with dichloromethane and the organic phase separated off after phase settling occurred, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (70/30). 3.7 g (80%) of the expected product were obtained.
    [283] (b) 1- (4'-formylbiphenyl-3-ylmethyl) -3-phenylurea
    [284] In a similar manner as in Example 1 (e), 2.5 g (8.2 mmol) of 1- (4'-bromobiphenyl-3-ylmethyl) -3-phenylurea was added 1.8 g (12.3 mmol) of 4-form Reaction with millbenzeneboronic acid gave 2.1 g (77%) of the expected product.
    [285] (c) 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -3-phenylurea
    [286] In a similar manner as in Example 1 (f), 2.1 g (6.4 mmol) of 1- (4'-formylbiphenyl-3-ylmethyl) -3-phenylurea was added 750 mg (6.4 mmol) of 2,4 By reaction with -thiazolidinedione, 1.4 g (53%) of the expected product were obtained.
    [287] (d) 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-phenylurea
    [288] 1.4 g (3.3 mmol) of 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] in a similar manner as in Example 1 (g) 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-phenyl having a melting point of 70 to 71 ° C starting with -3-phenylurea 300 mg (21%) of urea were obtained.
    [289] Example 10
    [290] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -1-methyl-3-phenylurea
    [291] (a) tert-butyl (4'-formylbiphenyl-3-ylmethyl) methylcarbamate
    [292] In a similar manner as in Example 1 (e), 10 g (13.7 g (45 mmol) of tert-butyl (3-bromobenzyl) -N-methylcarbamate (prepared in Example 1 (b)) 67 mmol) of 4-formylbenzeneboronic acid gave 11 g (76%) of the expected product.
    [293] (b) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] methylcarbamate
    [294] In a similar manner as in Example 1 (f), 8 g (25 mmol) of tert-butyl (4'-formylbiphenyl-3-ylmethyl) methylcarbamate was added 2.9 g (25 mmol) of 2,4 By reaction with -thiazolidinedione, 8.6 g (81%) of the expected product were obtained.
    [295] (c) 5- (3'-methylaminomethylbiphenyl-4-ylidenemethyl) thiazolidine-2,4-dione
    [296] 2 g (4.7 mmol) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] methylcarbamate and 20 ml of dichloromethane It was introduced into a round bottom flask. 2.2 mL (28.2 mmol) trifluoroacetic acid was added and the mixture was stirred at rt for 4 h. The reaction medium was poured into aqueous bicarbonate solution, extracted with dichloromethane, the organic phase was separated off after the phase settling occurred, dried over magnesium sulfate and evaporated. 1.3 g (85%) of the expected product were obtained.
    [297] (d) 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -1-methyl-3-phenylurea
    [298] In a similar manner as in Example 9 (a), 190 μl (1.8) of 300 mg (0.9 mmol) of 5- (3′-methylaminomethylbiphenyl-4-ylmethylene) thiazolidine-2,4-dione Reaction with mmol) of phenyl isocyanate gave 450 mg (98%) of the expected product.
    [299] (e) 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -1-methyl-3-phenylurea
    [300] In a similar manner as in Example 1 (g), 450 mg (0.8 mmol) of 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] having a melting point of 70 to 71 ° C. starting with -1-methyl-3-phenylurea 100 mg (28%) of -1-methyl-3-phenylurea were obtained.
    [301] Example 11
    [302] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamate
    [303] In a similar manner as in Example 1 (g), 500 mg (1.2 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl ] Tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) ratio having a melting point of 45-46 ° C. starting with] methylcarbamate (prepared in Example 10 (b)) 250 mg (49%) of phenyl-3-ylmethyl] methylcarbamate were obtained.
    [304] Example 12
    [305] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylnonanamide
    [306] (a) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methylnonanamide
    [307] In a similar manner as in Example 1 (d), 330 μl (1.8 μl of 500 mg (0.9 mmol) of 5- (3′-methylaminomethylbiphenyl-4-ylmethylene) thiazolidine-2,4-dione Reaction with mmol) nonanoyl chloride yielded 350 mg (66%) of the expected product.
    [308] (b) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylnonanamide
    [309] In a similar manner as in Example 1 (g), 330 mg (0.7 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] Starting with -N-methylnonanamide, 70 mg (21) of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylnonanamide %) Was obtained.
    [310] Example 13
    [311] (S) -2-ethoxy-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [312] (a) N- {4 '-[(1R, 2S) -3-((S) -4-benzyl-2-oxooxazolidin-3-yl) -2-ethoxy-1-hydroxy-3 -Oxopropyl] biphenyl-3-ylmethyl} -N-methylbenzamide
    [313] 1.8 g (6.7 mmol) of (S) -4-benzyl-3- (2-ethoxyethanoyl) oxazolidin-2-one and 15 mL of dichloromethane were introduced into a three neck flask under argon. 7.3 mL (8 mmol) dibutylborane trifluoromethane sulfonate and 1.3 mL (8 mmol) diisopropylethylamine were added dropwise successively at 0 ° C. and the mixture was stirred for 1 h. At -78 ° C, a solution of 2 g (6 mmol) of N- (4'-formylbiphenyl-3-ylmethyl) -N-methylbenzamide (prepared in Example 1 (e)) in 25 ml of dichloromethane Was added and the mixture was stirred for 1 h. The mixture was allowed to warm to 0 ° C. and treated with pH 7 buffer solution (16 mL) in 45 mL methanol and then with aqueous hydrogen peroxide solution (16 mL) in 45 mL methanol and stirred at 0 ° C. for 1 h. The reaction medium is poured into water, extracted with dichloromethane, the organic phase is separated off after phase settling has occurred, dried over magnesium sulphate and evaporated. The residue obtained was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (60/40). N- {4 '-[(1R, 2S) -3-((S) -4-benzyl-2-oxooxazolidin-3-yl) -2-ethoxy-1-hydroxy-3-oxopropyl ] 1.7 g (48%) of biphenyl-3-ylmethyl} -N-methylbenzamide were obtained.
    [314] (b) N- {4 '-[(S) -3-((S) -4-benzyl-2-oxooxazolidin-3-yl) -2-ethoxy-3-oxopropyl] biphenyl- 3-ylmethyl} -N-methylbenzamide
    [315] 320 μl (2.6 mmol) of boron trifluoride etherate and 5 mL of dichloromethane were introduced into a three neck flask under a stream of nitrogen. At 0 ° C., 800 μl (5 mmol) trimethylsilyl hydride is added dropwise followed by 380 mg (0.64 mmol) of N- {4 ′-[(1R, 2S) -3-((S) -4-benzyl -2-oxooxazolidin-3-yl) -2-ethoxy-1-hydroxy-3-oxopropyl] biphenyl-3-ylmethyl} -N-methylbenzamide was added in portions. After 1 hour at room temperature, the mixture was heated at 50 ° C. for 20 hours. The reaction medium was poured into water, extracted with ethyl acetate, and the organic phase was separated off after phase settling occurred, dried over magnesium sulfate and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (70/30). 280 mg (76%) of the expected product were obtained.
    [316] (c) (S) -2-ethoxy-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    [317] 600 mg (1 mmol) N- {4 '-[(S) -3-((S) -4-benzyl-2-oxooxazolidin-3-yl) -2-ethoxy-3-oxopropyl ] Biphenyl-3-ylmethyl} -N-methylbenzamide and 10 mL of THF were introduced into a round bottom flask. At 0 ° C., 4.2 mL (2 mmol) of aqueous lithium hydroxide solution (0.5 M) was added and the mixture was stirred for 1 hour. The reaction medium was poured into water, acidified to pH 1, extracted with ethyl acetate, and the organic phase separated off after sedimentation of the phase occurred, dried over magnesium sulfate and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (50/50). 200 mg (47%) of (S) -2-ethoxy-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid with a melting point of 53-54 ° C ) Was obtained.
    [318] Example 14
    [319] Monomethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [320] (a) diethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethylene) malonate
    [321] 600 mg (1.8 mmol) N- (4'-formylbiphenyl-3-ylmethyl) -N-methylbenzamide (prepared in Example 1 (e)), 10 ml toluene, 300 μl (1.8 mmol) Diethyl malonate and 50 mg (0.35 mmol) of piperidine acetate were introduced into a three neck flask under a stream of nitrogen. The mixture was refluxed for 6 hours while separating off the water formed using the Deanstock apparatus. The reaction medium was cooled down, extracted with ethyl acetate and washed with water. The organic phase was separated after sedimentation occurred, dried over magnesium sulfate and evaporated. The crude product was purified by chromatography on a silica column eluting with a mixture of heptane and ethyl acetate (75/25). After evaporation of the solvent 700 mg (84%) of the expected product was collected.
    [322] (b) diethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [323] 700 mg (1.5 mmol) diethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethylene) malonate, 7 ml of THF and 1 ml of methanol Was introduced into a three neck flask under a stream of nitrogen. The reaction medium was degassed and 80 mg of palladium on charcoal (5%) were introduced and the mixture was hydrogenated at atmospheric temperature for 20 hours at room temperature. The reaction medium was filtered through celite and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvent 450 mg (63%) of the desired product were collected.
    [324] (c) monomethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [325] 400 mg (0.85 mmol) of diethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethylene) malonate, 5 ml of methanol and 100 mg of carbonic acid Potassium was placed in a round bottom flask. The mixture was stirred for 18 h at room temperature, acidified with sulfuric acid to pH 3 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvent, 160 mg (44%) of the desired product with a melting point of 67 ° C. were collected.
    [326] Example 15
    [327] Dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [328] (a) Dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethylene) malonate
    [329] 1.4 g (4.25 mmol) N- (4'-formylbiphenyl-3-ylmethyl) -N-methylbenzamide (prepared in Example 1 (e)), 20 ml toluene, 560 mg (4.25 mmol) Dimethyl malonate and 125 mg (0.85 mmol) of piperidine acetate were introduced into a three neck flask under a stream of nitrogen. The mixture was refluxed for 6 hours while separating off the water formed using the Deanstock apparatus. The reaction medium was cooled down, extracted with ethyl acetate and washed with water. The organic phase was separated after the phase settling occurred, dried over magnesium sulfate and evaporated. The crude product was purified by chromatography on a silica column eluting with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvent 1.4 g (75%) of the expected product was collected.
    [330] (b) dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [331] 1.3 g (2.9 mmol) of dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethylene) malonate, 10 ml dioxane and 2 ml methanol Was introduced into a three neck flask under a stream of nitrogen. The reaction medium was degassed and 80 mg of palladium on charcoal (5%) were introduced and the mixture was hydrogenated at atmospheric temperature for 8 hours at atmospheric pressure. The reaction medium was filtered through celite and evaporated. The residue obtained was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (60/40). After evaporation of the solvent, 1 g (78%) of the desired product was collected in oil form.
    [332] Example 16
    [333] Methyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamate
    [334] (a) Dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethylene) malonate
    [335] 1.54 g (4.25 mmol) N- (4'-formylbiphenyl-3-ylmethyl) -N-methylbenzamide (prepared as in Example 1 (e)), 20 mL of toluene, 0.56 g (4.25 mmol) dimethyl malonate and 123 mg (0.85 mmol) piperidine acetate were introduced into a three neck flask under a stream of nitrogen. The mixture was refluxed for 5 hours while separating off the water formed using the Deanstock apparatus. The reaction medium was cooled down, extracted with ethyl acetate and washed with water. The organic phase was separated after the phase settling occurred, dried over magnesium sulfate and evaporated. The crude product was purified by chromatography on a silica column eluting with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvent 1.4 g (75%) of the expected product was collected.
    [336] (b) dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [337] 1.3 g (2.9 mmol) of dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethylene) malonate, 10 ml dioxane and 2 ml methanol Was introduced into a three neck flask under a stream of nitrogen. 76 mg of palladium on charcoal (5%) was added and the mixture was hydrogenated at atmospheric pressure for 8 hours. The reaction medium was filtered through celite and evaporated. The residue obtained was purified by chromatography on a silica column eluting with a mixture of heptane and ethyl acetate (60/40). 1 g (78%) of the desired product was obtained.
    [338] (c) monomethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    [339] 920 mg (2 mmol) dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate (prepared in Example 15 (b)), 4 ml of tetrahydrofuran and 8 ml of methanol were introduced into a round bottom flask. At 0 ° C., 0.24 mL (2.1 mmol) of 35% aqueous sodium hydroxide solution was added dropwise. The reaction medium was stirred for 18 hours, poured into water, acidified to pH 4-5 with 1N hydrochloric acid solution and extracted with ethyl acetate. Once settling occurred, the phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated. 820 mg (92%) of the desired product were obtained.
    [340] (d) methyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethylmalonamate
    [341] 780 mg (1.8 mmol) of monomethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate and 8 ml of dichloromethane under nitrogen stream Introduced to a three neck flask. At 0 ° C., 180 μl (2 mmol) of oxalyl chloride was added dropwise and then stirred for 4 hours. The reaction medium was evaporated to dryness and the residue was taken up in 2 ml of acetone and 1 ml of 32% aqueous ammonia solution. The reaction medium was stirred for 2 hours at room temperature, immersed in water, acidified to pH 5 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. The obtained residue was washed with a mixture of heptane and ether (50/50). 400 mg (52%) of the desired product were obtained having a melting point of 62 ° C.
    [342] Example 17
    [343] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-ethylbenzamide
    [344] (a) N- (3-bromobenzyl) benzamide
    [345] 7 g (31.6 mmol) of 3-bromobenzylamine, 100 mL of THF and 9.6 mL (69.2 mmol) of triethylamine were placed in a three neck flask under a stream of nitrogen. 4 mL (34.6 mmol) benzoyl chloride was added dropwise and the mixture was stirred at rt for 1 h. The reaction medium was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. 9.2 g (100%) of the desired product were obtained.
    [346] (b) N- (4'-formylbiphenyl-3-ylmethyl) benzamide
    [347] In a manner similar to that in Example 1 (e), by reacting 7.4 g (25.4 mmol) of N- (3-bromobenzyl) benzamide with 5.7 g (38.2 mmol) of 4-formylbenzeneboronic acid, the expected product 4 g (50%) were obtained.
    [348] (c) N- (4 '-[1,3] dioxolan-2-ylbiphenyl-3-ylmethyl) benzamide
    [349] 3.2 g (10 mmol) of N- (4-formylbiphenyl-3-ylmethyl) benzamide, 50 ml of toluene, 2.8 ml (50 mmol) ethylene glycol and 38 mg (0.2 mmol) para-toluenesulfonic acid Was placed in a three neck flask under a stream of nitrogen. The reaction medium was refluxed for 3 hours and the water formed was separated off using a Deanstock apparatus. The reaction medium was extracted with dichloromethane, washed with water and the organic phase was separated off after the phase settling occurred. The organic phase was dried over magnesium sulfate and filtered. 3.7 g (100%) of the desired product were obtained.
    [350] (d) N- (4 '-[1,3] dioxolan-2-ylbiphenyl-3-ylmethyl) -N-ethylbenzamide
    [351] 600 mg (1.7 mmol) N- (4 '-[1,3] dioxolan-2-ylbiphenyl-3-ylmethyl) benzamide, 5 ml THF and 206 mg (1.85 mmol) potassium tert-butoxide Seeds were introduced into a three neck flask under nitrogen. 300 μl (3.7 mmol) of iodoethane was added dropwise. The reaction mixture was stirred for 3 hours at room temperature, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (70/30). 400 mg (64%) of the desired product were obtained.
    [352] (e) N-ethyl-N- (4'-formylbiphenyl-3-ylmethyl) benzamide
    [353] 400 mg (1 mmol) N- (4 '-[1,3] dioxolan-2-ylbiphenyl-3-ylmethyl) -N-ethylbenzamide, 5 ml of methanol, 2 g of silica and water drops Sulfuric acid was introduced into a round bottom flask. The mixture was stirred at rt for 24 h. The reaction medium is poured into water, extracted with dichloromethane, the organic phase is separated off after phase settling has occurred, dried over magnesium sulphate and evaporated. 320 mg (91%) of the desired product were obtained.
    [354] (f) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-ethylbenzamide
    [355] In a similar manner as in Example 1 (f), 300 mg (0.9 mmol) of N-ethyl-N- (4'-formylbiphenyl-3-ylmethyl) benzamide was added to 100 mg (0.9 mmol) of 2, By reacting with 4-thiazolidinedione, 340 mg (88%) of the expected product were obtained.
    [356] (g) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl-N-ethylbenzamide
    [357] In a similar manner as in Example 1 (g), 300 mg (0.7 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3 in 10 ml THF N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl-N having a melting point of 157 ° C. starting with -ylmethyl] -N-ethylbenzamide 150 mg (50%) of ethylbenzamide was obtained.
    [358] Example 18
    [359] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-pentylbenzamide
    [360] (a) N- (4 '-[1,3] dioxolan-2-ylbiphenyl-3-ylmethyl) -N-pentylbenzamide
    [361] In a similar manner as in Example 17 (d), 1 g (2.8 mmol) of N- (4 '-[1,3] dioxolan-2-ylbiphenyl-3-ylmethyl) benzamide (Example 17 ( 600 mg (50%) of N- (4 '-[1,3] dioxolan-2-ylbiphenyl-3-ylmethyl starting from c)) and starting with 2.4 ml (18.3 mmol) iodopentane ) -N-pentylbenzamide was obtained.
    [362] (b) N- (4'-formylbiphenyl-3-ylmethyl) -N-pentylbenzamide
    [363] In a similar manner as in Example 17 (e), with 550 mg (1.2 mmol) of N- (4 '-[1,3] dioxolan-2-ylbiphenyl-3-ylmethyl) -N-pentylbenzamide Starting, 400 mg (82%) of N- (4'-formylbiphenyl-3-ylmethyl) -N-pentylbenzamide was obtained.
    [364] (c) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl) -N-pentylbenzamide
    [365] In a similar manner as in Example 1 (f), 320 mg (0.8 mmol) of N- (4'-formylbiphenyl-3-ylmethyl) benzamide was added to 100 mg (0.8 mmol) of 2,4-thiazoli By reacting with dindione, 350 mg (87%) of the expected product were obtained.
    [366] (d) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-pentylbenzamide
    [367] In a similar manner as in Example 1 (g), 330 mg (0.7 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-) in 10 ml of ethyl acetate and 10 ml of ethanol N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) ratio starting at iridenmethyl) biphenyl-3-ylmethyl) -N-pentylbenzamide and having a melting point of 57 ° C. 220 mg (65%) of phenyl-3-ylmethyl] -N-pentylbenzamide were obtained.
    [368] Example 19
    [369] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] ethylcarbamate
    [370] (a) tert-butyl (3-bromobenzyl) ethylcarbamate
    [371] In a similar manner as in Example 17 (d), 3 g (10.5 mol) of tert-butyl (3-bromobenzyl) carbamate (prepared as in Example 1 (a)) and 4.2 ml (52.5 mmol) Starting with iodoethane, 3.2 g (97%) of the desired product were obtained.
    [372] (b) tert-butyl ethyl- (4'-formylbiphenyl-3-ylmethyl) carbamate
    [373] In a manner similar to that of Example 1 (e), by reacting 3.2 g (10 mmol) of tert-butyl (3-bromobenzyl) ethylcarbamate with 2.3 g (15 mmol) of 4-formylbenzeneboronic acid , 1.4 g (41%) of the expected product were obtained.
    [374] (c) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] ethylcarbamate
    [375] In a similar manner as in Example 1 (f), 1.470 g (4 mmol) of tert-butyl ethyl (4'-formylbiphenyl-3-ylmethyl) carbamate was added to 470 mg (4 mmol) of 2,4. By reaction with -thiazolidinedione, 1.6 g (92%) of the expected product were obtained.
    [376] (d) tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] ethylcarbamate
    [377] In a similar manner as in Example 1 (g), 500 mg (1.15 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) ratio in 5 ml of ethyl acetate Starting with phenyl-3-ylmethyl] ethylcarbamate, 100 mg (20%) of the desired product with a melting point of 103 ° C. were obtained.
    [378] Example 20
    [379] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] propylcarbamate
    [380] (a) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] carbamate
    [381] In a manner similar to that of Example 1 (f), 7.4 g (24 mmol) tert-butyl (4'-formylbiphenyl-3-ylmethyl) carbamate (tert-butyl (3-bromobenzyl) carbamide 9 g (95%) of the expected product was obtained by reacting from Bamate as prepared in Example 1 (e) with 2.8 g (24 mmol) of 2,4-thiazolidinedione.
    [382] (b) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] propylcarbamate
    [383] In a similar manner as in Example 17 (d), 700 mg (1.7 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl ] Starting with carbamate and 350 μl (3.8 mmol) of 1-bromopropane, 600 mg (78%) of the desired product were obtained.
    [384] (c) tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] propylcarbamate
    [385] In a similar manner as in Example 1 (g), 600 mg (1.3 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-) in 7 ml of ethyl acetate and 7 ml of dimethylformamide Starting with 5-ylidenemethyl) biphenyl-3-ylmethyl] propylcarbamate, 50 mg (10%) of the desired product were obtained.
    [386] Example 21
    [387] 9H-fluorene-9-ylmethyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamate
    [388] (a) 9H-fluorene-9-ylmethyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] methylcarbamate
    [389] 500 mg (0.9 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethylene) thiazolidine-2,4-dione in 12 mL of 10% aqueous sodium carbonate solution (prepared in Example 12 (c)) ) Was introduced into a round bottom flask. At 0 ° C., 240 mg of 9H-fluorene-9-ylmethyl chloride in 5 ml dioxane was added dropwise. The mixture was stirred for 4 h from 0 ° C to room temperature. The reaction medium was immersed in water, acidified to pH 4 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. 490 mg (100%) of the expected product were obtained.
    [390] (b) 9H-fluorene-9-ylmethyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamate
    [391] In a similar manner as in Example 1 (g), 500 mg (0.9 mmol) of 9H-fluorene-9-ylmethyl [4 '-(2,4-dioxothiazolidine-5-] in 10 ml dioxane Starting with iridenmethyl) biphenyl-3-ylmethyl] methylcarbamate, 200 mg (40%) of the desired product with a melting point of 94 ° C. were obtained.
    [392] Example 22
    [393] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2,2, N-trimethylpropionamide
    [394] (a) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -2,2, N-trimethylpropionamide
    [395] In a similar manner as in Example 1 (d), 500 mg (0.9 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethylene) thiazolidine-2,4-dione (Example 12 ( 240) (65%) of the expected product were obtained by reacting 0.3 mL (2.3 mmol) with 2,2-dimethylpropionyl chloride.
    [396] (b) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2,2, N-trimethylpropionamide
    [397] In a similar manner as in Example 1 (g), 240 mg (0.6 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl in 20 ml of tetrahydrofuran Starting with -3-ylmethyl] -2,2, N-trimethylpropionamide, 100 mg (40%) of the desired product with a melting point of 78 ° C. were obtained.
    [398] Example 23
    [399] N-octyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [400] (a) ethyl 4'-formylbiphenyl-3-carboxylate
    [401] In a similar manner as in Example 1 (e), 12 g (60 mmol) of the expected product was reacted by reacting 12.6 mL (79 mmol) of ethyl 3-bromobenzoate with 15 g (100 mmol) of 4-formylbenzeneboronic acid. %) Was obtained.
    [402] (b) ethyl 4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxylate
    [403] In a manner similar to that of Example 1 (f), 11.7 g (46 mmol) of ethyl 4'-formylbiphenyl-3-carboxylate is reacted with 5.4 g (46 mmol) of 2,4-thiazolidinedione This gave 13 g (83%) of the expected product.
    [404] (c) 4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxylic acid
    [405] 12.6 g (37 mmol) ethyl 4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxylate, 150 ml tetrahydrofuran, 15 ml methanol, water Drops of water and 7.4 g (186 mmol) of sodium hydroxide pellets were introduced into a round bottom flask. The mixture was refluxed for 18 hours. The reaction medium was poured into water, acidified to pH 2 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. 11.4 g (94%) of the desired product were obtained.
    [406] (d) N-octyl-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxamide
    [407] 1 g (3.1 mmol) of 4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxylic acid, 15 mL of dimethylformamide, 460 mg (3.4 mmol) 1-hydroxybenzotriazole and 500 μl (3.1 mmol) of n-octylamine were introduced into a three neck flask under a stream of nitrogen. At 0 ° C., 0.59 g (3.4 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added in portions. The mixture was stirred for 3 days while allowing the temperature to rise. The reaction medium was poured into water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. 450 mg (33%) of the desired product were obtained.
    [408] (e) N-octyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [409] 150 mg (0.35 mmol) of N-octyl-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxamide, 20 ml of dimethylformamide and 150 mg of Palladium on charcoal (10%) was introduced into the reactor under a stream of nitrogen. The medium was heated to 80 ° C. and hydrogenated at 3 atm atmosphere for 5 hours. The reaction medium was filtered through celite. The filtrate was poured into water, extracted with ethyl acetate and washed thoroughly with water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on a silica column eluting with a mixture of heptane and ethyl acetate (30/70). 100 mg (65%) of the expected product with a melting point of 137-138 ° C. were obtained.
    [410] Example 24
    [411] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-3-phenylpropionamide
    [412] (a) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyl-3-phenylpropionamide
    [413] In a similar manner as in Example 1 (d), 500 mg (0.9 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethylene) thiazolidine-2,4-dione (Example 10 ( 220 mg (54%) of the expected product was obtained by reacting (prepared in c)) with 0.35 mL (2.3 mmol) of 3-phenylpropionyl chloride.
    [414] (b) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-3-phenylpropionamide
    [415] In a similar manner as in Example 1 (g), 210 mg (0.45 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl in 15 ml of tetrahydrofuran Starting with 3-ylmethyl] -N-methyl-3-phenylpropionamide, 95 mg (45%) of the desired product with a melting point of 325 ° C. were obtained.
    [416] Example 25
    [417] 2- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-3-phenylacetamide
    [418] (a) 2- (3-bromophenyl) -N-methyl-N-phenylacetamide
    [419] 6 g (28 mmol) of (3-bromophenyl) acetic acid in 50 ml of dichloromethane were introduced into a three neck flask under a stream of nitrogen. At 0 ° C., 2.7 mL (28 mmol) of oxalyl chloride was added dropwise and then the mixture was stirred at rt for 18 h. The reaction medium is evaporated to dryness and the residue is taken up in 10 ml of tetrahydrofuran and 3.2 g (28 mmol) of N-methylaniline, 50 ml of tetrahydrofuran and 4.6 ml (33 mmol) of triethylamine Dropwise to the mixture. The reaction medium was stirred overnight at room temperature, immersed in water and extracted with ethyl acetate. Once settling occurred and the phases separated, the organic phase was dried over magnesium sulfate, filtered and evaporated. 5.7 g (67%) of the desired product were obtained having a melting point of 60 ° C.
    [420] (b) 2- (4'-acetylbiphenyl-3-yl) -N-methyl-N-phenylacetamide
    [421] In a similar manner as in Example 1 (e), 2.2 g (14.2 mmol) of 4-formyl was added to 2.9 g (9.5 mmol) of 2- (3-bromophenyl) -N-methyl-N-phenylacetamide. By reaction with benzeneboronic acid, 2.25 g (95%) of the expected product were obtained.
    [422] (c) 2- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -N-methyl-N-phenylacetamide
    [423] In a similar manner as in Example 1 (f), 460 mg (4 mmol) of 1 g (4 mmol) of 2- (4'-acetylbiphenyl-3-yl) -N-methyl-N-phenylacetamide Reaction with 2,4-thiazolidinedione gave 1.2 g (71%) of the expected product.
    [424] (d) 2- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl) -N-methyl-N-phenylacetamide
    [425] In a similar manner as in Example 1 (g), 1.1 g (2.6 mmol) of 2- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl- in 20 ml of ethyl acetate Starting with 3-yl] -N-methyl-N-phenylacetamide, 660 mg (60%) of the desired product with a melting point of 158 ° C. were obtained.
    [426] Example 26
    [427] N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-propylbenzamide
    [428] (a) tert-butyl (3-bromobenzyl) propylcarbamate
    [429] In a similar manner as in Example 17 (d), starting with 3 g (10.5 mmol) of tert-butyl (3-bromobenzyl) carbamate and 1.15 mL (11.5 mmol) of iodopropane, the desired product was 3.35 g (97%) was obtained.
    [430] (b) (3-bromobenzyl) propylamine
    [431] In a similar manner as in Example 10 (c), starting with 2 g (6 mmol) of tert-butyl (3-bromobenzyl) propylcarbamate, 1.3 g (92%) of the desired product were obtained.
    [432] (c) N- (3-bromobenzyl) -N-propylbenzamide
    [433] In a manner similar to that in Example 1 (d), by reacting 1.3 g (5.6 mmol) of (3-bromobenzyl) propylamine with 700 μl (6.2 mmol) of benzoyl chloride, 1.4 g (74%) of the expected product Was obtained.
    [434] (d) N- (4'-formylbiphenyl-3-ylmethyl) -N-propylbenzamide
    [435] In a similar manner as in Example 1 (e), 1.4 g (4.2 mmol) of N- (3-bromobenzyl) -N-propylbenzamide was reacted with 940 mg (6.2 mmol) of 4-formylbenzeneboronic acid This gave 780 mg (53%) of the expected product.
    [436] (e) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-propylbenzamide
    [437] In a similar manner as in Example 1 (f), 580 mg (1.6 mmol) of N- (4'-formylbiphenyl-3-ylmethyl) -N-propylbenzamide was added to 190 mg (1.6 mmol) of 2, Reaction with 4-thiazolidinedione gave 530 mg (72%) of the expected product having a melting point of 250-251 ° C.
    [438] Example 27
    [439] tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] carbamate
    [440] (a) tert-butyl (3-bromophenyl) carbamate
    [441] 19 ml of 3-bromoaniline in 300 ml of tetrahydrofuran was introduced into a three neck flask under a stream of nitrogen. 8.4 g (209 mmol) of sodium hydride (60% in oil) were added portionwise and the mixture was stirred until gas evolution ceased. Then 38 g (174.5 mmol) of di-tert-butyl dicarbonate were added dropwise. The mixture was refluxed for 36 hours. The reaction medium was immersed in water and extracted with ethyl acetate. Once settling occurred and the phases separated, the organic phase was dried over magnesium sulfate, filtered and evaporated. 43 g (92%) of the desired product were obtained.
    [442] (b) tert-butyl (4'-formylbiphenyl-3-yl) carbamate
    [443] In a manner similar to that of Example 1 (e), by reacting 19.3 g (71 mmol) of tert-butyl (3-bromophenyl) carbamate with 16 g (107 mmol) of 4-formylbenzeneboronic acid, 21 g (63%) of the expected product were obtained.
    [444] (c) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] carbamate
    [445] In a similar manner as in Example 1 (f), 9.5 g (32 mmol) of tert-butyl (4'-formylbiphenyl-3-yl) carbamate was added to 3.8 g (32 mmol) of 2,4-thia By reacting with zolidinedione, 12.7 g (91%) of the expected product were obtained.
    [446] (d) tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] carbamate
    [447] In a similar manner as in Example 1 (g), 700 mg (1.8 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) ratio in 10 ml of dioxane Starting with phenyl-3-yl] carbamate, 700 mg (60%) of the desired product with a melting point of 158 ° C. were obtained.
    [448] Example 28
    [449] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3,4-diethoxy-N-methylbenzamide
    [450] (a) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -3,4-diethoxy-N-methylbenzamide
    [451] In a similar manner as in Example 1 (d), 500 mg (0.9 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethylene) thiazolidine-2,4-dione (Example 10 ( c) was reacted with 520 mg (2.3 mmol) of 3,4-diethoxybenzoyl chloride to give 370 mg (80%) of the expected product.
    [452] (b) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3,4-diethoxy-N-methylbenzamide
    [453] In a similar manner as in Example 1 (g), 360 mg (0.7 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl- in 15 mL of methanol Starting with 3-ylmethyl] -3,4-diethoxy-N-methylbenzamide, 150 mg (40%) of the desired product with a melting point of 66 ° C were obtained.
    [454] Example 29
    [455] 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamic acid
    [456] 180 mg (0.4 mmol) of methyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamate in 2 mL methanol (Example 16 prepared in d)), 2 ml of tetrahydrofuran, and 250 µl (0.5 mmol) of 2N aqueous sodium hydroxide solution were introduced. The reaction medium was stirred for 36 h at room temperature, acidified to pH 3 with hydrochloric acid solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. 80 mg (46%) of the desired product were obtained having a melting point of 117 ° C.
    [457] Example 30
    [458] N-benzyl-N-methyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [459] (a) N-benzyl-N-methyl-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxamide
    [460] 500 mg (1.54 mmol) of 4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxylic acid (prepared in Example 23 (c)), 5 ml of dimethyl Formamide, 230 mg (1.7 mmol) of 1-hydroxybenzotriazole and 200 μl (1.5 mmol) of benzylmethylamine were introduced into a three neck flask under a stream of nitrogen. At 0 ° C., 350 mg (1.7 mmol) of dicyclohexylcarbodiimide were added in portions. The mixture was stirred for 18 hours while letting the temperature rise. The reaction medium was immersed in water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue obtained was washed with dichloromethane and filtered. 400 mg (61%) of the desired product were obtained.
    [461] (b) N-benzyl-N-methyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [462] In a similar manner as in Example 1 (g), 400 mg (0.9 mmol) of N-benzyl-N-methyl-4 '-(2,4-dioxothiazolidine-5-yly in 5 ml dioxane Starting with denmethyl) biphenyl-3-carboxamide, 170 mg (43%) of the desired product with a melting point of 66 ° C. were obtained.
    [463] Example 31
    [464] N-benzyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [465] (a) N-benzyl-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxamide
    [466] 600 mg (1.84 mmol) of 4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-carboxylic acid (prepared in Example 23 (c)), 5 ml of dimethyl Formamide, 340 mg (2.5 mmol) of 1-hydroxybenzotriazole and 250 μl (2.3 mmol) of benzylamine were introduced into a three neck flask under a stream of nitrogen. At 0 ° C., 480 mg (2.5 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added in portions. The mixture was stirred for 24 hours while allowing the temperature to rise. The reaction medium was immersed in water, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated. The residue obtained was washed with dichloromethane and filtered. 460 mg (60%) of the desired product were obtained.
    [467] (b) N-benzyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    [468] In a similar manner as in Example 1 (g), 430 mg (1 mmol) of N-benzyl-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) in 7 ml of dimethylformamide Starting with biphenyl-3-carboxamide, 100 mg (23%) of the desired product with a melting point of 148 ° C. were obtained.
    [469] Example 32
    [470] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyldecanamide
    [471] (a) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyldecanamide
    [472] In a similar manner as in Example 1 (d), 1 g (1.8 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylidenemethyl) thiazolidine-2,4-dione (Example 10 500 mg (60%) of the expected product were obtained by reacting (produced in (c)) with 410 μl (2 mmol) of decanoyl chloride.
    [473] (b) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyldecanamide
    [474] In a similar manner as in Example 1 (g), 460 mg (1 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl in 8 ml of dioxane Starting with -3-ylmethyl] -N-methyldecanamide, 300 mg (65%) of the desired product were obtained in the form of a film.
    [475] Example 33
    [476] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -2-phenylacetamide
    [477] (a) 5- (3'-aminobiphenyl-4-ylmethylene) thiazolidine-2,4-dione
    [478] In a manner similar to that in Example 10c, 5 g (13 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] carbamate Starting from (prepared in Example 27 (c)), 5.2 g (100%) of the expected product were obtained.
    [479] (b) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -2-phenylacetamide
    [480] In a similar manner as in Example 1 (d), 430 μl (3 mmol) of 1.2 g (2.3 mmol) of 5- (3′-aminobiphenyl-4-ylmethylene) thiazolidine-2,4-dione By reaction with phenylacetyl chloride, 920 mg (97%) of the expected product were obtained.
    [481] (c) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -2-phenylacetamide
    [482] In a similar manner as in Example 1 (g), 580 mg (1.4 mmol) of N- [4 '-(2,4-dioxotia) in 10 ml of dioxane / methanol mixture (50/50) under 3 atm Starting with zolidine-5-ylidenemethyl) biphenyl-3-yl] -2-phenylacetamide, 140 mg (15%) of the desired product with a melting point of 165 ° C were obtained.
    [483] Example 34
    [484] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [485] (a) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [486] In a similar manner as in Example 1 (d), 500 mg (0.9 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylidenemethyl) thiazolidine-2,4-dione (Example 10c ) Was reacted with 170 μl (1 mmol) of octanoyl chloride to give 250 mg (62%) of the expected product.
    [487] (b) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [488] In a similar manner as in Example 1 (g), 220 mg (0.5 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl in 10 ml of dioxane Starting with -3-ylmethyl] -N-methyloctanamide, 120 mg (53%) of the desired product with a melting point of 36 ° C. were obtained.
    [489] Example 35
    [490] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylheptanamide
    [491] (a) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methylheptanamide
    [492] In a similar manner as in Example 1 (d), 1 g (1.8 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylidenemethyl) thiazolidine-2,4-dione (Example 10 reaction (prepared in (c)) with 300 μl (2 mmol) of heptanoyl chloride yielding 450 mg (57%) of the expected product.
    [493] (b) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylheptanamide
    [494] In a similar manner as in Example 1 (g), 360 mg (0.8 mmol) of N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl in 15 ml of dioxane under 3 atm Starting with) biphenyl-3-ylmethyl] -N-methylheptanamide, 230 mg (66%) of the desired product were obtained in the form of a colorless film.
    [495] Example 36
    [496] N-hydroxy-2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamic acid
    [497] 130 mg (0.3 mmol) dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate (prepared in Example 15 (b)), A mixture of 2 mL methanol, 2 mL tetrahydrofuran, 480 mg sodium carbonate (4.5 mmol) and 200 mg (1.5 mmol) hydroxylamine hydrochloride was heated to 60 ° C. for 18 hours. The reaction medium was neutralized with hydrochloric acid solution to pH 6-7 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (75/25). 90 mg (72%) of the desired product with a melting point of 60 ° C. were obtained.
    [498] Example 37
    [499] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-2-phenylacetamide
    [500] (a) tert-butyl (4'-formylbiphenyl-3-ylmethyl) methylcarbamate
    [501] In a similar manner as in Example 1 (e), 125 g (410 mmol) of tert-butyl (3-bromobenzyl) -N-methylcarbamate (prepared in Example 1 (b)) and 82 g ( Starting with 510 mmol) of 4-formylbenzeneboronic acid, 90 g (67%) of the desired product were obtained.
    [502] (b) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] methylcarbamate
    [503] In a similar manner as in Example 1 (f), 75 g (230 mmol) of tert-butyl (4'-formylbiphenyl-3-ylmethyl) methylcarbamate and 35 g (275 mmol) of 2,4 Starting with -thiazolidinedione, 84 g (86%) of the expected product were obtained.
    [504] (c) tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamate
    [505] 30 g (71 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] methylcarbamate in 500 mL of dioxane Into the reactor. The reaction medium was degassed and then 30 g (10 equivalents by weight) of 10% charcoal palladium was added. The system was placed under 3 bar of hydrogen and heated to 50 ° C. for 7 hours. The reaction medium was filtered through celite, evaporated and the residue obtained was purified by chromatography on a silica column, with an eluent mixture of dichloromethane and methanol (98/2). After evaporation of the solvent, 18 g (60%) of the expected product was collected.
    [506] (d) 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione
    [507] 16 ml (210 mmol) trifluoroacetic acid in 18 g (42 mmol) tert-butyl 4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl- in 250 ml dichloromethane To the solution of 3-ylmethyl] methylcarbamate. The reaction medium was stirred at rt for 18 h and then evaporated to dryness. The residue obtained was washed with ethyl acetate and dried. 14 g (78%) of the product in the form of trifluoroacetate were collected.
    [508] (e) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-2-phenylacetamide
    [509] 500 mg (1.1 mmol) 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate, 2 ml of tetrahydrofuran and 500 μl (3.3 mmol Triethylamine) was introduced into a round bottom flask under a stream of nitrogen. 230 μl of phenylacetyl chloride was added dropwise and the mixture was stirred for 1 hour at room temperature. The reaction medium was poured into water, extracted with ethyl acetate, and the organic phase separated off after phase settling occurred, washed with water, dried over magnesium sulfate and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol (97/3). 360 mg (72%) of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-2-phenylacetamide has a melting point of 73 Obtained in the form of a white solid which is ° C.
    [510] Example 38
    [511] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-methoxy-N-methylbenzamide
    [512] In a similar manner as in Example 37 (e), 500 mg (1.1 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reaction with 170 μl (1.25 mmol) of 4-methoxybenzoyl chloride, N- [4 ′-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] 300 mg (50%) of 4-methoxy-N-methylbenzamide were obtained in the form of a white solid with a melting point of 170 ° C.
    [513] Example 39
    [514] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-methoxy-N-methylbenzamide
    [515] In a similar manner as in Example 37 (e), 540 mg (1.2 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reaction with 300 μl (2 mmol) of 3-methoxybenzoyl chloride, N- [4 ′-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] 400 mg (70%) of 3-methoxy-N-methylbenzamide were obtained in the form of a white solid having a melting point of 173 ° C.
    [516] Example 40
    [517] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-N-dimethylbenzamide
    [518] In a similar manner as in Example 37 (e), 500 mg (1.1 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reacting with 170 μl (1.25 mmol) of 3-methylbenzoyl chloride, N- [4 ′-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl]- 350 mg (70%) of 3-N-dimethylbenzamide were obtained in the form of a white solid with a melting point of 98 ° C.
    [519] Example 41
    [520] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-4-propylbenzamide
    [521] In a similar manner as in Example 37 (e), 500 mg (1.1 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. Purification by reaction with 210 μl (1.2 mmol) of 4-propylbenzoyl chloride followed by N- [4 ′-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3 having a melting point of 280 ° C. 300 mg (55%) of -ylmethyl] -N-methyl-4-propylbenzamide were obtained.
    [522] Example 42
    [523] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4, N-dimethylbenzamide
    [524] In a similar manner as in Example 37 (e), 500 mg (1.1 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reacting with 170 μl (1.25 mmol) of 4-methylbenzoyl chloride, N- [4 ′-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl]- 350 mg (70%) of 4, N-dimethylbenzamide were obtained in the form of a white solid having a melting point of 198 ° C.
    [525] Example 43
    [526] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylisoxazole-5-carboxamide
    [527] In a similar manner as in Example 37 (e), 500 mg (1.1 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reacting with 170 mg (1.3 mmol) of 5-isoxazolecarboxylic acid chloride, N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl 120 mg (26%) of methyl] -N-methylisoxazole-5-carboxamide were obtained in the form of a white solid having a melting point of 160 ° C.
    [528] Example 44
    [529] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-ethoxy-N-methylbenzamide
    [530] In a similar manner as in Example 37 (e), 1 g (2.2 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reacting with 460 mg (2.5 mmol) 4-ethoxybenzoyl chloride, N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] 960 mg (88%) of 4-ethoxy-N-methylbenzamide were obtained in the form of a white solid having a melting point of 182 ° C.
    [531] Example 45
    [532] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-fluoro-N-methylbenzamide
    [533] In a similar manner as in Example 37 (e), 1 g (2.2 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reaction with 290 μl (2.5 mmol) of 4-fluorobenzoyl chloride, N- [4 ′-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl- having a melting point of 212 ° C. 1 g (98%) of 3-ylmethyl] -4-fluoro-N-methylbenzamide was obtained.
    [534] Example 46
    [535] 4-dimethylamino-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [536] In a similar manner as in Example 37 (e), 1 g (2.2 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. Purification by reaction with 500 mg (3 mmol) 4-dimethylaminobenzoyl chloride followed by purification of 4-dimethylamino-N- [4 '-(2,4-dioxothiazolidin-5-yl having a melting point of 100 ° C. 200 mg (20%) of methyl) biphenyl-3-ylmethyl] -N-methylbenzamide were obtained.
    [537] Example 47
    [538] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylnicotinamide
    [539] In a similar manner as in Example 37 (e), 1 g (2.2 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reaction with 450 mg (2.5 mmol) nicotinoyl chloride, N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N 400 mg (40%) of methylnicotinamide were obtained in the form of a white solid with a melting point of 115 ° C.
    [540] Example 48
    [541] 3,5-Dichloro-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [542] In a similar manner as in Example 37 (e), 1 g (2.2 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reaction with 350 μl (2.5 mmol) of 3,5-dichlorobenzoyl chloride, the ratio of 3,5-dichloro-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) 400 mg (50%) of phenyl-3-ylmethyl] -N-methylbenzamide were obtained in the form of a white solid with a melting point of 106 ° C.
    [543] Example 49
    [544] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylthiophene-2-carboxamide
    [545] In a similar manner as in Example 37 (e), 1 g (2.2 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione trifluoroacetate was added. After purification by reaction with 200 μl (2.5 mmol) of 2-thiophenecarboxylic acid chloride, N- [4 ′-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl 500 mg (50%) of methyl] -N-methylthiophene-2-carboxamide were obtained in the form of a white solid having a melting point of 160 ° C.
    [546] Example 50
    [547] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylhexaneamide
    [548] In a similar manner as in Example 37 (e), 220 μl (1.6 of 500 mg (1.5 mmol) of 5- (3′-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione mmol) hexanoyl chloride, followed by purification to give N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N having a melting point of 45 ° C. 430 mg (66%) of -methylhexanamide were obtained.
    [549] Example 51
    [550] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2-methoxy-N-methylbenzamide
    [551] In a similar manner as in Example 37 (e), 230 μl (1.5 μl of 500 mg (1.5 mmol) of 5- (3′-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione after purification by reaction with 2-methoxybenzoyl chloride of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2-meth 500 mg (70%) of oxy-N-methylbenzamide were obtained in the form of a white solid with a melting point of 96 ° C.
    [552] Example 52
    [553] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylpyridine-2-carboxamide
    [554] Preparation of Picolinic Chloride:
    [555] 800 μl (4.1 mmol) of dicyclohexylamine was added to 500 mg (4.1 mmol) of picolinic acid placed in 9 mL of dichloromethane and the solution was stirred at room temperature for 30 minutes. Then 300 μl (4.1 mmol) thionyl chloride were added and the mixture was stirred for 2 hours at room temperature. The reaction medium was diluted with ethyl ether. The precipitate was filtered off and rinsed with ethyl ether. The filtrate was concentrated to give the expected acid chloride.
    [556] In a similar manner as in Example 37 (e), 220 mg (1.6) of 500 mg (1.5 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione mmol), followed by purification, followed by N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylpyridine-2 330 mg (50%) of -carboxamide were obtained in the form of a colorless oil.
    [557] Example 53
    [558] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylfuran-2-carboxamide
    [559] Preparation of 2-furoyl chloride:
    [560] 900 μl (4.5 mmol) of dicyclohexylamine was added to 500 mg (4.5 mmol) of 2-furoic acid placed in 5 mL of dichloromethane and the solution was stirred at room temperature for 30 minutes. Then 300 μl (4.5 mmol) thionyl chloride was added and the mixture was stirred for 2 hours at room temperature. The reaction medium was diluted with ethyl ether. The precipitate was filtered off and rinsed with ethyl ether. The filtrate was concentrated to give 2-furoyl chloride.
    [561] In a similar manner as in Example 37 (e), 200 mg (1.5) of 500 mg (1.5 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione after purification by reaction with 2-furoyl chloride of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylfuran 350 mg (50%) of 2-carboxamide were obtained in the form of a white solid having a melting point of 150 ° C.
    [562] Example 54
    [563] 4-butoxy-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [564] In a similar manner as in Example 37 (e), 290 μl (1.5 μl of 500 mg (1.5 mmol) of 5- (3′-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione 4-butoxy-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl after purification by reaction with 4-butoxybenzoyl chloride of mmol) 550 mg (83%) of] -N-methylbenzamide were obtained in the form of a white solid having a melting point of 116 ° C.
    [565] Example 55
    [566] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylthiophene-3-carboxamide
    [567] Preparation of 3-thiophenecarboxylic acid chloride:
    [568] 800 μl (3.9 mmol) of dicyclohexylamine was added to 500 mg (3.9 mmol) of 3-thiophenecarboxylic acid in 5 mL of dichloromethane and the solution was stirred for 30 minutes at room temperature. Then 300 μl (3.9 mmol) of thionyl chloride were added and the mixture was stirred for 2 hours at room temperature. The reaction medium was diluted with ethyl ether. The precipitate was filtered off and rinsed with ethyl ether. The filtrate was concentrated to give the expected acid chloride.
    [569] In a similar manner as in Example 37 (e), 200 mg (1.5) of 500 mg (1.5 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N after purification by reaction with 3-thiophencarboxylic acid chloride of mmol) 450 mg (68%) of methylthiophene-3-carboxamide were obtained in the form of a white powder having a melting point of 150 ° C.
    [570] Example 56
    [571] 4-{[4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamoyl} phenyl acetate
    [572] Preparation of 4-acetoxybenzoyl chloride:
    [573] 1.1 mL (5.6 mmol) of dicyclohexylamine was added to 1 g (5.6 mmol) of 4-acetoxybenzoic acid in 10 mL of dichloromethane and the solution was stirred for 30 minutes at room temperature. 400 μl (5.6 mmol) thionyl chloride was added and the mixture was stirred for 2 h at room temperature. The reaction medium was diluted with ethyl ether. The precipitate was filtered off and rinsed with ethyl ether. The filtrate was concentrated to give 4-acetoxybenzoyl chloride.
    [574] In a similar manner as in Example 37 (e), 600 mg (3) of 1 g (3 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione mmol) 4-acetoxybenzoyl chloride, followed by purification to provide 4-{[4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarba 1.3 g (90%) of moyl} phenyl acetate were obtained in the form of a white powder having a melting point of 167 ° C.
    [575] Example 57
    [576] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-hydroxy-N-methylbenzamide
    [577] 110 mg (1.3 mmol) of sodium hydrogen carbonate was added 350 mg (6.7 mmol) of 4-{[4 '-(2,4-dioxothiazolidine-5-) in 5 ml of tetrahydrofuran and 500 µl of water. Monomethyl) biphenyl-3-ylmethyl] methylcarbamoyl} phenyl acetate (prepared in Example 56). The reaction medium was stirred for 48 hours at room temperature, then diluted with ethyl acetate and acidified to pH 3-4 with 1N hydrochloric acid solution. The organic phase was separated after the bed settling occurred, dried over sodium sulfate, filtered and evaporated. The residue obtained was purified by chromatography on a silica column, eluting with a 99/1 dichloromethane / methanol mixture. After evaporation of the solvent, 250 mg of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-hydroxy-N-methylbenzamide (83 %) Was collected in the form of a white powder with a melting point of 110 ° C.
    [578] Example 58
    [579] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2N-dimethylbenzamide
    [580] In a similar manner as in Example 37 (e), 160 μl (1.2) of 400 mg (1.2 mmol) of 5- (3′-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione after purification by reaction with 2-methylbenzoyl chloride of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2N-dimethylbenz 500 mg (94%) of amides were obtained in the form of a white powder having a melting point of 78 ° C.
    [581] Example 59
    [582] 2-butyl-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [583] Preparation of 2-butyloctanoyl chloride:
    [584] 500 μl (2.5 mmol) of dicyclohexylamine was added to 500 mg (2.5 mmol) of 2-butyloctanoic acid in 5 mL of dichloromethane and the solution was stirred at room temperature for 30 minutes. Then 200 μl (2.5 mmol) thionyl chloride was added and the mixture was stirred for 2 h at room temperature. The reaction was diluted with ethyl ether. The precipitate was filtered off and rinsed with ethyl ether. The filtrate was concentrated to give 2-butyloctanoyl chloride.
    [585] In a similar manner as in Example 37 (e), 340 mg (1.5) of 500 mg (1.5 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione 2-butyl-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] after purification by reaction with 2-butyloctanoyl chloride of 430 mg (55%) of -N-methyloctanamide were obtained in the form of a colorless oil.
    [586] Example 60
    [587] 4-acetylamino-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    [588] 320 mg (1.7 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 230 ml of 270 mg (1.5 mmol) 4-acetamidobenzoic acid in 5 ml of dichloromethane, 230 μl (1.6 mmol) ) Triethylamine, 230 mg (1.7 mmol) 1-hydroxybenzotriazole and 500 mg (1.5 mmol) 5- (3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2 To a solution of, 4-dione was added portionwise at 0 ° C. The reaction medium was stirred for 18 h from 0 ° C. to room temperature, washed with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was separated after the bed settling occurred, dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a 99/1 dichloromethane / methanol mixture. After evaporation of the solvent 600 mg (80 of 4-acetylamino-N- [4 ′-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide %) Was obtained in the form of a white solid having a melting point of 207 ° C.
    [589] Example 61
    [590] Hexyl N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylcarbamate
    [591] A solution of 400 μl (2.5 mmol) of hexyl chloroformate in 5 mL of dichloromethane was added with 1 g (2.3 mmol) of 5- (3′-methylaminomethylbiphenyl-4-ylmethyl) thiazoli in 15 mL of dichloromethane. To the solution of dean-2,4-dione trifluoroacetate and 1 ml (7.0 mmol) triethylamine was added dropwise. The reaction medium was stirred for 3 hours at room temperature, poured into water and extracted with ethyl acetate. The organic phase was separated after the bed settling occurred, dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (8/2). After evaporation of the solvent, 300 mg (30%) of hexyl N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylcarbamate Obtained in the form of a colorless oil.
    [592] Example 62
    [593] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-phenylurea
    [594] (a) 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -3-phenylurea
    [595] 500 μl (4.6 mmol) of phenyl isocyanate was added 1.2 g (2.3 mmol) of 5- (3′-aminobiphenyl-4-ylmethylene) thiazolidine-2,4-dione in 12 mL of dichloromethane (Example 33 was prepared as in (a)) and 0.9 mL (6.4 mmol) of triethylamine. The reaction medium was stirred for 2 hours at room temperature. It was extracted with dichloromethane, washed with water, and the organic phase was separated off after phase settling occurred. The organic phase was evaporated and the residue obtained was washed with dichloromethane and dried. 950 mg (50%) of the expected product was collected.
    [596] (b) 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-phenylurea
    [597] 460 mg (1.1 mmol) of 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] in 20 ml of methanol / dioxane mixture (1/1) 3-phenylurea was placed in the reactor. After degassing the reaction medium, 560 mg (1.2 equivalents by weight) of 10% charcoal palladium was added. The system was placed under 3 bar of hydrogen and heated to 50 ° C. for 5 hours. The reaction medium was filtered through celite, evaporated and the residue obtained was subjected to chromatography on a silica column by gradually increasing the polarity of the 9/1 mixture of heptane and ethyl acetate to a 4/6 mixture of heptane and ethyl acetate. Purification by After evaporation of the solvent, 150 mg (33%) of 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-phenylurea have a melting point of 185 ° C. Obtained in the form of a phosphorus white solid.
    [598] Example 63
    [599] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2-phenylacetamide
    [600] (a) (3-bromophenyl) methylamine
    [601] 10 g (58 mmol) of 3-bromoaniline and 34 mL (203 mmol) of triethylorthoformate were introduced into a three neck flask under nitrogen. The reaction medium was stirred and refluxed for 7 hours. Excess triethyl orthoformate was evaporated, the reaction medium was cooled to 0 ° C. and 100 ml of ethanol and 5 g (130 mmol) of sodium borohydride were added. The reaction medium was stirred for 20 hours at room temperature. Ethanol was evaporated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate (90/10). After evaporation of the solvent, 5 g (46%) of the expected product were collected.
    [602] (b) 3'-methylaminobiphenyl-4-carboxaldehyde
    [603] 2.9 g of the expected product by reacting 4.3 g (23.2 mmol) of (3-bromophenyl) methylamine with 5.2 g (34.8 mmol) of 4-formylbenzeneboronic acid in a similar manner as in Example 1 (e) (60%) was obtained.
    [604] (c) 5- (3'-methylaminobiphenyl-4-ylmethylene) thiazolidine-2,4-dione
    [605] In a similar manner as in Example 1 (f), starting with 2.9 g (13.7 mmol) of 3'-methylaminobiphenyl-4-carboxaldehyde and 1.6 g (13.7 mmol) of 2,4-thiazolidinedione This gave 3.9 g (91%) of the expected product.
    [606] (d) N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -N-methyl-2-phenylacetamide
    [607] In a similar manner as in Example 37 (e), 470 μl (3.5 mmol) of 1 g (3.2 mmol) of 5- (3′-methylaminobiphenyl-4-ylmethylene) thiazolidine-2,4-dione N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -N-methyl-2-phenyl after purification by reaction with phenylacetyl chloride of 1.4 g (50%) of acetamide were obtained.
    [608] (e) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2-phenylacetamide
    [609] In a similar manner as in Example 62 (b), 660 mg (1.5 mmol) of N- [4 '-(2,4-dioxothiazolidin-5-ylidenemethyl) biphenyl-3-yl]- N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2-phenyl starting with N-methyl-2-phenylacetamide 360 mg (54%) of acetamide were obtained in the form of a white solid with a melting point of 138 ° C.
    [610] Example 64
    [611] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3-phenylurea
    [612] (a) 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -1-methyl-3-phenylurea
    [613] In a similar manner as in Example 62 (a), 1 g (3.2 mmol) of 5- (3'-methylaminobiphenyl-4-ylmethylene) thiazolidine-2,4-dione and 700 μl (6.4 mmol) Starting with phenyl isocyanate, 1.2 g (86%) of the expected product were obtained.
    [614] (b) 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3-phenylurea
    [615] In a similar manner as in Example 62 (b), 1.2 g (2.8 mmol) of 1- [4 '-(2,4-dioxothiazolidin-5-ylidenemethyl) biphenyl-3-yl]- Starting with 1-methyl-3-phenylurea, 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3-phenylurea 700 mg (56%) were obtained in the form of a white solid with a melting point of 183 ° C.
    [616] Example 65
    [617] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-heptyl-1-methylurea
    [618] (a) 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -3-heptyl-1-methylurea
    [619] In a similar manner as in Example 62 (a), 500 mg (1.6 mmol) of 5- (3'-methylaminomethylbiphenyl-4-ylmethylene) thiazolidine-2,4-dione and 500 μl (3.2 Starting with mmol) of heptyl isocyanate, 500 mg (71%) of the expected product were obtained.
    [620] (b) 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-heptyl-1-methylurea
    [621] In a similar manner as in Example 62 (b), 500 mg (1.1 mmol) of 1- [4 '-(2,4-dioxothiazolidin-5-ylidenemethyl) biphenyl-3-yl]- 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-heptyl-1-methylurea starting with 3-heptyl-1-methylurea 300 mg (56%) were obtained in the form of a white solid with a melting point of 55 ° C.
    [622] Example 66
    [623] 4-monomethyl ester of 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4-ylmethyl} succinic acid
    [624] (a) 4-monomethyl ester of 2- {3 '-[(tert-butoxycarbonylmethylamino) methyl] biphenyl-4-ylmethylene} succinic acid
    [625] 3.5 mL (18.5 mmol) of a 30% solution of sodium methoxide in methanol was added to 2.6 mL (15.4 mmol) of ethyl succinate in 30 mL of methanol in a round bottom flask under a stream of nitrogen. The reaction medium was stirred for 15 minutes, and then 5 g (15.4 mmol) of tert-butyl (4'-formylbiphenyl-3-ylmethyl) methylcarbamate obtained in Example 37 (a) were added dropwise. The reaction medium was heated to 60 ° C. overnight. It was extracted with ethyl acetate, washed with water and the organic phase was separated off after phase settling occurred. The organic phase was dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a mixture of heptane and ethyl acetate 50/50. After evaporation of the solvent 2.8 g (41%) of the expected product were collected.
    [626] (b) methyl ethyl 2- {3 '-[(tert-butoxycarbonylmethylamino) methyl] biphenyl-4-ylmethylene} succinate
    [627] 1.10 ml (13 mmol) of ethyl iodide and 1.88 g (13.6 mmol) of potassium carbonate were added to 2- {3 '-[(tert-butoxycarbonylmethylamino) methyl] biphenyl in 30 ml of 2-butanone. To 2.75 g (6.0 mmol) of the 4-monomethyl ester of -4-ylmethylene} succinic acid. The reaction medium was refluxed for 1 hour and then filtered. The obtained residue was purified by chromatography on a silica column, eluting with a 75/25 mixture of heptane and ethyl acetate. 2.1 g (75%) of the expected product were obtained.
    [628] (c) Methyl ethyl 2- (3'-methylaminomethylbiphenyl-4-ylmethylene) succinate
    [629] 2.8 ml (36.8 mmol) trifluoroacetic acid was dissolved in 2.1 g (4.5 mmol) of methyl ethyl 2- {3 '-[(tert-butoxycarbonylmethylamino) methyl] biphenyl-4- in 25 ml of dichloromethane. Ilmethylene} succinate. The reaction medium was stirred for 18 hours at room temperature, washed with saturated sodium carbonate solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and evaporated. 1.5 g (95%) of the expected product were obtained.
    [630] (d) methyl ethyl 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4-ylmethylene} succinate
    [631] In a similar manner as in Example 37 (e), 740 μl (4.8 mmol) of heptanoyl were added 1.5 g (4.2 mmol) of methyl ethyl 2- (3′-methylaminomethylbiphenyl-4-ylmethylene) succinate. By reaction with chloride, 1.8 g (89%) of the expected product was obtained after purification.
    [632] (e) methyl ethyl 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4-ylmethyl} succinate
    [633] In a similar manner as in Example 1 (g), 1.70 g (3.5 mmol) of methyl ethyl 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4-ylmethylene} succinate in 20 ml of ethyl acetate Starting with nate and 170 mg (10 mass%) of 10% charcoal on palladium, 1.30 g (77%) of the expected product was obtained.
    [634] (f) 4-monomethyl ester of 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4-ylmethyl} succinic acid
    [635] 300 μl (0.7 mmol) of 2M aqueous sodium hydroxide solution was added with 0.3 g (0.6 mmol) of methyl ethyl 2- {3 ′-[(heptanoylmethylamino) methyl] biphenyl-4 in 3 ml of methanol and 1.5 ml of tetrahydrofuran. -Ylmethyl} succinate was added at 0 ° C. The reaction medium was stirred for 18 h at room temperature, acidified to pH 5 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a 99/1 dichloromethane / methanol mixture. After evaporation of the solvent, 130 mg (46%) of 4-monomethyl ester of 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4-ylmethyl} succinic acid were collected in the form of a colorless film.
    [636] Example 67
    [637] 2- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-ylmethyl} succinic acid
    [638] A 2.4 mL (5.6 mmol) aqueous 2N sodium hydroxide solution was added with 900 mg (1.9 mmol) of methyl ethyl 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4 in 9 mL of methanol and 4.5 mL of tetrahydrofuran. -Ylmethyl} succinate (obtained in Example 66 (e)). The reaction medium was stirred for 36 hours at room temperature, then for 3 hours at 50 ° C., acidified to pH 5 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with a 99/1 dichloromethane / methanol mixture. After evaporation of the solvent, 300 mg (35%) of 2- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-ylmethyl} succinic acid were collected in the form of a white solid with a melting point of 57 ° C.
    [639] Example 68
    [640] N- [4 '-(2,5-dioxopyrrolidin-3-ylmethyl) biphenyl-3-ylmethyl] -N-methylheptanamide
    [641] 180 mg (3 mmol) of urea were added to 420 mg (0.97 mmol) of 2- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-ylmethyl} succinic acid obtained in Example 67. The reaction medium was heated to 180 ° C. for 4 hours and then cooled. The obtained residue was purified by chromatography on a silica column, eluting with a 99/1 dichloromethane / methanol mixture. After evaporation of the solvent, 220 mg (55%) of N- [4 '-(2,5-dioxopyrrolidin-3-ylmethyl) biphenyl-3-ylmethyl] -N-methylheptanamide were obtained as colorless film. Collected in form.
    [642] Example 69
    [643] 3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-phenylcarbamate
    [644] (a) 3'-hydroxybiphenyl-4-carbaldehyde
    [645] In a similar manner as in Example 1 (e), starting with 20 g (115 mmol) of 3-bromophenol and 26 g (173 mmol) of 4-formylbenzeneboronic acid, 15 g (65%) of the expected product ) Was obtained.
    [646] (b) 5- (3'-hydroxybiphenyl-4-ylmethylene) thiazolidine-2,4-dione
    [647] In a similar manner as in Example 1 (f), starting with 15 g (75.7 mmol) of 3'-hydroxybiphenyl-4-carbaldehyde and 8.85 g (75.7 mmol) of 2,4-thiazolidinedione This gave 22.5 g (100%) of the expected product.
    [648] (c) 3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-phenylcarbamate
    [649] In a similar manner as in Example 9 (a), 800 μl of pyridine and 1.5 g (5 mmol) of 5- (3′-hydroxybiphenyl-4-ylmethylene) thiazolidine-2,4 in 10 mL of THF 750 mg 3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-phenylcarbamate starting with dione and 1.1 ml (10.1 mmol) phenyl isocyanate (36%) was obtained.
    [650] Example 70
    [651] 3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-heptylcarbamate
    [652] 2 g (6.7 mmol) of 5- (3'-hydroxybiphenyl-4-ylmethylene) thiazolidine-2 with 1.3 ml (8.1 mmol) of heptyl isocyanate in 30 ml of acetonitrile and 5 ml of triethylamine , 4-dione (prepared in Example 69 (b)), and the mixture was heated to 40 ° C. for 5 hours. Then 480 mg (3.9 mmol) of 4- (dimethylamino) pyridine were added and the mixture was refluxed for 24 hours. The reaction medium was poured into water and extracted with ether. The organic phase was evaporated. The residue obtained was washed with 80/20 ethyl acetate / methanol mixture and dried. 1.3 g (44%) of 3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-heptylcarbamate were collected in the form of a yellow solid with a melting point of 316 ° C. It became.
    [653] Example 71
    [654] 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl phenylacetate
    [655] (a) 3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl phenylacetate
    [656] In a similar manner as in Example 37 (e), 2 g (6.7 mmol) of 5- (3'-hydroxybiphenyl-4-ylmethylene) thiazolidine-2,4-dione (Example 69 (b ) Is reacted with 1 ml (7.4 mmol) of phenylacetyl chloride to give 2.1 g (75%) of the expected product in the form of a yellow solid.
    [657] (b) 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl phenylacetate
    [658] In a similar manner as in Example 1 (g), 2.1 g (5 mmol) of 3- [4 '-(2,4-dioxothiazolidine-5) in 40 ml of a dioxane / methanol mixture (50/50) -Ylidenemethyl)] biphenyl phenylacetate, purified by chromatography on a silica column eluting with a heptane / ethyl acetate mixture (8/2), and then 3- [4 '-(2,4-di 810 mg (38%) of oxothiazolidin-5-ylmethyl)] biphenyl phenylacetate were obtained in the form of a yellow solid with a melting point of 147 ° C.
    [659] Example 72
    [660] 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl nonanoate
    [661] (a) 5- (3'-hydroxybiphenyl-4-ylmethyl) thiazolidine-2,4-dione
    [662] In a similar manner as in Example 1 (g), 3 g (10.1 mmol) of 5- (3'-hydroxybiphenyl-4-ylmethylene) thiazolidine- in a dioxane / methanol mixture (50/50) Starting with 2,4-dione and purified by chromatography on a silica column eluting with a heptane / ethyl acetate mixture (7/3), 800 mg (27%) of the expected product were obtained.
    [663] (b) 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl nonanoate
    [664] In a similar manner as in Example 37 (e), 400 μl (2.2 mmol) of 600 mg (2 mmol) of 5- (3′-hydroxybiphenyl-4-ylmethyl) thiazolidine-2,4-dione 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl by reacting with nonanoyl chloride) and 50 mg (0.4 mmol) 4- (dimethylamino) pyridine. 780 mg (89%) of nonanoate were obtained in the form of a white solid with a melting point of 70 ° C.
    [665] Example 73
    [666] 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl N-heptylcarbamate
    [667] In a similar manner as in Example 1 (g), 950 mg (2.2 mmol) of 3- [4 '-(2,4-dioxothiazoli) in dioxane / methanol mixture (50/50) under 3 atm of hydrogen Din-5-ylidenemethyl)] biphenyl N-heptylcarbamate (obtained in Example 70), starting with 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) ] 130 mg (13%) of biphenyl N-heptylcarbamate were obtained in the form of a white solid with a melting point of 315 ° C.
    [668] Example 74
    [669] 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl N-phenylcarbamate
    [670] In a similar manner as in Example 1 (g), 740 mg (1.78 mmol) of 3- [4 '-(2,4-dioxothiazolidine-5-ylidene) in 25 ml of dioxane under 3 atm of hydrogen Methyl)] biphenyl N-phenylcarbamate (obtained in Example 69), starting with 3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl N-phenyl 310 mg (42%) of carbamate were obtained in the form of a white solid with a melting point of 142 ° C.
    [671] Example 75
    [672] N- [6-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [673] (a) 4-benzyloxy-3-bromobenzaldehyde
    [674] 25 g (124 mmol) of 3-bromo-4-hydroxybenzaldehyde, 250 ml of 2-butanone, 14.8 ml (124 mmol) of benzyl bromide and 42.8 g (310 mmol) of potassium carbonate were rounded under a stream of nitrogen Introduced to the bottom flask. The reaction medium was refluxed for 4 hours, filtered and evaporated. The residue was taken up with diisopropyl ether, then filtered and dried. 28 g (77%) of the expected product were obtained in the form of a beige powder having a melting point of 93 ° C.
    [675] (b) N- (4-benzyloxy-3-bromobenzyl) -N-methylamine
    [676] 25 g (86 mmol) 4-benzyloxy-3-bromobenzaldehyde, 500 ml methanol, 29 g (430 mmol) methylamine hydrochloride and 8 g (127 mmol) sodium cyanoborohydride were nitrogen It was introduced into a round bottom flask under airflow. The reaction medium was stirred at rt for 48 h. Methanol was evaporated. The residue was taken up with ethyl acetate and water and then acidified. Once settling occurred and the phases separated, the aqueous phase was returned to basic pH with sodium hydroxide and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and then evaporated. The residue was purified by chromatography on a silica column, eluting with a dichloromethane / ethanol mixture (9/1). 9.9 g (38%) of the expected product were obtained in the form of a colorless oil.
    [677] (c) N- (4-benzyloxy-3-bromobenzyl) -N-methyloctanamide
    [678] In a similar manner as in Example 37 (e), 5.3 g (32 mmol) of 9.9 g (32 mmol) of N- (4-benzyloxy-3-bromobenzyl) -N-methylamine in 90 mL of dichloromethane By reacting with octanoyl chloride, 13.6 g (97%) of the expected product were obtained in the form of a colorless oil.
    [679] (d) N- (6-benzyloxy-4'-formylbiphenyl-3-ylmethyl) -N-methyloctanamide
    [680] In a similar manner as in Example 1 (e), 13.6 g (31 mmol) of N- (4-benzyloxy-3-bromobenzyl) -N-methyloctanamide and 6.1 g (40 mmol) of 4-port By reacting millbenzeneboronic acid, 11.5 g (69%) of the expected product were obtained in the form of a yellow oil.
    [681] (e) N- [6-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [682] In a similar manner as in Example 1 (f), 11.5 g (22 mmol) of N- (6-benzyloxy-4'-formylbiphenyl-3-ylmethyl) -N-methyloctanamide and 2.5 g (22 By reacting 2,4-thiazolidinedione of mmol), the expected product was obtained in the form of a pale yellow powder with a melting point of 162 ° C.
    [683] Example 76
    [684] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -6-hydroxybiphenyl-3-ylmethyl] -N-methyloctanamide
    [685] (a) N- [6-benzyloxy-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [686] In a similar manner as in Example 1 (g), 1 g (1.8 mmol) of N- [6-benzyloxy-4 '-(2,4) in 30 ml of dioxane and 1 ml of triethylamine under 3 atm of hydrogen Starting with -dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide (obtained in Example 75), the expected product 270 mg (27%) Obtained in form.
    [687] (b) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -6-hydroxybiphenyl-3-ylmethyl] -N-methyloctanamide
    [688] 250 mg (0.45 mmol) N- [6-benzyloxy-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide, 4 ML acetonitrile and 130 mg (0.65 mmol) of iodotrimethylsilane were introduced into a round bottom flask under a stream of nitrogen. The reaction medium was heated to 50 ° C. for 3 hours. At room temperature, 450 μl of 1N hydrochloric acid and 450 μl of tetrabutylammonium fluoride were added. The medium is then diluted with ethyl acetate and washed with sodium thiosulfate solution. Once settling occurred and the phases separated, the organic phase was dried over magnesium sulfate, filtered and evaporated. The obtained residue was purified by chromatography on a silica column, eluting with an ethyl acetate / heptane mixture (6/4). 150 mg (72%) of N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -6-hydroxybiphenyl-3-ylmethyl] -N-methyloctanamide is yellowish Obtained in the form of a foam.
    [689] Example 77
    [690] N- [4-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [691] (a) 2-benzyloxy-5-bromobenzaldehyde
    [692] In a similar manner as in Example 75 (a), by reacting 30 g (150 mmol) of 5-bromo-2-hydroxybenzaldehyde with 17.8 mL (150 mmol) of benzyl bromide in 300 mL of acetone, After purification by chromatography eluting with a heptane / ethyl acetate mixture (8/2), 22.8 g (52%) of the expected product were obtained in the form of a yellow solid.
    [693] (b) N- (2-benzyloxy-5-bromobenzyl) -N-methylamine
    [694] In a similar manner as in Example 75 (b), 22.5 g (77 mmol) 2-benzyloxy-5-bromobenzaldehyde, 26.1 g (386 mmol) methylamine hydrochloride and 7.3 g (116 mmol) sodium By reacting cyanoborohydride, eluting with dichloromethane / methanol mixture (9/1) and 0.5% isopropylamine by chromatography on a silica column, the expected product 12.2 g (51%) was light yellow oil. Obtained in the form of.
    [695] (c) N- (2-benzyloxy-5-bromobenzyl) -N-methyloctanamide
    [696] In a similar manner as in Example 37 (e), 6 g (19.6 mmol) of N- (2-benzyloxy-5-bromobenzyl) -N-methylamine were added with 3.4 mL (19.6 mmol) of octanoyl chloride. By reaction, the residue was purified by chromatography on a silica column eluting with a heptane / ethyl acetate mixture (8/2) to give 8 g (95%) of the expected product in the form of a colorless oil.
    [697] (d) N- (4-benzyloxy-4'-formylbiphenyl-3-ylmethyl) -N-methyloctanamide
    [698] In a similar manner as in Example 1 (e), 8 g (18.5 mmol) of N- (2-benzyloxy-5-bromobenzyl) -N-methyloctanamide and 3.6 g (24 mmol) of 4-form By reacting millbenzeneboronic acid, eluting with a heptane / ethyl acetate mixture (8/2) by chromatography on a silica column, 5.8 g (69%) of the expected product were obtained in the form of a white solid.
    [699] (e) N- [4-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    [700] In a similar manner as in Example 1 (f), 1.5 g (13) with 5.8 g (13 mmol) of N- (4-benzyloxy-4'-formylbiphenyl-3-ylmethyl) -N-methyloctanamide N- [4-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl by reacting 2,4-thiazolidendione of mmol) 5.2 g (74%) of N-methyloctanamide were obtained in the form of a bright yellow powder with a melting point of 158 ° C.
    [701] Example 78
    [702] N- [4 "-(2,4-dioxothiazolidin-5-ylmethyl) [1,1 '; 3', 1"] terphenyl-5'-ylmethyl] -N-methyloctanamide
    [703] (a) 3-bromo-5-iodo-N-methylbenzamide
    [704] 37.5 g (115 mmol) of 3-bromo-5-iodobenzoic acid in 300 ml of dimethylformamide were introduced into a round bottom flask under a stream of nitrogen. 17.6 mL (127 mmol) triethylamine, 17 g (126 mmol) 1-hydroxybenzotriazole and 7.75 g (115 mmol) methylamine hydrochloride were added. The reaction medium was cooled to 0 ° C. and 24.2 g (126 mmol) of 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride were added in portions. The medium was allowed to warm to room temperature and stirred for 18 hours. Then poured into water and the precipitate obtained was filtered off, washed with heptane and dried. 37.3 g (96%) of the expected product were obtained in the form of a beige powder having a melting point of 205 ° C.
    [705] (b) 5-bromo-N-methyl-3-biphenylcarboxamide
    [706] In a manner similar to that of Example 1 (e), silica was reacted by reacting 4.9 g (14 mmol) of 3-bromo-5-iodo-N-methylbenzamide with 1.93 g (15.8 mmol) of phenylboronic acid. After purification by column chromatography eluting with a heptane / ethyl acetate mixture (8/2), 2.1 g (50%) of the expected product were obtained in the form of a white solid with a melting point of 132 ° C.
    [707] (c) 4 "-formyl-N-methyl [1,1 '; 3', 1"] terphenyl-5'-carboxamide
    [708] In a manner similar to that of Example 1 (e), 2 g (7 mmol) of 5-bromo-N-methyl-3-biphenylcarboxamide and 1.4 g (9.3 mmol) of 4-formylbenzeneboronic acid By reaction, after purification by recrystallization from acetonitrile, 1.4 g (63%) of the expected product were obtained in the form of a beige solid.
    [709] (d) (5'-methylaminomethyl [1,1 '; 3', 1 "] terphenyl-4" -yl) methanol
    [710] 1 g (26 mmol) of lithium aluminum hydride in 20 mL of tetrahydrofuran was introduced into a round bottom flask under a stream of nitrogen. The medium is cooled to 0 ° C. and 1.4 g (4.4 mmol) of 4 ″ -formyl-N-methyl [1,1 ′; 3 ′, 1 ″] terphenyl-5′-carbox in 30 mL tetrahydrofuran A solution of amide was added dropwise. The reaction medium was refluxed for 48 hours. Thereafter, it was allowed to cool to room temperature, and an aqueous sodium sulfate solution was added dropwise. After 30 minutes, the medium was acidified to pH 5 and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and then evaporated. The residue was purified by chromatography on a silica column, eluting with a dichloromethane / ethanol mixture (9/1) to give 660 mg (49%) of the expected product in the form of a white solid.
    [711] (e) 5'-methylaminomethyl [1,1 '; 3', 1 "] terphenyl-4" -carbaldehyde
    [712] 660 mg (2.2 mmol) of (5'-methylaminomethyl- [1,1 '; 3', 1 "] terphenyl-4" -yl) methanol and 1.9 g (22 mmol) of manganese dioxide in 30 ml of dichloromethane Was introduced into a round bottom flask. The reaction medium was stirred at rt for 24 h. Then filtered through celite and evaporated. 410 mg (62%) of the expected product were obtained in the form of a pale yellow solid.
    [713] (f) 5- (5'-methylaminomethyl [1,1 '; 3', 1 "] terphenyl-4" -ylmethylene) thiazolidine-2,4-dione
    [714] In a similar manner as in Example 1 (f), 400 mg (1.3 mmol) of 5'-methylaminomethyl [1,1 '; 3', 1 "] terphenyl-4" -carbaldehyde and 160 mg ( By reacting 1.3 mmol) of 2,4-thiazolidinedione, 530 mg (100%) of the expected product were obtained in the form of an orange powder.
    [715] (g) N- [4 "-(2,4-dioxothiazolidine-5-ylidenemethyl) [1,1 '; 3', 1"] terphenyl-5'-ylmethyl] -N- Methyloctaneamide
    [716] In a manner similar to that in Example 37 (e), 530 mg (1.3 mmol) of 5- (5'-methylaminomethyl [1,1 '; 3', 1 "] terphenyl-4" -ylmethylene) thia Purification by reacting zolidine-2,4-dione with 230 μl (1.3 mmol) of octanoyl chloride, eluting with a dichloromethane / methanol mixture (95/5) by chromatography on a silica column, then predicted product 390 mg (56%) was obtained in the form of an orange oil.
    [717] (h) N- [4 "-(2,4-dioxothiazolidin-5-ylmethyl) [1,1 '; 3', 1"] terphenyl-5'-ylmethyl] -N-methyl Octanamide
    [718] In a similar manner as in Example 1 (g), 370 mg (7 mmol) of N- [4 "-(2,4-dioxothiazolidine-5-ylidene in 5 ml of dioxane under 3 atm of hydrogen Methyl) [1,1 '; 3', 1 "] terphenyl-5'-ylmethyl] -N-methyloctanamide, starting with chromatography on a silica column, a heptane / ethyl acetate mixture (6/4) Purified by eluting with N- [4 "-(2,4-dioxothiazolidin-5-ylmethyl) [1,1 '; 3', 1"] terphenyl-5'-ylmethyl] 170 mg (47%) of -N-methyloctanamide were obtained in the form of a pale yellow foam.
    [719] Example 79
    [720] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -2'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide
    [721] (a) tert-butyl (3-bromobenzyl) carbamate
    [722] In a similar manner as in Example 1 (a), starting with 50 g (220 mmol) of 3-bromobenzylamine hydrochloride, 65.1 g (100%) of the expected product were obtained in the form of a light brown solid.
    [723] (b) tert-butyl (3-bromobenzyl) -N-methylcarbamate
    [724] In a similar manner as in Example 1 (b), starting with 85 g (297 mmol) of tert-butyl (3-bromobenzyl) carbamate, 92.5 g (100%) of the expected product were obtained.
    [725] (c) tert-butyl (4'-formyl-2'-methylbiphenyl-3-ylmethyl) -N-methylcarbamate
    [726] In a similar manner as in Example 1 (e), 6.1 g (20.3 mmol) of tert-butyl (3-bromobenzyl) -N-methylcarbamate was charged with 4.3 g (26.2 mmol) of 2-methyl-4- By reacting with formylbenzeneboronic acid, eluting with a heptane / ethyl acetate mixture (8/2) by chromatography on a silica column, 4 g (58%) of the expected product were obtained in the form of an orange oil.
    [727] (d) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) -2'-methylbiphenyl-3-ylmethyl] -N-methylcarbamate
    [728] In a manner similar to that of Example 1 (f), 3.95 g (11.6 mmol) of tert-butyl (4'-formyl-2'-methylbiphenyl-3-ylmethyl) -N-methylcarbamate 1.4 Purification by reaction with g (11.6 mmol) of 2,4-thiazolidinedione, eluting with a heptane / ethyl acetate mixture (8/2) by chromatography on a silica column, followed by 3 g (59%) of the expected product. This melting point was obtained in the form of a yellow solid having a temperature of 156 ° C.
    [729] (e) tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -2'-methylbiphenyl-3-ylmethyl] -N-methylcarbamate
    [730] In a similar manner as in Example 1 (g), 1.5 g (3.4 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) -2'-methylbiphenyl Starting with -3-ylmethyl] -N-methylcarbamate, purified by chromatography on a silica column eluting with a heptane / ethyl acetate mixture (8/2), yielded 1.2 g (82%) of the expected product. Obtained in the form of a yellowish oil.
    [731] (f) 5- (2-methyl-3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione
    [732] In a manner similar to that of Example 1 (c), 1.2 g (2.7 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -2'-methylbiphenyl- Starting with 3-ylmethyl] -N-methylcarbamate, 720 mg (78%) of the expected product were obtained in the form of a white solid.
    [733] (g) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -2'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide
    [734] In a similar manner as in Example 37 (e), 300 mg (0.88 mmol) of 5- (2-methyl-3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione was added. Purification by reaction with 140 mg (0.88 mmol) octanoyl chloride, eluting with a heptane / ethyl acetate mixture (6/4) by chromatography on a silica column, followed by N- [4 '-(2,4-di 250 mg (63%) of oxothiazolidin-5-ylmethyl) -2'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide were obtained in the form of a white solid having a melting point of 130 ° C.
    [735] Example 80
    [736] N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -3'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide
    [737] (a) tert-butyl (4'-formyl-3'-methylbiphenyl-3-ylmethyl) -N-methylcarbamate
    [738] In a similar manner as in Example 1 (e), 750 mg (1.1 g (3.5 mmol) of tert-butyl (3-bromobenzyl) -N-methylcarbamate (obtained in Example 79 (b))) was obtained. 4.6 mmol), and then purified by chromatography on a silica column, eluting with a heptane / ethyl acetate mixture (7/3) by reaction with 3-methyl-4-formylbenzeneboronic acid, then 1 g (87%) of the expected product. This was obtained in the form of a yellow oil.
    [739] (b) tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) -3'-methylbiphenyl-3-ylmethyl] -N-methylcarbamate
    [740] In a similar manner as in Example 1 (f), 1 g (2.9 mmol) of tert-butyl (4'-formyl-3'-methylbiphenyl-3-ylmethyl) -N-methylcarbamate was added to 350 Purification by reaction with mg (2.9 mmol) 2,4-thiazolidinedione eluting with a heptane / ethyl acetate mixture (6/4) by chromatography on a silica column, followed by 740 mg (57%) of the expected product. This was obtained in the form of a yellow oil.
    [741] (c) tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -3'-methylbiphenyl-3-ylmethyl] -N-methylcarbamate
    [742] In a similar manner to in Example 1 (g), 740 mg (1.7 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) -3'-methylbiphenyl Starting with -3-ylmethyl] -N-methylcarbamate, 720 mg (97%) of the expected product were obtained in the form of a yellow oil.
    [743] (d) 5- (3-methyl-3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione
    [744] In a similar manner as in Example 1 (c), 720 mg (1.6 mmol) of tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -3'-methylbiphenyl- Starting with 3-ylmethyl] -N-methylcarbamate, 320 mg (58%) of the expected product were obtained in the form of a white powder with a melting point of 135 ° C.
    [745] (e) N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -3'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide
    [746] In a similar manner as in Example 37 (e), 310 mg (0.9 mmol) of 5- (3-methyl-3'-methylaminomethylbiphenyl-4-ylmethyl) thiazolidine-2,4-dione was added. Purification by reaction with 160 mg (0.9 mmol) octanoyl chloride, eluting with a heptane / ethyl acetate mixture (6/4) by chromatography on a silica column, followed by N- [4 '-(2,4-di 230 mg (55%) of oxothiazolidin-5-ylmethyl) -3'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide were obtained in the form of a yellowish oil.
    [747] Example 81
    [748] (S) -2-ethoxy-3- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-yl} propionic acid
    [749] (a) tert-butyl (4'-formylbiphenyl-3-ylmethyl) -N-methylcarbamate
    [750] In a similar manner as in Example 1 (e), 25.6 g (38 g (127 mmol) of tert-butyl (3-bromobenzyl) -N-methylcarbamate (obtained in Example 79 (b))) 170 mmol) of 4-formylbenzeneboronic acid, which was purified by chromatography on a silica column eluting with a heptane / ethyl acetate mixture (9/1) to give 20 g (57%) of the expected product.
    [751] (b) ethoxyacetyl chloride
    [752] 25 g (240 mmol) of ethoxyacetic acid in 300 mL of dichloromethane were introduced into a round bottom flask under a stream of nitrogen. 47.6 mL (239 mmol) of dicyclohexylamine was added. The medium was stirred at rt for 1 h. Then 19.2 mL (265 mmol) thionyl chloride were added and the mixture was stirred for 3 h. Ethyl ether was added to the reaction medium and the formed precipitate was filtered off and rinsed with ether. After evaporation of the filtrate, 29 g (100%) of the expected product were obtained in the form of a brown liquid.
    [753] (c) 3- (2-ethoxyethanoyl) -4-benzyloxazolidin-2-one
    [754] 36.7 g (207 mmol) of (S) -4-benzyloxazolidin-2-one in 800 mL THF was introduced into a round bottom flask under a stream of nitrogen. The reaction medium was cooled to -78 ° C and 83 mL (207 mmol) of 2.5M n-butyllithium hexane was added dropwise. After 30 minutes, 25.4 g (207 mmol) of ethoxyacetyl chloride (obtained in Example 81 (b)) were added at -78 ° C. The reaction medium was stirred for 24 hours, then poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and evaporated. After purification by chromatography on a silica column eluting with a heptane / ethyl acetate mixture (6/4), the expected product 30.6 g (56%) of orange oil Obtained in form.
    [755] (d) methyl (2S, 3R) -3-({3 '-[(tert-butoxycarbonylmethylamino) methyl] biphenyl-4-yl} -2-ethoxy-3-hydroxypropionate
    [756] In a similar manner as in Example 13 (a), 23.5 g (69 mmol) of tert-butyl (4'-formylbiphenyl-3-ylmethyl) -N-methylcarbamate (in Example 81 (a) Preparative) was reacted with 21.9 g (83 mmol) of 3- (2-ethoxyethanoyl) -4-benzyloxazolidin-2-one, by chromatography on a silica column to prepare a heptane / ethyl acetate mixture (7 After purification by eluting with 3), 21 g (51%) of the expected product were obtained.
    [757] (e) Methyl (2S, 3R) -2-ethoxy-3-hydroxy-3- (3'-methylaminomethylbiphenyl-4-yl) propionate
    [758] 21 g (47.3 mmol) of methyl (2S, 3R) -3- {3 '-[(tert-butoxycarbonylmethylamino) methyl] biphenyl-4-yl} -2- in 300 ml of trifluoroacetic acid Ethoxy-3-hydroxypropionate and 8.76 mL (54.9 mmol) triethylsilane were introduced into a round bottom flask under a stream of nitrogen. The reaction medium was stirred at rt for 4 h. Then ethyl acetate was added and the mixture was neutralized with sodium hydroxide. The organic phase was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. 19.6 g (100%) of crude product which was deprotected but still hydroxylated were obtained.
    [759] (f) Methyl (S) -2-ethoxy-3- (3'-methylaminomethylbiphenyl-4-yl) propionate
    [760] 19.6 g of the crude product obtained in Example 81 (e) was dissolved in 200 mL of trifluoroacetic acid, and 41.7 mL (297 mmol) of triethylamine were added. The reaction medium was stirred for 48 hours at room temperature and then extracted with ethyl acetate. The organic phase was separated after the phase settling occurred, washed with sodium hydroxide solution, then with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained was purified by chromatography on a silica column eluting with a dichloromethane / methanol mixture (95/5). 1.6 g (10%) of the expected product were obtained.
    [761] (g) methyl (S) -2-ethoxy-3- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-yl} propionate
    [762] In a similar manner as in Example 37 (e), 500 mg (1.5 mmol) of methyl (S) -2-ethoxy-3- (3'-methylaminomethylbiphenyl-4-yl) propionate 550 By reacting with [mu] l (3.18 mmol) octanoyl chloride, eluting with a heptane / ethyl acetate mixture (70/30) by chromatography on a silica column yielded 200 mg (29%) of the expected product.
    [763] (h) (S) -2-ethoxy-3- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-yl} propionic acid
    [764] In a similar manner as in Example 13 (c), 180 mg (0.4 mmol) of methyl (S) -2-ethoxy-3- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-yl } Propionate was reacted with 17 mg (0.4 mmol) of lithium hydroxide monohydrate, eluted and purified with a heptane / ethyl acetate mixture (50/50) by chromatography on a silica column, then 130 mg (74) of the expected product. %) Was obtained in the form of a colorless oil.
    [765] Example 82
    [766] 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-ethyl-3-phenylurea
    [767] (a) (3-bromophenyl) ethylamine
    [768] 5 g (29.1 mmol) of 3-bromoaniline in 500 ml of ether were introduced into a round bottom flask under a stream of nitrogen. 4.5 mL (32 mmol) of triethylamine and 15.2 mL (117 mmol) of diethyl sulfate were added. The medium was refluxed for 24 hours and then left at room temperature for 8 days. Then poured into water and extracted with ether. The organic phase was washed with saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on a silica column eluting with a heptane / ethyl acetate mixture (95/5) to give 2.5 g (43%) of the expected product.
    [769] (b) 3'-ethylaminobiphenyl-4-carbaldehyde
    [770] In a similar manner as in Example 1 (e), chromatography on a silica column was carried out by reacting 1.25 g (6.25 mmol) of (3-bromophenyl) ethylamine with 1.4 g (9.4 mmol) of 4-formylbenzeneboronic acid. After purification by chromatography with a heptane / ethyl acetate eluent mixture (75/25), 1 g (71%) of the expected product was obtained in the form of a yellow solid.
    [771] (c) 5- (3'-ethylaminobiphenyl-4-ylmethylene) thiazolidine-2,4-dione
    [772] In a similar manner as in Example 1 (f), 900 mg (4 mmol) of 3'-ethylaminobiphenyl-4-carbaldehyde is reacted with 470 mg (4 mmol) of 2,4-thiazolidinedione 1 g (77%) of the expected product was obtained in the form of an orange solid.
    [773] (d) 1- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-yl] -1-ethyl-3-phenylurea
    [774] In a similar manner as in Example 9 (a), 340 μl (3.1 mmol) of 500 mg (1.54 mmol) of 5- (3′-ethylaminobiphenyl-4-ylmethylene) thiazolidine-2,4-dione Reaction with phenyl isocyanate gave 650 mg (95%) of the expected product in the form of a yellow solid.
    [775] (e) 1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-ethyl-3-phenylurea
    [776] In a manner similar to that of Example 1 (g), 650 mg (1.4 mmol) of 1- [4 '-(2,4-dioxothiazolidin-5-ylidenemethyl) biphenyl-3-yl]- Starting with 1-ethyl-3-phenylurea, eluting and purifying with a heptane / ethyl acetate mixture (70/30) by chromatography on a silica column, then 1- [4 '-(2,4-dioxothia 400 mg (61%) of zolidin-5-ylmethyl) biphenyl-3-yl] -1-ethyl-3-phenylurea were obtained in the form of a white powder having a melting point of 186 ° C.
    [777] Example 83
    [778] The agonistic activity of the compounds according to the invention on PPARγ receptors can be assessed by binding tests and transcriptional activation tests. The results obtained for the compounds according to the invention are compared in the table below.
    [779] compound% Activation of PPARα% Activation of PPARγBinding of PPARγKd (nM) Reference 1: Wy 14643100 *n.a.n.a. Reference 2: SB 219994n.a.1000.5 Reference 3: BRL 49,65338323 Example 18.2102.255 Example 28.242.9263 Example 10022.1800 Example 112.474.5289 Example 12060.47 Example 13070.224 Example 2114.990190 Example 227.595.376.6 Example 248.79572.3 Example 262.188.6N.T. Example 281.179.8N.T. Example 308.980.3N.T. Example 32074.9N.T. Example 3417.6102.52 Example 351156N.T. n.a. Means no activity. Means not tested. *:% Activation at a concentration of 1 μM
    [780] These results show the affinity of the compounds for PPARγ and their transcriptional activation activity. These results more particularly show the specificity of the activation of the compounds of the invention for PPARγ subtypes, as compared to the activation of compounds for PPARα subtypes.
    [781] Example 84
    [782] Various specific formulations based on the compounds according to the invention are described in this example.
    [783] A- oral route
    [784] (a) 0.2 g tablets
    [785] 10.001 g of compound
    [786] Starch 0.114 g
    [787] -Dicalcium phosphate0.020 g
    [788] -Silica 0.020 g
    [789] -Lactose0.030 g
    [790] -Talc0.010 g
    [791] -Magnesium stearate0.005 g
    [792] (b) beverage suspension in 5 ml ampoules
    [793] 50.001 g of compound
    [794] Glycerol0.500 g
    [795] 70% sorbitol0.500 g
    [796] Sodium saccharate0.010 g
    [797] Methyl para-hydroxybenzoate0.040 g
    [798] -Flavor
    [799] -5 ml of purified water
    [800] (c) 0.8 g tablets
    [801] 20.500 g of compound
    [802] -Pregelatinized starch 0.100 g
    [803] -0.115 g of microcrystalline cellulose
    [804] -Lactose0.075 g
    [805] -Magnesium stearate0.010 g
    [806] (d) beverage suspensions in 10 ml ampoules
    [807] 40.200 g of compound
    [808] Glycerol 1.000 g
    [809] 70% sorbitol 1.000 g
    [810] Sodium saccharate0.010 g
    [811] Methyl para-hydroxybenzoate0.080 g
    [812] -Flavor
    [813] -10 ml of purified water
    [814] B- local route
    [815] (a) ointment
    [816] 60.020 g of compound
    [817] -Isopropyl myristate 81.700 g
    [818] -Liquid petroleum jelly 9.100 g
    [819] Silica ("Aerosil 200", manufactured by Degussa)
    [820] 9.180 g
    [821] (b) ointment
    [822] 20.300 g of compound
    [823] White petroleum jelly codex
    [824] 100 g of quantity
    [825] (c) nonionic water-in-oil cream
    [826] 10.100 g of compound
    [827] Mixtures of emulsified lanolin alcohols, waxes and oils
    [828] ("Anhydrous Eucerin", BDF) 39.900 g
    [829] Methyl para-hydroxybenzoate0.075 g
    [830] Propyl para-hydroxybenzoate0.075 g
    [831] -100 g of sterile demineralized water
    [832] (d) lotion
    [833] 30.100 g of compound
    [834] Polyethylene glycol (PEG 400)
    [835] 95% ethanol30.000 g
    [836] (e) hydrophobic ointment
    [837] 50.300 g of compound
    [838] -Isopropyl myristate 36.400 g
    [839] -Silicone oil ("Rhodorsil 47 V 300", made by Rhone-Poulenc)
    [840] 36.400 g
    [841] Beeswax 13.600 g
    [842] -Silicone oils ("Abil 300,000 CST", produced by Goldschmidt)
    [843] 100 g of quantity
    [844] (f) nonionic oil-in-water cream
    [845] 21.000 g of compound
    [846] Cetyl alcohol4.000 g
    [847] Glyceryl monostearate2.500 g
    [848] PEG-50 stearate2.500 g
    [849] -Karite butter-9.200 g
    [850] -Propylene glycol2.000 g
    [851] Methyl para-hydroxybenzoate0.075 g
    [852] Propyl para-hydroxybenzoate0.075 g
    [853] -100 g of sterile demineralized water
    权利要求:
    Claims (20)
    [1" claim-type="Currently amended] Compounds characterized by corresponding to formula (I), and optical and geometric isomers of the compounds of formula (I), and salts thereof:
    [Formula I]
    {In the meal,
    R 1 represents a radical of the formula (a) or (b):
    [Formula a]
    [Formula b]
    (Y, R 5 and R 6 have the following meanings),
    R 2 and R 3 may be the same or different and have a hydrogen atom, an alkyl radical of 1 to 12 carbon atoms, an aryl radical, a halogen atom, an -OR 7 radical, a polyether radical, a nitro radical, or one having 1 to 12 carbon atoms An amino radical which may be optionally substituted with (or more) alkyl radical (s),
    (R 7 has the meaning below),
    X represents the following structural linkages:
    -(CH 2 ) m- (Z) n- (CO) p- (W) q-
    (The structural connection can be read from left to right and vice versa)
    (Z, W, m, n, p and q have the following meanings),
    R 4 represents an alkyl radical having 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, a heteroaryl radical or a 9-fluorenylmethyl radical,
    Y represents a CH 2 radical or a sulfur atom,
    R 5 represents a hydroxyl radical, an alkoxy radical having 1 to 6 carbon atoms, an NH-OH radical, or an N (R 8 ) (R 9 ) radical,
    (R 8 and R 9 have the following meanings),
    R 6 represents an alkyl radical having 1 to 12 carbon atoms, an OR 10 radical, an SR 10 radical or a (CH 2 ) r -COR 11 radical,
    (r, R 10 and R 11 have the following meanings),
    R 7 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, or an aralkyl radical,
    Z represents an oxygen or sulfur atom or an NR 12 radical,
    (R 12 has the following meaning),
    W represents an oxygen or sulfur atom, an NR 13 radical, or a CH 2 radical,
    (R 13 has the following meaning),
    m, n, p and q can be the same or different and can take a value of 0 or 1 (where the sum m + n + p + q is 2 or more and p takes a value of 0, understand that n or q is 0),
    R 8 represents a hydrogen atom or an alkyl radical having 1 to 12 carbon atoms,
    R 9 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, or an aryl radical,
    -r represents 0 or 1,
    R 10 represents an alkyl radical having 1 to 12 carbon atoms, an aryl radical, or an aralkyl radical,
    R 11 represents a hydroxyl radical, an OR 14 radical, or an N (R 15 ) (R 16 ) radical,
    R 12 represents a hydrogen atom or an alkyl radical having 1 to 12 carbon atoms,
    R 13 represents a hydrogen atom or an alkyl radical having 1 to 12 carbon atoms,
    R 14 represents an alkyl radical having 1 to 12 carbon atoms, an aryl radical, or an aralkyl radical,
    R 15 represents a hydrogen atom or an alkyl radical having 1 to 12 carbon atoms,
    R 16 represents a hydrogen atom, an alkyl radical having 1 to 12 carbon atoms, an aryl radical, an aralkyl radical, or a heteroalkyl radical.
    [2" claim-type="Currently amended] 2. Compounds according to claim 1, in the form of alkali metal or alkaline earth metal salts, zinc salts or organic amine salts.
    [3" claim-type="Currently amended] A compound according to claim 1 or 2, wherein the alkyl radical having 1 to 12 carbon atoms is selected from methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl, and dodecyl radicals.
    [4" claim-type="Currently amended] The polyether radical according to claim 1 or 2, wherein the polyether radical is selected from a polyether radical having 1 to 6 carbon atoms which is interrupted by one or more oxygen atoms such as methoxymethoxy, ethoxymethoxy, or methoxyethoxymethoxy radicals. Compound which is characterized in that.
    [5" claim-type="Currently amended] The compound according to claim 1 or 2, wherein the halogen atom is selected from the group consisting of fluorine atom, chlorine atom, and bromine atom.
    [6" claim-type="Currently amended] The compound according to claim 1 or 2, wherein the alkoxy radical having 1 to 6 carbon atoms is selected from the group consisting of methoxy, ethoxy, isopropoxy, tert-butoxy, and hexyloxy radicals.
    [7" claim-type="Currently amended] The aryl radical is optionally protected with a halogen atom, a CF 3 radical, an alkyl radical having 1 to 12 carbon atoms, an alkoxy radical having 1 to 6 carbon atoms, a nitro function, a polyether radical, an acetyl or benzoyl group. And a phenyl radical which may be monosubstituted or disubstituted with an amino function optionally protected with a hydroxyl radical or an acetyl or benzoyl group or optionally substituted with one or more alkyl of 1 to 12 carbon atoms.
    [8" claim-type="Currently amended] The aralkyl radical according to claim 1 or 2, wherein the aralkyl radical is a halogen atom, a CF 3 radical, an alkyl radical having 1 to 12 carbon atoms, a hydroxyl radical, an alkoxy radical having 1 to 6 carbon atoms, a nitro function, a polyether radical, or acetyl. Or benzyl or phenethyl radicals which may be monosubstituted or disubstituted with hydroxyl radicals optionally protected with benzoyl groups, or amino functions optionally protected with acetyl or benzoyl groups or optionally substituted with one or more alkyl groups of 1 to 12 carbon atoms. Characterized by a compound.
    [9" claim-type="Currently amended] 3. The hydroxyl of claim 1 or 2, wherein the heteroaryl radical is optionally protected with at least one halogen, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 6 carbon atoms, nitro function, polyether radical, acetyl or benzoyl group, Or a pyridyl, furyl, thienyl or isoxazolyl radical optionally protected with an acetyl or benzoyl group or optionally substituted with an amino function optionally substituted with one or more alkyl of 1 to 12 carbon atoms. .
    [10" claim-type="Currently amended] A compound according to claim 1, which is taken alone or as a mixture in the group consisting of:
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    5- {3 '-[(methylpyrid-2-ylamino) methyl] biphenyl-4-ylmethyl} thiazolidine-2,4-dione
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] benzamide
    Ethyl 3- {3 '-[(benzoylmethylamino) methyl] biphenyl-4-yl} -2-methylpropionate
    2-Methyl-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    N- [4 '-(2-carbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    N-methyl-N- [4 '-(2-phenylcarbamoylpropyl) biphenyl-3-ylmethyl] benzamide
    N- [4 '-(2-hydroxycarbamoylpropyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-phenylurea
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -1-methyl-3-phenylurea
    tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamate
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylnonanamide
    (S) -2-ethoxy-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    Monomethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    Dimethyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonate
    Methyl 2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamate
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-ethylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-pentylbenzamide
    tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] ethylcarbamate
    tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] propylcarbamate
    9H-fluorene-9-ylmethyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamate
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2,2, N-trimethylpropionamide
    N-octyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-3-phenylpropionamide
    2- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-N-phenylacetamide
    N- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-propylbenzamide
    tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] carbamate
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3,4-diethoxy-N-methylbenzamide
    2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamic acid
    N-benzyl-N-methyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    N-benzyl-4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-carboxamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyldecanamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -2-phenylacetamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylheptanamide
    N-hydroxy-2- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-ylmethyl) malonamic acid
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-2-phenylacetamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-methoxy-N-methylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3-methoxy-N-methylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -3, N-dimethylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyl-4-propylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4, N-dimethylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylisoxazole-5-carboxamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-ethoxy-N-methylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-fluoro-N-methylbenzamide
    4-dimethylamino-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylnicotinamide
    3,5-Dichloro-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylthiophene-2-carboxamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylhexaneamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2-methoxy-N-methylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylpyridine-2-carboxamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylfuran-2-carboxamide
    4-butoxy-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylthiophene-3-carboxamide
    4-{[4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] methylcarbamoyl} phenyl acetate
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -4-hydroxy-N-methylbenzamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -2N-dimethylbenzamide
    2-butyl-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    4-acetylamino-N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylbenzamide
    Hexyl N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-ylmethyl] -N-methylcarbamate
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-phenylurea
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2-phenylacetamide
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3-phenylurea
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -3-heptyl-1-methylurea
    4-monomethyl ester of 2- {3 '-[(heptanoylmethylamino) methyl] biphenyl-4-ylmethyl} succinic acid
    2- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-ylmethyl} succinic acid
    N- [4 '-(2,5-dioxopyrrolidin-3-ylmethyl) biphenyl-3-ylmethyl] -N-methylheptanamide
    3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-phenylcarbamate
    3- [4 '-(2,4-dioxothiazolidine-5-ylidenemethyl)] biphenyl N-heptylcarbamate
    3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl phenylacetate
    3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl nonanoate
    3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl N-heptylcarbamate
    3- [4 '-(2,4-dioxothiazolidin-5-ylmethyl)] biphenyl N-phenylcarbamate
    N- [6-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -6-hydroxybiphenyl-3-ylmethyl] -N-methyloctanamide
    N- [4-benzyloxy-4 '-(2,4-dioxothiazolidine-5-ylidenemethyl) biphenyl-3-ylmethyl] -N-methyloctanamide
    N- [4 "-(2,4-dioxothiazolidin-5-ylmethyl) [1,1 '; 3', 1"] terphenyl-5'-ylmethyl] -N-methyloctanamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -2'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) -3'-methylbiphenyl-3-ylmethyl] -N-methyloctanamide
    (S) -2-ethoxy-3- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-yl} propionic acid
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-ethyl-3-phenylurea
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyldecanamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methylnonanamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2- (4-butoxyphenyl) acetamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2- (4-methoxyphenyl) acetamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2- (4-ethoxyphenyl) acetamide
    N- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -N-methyl-2- (4-hydroxyphenyl) acetamide
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3- (4-butoxyphenyl) urea
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3- (4-methoxyphenyl) urea
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3- (4-ethoxyphenyl) urea
    1- [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] -1-methyl-3- (4-hydroxyphenyl) urea
    (S) -2-ethoxy-3- (3 '-{[methyl- (1- (4-butoxy) phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-ethoxy-3- (3 '-{[methyl- (1- (4-methoxy) phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-ethoxy-3- (3 '-{[methyl- (1- (4-ethoxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-ethoxy-3- (3 '-{[methyl- (1- (4-hydroxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-phenoxy-3- (3 '-{[methyl- (1- (4-butoxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-phenoxy-3- (3 '-{[methyl- (1- (4-methoxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-phenoxy-3- (3 '-{[methyl- (1- (4-ethoxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-phenoxy-3- (3 '-{[methyl- (1- (4-hydroxyphenyl) methanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-phenoxy-3- (3 '-{[methyl- (1-phenylmethanoyl) amino] methyl} biphenyl-4-yl) propionic acid
    (S) -2-phenoxy-3- {3 '-[(methyloctanoylamino) methyl] biphenyl-4-yl} propionic acid
    5- {3 '-[methyl- (2-oxo-2-phenylethyl) amino] biphenyl-4-ylmethyl} thiazolidine-2,4-dione
    5- [3 '-(methylphenethylamino) biphenyl-4-ylmethyl] thiazolidine-2,4-dione
    Phenyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] methylcarbamate
    tert-butyl [4 '-(2,4-dioxothiazolidin-5-ylmethyl) biphenyl-3-yl] methylcarbamate.
    [11" claim-type="Currently amended] A compound according to claim 1 or 2 having at least one of the following characteristics:
    R 1 represents a radical of formula (a) or a radical of formula (b), wherein R 5 represents a hydroxyl radical and R 6 represents an OR 10 radical,
    X represents a structural linkage selected from -CH 2 -N (R 12 ) -CO-, -NR 12- (CO) -NR 13 or NR 12- (CO) -CH 2- (where Read to the right or vice versa).
    [12" claim-type="Currently amended] Cosmetic composition, characterized in that it contains at least one compound according to any one of claims 1 to 11 in a physiologically acceptable support.
    [13" claim-type="Currently amended] 13. A composition according to claim 12, wherein the concentration of the compound (s) according to any one of claims 1 to 11 is from 0.001 to 3% by weight relative to the total weight of the composition.
    [14" claim-type="Currently amended] Cosmetic use of the composition according to claim 12 or 13 for body or hair hygiene.
    [15" claim-type="Currently amended] 12. A compound according to any one of claims 1 to 11 as a pharmaceutical product.
    [16" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 11 in the manufacture of a composition for regulating and / or repairing skin lipid metabolism.
    [17" claim-type="Currently amended] Use of a compound according to any one of claims 1 to 11 in the preparation of a composition to be treated:
    Dermatological complications associated with keratin disorders related to differentiation and proliferation, in particular common acne, scrim, polymorphs, injectable acne, crystalline cystic acne, clotting acne, senile acne, and Secondary acne, such as sunburn, drug or occupational acne,
    Sclerosis, sunburn symptoms, Darrier's disease, plantar scleroderma, leukoplakia and leukoplakiform symptoms, and skin or mucous membrane (oral) limbs,
    Dermatological lesions with or without cell proliferative disorders, in particular skin, mucous or nail psoriasis, psoriatic arthrosis, or skin atopic dermatitis, such as eczema, respiratory atopic or gingival hypertrophy, with inflammatory allergic immune components,
    Dermal or epidermal growth, whether of benign or malignant or viral origin, in particular common warts, squamous warts, and warty epidermal dysplasia, oral or floral papillomas, T lymphomas,
    Proliferation that can be induced by ultraviolet radiation, in particular basal cells and spine cell epithelioma,
    Precancerous skin lesions, especially keratinocytes,
    Immune dermatites, especially lupus erythematosus,
    -Bullous immune disease,
    Collagen diseases, especially scleroderma,
    Dermatological or systemic lesions with immunological components,
    Skin disorders due to exposure to UV radiation, photoinduced or life-long aging of the skin, actinic keratosis and pigmentation, or any pathology associated with life-long or chemical aging, in particular dryness,
    -Sebaceous gland dysfunction, especially hyper seborrhea of acne, or simple seborrhea,
    -Cicatrization disorders, or stretch marks,
    Pigmentation disorders such as hyperpigmentation, melanoma, hypopigmentation or vitiligo,
    Lipid metabolic lesions such as obesity, hyperlipidemia, or non-insulin dependent diabetes mellitus,
    -Inflammatory lesions such as arthritis,
    -Cancerous or precancerous symptoms,
    Alopecia of various origins, in particular alopecia caused by chemotherapy or radiation,
    Immune system disorders such as asthma, type I sugar diabete, multiple sclerosis, or other selective dysfunction of the immune system,
    -Cardiovascular lesions such as atherosclerosis or high blood pressure.
    [18" claim-type="Currently amended] A pharmaceutical composition comprising, in a physiologically acceptable support, at least one compound according to any one of claims 1 to 11.
    [19" claim-type="Currently amended] 19. A composition according to claim 18, wherein the concentration of the compound (s) according to any one of claims 1 to 11 is from 0.001 to 10% by weight relative to the total weight of the composition.
    [20" claim-type="Currently amended] 19. A composition according to claim 18, wherein the concentration of the compound (s) according to any one of claims 1 to 11 is 0.01 to 1% by weight relative to the total weight of the composition.
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    同族专利:
    公开号 | 公开日
    WO2002012210A1|2002-02-14|
    PT1309575E|2005-10-31|
    AR032888A1|2003-12-03|
    DE60111393D1|2005-07-14|
    PL360292A1|2004-09-06|
    US20040039038A1|2004-02-26|
    JP2004505958A|2004-02-26|
    DE60111393T2|2006-03-23|
    ES2245373T3|2006-01-01|
    ZA200300667B|2004-02-11|
    BR0113251A|2003-06-24|
    DK1309575T3|2005-09-12|
    AU8598101A|2002-02-18|
    MXPA03001184A|2003-10-15|
    RU2280033C2|2006-07-20|
    EP1309575B1|2005-06-08|
    CA2418895A1|2002-02-14|
    CN1468226A|2004-01-14|
    FR2812876A1|2002-02-15|
    AU2001285981B2|2006-01-19|
    FR2812876B1|2002-09-27|
    AT297386T|2005-06-15|
    US6927228B2|2005-08-09|
    WO2002012210A9|2002-04-18|
    EP1309575A1|2003-05-14|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-08-08|Priority to FR0010447A
    2000-08-08|Priority to FR00/10447
    2001-08-03|Application filed by 갈데르마 리써어치 앤드 디벨로프먼트,에스.엔.씨.
    2001-08-03|Priority to PCT/FR2001/002543
    2003-06-25|Publication of KR20030051611A
    优先权:
    申请号 | 申请日 | 专利标题
    FR0010447A|FR2812876B1|2000-08-08|2000-08-08|Novel biaromatic compounds that activate ppar-gamma type receptors and their use in cosmetic or pharmaceutical compositions|
    FR00/10447|2000-08-08|
    PCT/FR2001/002543|WO2002012210A1|2000-08-08|2001-08-03|Biphenyl derivatives and their use as ppar-gamma receptor activators|
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