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    • 专利摘要:
    The present invention relates to compounds of formula (I): Formula (I)] (Wherein A, X, Y and R1 are as defined in claim 1) It is about. This compound can be used for the treatment of lesions associated with insulin resistance syndrome.
    公开号:KR20030086312A
    申请号:KR10-2003-7012151
    申请日:2002-02-27
    公开日:2003-11-07
    发明作者:무아네제라드；크라보다니엘
    申请人:메르크 파텐트 게엠베하；
    IPC主号:
    专利说明:

    Bicyclic guanidine derivatives and their therapeutic uses {BICYCLIC GUANIDINE DERIVATIVES AND THERAPEUTIC USES THEREOF}
    [2] Bicyclic derivatives having antihypertensive or antimicrobial properties are described in US Pat. No. 3,855,242, US Pat. No. 4,260,628 and Yaoxue Xuebao, 1982, 17 (3), 229-232.
    [1] The present invention relates to bicyclic guanidine derivatives useful for the treatment of lesions associated with insulin resistance syndrome.
    [3] The present invention is directed to providing novel bicyclic guanidine compounds with novel properties.
    [4] Accordingly, the present invention relates to compounds of formula (I):
    [5]
    [6] (Wherein
    [7] A is a group of:
    [8] Branched or straight chain (C 1 -C 20 ) alkyl,
    [9] -R2
    [10] -H,
    [11] Branched or straight chain (C 1 -C 5 ) alkyl,
    [12] -(C 3 -C 8 ) cycloalkyl, or
    [13] -Benzyl
    [14] OR2 representing
    [15] R3 and R4 are independent of each other
    [16] -H,
    [17] Branched or straight chain (C 1 -C 20 ) alkyl,
    [18] -Benzyl,
    [19] Acetyl,
    [20] -(C 3 -C 8 ) cycloalkyl
    [21] Indicates or
    [22] Or optionally NR3R4, wherein R3 and R4 together form a 3- to 8-membered ring containing a nitrogen atom,
    [23] -R5
    [24] -H,
    [25] Branched or straight chain (C 1 -C 5 ) alkyl,
    [26] -(C 3 -C 8 ) cycloalkyl, or
    [27] -Benzyl
    [28] SR5, indicating
    [29] Halogen
    [30] -Cyano
    [31] Nitro
    [32] -R6
    [33] -H or
    [34] Branched or straight chain (C 1 -C 5 ) alkyl
    [35] CO 2 R6, or
    [36] Trifluoromethyl
    [37] A benzene or pyridine ring optionally substituted by one or more of
    [38] X represents a -CH =, -CH 2- , -N = or -NH- radical,
    [39] Y is a CH 2 radical, oxygen or sulfur atom, or R 7 is
    [40] -H,
    [41] Branched or straight chain (C 1 -C 5 ) alkyl,
    [42] -Benzyl,
    [43] -(C 3 -C 8 ) cycloalkyl, or
    [44] -CH 2 CO 2 H group
    [45] Represents a -NR7 group,
    [46] R1 is a group of:
    [47] -H,
    [48] Branched or straight chain (C 1 -C 5 ) alkyl, or
    [49] -Benzyl
    [50] Represents one of
    [51] but,
    [52] a-A represents a benzene ring, X represents -CH = or -CH 2- , Y represents an oxygen atom and R1 is a hydrogen atom;
    [53] b-A represents a benzene ring substituted at the position 5 'of a double ring having a halogen atom, X represents -CH =, Y represents a sulfur atom and R1 is a hydrogen atom,
    [54] c-A represents an unsubstituted benzene ring, X represents -CH 2- , R 1 is a hydrogen atom or a branched or straight chain (C 1 -C 5 ) alkyl radical and Y is R 7 a hydrogen atom, a branched chain or NR7 representing a straight chain (C 1 -C 5 ) alkyl radical or benzyl radical,
    [55] d-A represents an unsubstituted benzene ring, X represents -CH =, except for compounds of formula (I), wherein R 1 represents a hydrogen atom and Y represents NR 7 where R 7 represents an ethyl radical),
    [56] And also tautomers, enantiomers, diastereomers and epimers, solvates and pharmaceutically acceptable salts.
    [57] Among the branched or straight chain C 1 -C 20 alkyl radicals which may be mentioned in particular are methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, Decyl, dodecyl, pentadecyl and hexadecyl radicals.
    [58] One particular group of compounds of formula (I) is those in which the alkyl radical is a C 1 -C 5 alkyl radical.
    [59] Among the C 3 -C 8 cycloalkyl radicals which may be mentioned in particular are the cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl radicals.
    [60] Particularly mentioned, 3- to 8-membered rings comprising nitrogen atoms include aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidyl rings to be.
    [61] Another particular group of compounds of formula (I) are those in which A represents a benzene ring optionally substituted. One particular sub-group is wherein X represents a -CH = radical or a -CH 2 -radical. Another particular sub-group is wherein X represents an -N = radical or an -NH- radical.
    [62] Another particular group of compounds of formula (I) is wherein Y represents a -CH 2 -radical, a sulfur atom or NR 7, and X preferably represents -CH = or -CH 2- .
    [63] One sub-group is directed to a substituted benzene ring, more preferably a monosubstituted benzene ring at a position other than the 5 'position of the double ring, or a benzene ring substituted by two or more groups.
    [64] One particular sub-group of compounds of formula (I) represents a benzene ring substituted by two or more groups, or a monosubstituted benzene ring where Y is a sulfur atom and A is other than the 5 'position of the double ring will be.
    [65] Another particular subgroup of compounds of formula (I) is those in which Y is a -NR7 group and A represents a benzene ring substituted.
    [66] Another specific group of compounds of formula (I) is wherein Y represents a -CH 2 -radical, a sulfur atom or a -NR 7 group, and A is preferably other than the 5 'position of the substituted benzene ring, more preferably a double ring. A monosubstituted benzene ring at the position, or a benzene ring substituted by two or more groups.
    [67] The present invention also relates to tautomers, enantiomers, diastereomers and epimers of the compounds of formula (I).
    [68] Compounds of formula (I) comprise basic nitrogen atoms which may be mono- or di-chloride with organic or inorganic acids.
    [69] Compounds of formula (I) are compounds of formula (II):
    [70]
    [71] (Wherein A, X, Y and R1 have the above definition)
    [72] It can be prepared according to the method for obtaining guanidine from and described in the literature.
    [73] By way of example, these methods are described in particular in the following references: Tetrahedron Letters, 1993, 34 (48), 7677-7680; Tetrahedron Letters, 1993, 34 (21), 3389-3392; Tetrahedron Letters, 1996, 37 (14), 2483-2486; WO 98/52917; Journal of Medicinal Chemistry, 1990, 33 (1), 434-444; Journal of Organic Chemistry, 1998, 63, 3804-3805; WO 94/29269; Tetrahedron Letters, 1994, 35 (7), 977-980; Journal of Organic Chemistry, 1992, 57, 2497-2502; Synthesis, 1986, 777-779; Synthetic Communications, 1987, 17 (15), 1861-1864.
    [74] Compounds of formula (II) can be prepared by simple and standard reactions which can be readily used by those skilled in the art. By way of example, the following references illustrate this synthesis: Oppi Briefs, 1996, 28 (6), 702-704; Heterocycles, 1998, 27 (6), 1421-1429; Pharmazie, 1999, 54 (9), 651-654; WO 95/09159; WO 91/09023; WO 97/42183; Synthetic Communications, 1993, 23 (6), 743-748; Journal of The American Chemical Society, 1952, 74, 664-665; DE 2 739 723; Journal of Medicinal Chemistry, 1994, 37 (23), 3956-3968; WO 93/17025; WO 96/00730; Heterocycles, 1995, 41 (3), 477-486; Journal of Medicinal Chemistry, 1968, 11, 1164-1167; Monatshefte fur Chemie, 1957, 1087-1094; Journal of Medicinal Chemistry, 1989, 32, 1988-1996.
    [75] Compounds according to the invention, and more generally compounds of formula (I):
    [76] Formula (I)]
    [77]
    [78] (Wherein
    [79] A is a group of:
    [80] Branched or straight chain (C 1 -C 20 ) alkyl,
    [81] -R2
    [82] -H,
    [83] Branched or straight chain (C 1 -C 5 ) alkyl,
    [84] -(C 3 -C 8 ) cycloalkyl, or
    [85] -Benzyl
    [86] OR2 representing
    [87] R3 and R4 are independent of each other
    [88] -H,
    [89] Branched or straight chain (C 1 -C 20 ) alkyl,
    [90] -Benzyl,
    [91] Acetyl,
    [92] -(C 3 -C 8 ) cycloalkyl
    [93] Indicates or
    [94] Or optionally NR3R4, wherein R3 and R4 together form a 3- to 8-membered ring containing a nitrogen atom,
    [95] -R5
    [96] -H,
    [97] Branched or straight chain (C 1 -C 5 ) alkyl,
    [98] -(C 3 -C 8 ) cycloalkyl, or
    [99] -Benzyl
    [100] SR5, indicating
    [101] Halogen
    [102] -Cyano
    [103] Nitro
    [104] -R6
    [105] -H or
    [106] Branched or straight chain (C 1 -C 5 ) alkyl
    [107] CO 2 R6, or
    [108] Trifluoromethyl
    [109] A benzene or pyridine ring optionally substituted by one or more of
    [110] X represents a -CH =, -CH 2- , -N = or -NH- radical,
    [111] Y is a CH 2 radical, oxygen or sulfur atom, or R 7 is
    [112] -H,
    [113] Branched or straight chain (C 1 -C 5 ) alkyl,
    [114] -Benzyl,
    [115] -(C 3 -C 8 ) cycloalkyl, or
    [116] -CH 2 CO 2 H group
    [117] Represents a -NR7 group,
    [118] R1 is a group of:
    [119] -H,
    [120] Branched or straight chain (C 1 -C 5 ) alkyl,
    [121] -Benzyl
    [122] Represents one of),
    [123] And also tautomers, enantiomers, diastereomers and epimers, solvates and pharmaceutically acceptable salts thereof, are useful for the treatment of lesions associated with insulin resistance syndrome (syndrome X).
    [124] Insulin resistance is characterized by a decrease in insulin action (cf. Presse Medicale, 1997, 26 (No. 14), 671-677) diabetes and more specifically insulin independent diabetes (type 2 diabetes or NIDDM), It is involved in numerous pathological conditions such as dyslipidaemia, obesity and also certain microvascular or macrovascular complications such as, for example, atherosclerosis, retinopathy and neuropathy.
    [125] In this regard, for example, Diabetes, Vol. 37, 1988, 1595-1607; Journal of Diabetes and its Complications, 1998, 12, 110-119 or Horm. Res., 1992, 38, 28-32 ).
    [126] The compounds of the present invention have particularly strong hypoglycemic activity.
    [127] The present invention therefore also relates to pharmaceutical compositions comprising the compound according to the invention as an active ingredient.
    [128] The pharmaceutical compounds according to the invention may exist in various forms for parenteral, oral, rectal, permucous or intradermal administration.
    [129] Thus, they may be used in the form of injections or suspensions or multi-dose bottles, in the form of injections or suspensions or multi-dose bottles, for transdermal or mucus in polar solvents, tablets, dragees, wafer capsules, gel capsules, pills, It may be in the form of a casein, powder, suppository or rectal capsule, solution or suspension.
    [130] Suitable excipients for such administration are, for solid forms, cellulose derivatives, microcrystalline cellulose derivatives, alkaline earth metal carbonates, magnesium phosphate, starch, modified starch and lactose.
    [131] Cocoa butter or polyethylene glycol stearate is the preferred excipient for rectal use.
    [132] Water, aqueous solutions, saline and isotonic solutions are the most suitable vehicles for parenteral use.
    [133] Dosages can vary within a wide range (0.5 mg or less, to 1000 mg), depending on the therapeutic indication and the route of administration, and also the age and weight of the individual.
    [134] The following examples illustrate the preparation of compounds of formula (I).
    [135] Example 1
    [136] Synthesis of 2- (aminoiminomethyl (methylamino) methyl) -benzothiazole hydrochloride
    [137] Step 1: 2-chloromethylbenzothiazole ( A )
    [138] While maintaining the temperature below 40 ° C., chloroacetyl chloride (81.6 mL) is added dropwise to a solution consisting of 2-aminothiophenol (112 mL, 1.04 mol), dichloromethane (1.2 L) and three drops of dimethylformamide. After stirring for 18 hours, the precipitate formed is suction filtered and then dissolved in the minimum amount of water. This aqueous phase is extracted with pentane and the extract is concentrated in vacuo at room temperature to give 120 g (65%) of flake solids.
    [139] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 8.32, d, 1H, aromatic H; 8.21, d, 1H, aromatic H; 7.77-7.63, m, 2H, aromatic H, 5.43, s, 2H, CH 2 Cl
    [140] Step 2: 2-methylaminomethylbenzothiazole ( B )
    [141] A (115 g, 0.62 mol) and 580 mL aqueous 40% methylamine solution are heated in an autoclave at 60 ° C. for 18 h. The reaction medium is concentrated and the residue is purified on a silica column (7/3 petroleum ether / dichloromethane) to give 96 g (87%) of orange oil.
    [142] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 8.03-7.39, m, 4H, aromatic H; 4.24, s, 1 H, CH 2 ; 2.61, s, 3 H, CH 3
    [143] Step 3: 2- (aminoiminomethyl (methylamino) methyl) benzothiazole hydrochloride
    [144] Portionwise 55.7 g (0.449 mol) of aminoiminomethylsulfonic acid in a solution consisting of dimethylformamide (400 mL) and B (80 g, 0.449 mol) cooled to 5 ° C. while maintaining the temperature below 5 ° C. Add. After stirring for 48 hours, the reaction medium is cooled to 5 ° C. and 75 ml (0.9 mol) of concentrated hydrochloric acid are added. After stirring for 1 hour, the solution is concentrated and the remaining oil is dissolved in acetonitrile. The precipitate formed is suction filtered and then recrystallized from water to give 40 g (35%) of a white solid.
    [145] m.p. = 203-205 ° C
    [146] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 8.32, d, 1H, aromatic H; 8.25-7.40, m, 8H, aromatic H, NH and HCl; 5.20, s, 2H, CH 2 ; 3.10, s, 3H, NCH 3
    [147] 13 C NMR (DMSO-d 6 , 50 MHz): δ: 168.32, 159.08, 154.12, 136.33, quaternary C; 128.20, 127.27, 124.30 and 124.15, aromatic CH; 53.19, CH 2 ; 38.88, NCH 3
    [148] Example 2
    [149] Synthesis of 2- (aminoiminomethylamino) methylbenzimidazole hydrochloride
    [150] Step 1: 2-Aminomethylbenzimidazole ( C )
    [151] A solution of 2-aminoaniline (27 g, 0.25 mol), glycine (27.7 g, 0.37 mol) and 250 ml of 5.5 M hydrochloric acid was refluxed for 30 hours and then stored in the refrigerator for 24 hours. The precipitate formed is suction filtered and then dissolved in 400 ml of methanol and treated with carbon black. The mixture was filtered and the solvent removed to give 22 g (49%) of a white solid.
    [152] m.p. 81-83 ° C.
    [153] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 7.40-6.90, m, 4H, aromatic H; 3.70, s, 2H, CH 2
    [154] Step 2: 2- (aminoiminomethylamino) methylbenzimidazole hydrochloride
    [155] A solution of C (15 g, 0.101 mol), 1- (aminoiminomethyl) pyrazole hydrochloride (15 g, 0.102 mol) and 50 ml of dioxane was refluxed for 18 hours and then concentrated to dryness. The crude product was dissolved in methanol (300 mL) and treated with carbon black. After filtration and concentration, the residue was dissolved in a minimum amount of water and the remaining insoluble material was filtered off. The solution is then lyophilized to yield 14 g (62%) of a white solid.
    [156] m.p. = 171-173 ℃
    [157] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 8.20-7.10, m, 8H, aromatic H, NH and HCl; 4.60, s, 2H, CH 2
    [158] 13 C NMR (DMSO-d 6 , 50 MHz): δ: 158.56, 151.26, 138.98, quaternary C; 122.88, 115.76, aromatic CH; 40.32, CH 2
    [159] Example 3
    [160] Synthesis of 2- (aminoiminomethylamino) methylindane sulfate
    [161] Step 1: 2-methylcarboxyindan ( D )
    [162] To a solution of diethyl malonate (127 g, 0.79 mol), sodium methoxide (314 mL, 1.70 mol), ethanol (100 mL) and ether (500 mL), α, α'-dibromo- in 1.5 L of ether o Add a solution of xylene (203.51 g, 0.77 mol). The mixture is refluxed for 5 hours, filtered and finally concentrated. The residue is dissolved in 500 ml of water. 173 g of potassium hydroxide are added and the mixture is refluxed for 18 hours. The reaction medium is placed in a hydrochloric acid solution and the precipitate formed is suction filtered and dried. The solid obtained is kept at 200 ° C. for 20 minutes and the new solid obtained is recrystallized from 400 ml of heptane. After addition of 5 drops of concentrated sulfuric acid, the obtained crystals are dissolved in 400 ml of methanol and the mixture is refluxed for 4 hours and then concentrated. The residue is dissolved in 600 ml of ether. The ether phase is washed with saturated sodium dicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 73.6 g (54%) of a clear oil.
    [163] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 6.96, m, 4H, aromatic H; 3.43, s, 3H, CH 3 ; 3.11, m, 1 H, CH; 2.91, m, 4H, CH 2
    [164] Step 2: 2-Methylcarboxamide-Indane ( E )
    [165] D (102.1 g, 0.58 mol) and 500 mL of concentrated ammonia solution are placed in an autoclave and the mixture is kept at 80 ° C. for 18 hours. The solid thus formed is suction filtered and washed with water (63.4 g, 68%).
    [166] m.p. = 181-183 ℃
    [167] 1 H NMR (DMSOd 6 , 200 MHz): δ: 7.39, s, 1H, NH; 7.11, m, 4H, aromatic H; 6.85, s, 1 H, NH; 3.12-2.97, m, 5H, CH 2 and CH
    [168] Step 3: 2-Aminomethyl-Indane ( F )
    [169] A solution of E (63 g, 0.391 mol) in tetrahydrofuran (1.5 L) in a suspension of LiAlH 4 (74.15 g, 1.95 mol) in tetrahydrofuran (300 mL) cooled using a cardice / acetone bath. Is added dropwise and the mixture is refluxed for 2 hours. The reaction medium is neutralized (75 mL water, 75 mL 5M sodium hydroxide and 225 mL water) and then filtered. Removal of the solvent leaves an oil (56.9 g, 99%) which forms the carbonate fairly easily.
    [170] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 6.95, m, 4H, aromatic H; 2.90-2.14, m, 7H, 3CH 2 and CH; 1.63, s, 2H, NH 2
    [171] Step 4: 2- (aminoiminomethylamino) methylindane sulfate
    [172] A mixture of F (20.63 g, 0.140 mol), S-methylisothiourea sulfate (19.5 g, 0.07 mol) and 10 ml of water is maintained at 90 ° C. for 30 minutes (termination of methanethiol gas evolution). The crude solid present is recrystallized from the water / ethanol mixture to give 12.7 g (38%) of a white solid.
    [173] m.p. = 231-233 ° C
    [174] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 7.05, m, 4H, aromatic H; 2.95, m, 2H, CH 2 ; 2.40, m, 5H, 2CH 2 and CH
    [175] 13 C NMR (DMSO-d 6 , 50 MHz): δ: 157.07, 142.57, quaternary C; 126.59, 124.83, aromatic CH; 45.28, CH 2 N; 38.74, CH; 36.57, 2CH 2
    [176] Example 4
    [177] Synthesis of 2- (aminoiminomethylamino) methylbenzothiophene hydrochloride
    [178] Step 1: 2-carboxyethylbenzothiophene ( G )
    [179] Ethyl 2-mercapto in a solution of dimethylformamide (800 mL), 2-nitrobenzaldehyde (73 g, 0.48 mol) and potassium carbonate (80 g, 0.57 mol) cooled to 0 ° C. while maintaining the temperature at 0 ° C. Acetate is added. After stirring for 24 hours, the mixture is poured into 2 liters of water and the aqueous phase is extracted with ether. The ether phase is dried over sodium sulfate and concentrated. The crude product obtained is purified on an alumina column (petroleum ether) to give 34 g (35%) of a yellow oil.
    [180] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 8.04, s, 1H, CH; 7.90, m, 2H, aromatic CH; 7.35, m, 2H, aromatic H; 4.20, q, 2H, CH 2 ; 1.93, t, 3H, CH 3
    [181] Step 2: 2-Carboxamidobenzothiophene ( H )
    [182] G (34 g, 0.165 mol), concentrated aqueous ammonia (120 mL) and ethanol (50 mL) are maintained in the autoclave at 80 ° C. for 24 hours. The solution is then concentrated and the crude solid is triturated in isopropyl ether and washed with pentane (26 g, 89%).
    [183] m.p. 209-211
    [184] 1 H NMR (DMSOd 6 , 200 MHz): δ: 8.59, s, 1H, NH; 8.32, s, 1 H, CH; 8.15, m, 2H, aromatic H; 7.89, s, 1 H, NH; 7.64, m, 2H, aromatic H
    [185] Step 3: 2-Aminomethylbenzothiophene ( I )
    [186] To a suspension of LiAlH 4 (33.5 g, 0.88 mol) in tetrahydrofuran (100 mL) is added a suspension of H (26 g, 0.146 mol) in tetrahydrofuran (500 mL) and the mixture is refluxed for 6 hours. do. The reaction medium is then cooled to 0 ° C. and excess LiAlH 4 is removed (33 mL of H 2 O, 33 mL of 5 moles sodium hydroxide and 99 mL of H 2 O). After filtration and concentration, the crude product obtained is purified on silica column (dichloromethane and 4/1 dichloromethane / methanol) to give 13 g (56%) of oil.
    [187] 1 H NMR (DMSO-d 6 , 200 MHz): δ: 7.65, m, 2H, aromatic H; 7.12, m, 2H, aromatic H; 7.08, s, 1 H, CH; 5.46, m, 2H, NH 2 ; 4.60, d, 2H, CH 2
    [188] Step 4: 2- (aminoiminomethylamino) ethylbenzothiophene hydrochloride
    [189] A solution of I (11 g, 0.067 mol), 1- (aminoiminomethyl) pyrazole hydrochloride (9.8 g, 0.067 mol) and isopropanol (50 mL) is refluxed for 24 hours. The reaction medium is concentrated and the crude solid is recrystallized from water (7 g, 41%).
    [190] m.p. = 163-165 ° C
    [191] 1 H NMR (200 MHz): δ: 8.44-7.26, m, 9H, aromatic H and exchangeable H; 4.70, d, 2H, CH 2
    [192] 13 C NMR (DMSO-d 6 , 50 MHz): δ: 157.56, 141.73, 139.49, 139.36, quaternary C; 124.90, 124.76, 123.88, 122.88, 122.68, aromatic CH; 40.28, CH 2
    [193] Tables 1a to 1d summarize the formulas and features of the compounds of formula (I).
    [194]
    [195]
    [196]
    [197]
    [198] The results of the pharmacological study will be given below.
    [199] Antidiabetic Activity Studies in NOSTZ Rats
    [200] In an experimental model of insulin-independent diabetes mellitus induced in mice using streptozotocin, the oral antidiabetic activity of the compound of formula (I) was confirmed.
    [201] Neonatal injection of streptozotocin into mice (on birth day) yields a model of insulin-independent diabetes.
    [202] The diabetic rats used were eight week old rats. The animals are housed in animal cages at controlled temperatures of 21 to 22 ° C. from birth to the day of the experiment, and in a fixed cycle of light (7 am to 7 pm) and darkness (7 pm to 7 am). Supply. Their diet consists of a maintenance diet, which is "optionally" watered and fed, except for fasting two hours before the test, during which the food is removed (post-absorption).
    [203] Mice are treated orally with test products for one day (D1) or four days (D4). Two hours after the last dose of the product and the animal was treated with pentobarbital sodium (Nembutal) 30 minutes after anesthesia), 300 μl of blood sample is taken from the end of the tail.
    [204] As an example, the obtained results are shown in Table 2. This result shows the efficacy of the compound of formula (I) in reducing blood glucose in diabetic animals. This result is expressed as the percent change in blood glucose at D1 and D4 (days of treatment) relative to D0 (prior to treatment).
    [205]
    权利要求:
    Claims (15)
    [1" claim-type="Currently amended] Compound of Formula (I):
    Formula (I)]
    (Wherein
    A is a group of:
    Branched or straight chain (C 1 -C 20 ) alkyl,
    -R2
    -H,
    Branched or straight chain (C 1 -C 5 ) alkyl,
    -(C 3 -C 8 ) cycloalkyl, or
    -Benzyl
    OR2 representing
    R3 and R4 are independent of each other
    -H,
    Branched or straight chain (C 1 -C 20 ) alkyl,
    -Benzyl,
    Acetyl,
    -(C 3 -C 8 ) cycloalkyl
    Indicates or
    Or NR3R4, optionally wherein R3-R4 together form a 3- to 8-membered ring containing a nitrogen atom,
    -R5
    -H,
    Branched or straight chain (C 1 -C 5 ) alkyl,
    -(C 3 -C 8 ) cycloalkyl, or
    -Benzyl
    SR5, indicating
    Halogen
    -Cyano
    Nitro
    -R6
    -H or
    Branched or straight chain (C 1 -C 5 ) alkyl
    CO 2 R6, or
    Trifluoromethyl
    A benzene or pyridine ring optionally substituted by one or more of
    X represents a -CH =, -CH 2- , -N = or -NH- radical,
    Y is a CH 2 radical, oxygen or sulfur atom, or R 7 is
    -H,
    Branched or straight chain (C 1 -C 5 ) alkyl, or
    -Benzyl,
    -(C 3 -C 8 ) cycloalkyl, or
    -CH 2 CO 2 H group
    Represents a -NR7 group,
    R1 is a group of:
    -H,
    Branched or straight chain (C 1 -C 5 ) alkyl,
    -Benzyl
    Represents one of
    but,
    a-A represents a benzene ring, X represents -CH = or -CH 2- , Y represents an oxygen atom and R1 is a hydrogen atom;
    b-A represents a benzene ring substituted at the position 5 'of a double ring having a halogen atom, X represents -CH =, Y represents a sulfur atom and R1 is a hydrogen atom,
    c-A represents an unsubstituted benzene ring, X represents -CH 2- , R 1 is a hydrogen atom or a branched or straight chain (C 1 -C 5 ) alkyl radical and Y is R 7 a hydrogen atom, a branched chain or NR7 representing a straight chain (C 1 -C 5 ) alkyl radical or benzyl radical,
    d-A represents an unsubstituted benzene ring, X represents -CH =, except for compounds of formula (I), wherein R1 represents a hydrogen atom and Y represents NR7 where R7 represents an ethyl radical),
    And also tautomers, enantiomers, diastereomers and epimers, solvates and pharmaceutically acceptable salts.
    [2" claim-type="Currently amended] The method of claim 1,
    A compound of formula (I), wherein the alkyl radical is a C 1 -C 5 alkyl radical.
    [3" claim-type="Currently amended] The method according to claim 1 or 2,
    A compound of formula (I) wherein A represents an optionally substituted benzene ring.
    [4" claim-type="Currently amended] The method according to any one of claims 1 to 3,
    A compound of formula (I) wherein Y represents a -CH 2 -radical, a sulfur atom or a -NR 7 group.
    [5" claim-type="Currently amended] The method of claim 4, wherein
    A compound of formula (I), wherein Y represents a sulfur atom and A represents a monosubstituted benzene ring at a position other than the 5 'position of the double ring, a benzene ring substituted with two or more groups.
    [6" claim-type="Currently amended] The method of claim 4, wherein
    A compound of formula (I), wherein Y represents a -NR7 group and A represents a substituted benzene ring.
    [7" claim-type="Currently amended] The method according to any one of claims 1 to 3,
    A compound of formula (I), wherein Y is an oxygen atom, X represents a -CH = radical or a -CH 2 -radical, and A is a substituted benzene ring.
    [8" claim-type="Currently amended] The method according to any one of claims 1 to 3,
    A compound of formula (I) wherein Y is an oxygen atom and X represents an -N = or -NH- radical.
    [9" claim-type="Currently amended] Compound of Formula (II):
    [Formula (II)]
    (Wherein A, X, Y and R1 are as defined in claim 1)
    Method for producing a compound according to claim 1 comprising the step of reacting with a guanidylating agent.
    [10" claim-type="Currently amended] A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 as an active ingredient.
    [11" claim-type="Currently amended] Compounds of formula (I) for the manufacture of a medicament for the treatment of lesions associated with insulin resistance syndrome:
    Formula (I)]
    (Wherein
    A is a group of:
    Branched or straight chain (C 1 -C 20 ) alkyl,
    -R2
    -H,
    Branched or straight chain (C 1 -C 5 ) alkyl,
    -(C 3 -C 8 ) cycloalkyl, or
    -Benzyl
    OR2 representing
    R3 and R4 are independent of each other
    -H,
    Branched or straight chain (C 1 -C 20 ) alkyl,
    -Benzyl,
    Acetyl,
    -(C 3 -C 8 ) cycloalkyl
    Indicates or
    Or optionally NR3R4, wherein R3 and R4 together form a 3- to 8-membered ring containing a nitrogen atom,
    -R5
    -H,
    Branched or straight chain (C 1 -C 5 ) alkyl,
    -(C 3 -C 8 ) cycloalkyl, or
    -Benzyl
    SR5, indicating
    Halogen
    -Cyano
    Nitro
    -R6
    -H or
    Branched or straight chain (C 1 -C 5 ) alkyl
    CO 2 R6, or
    Trifluoromethyl
    A benzene or pyridine ring optionally substituted by one or more of
    X represents a -CH =, -CH 2- , -N = or -NH- radical,
    Y is a CH 2 radical, oxygen or sulfur atom, or R 7 is
    -H,
    Branched or straight chain (C 1 -C 5 ) alkyl,
    -Benzyl,
    -(C 3 -C 8 ) cycloalkyl, or
    -CH 2 CO 2 H group
    Represents a -NR7 group,
    R1 is a group of:
    -H,
    Branched or straight chain (C 1 -C 5 ) alkyl, or
    -Benzyl
    Represents one of),
    And also the use of tautomers, enantiomers, diastereomers and epimers thereof, solvates and pharmaceutically acceptable salts thereof.
    [12" claim-type="Currently amended] The method of claim 11,
    Use, characterized in that the lesion is diabetes.
    [13" claim-type="Currently amended] The method of claim 11,
    Use of said lesion is dyslipidemia.
    [14" claim-type="Currently amended] The method of claim 11,
    Use, characterized in that the lesion is obese.
    [15" claim-type="Currently amended] The method of claim 14,
    And said lesion is selected from atherosclerosis, retinopathy and neuropathy.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-03-21|Priority to FR0103843
    2001-03-21|Priority to FR0103843A
    2002-02-27|Application filed by 메르크 파텐트 게엠베하
    2002-02-27|Priority to PCT/EP2002/002094
    2003-11-07|Publication of KR20030086312A
    优先权:
    申请号 | 申请日 | 专利标题
    FR0103843|2001-03-21|
    FR0103843A|FR2822463B1|2001-03-21|2001-03-21|Bicyclic guanidine derivatives and their therapeutic applications|
    PCT/EP2002/002094|WO2002076963A1|2001-03-21|2002-02-27|Bicyclic guanidine derivatives and therapeutic uses thereof|
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