• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:

    公开号:SU1417796A3
    申请号:SU843826165
    申请日:1984-12-21
    公开日:1988-08-15
    发明作者:Шеффлер Герхард；Энгель Юрген；Яковлев Владимир；Никель Бернд；Тимер Клаус
    申请人:Дегусса Аг (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new compounds of the pyridine series, namely, pyridine-2-ethers or pyridine-2-thioesters of the general formula,.
    Rj
    H, -Lh ..
    Rl -V-X-lCH2) p-, cH2) m /
    where R and Rj, are independent of each other. ha hydrogen, halogen, cyano-5 nitro or amino group, or amino group substituted by halobenzyl. a residue or phenyl-C-C; a C-C-alkanoyl amino group; C-C-al-. a coxycarbonylamino group, a hydroxyl, C-C-alkoxy, carbamoyl group - or a MON- or di C-C4 alkylcarbamoyl group; R is hydrogen, straight-branched or branched, C., - Cj-alkyl, lower alkyl 5 substituted by halogen hydroxy, phenyl, Cs-Cj-cycloalkyl, lower alkoxy, lower dialkyl-amino, or a 153-di oxolan-2-yl -25 group, cyclohexyl, lower alkenyl, lower alkylcarbonyl or cyclohexyl-lower alkylcarbonyl;
    X - oxygen5 sulfur, SO or SO ,,;
    m 1, 2., 3, 4 | thirty
    p Oh, 1, 2 ,. 3 |
    R Oh, P 2j
    )P
    group, whether / NKg- hinukli-35
    dylny or tropanyl residue; or their acid additive salts, or pyridine-N-oxides with analgesic activity, 40
    The purpose of the invention is the development, on the basis of known methods, of a method of obtaining new compounds5 with pronounced analgesic activity and low toxicity, 45
    Examples c, General description of the methodology for Table 1-2 examples 1 through the use of the starting compound II,
    0.05 mol of 80% sodium hydride is suspended in about 30 ml of the specified anhydrous solvent (see TabLo 1). With stirring at room temperature, drop 0.04 mol of the corresponding alcohol of formula III (Y OH) or 0, 05 mol of the corresponding mercaptan of formula III ,. moreover, Y means SH (usually dissolved in the same solvent). Reaction proceeds with fission
    five
    0
    5 - - 0 5
    0
    35
    40
    45
    hydrogenas The mixture is heated to. If a mercaptan is used, then 0.05 mol of NaH is dissolved in 50 of the appropriate solvent and dissolved. At the end of the reaction, 0.05 mol of the corresponding chloropyridine is added dropwise (usually in this same absolute solvent, preferably at room temperature), and the reaction mixture is refluxed for several hours (3-6 hours). When mercaptan is used at 80-100 ° C. After cooling, it is hydrolyzed with water and the resulting aqueous solution is extracted several times with diethyl ether or methylene chloride. After drying over magnesium sulfate and filtration, the solvent is distilled off in a vacuum. The treatment can be carried out in three different ways. :
    A) purification of the residue by preparative silica gel column chromatography and, if appropriate, by subsequent salt formation, e.g.
    with isopropanol solution HC1;
    B) purification by distillation in vacuum and possible post-salt salt formation (as in PoA);
    B) if the obtained residue is not heavily polluted, then salt formation can be carried out without the preceding one. . cleaning
    The residue is dissolved in isopropanol and mixed with isopropanoic hydrochloric acid.
    The crystallized salt is filtered and recrystallized from a solvent.
    Thus, the partial compounds of the formula listed below are listed in the table below. 1 o
    (SNg),, (CH2),
    Nn,
    m
    Example 22. 6-Chloro-2- (N-2-Fensch-ethyl) -piperidnl (4) -oxy-pyridine
    To a solution of 8.2 g (0.04 mol) of N (2-phenylethyl) -4-hydroxypiperidone in 60 ml of absolute dimethylacetamide with stirring at room temperature, 1.3 g of 75% sodium hydride are added in portions. Next, add 5 , 9 g (0.04 mol) of 2,6-dichloropyridine The reaction mixture is heated for 8 hours at 120130 ° C. After that, it is cooled to room temperature and poured into about 300 ml of water. The quenched crystalline product is separated. After 1 hour of stirring in 2N aqueous hydrochloric acid, it is sucked off, washed with water, dried and recrystallized from ethanol. TPLo hydrochloride 253-254. ° Co
    Example 23 of 6-Hdor-2- (piperidil- (A) -ti-pyridine ”
    The reaction is carried out in the amphosphere of argon. 0.27 g of 80% sodium hydride (0.009 mol) is suspended in 10 ml of dimethylacetamide; cooled with ice and added 0.615 g (0.004 mol) of solid 4-mercapto-piperidine hydrochloro-
    Yes and stir 10 minutes. To this mixture then a solution of 0.588 g (0.004 mol) of 2,6-dichloropyridine in 5 ml of dimethylacetamide is added dropwise and the reaction mixture is stirred for 2.5 hours at room temperature. Treatment of the reaction mixture: while cooling, 25 MP of water are added, then 20 ml of methylene chloride is added, the organic phase is separated, the aqueous phase is shaken 2 times with 15 ml of methylene chloride, the combined organic phases are washed twice with water with 10 ml each time dried over sodium sulfate, the solution is concentrated on a rotary evaporator, the residue is mixed with 10 ml of ab
    30 exceed 25 ° С. The injected hydrogen sulphide is absorbed in a commercial solution of sodium hypochlorite, - Upon completion of the addition, the cooling bath is removed and left to stand overnight
    salute ethanol and concentrate again. 1.5 ml of yellow are obtained at about 35 room temperature. Then the liquids, which are purified by colo-reaction mixture of about 60 minutes of night chromatography on 60 g of silica gel, (column filling height 400 mm, diameter 22 mm). Elute the mixture
    heated by uninterrupted elevation of the temperature to 80 ° C and left at this temperature for 2 hours.
    In order to lower the condenser in a weak vacuum (100 Torr), the isopropane is distilled off.
    850 ml of chloroform, 150 ml of ethanol and 10 MP of concentrated aqueous ammonia,
    The product decapitated after removal of the eluent is diluted with 10 ml of ether, an equivalent amount of HCl in isopropanol is added dropwise and the mixture after addition of seed for crystallization is left to stand for a few hours in the refrigerator
    To a solution of 1026 g (9.066 mol) of freshly distilled 1-methyl-PIPerdine- (4) in 1.5 l of isopropanol, hydrogen sulfide is passed through with intensive current with stirring. Temperature, reaction- The mixture is maintained at 10–15 s. Excess hydrogen sulfide is absorbed in a normal solution of sodium hypochlorite,
    After passing for about 2 hours, the reaction product begins to crystallize from the solution. The carbonation is continued for 2 hours. Thus, the obtained 1-methylpiperidine-4-bis (hydrosulfide) -hydrate is sucked off, further washed twice with 300 ml of cold isopropanol and twice with 500 ml of diethyl ether. The substance is stored in a desiccator over phosphorus pentoxide in the dark and needs to be quickly further processed,
    350 g (9, -23 mol) of powdered sodium borohydride are suspended in 2.5 L of isopropanol. While mixing, 1396 g are added in portions.
    (7.7 mol) 1-methylpipe15idin-4-bis- (hydrosulfide) hydrate. The reaction proceeds exothermically cooled in an ice bath, the temperature should not
    exceed 25 ° C. The injected hydrogen sulphide is absorbed in a commercial sodium hypochlorite solution. After the addition is complete, the cooling bath is removed and left to stand overnight.
     room temperature. Then the reaction mixture is about 60 minutes
     room temperature. Then the reaction mixture is about 60 minutes
    is heated by uninterrupted raising the temperature to 80 ° C and left at this temperature for 2 hours. When using a descending cooler in a weak vacuum (100 Torr), further isopropane is distilled off.
    The pasty residue is cooled to about ffla temperature and then mixed with 1.5 liters of diethyl ether. The suspension is well stirred. With further cooling, 740 ml of ice water is slowly added dropwise. After being dripped at
    nike The crystallized hydrochloride-50P is half the amount of water; the 6-chloro-2- (piperidyl- (4) -thio) -filled flask is again a difficult to mix paste-like consistency. Further additive
    , Ridine is filtered off with suction, washed with ether and dried under vacuum of an oil pump at, T, mp, hydrochloride 132-1ЗЗ С
     water again leads to a better mixing and distinct separation between the organic phase and the inorganic residue of borane. Stop stirring and the ether phase is separated. The residue is mixed 3 times with 500 ml.
    4-mercaptopiperidine (hydrochloride) can be prepared, for example, starting from 1-methyl-piperidinone- (4) as follows.
     water again leads to a better mixing and distinct separation between the organic phase and the inorganic residue of borane. Stop stirring and the ether phase is separated. The residue is mixed 3 times with 500 ml.
    with fresh ether The combined organic phases are dried over magnesium sulphate. After the filterer, the solution is concentrated under reduced pressure on a rotary evaporator. The residue is subjected to vacuum distillation. Due to its low boiling point (Tokip, GO-AO With 2 mm or Rto steel), 1 methyl 4-mercapto-piperidine is trapped in a vessel cooled by a mixture of methanol and dry with ice, To a solution of 65.5 g (0.5 mol) of 1 methyl 4-mercapto-piperidine in 300 ml of acetone with stirring 59.5 g (0.56 mol) of chloroethylformate, under stirring 1-methyl 4-ethoxycarbonylmer hydrochloride Captopiperidine is thus isolated in the form of a crystalline product and along windows The reaction is filtered off with suction and washed with acetone and evaporated. A base is added to the aqueous solution of the salt; a concentrated aqueous solution of ammonia is added. Ethereal: the solution is dried, the mixture is filtered with Na SO j and the mixture is distilled. ° С 12 mm рТССТс
    To a solution of 100 g (0.48 mol) of 1 methyl 4-ethoxycarbonyl mercapto-piperidine heated to 90 ° C in 106 ml of toluene, 106.3 g (mol) of chlorofortil formate are added dropwise with stirring for 30 minutes. -110 ° C. After re-addition, 40 g of chloroethyl formate is heated for an additional 3 hours. After standing overnight at room temperature, the mixture is suction filtered from a glass fiber into the solution and concentrated on a rotary evaporator. The residue is distilled. 120 g of mercapto-piperidine „is obtained. Tokip 138-140 ° C mm Hg
    269.7 g (Is, 032 papa) of 1-ethoxycar ™ bonil 4-ethoxycarbonyl5ercapto ™ pipa ™ of ridine is dissolved in a mixture of 886 ml (10.3 mol) of concentrated aqueous hydrochloric acid and 443 ml of ice acetic acid. stirring for 1 h, boil with reverse cold, DILNIKOM
    After 60 hours of reaction, the solution is concentrated on a rotary evaporator,
    For TorOj, in order to remove the residual mixture of solvents, the crystalline residue is mixed 2 times in 200 ml each with isopropanol. After that, the solvent is distilled off. The resulting 4-mercapto-piperidine hydrochloride recrystalline
    66
    lick off ethanol. T „pl.183-184 ° C (decomposition). The yield is 117.6 g and rises after treatment of the mother liquor by 27.5 g; this is about 96% of theory.
    Example 24 of 6-chloro-2-N-methyl-piperidyl (4) -thio-pyridine-N-oxide, 4.9 g (0.03 mol) of 2,6-dichloro-pyridine M-oxide is added to the solution of 4j5 g (0.035 mol) of N-methyl-4-mercapto-piperidine in 20 ml of ethanol The piperidine compound is in the form of sodium salt and is prepared preliminarily with the help of 11.9 g (0.035 mol) of a 20% sodium methoxide solution. The reaction mixture is heated to 50 ° C and left for 3 hours at this temperature. Then the reaction mixture is distilled.
    approximately 200 ice water, and a crystalline substance precipitates. It is sucked off, repeatedly washed with additional water, dried and recrystallized from
    ethanol. T, pl. 129-130 С,
    The starting material, 2,6-dichloropyridine N oxide, is prepared, for example, as follows: A solution of 16 g (0.108 mol) of 2,6-dichloro-pyridine and
    17 g of 35% perhydrol (respectively, 5.9 g of active HgOj, approximately 05.17 mol) and 250 g of trifluoroacetic acid are heated for 8 hours in a water bath. The internal temperature is about 75 ° C. After that, the solution is poured into 1.5 liters of water. This precipitates a small amount of crystalline product, which I
    It is unchanged 2,6-di-.
    chlorine-pyridine after it is removed, the solution is concentrated further in a vacuum of a water-free pump at the Tei-inepara bath 30–35 ° C. The liquid residue is dissolved in 500 ml of shoroform and
    anhydrous potash is added to it with stirring; until gasification stops and, moreover, until water is bound. The mixture is filtered at a temperature of 30-35 ° C and concentrated in a small vacuum to dryness. 2 5 b-d-chloro-pyridine-M-oxide is obtained as a crystalline residue, mp 137-138 ° C.
    Example 25, Preparation from a compound On, where Z is SH or OH, and compounds Ilia, where Y is halo
    A mixture of 0.06 mol of the compound form IvIly Ilia, where Y is halogen, and.
    71
    0.06 mol of 6-chloro-2-mercapto-pyridine-sodium salt, for example, in 60 ml of n-; propanol is boiled under reflux for several hours (for example, 6 hours) with stirring. After cooling, remove from the insoluble residue. The solution is concentrated and the syrupy residue is acidified with isopropanol hydrochloric acid. After dilution with acetone, the hydrochloride crystallizes. The crystals are concentrated, washed with acetone and then with water. Further purification is carried out by recrystallization
    From 9.3 g of N-metsh-2- (2-chloroethyl) -piperidine and 9, 6 g of 2-sodium mercapto-6-ghlor-pyridine in this way, 2- (2) -H-methylpiperidyl (2) -ethylmercapto- 6-x-pop-pyridine. M.pLo hydrochloride 165-167 ° C; Recrystallization is carried out from a mixture of ethanol and ether.
    The compounds according to Examples 13-16, TabLo 1, are additionally also prepared as follows.
    6-Chloro-2-mercapto-pyridine can be obtained, for example, as follows
    103.1 g (0.70 mol) of 2,6-dichloropyrid and 110.0 g (2 x 0.70 mol) of sodium bisulfide x HjO (71%) and c. Are added to 700 ml of n-butanol. Altogether, the mixture was heated under reflux for 10 hours. At 35 ° C, suction was carried out and the filtrate was evaporated in vacuo at (170 g of residue). The residue is stirred with 1 l of ether and left to stand overnight. The resulting solid (sodium salt) is filtered off with suction, washed well with ether and dried under vacuum for 24 hours at 35 ° C.
    Examples 24-46 (Table 2) refer to the introduction of the residue Rj into compounds of the formula I, where Rj is hydrogen, by alkylation or acylation.
    General methods for examples 24-43
    The amine of formula I, where R is hydrogen, is boiled under reflux with a halide of the formula HalRz (excess halide 10-300 mol -,%) and a base (2-6 times excess) in a solvent for several hours (until until further control is carried out by thin layer chromatography; no further reaction takes place. After cooling, filtering
    177968
    sedimentation and concentration by removal of the solvent, further processing is carried out in the usual manner by means of salt formation; In some cases chromatographic purification on silica gel is required.
    The compounds of the formula thus obtained
    ten
    C1
    X s
    are listed in table 2
    For the compounds of Examples 40 and 44, the melting point cannot be indicated. Instead, the corresponding Rf values are given to characterize these compounds. For compound of Example 40, Rf 0.79; for the compound of Example 44, Rf 0.50,
    In both cases, the eluting agent: chloroform, methanol, 25%
    NHj in the ratio 95: 4: 1,
    The conditions under which Bbmie was determined for the Rf values, are as follows. The determination of the Rf value occurred in the chamber with saturation of the chamber at room temperature; stationary phase: silica gel with a layer thickness of 0.25 mm (a layer of type 60 F 254, E Merck is ready); amount of substance applied mg; eluent: chloroform, methanol, 25% NHj
    (95: 4: 1); 14 cm solvent run.
    Identification was performed using the following 1x special coloring agents: ultraviolet, 254 nm; iodine
    HC1, 25%,
    Example 46, (2,3-Dioxy-propyl) -piperidyl- (4) -thio-6-chloropyrIDINo
    4.85 g (0.0212 mol) of 2-piperidyl) - (4) -thio-6-chloro-pyridine (free base) along with 1.4 ml of glycide and 40 ml of isopropanol are boiled for 5 h. Isopropanol solution concentrate and mix with 6 ml of isopropanolic HC1, the hydrochloride crystallizes slowly about T, III, hydrolide 115-12GS
    Example 47, 2-K-methylpiperidyl) - (4) -oxy-3-acetylamino-6- (4-fluoro-benzylamino) -pyridine,
    To paCjTBOpy after hydrogenation of 0.025 mol of 2-H-metsh1piperidyl- (4) - hydroxy-3-amino-6- (4-fluorobenzylamino) - pyridine, which is obtained by hydrating9 .14
    In order to extract 4.5 g (0.025 mol) of the corresponding 3-nitro compound in 125 MP dioxane in the presence of a palladium-carbon catalyst at 60 ° C and a pressure of 5 bar under nitrogen atmosphere, 1.8 ml of acetyl chloride was added. The hydrochloride precipitate is precipitated out at the bottom and, with the help of sodium hydroxide solution, the base is extracted in the usual way. So pl hydrochloride 188-190 ° C.
     Example 48. 2-C-Methylpiperidyl (4) -oxide-3-ethoxycarbonyl-amino-6- (4-fluorobenzyl-amino) -pyridine „
    After hydrogenation of 0.02 mol of 2-tN-methylpiperidyl- (4) - hydroxy-3-amino-6- (4-fluorobenzylamino) pyridine to the solution, which is obtained by hydrogenation of 7.2 g (0.02 mol) of the corresponding 3- nitro compounds in 125 ml of dioxane in the presence of a palladium-on-the-catalyst at 60 ° C and a pressure of 5 bar, 4 ml of ethyl chloroformate, acid is stirred at room temperature for 1 1/2 hours under stirring and under nitrogen atmosphere, the solution is concentrated and the residue is stirred with a mixture of benzap ether in a ratio of 1: 1, the crystallized substance is sucked off and recrystallized from methanol. M.p. di-hydrochloride 202-207 C,
    The free base is obtained from dihydrochloride, for example, by treatment with a solution of sodium hydroxide. Base temperature 168-169 ° G (without recrystallization)
    Examples 49-55 (table, 3). These examples relate to the exchange of the methyl group in the piperidine ring of the compounds of formula I () for the ethoxycarbonyl group and to the subsequent cleavage of the latter,
    General technique
    0.09 mol of the compound of the formula I, where it is dissolved in 30 ml of todol-vodka and with stirring for about 30 minutes they are dropped onto a solution of 0.18 mol of ethyl chloroformic acid in 30 ml of toluene heated to 85 ° C. The mixture is filtered and the solution is concentrated to dryness for 6 hours. The resulting N-carboethoxy product, as a rule, is no longer purified and used in
    779610
    as a raw product. The crude product (compound of formula-1, where Rj CG-OCjHj-) is dissolved in a mixture of 80 g of concentrated aqueous hydrochloric acid and 40 ml of glacial acetic acid. Boil for 15 hours under reflux. Then it is concentrated to dryness, the residue is mixed with isopropanol and concentrated again. The solid residue is purified by recrystallization. The resulting compounds of the following formula
    15
    R.
    NH
    listed in tabLoZ.
    Example 56. Methyl exchange
    groups of the PIPERIDINE ring on ethoxycarbonyl and cleavage of the latter.
    6-Chloro-2 piperidyl- (4) -thio-piperidine-M-hydroxy.
    A solution of 3.5 g of 2- (1-methylpiperidine-4-mercapto) -6-chloropyridin-N-oxide in 20 ml of chloropryphenylic acid ethyl ester is heated under reflux with stirring. After 3 h
    the next 20 ml of ethyl chloroformic acid ester is added (3 times in total). In general, therefore, 9 hours are heated. After that, it is concentrated to dryness. The solid residue is recrystallized from ethanol. In this manner, the resulting 6-chloro-2-N-carbe topo-piperidyl- (4) -thio-pyridine melts at 151-152 ° C.
    . 2.4 g (0.0075 mol) of carbethoxiso, combine with 7.6 g of concentrated HCl (0.075 mol) and 5 ml of glacial acetic acid for 16 hours while being stirred, heated under reflux,. Then the solution is concentrated and the crystalline residue is mixed with 25 ml of methanol. Evaporated to dryness again. After this, the residue is dissolved in the required amount of methanol at the boiling point. After the addition of kieselguhr, it is filtered and mixed with ether until the beginning of turbidity. 6-Chloro-2-piperidyl- (4) -thioZ-pyridine-N-hydroxyhydrochloride crystallizes out. After standing for 1 h in the ice bath, it is sucked off, washed with acetone and dried. TC Sh1, hydrochloride 232-233 C (decomposition),
    11141779612
    Example 57. 2-K-Methyl-ipnic phase The solvent is distilled off
    Ridyl- (4) -oxy-3-nitro-6- (4-fluoroben-in vacuo, the crystalline residue of zylamino) -pyridine, is purified by column chromatography
    31 g (0.114 mol) of 2-CH-methylpiperi-5 Phy on silica gel (eluorized as middle-dil- (4) -oxy-3-nitro-6-chloropyridine, methanol: ammonia 90: 9: 1). 15.6 (0.125 mol) of 4-fluorobenzylamine, Two substances are injected: 400 mg of sulfo-34.5 MP (0.125 mol) of triethylamine, m.p., 123-124 ° C; 2.3 g of sulfoxia 70 ml of isopropanol for 7 hours. yes, t, pl. 136-137 ° C, boiled with a reverse cold air cooler; 10 Sulfone can be prepared, for example.
    The precipitate after cooling in high yield is obtained in the following way,
    the triethylammonium chloride is separated and the uterine base 3 g (0.012 mol) of the 2-K methyl methyl solution is concentrated in vacuo with a ryd- 1 (4) -thioz-6-chloropyridine solution. In this way, 30 ml of crystalline acetic acid crystallizes out free base, ko-15 lots. Under stirring, they are thawed on the bottom of the pump and dried at 40 ° C with a solution of 3.5 g (0.022 mol) of TLO 90-94 ° of potassium caltsenmanganate in 50 ml of water (in teP p. And measure 58, 2-N-Methylpiperidine). 60 min.) At the end of the addition, (4) -oxy-3-amino-6- (4-fluorobenzyl) is heated for 2 hours at 0 ° C, Obramino-pyridine 20 and the resulting precipitate is filtered and
    4.5 g (0.0125 mol) of a 2-1Y-mets1-solution is concentrated to dryness, Poluperidyl- (4) -oxy-3-nitro-6- (4-fluorochlorine, crystalline benzylamino) -pyridine and 0, 6 g of palladium residue is stirred with ether and suspended on active carbon (5%) is suspended. So pl, 124-125 ° C
    rut in 125 ml of dioxane and for 25 approx 60, 6-oxy-2-piperi-5 hours at 60 ° C and a pressure of 5 bar hydride-1- (4) -thio-pyridine (cipher code D18 219). mortgage equipment for hydrogenation. After removal of the catalyst is mixed with an excess amount of isopropanol - Q
    HClo's foot. The precipitated dihydrochloride 30 is sucked off on a nucch and the recrystallized 6-ethoxy-2-piperidip- (4) -thiol is extracted from ethanol with the addition of unsaturated pyridine together with 10–15 times the amount of ether O. With a quantity of 36% water, soda 245-248 hydrochloric acid is boiled with a reverse solution. Example 59, “2-N-Methylpipot- 35”, until a good amount of salt (6) -thio -6- chlorpyridinesulfono-control using thin-layer
    xid and sulfoHo chromatography, no longer detect 5 g (0.018 mol) of 2-N-metric type of any ethoxy compound (several- (4) -thio-6-chloropyridine hydrochloric acid, for hours). After cooling, the evaporation is dissolved in 50 ml of methanol, 40 is heated under vacuum and the residue is recrystallized with 1N, the aqueous hydrochloric acid is acidified from ethanol. Yield 47%, T, mp, you set. Pour in pH 4 and the solution of 284 ° С, dihydrochloride.
    heat to 50 Co. With stirring. Preparation of Compounds with a total form of 2.4 g (approximately 0.021 mol). . 2.4 g (approximately 0.021 mol) are dropped to 45
    30% HjOj, Reaction mixture on-jl2 l / -
    warm to a boil. After about „S- / NH
    2 h again add 2.5 g of 30% 2 -
    HjOj After 16 hours of reaction, the excess
    HjOj is destroyed by addition of the concentrate. The general method of the method for the tried-on formic acid, 4, when using the initial thief is concentrated at room temperature compound II.
    Perature and syrupy residue. To 0.02 mol of 4-mercapto piperidine, it is dissolved in a small amount of hydrochloride suspended in 30 water. Using concentrated gg 50 ml of anhydrous solvent, added sodium hydroxide solution is made alkaline with 0.04 mol of NaH or methylate the base has become ri. In this case, the temperature should not be by repeated extraction with a temperature exceeding 30 ° Cs. It is stirred with additional ether. After drying, it is preferably ½ h. Then at room temperature
    N-Ls-NH
    ep 60, 6-Oxy-2-p-pyridine (code D18
    hydroxy-2- piperidip- (4
    N-Ls-NH
    31417796
    0.02 mol of the corresponding 2-chloropyridine is added to the temperature (discussed in the same anhydrous solvent, 10-30 ml). Partially exothermic reaction occurs. The mixture is stirred for several hours at room temperature until the boiling temperature is maintained under reflux until the control by thin layer chromatography shows further reaction. After cooling, the solvent is distilled off in vacuum, the residue is dissolved in water and the solvent ( preferably in ether or dichloromethane) and the phase of the pa; The aqueous phase is extracted once more, the combined organic phases, after drying over magnesium or sodium sulphate, are evaporated in vacuo. The treatment can be carried out in two different ways. A) purification-residue using preparative column chromatography on silica gel and, in limestones, subsequent salt formation, for example, with a solution of HCl in isopropanol or with the help of another acid; B) if the obtained residue is not heavily polluted, then direct salt formation can be carried out. In certain cases, it is still necessary to overlap
    Analgesic effect of compounds I.
    Method Description
    Haffner test.
    Experiments (tests) were carried out, by the guidance of: Haffner method. As a painful irritation, the arterial clip was attached to the base of the mouse tail. The test substances were administered orally together With a Methpcel carrier (commercially based on methylcellulose) in the form of an aqueous suspension, The number of animals that for 30 s did not show a painful reaction (nibbling the terminal), expressed as a percentage of the total number of animals in the group, gives an analgesic effect in the dose indicated.
    Electrical pain test / test for pain caused by electric current.55
    By the guidance of the method, individual targets were placed in the arena, where they were irritated through the grid on the floor.
    po for
    g ne da roll about
    10 in the room
    pr, bo
    15 sec
    C.T. and
    20 D1
    not wa
    25 pr in and l
    30 CD gi
    that
    35 uk ak si
    40 F
    ri; po
    50 g
    14
    until the animals began to respond with a sound expression (vocalization) about Ispx ye fye substances were injected
    orally together with a carrier (methyl cellulose-based pass-through carrier) in the form of an aqueous suspension. The control group received, as the case may be, the same amount of suspension, which contained only Methocel.
    The analgesic effect of substances at the indicated dose in the form of an increase in the pain threshold (in mA) compared to
    with the control group expressed as a percentage
    Comparison of the analgesic action of C. I of compounds I in the Haffner test and the electric pain test with the compound
    D1126, are given in table. 5.and 6
    The toxicity of the compounds when tested on white sheets, which is indicated in the form of the CD500 Methodology.
    Determination of oral toxicity when tested on white mice was made using the installation of Miller and Tainter. The observation time was 24 hours.
    Tickness is indicated as a CD. is the dose leading to the death of 50% of experimental animals.
    The results of the experiments are given in table. 7
    Thus, these data indicate a high analgesic activity of compounds I and the low toxicity of these compounds.
    Formula of invention

    1c. Method for the preparation of pyridine-2-ethers or pyridine-2-thioethers of the general formula
    .with",,
    independently of each other hydrogen, halogen, cyano, nitro, or amino group or amino group substituted by a halogenbenzyl residue or a phenyl-C-C 4. -alkyl residue, C-C-alkanoylamino group; C-Cr-alkoxy where R and RJ 15. , 1A
    carbonylamino, hydroxyl, C-C4-alkoxy, carbamoyl group or mono- or di-CJ-C-alkylcarbamoyl group;
    - hydrogen, unbranched or branched, C-C-alkyl, lower alkyl, halogen-substituted hydroxyphenyl, CJ-C-cycloalkyl, lower alkoxy, lower dialkylamino, or 1,3-dioxalan-2-yl group, cyclohexyl, nizy alkenyl, lower alkylcarbonyl or cyclohexyl-lower alkyl-carbonyl;
    - oxygen, sulfur, SO or
    - 1, 2, 3, 4; .
     O, 1, 2, 3;
     O, 1, 2;
    grouping
    x CHzbv
    - quinuclidyl or
    tropanil residue; or their acid additive salts, or pyridine-N-oxides, differing
    so that the connection is about- jl

    where R and RJ have the indicated meanings; Hal-halogen, or its pyridine-N-oxide is reacted with a compound of the general formula
    R N / R
    (CH2) p-Y
    where n, m and p have the indicated meanings; R has the indicated values of the city, or means an amino-protecting group; Y is hydroxy or mercapto;
    and the target product is converted or, if necessary, transferred to sul1779616
    backgrounds or sufoxides, remove the amino-protecting group and the resulting compounds are selected in free form, or in salts, or pyridine-K-oxides 2, Method of producing pyridine-2-ethers or pyridine-2-thioethers of the general formula
    ten
    ,,, ± Y--
    five
    0
    five
    0
    five
    0
    where R and R, j are independently of each other hydrogen, halogen, cyano, nitro, amino group or amino group, substituted by a halogen-benzyl residue or a phenyl-C-C-alkyl residue, canoem footpra, C f-C. an alkoxycarbonylamino group, a hydroxyl group, a C-C alkoxy group, a carbamoyl group, or a mono- or alkyl car bamoid group;
    RJ-hydrogen, unbranched or branched, - C —C-alkyl, lower alkyl, substituted by halogen, hydroxy,: phenyl, C —C-cycloal-KIL-, lower alkoxy, lower dialklamino or 1,3-dioxxP1an A -2-yl group, cyclohexyl, lower alkenyl, lower alkylcarbonyl or cyclohexyl-lower alkylcarbonyl; oxygen, sulfur, SO or SO,
    five
    X -.
    m 1,2, 3, 4; n O, 1, 2, 3; P Oh, 1. 2;
    0
    grouping
    -
    sn) „
    tCHaln,
    NRs
    a quinuclear or tropanilic residue;
    55
    or their acid additive salts, or pyridine-K-oxides, characterized by the formula
    that connection
    where R and RJ have the indicated meanings; Z - hydroxyl - or mercapto, or its pyridine-N-oxide
    subjected to interaction with the compound of the General formula
     n, m and p have the indicated meanings;
    Rj has the indicated meanings, with the exception of hydrogen, or means an amino-protecting group; Y is halogen, C — C-alkylsulfonyloxy or arylsulfonyloxy,
    and the target product is reduced or, if necessary, converted into sulphons or sulfoxides, the amino-protecting group is removed, and the resulting compounds are incorporated in free form, or p as salts, or pyridine-X-oxides,
    Table
    i: L :: riini: i: i a :: i ::: z:
    ..J
    16 6-Cl
    b-CH,
    6-OSS
    6-B 5-C1
    3-C1
    n n n
    n
    S
    Note: DMSO dimethylsuppoxide; DMF dimethylformamide} DMAC
     dimethylacetamido Stroke (-) in the Alc column means that Alk group is absent here

    Maleates were obtained using isopropanol solution
    maleic acid

    Maleates were obtained using maleic acid in acetone and recrystallized from ethanol,
    .Table 2
    26
    (sn,) 27 CHjCH CHj
    28 CHjCHjOH
    29 CHjCHjCO: i ::: z:
    ..J.
    in 184-187
    DMSO
    216-218 dihydr cooled
    165-167 198-199
    134-136 maleate
    125-126 maleate
    T.plo, C
    -TEA
    TEA
    wal NaHCOj
    TEA
    TEA
    K, CO,
    TEA TEA TEA
    Maleat
    Oxalate
    Base
    HC1
    HC1
    Oxalate
    Oxalate
    HC1
    Oxalate
    126-127 134-136
    67-70 169-173 172-175 175-178 155-1-56 203-205
    160
    35 CH, CH (CH.) -CH,
    36 CHjCHjCHjF
    CHjCHjCHjNCCHj)
    - (N)
    COCHj
    COCHjCH- / H /
    CH, -
    / 0-1
    (CH.) JCH (
    43 (CH, h)
    and
    44 (CHj) j-CbCH3
    Note: TEA triethy amine DMAC dimethylacetamide,
    i: i: i: ii: i:
    3
    NaHCOjMaleate135-136
    NaHCO, HC1167-169
    NaHCO, HC1273-277
    NaHCOj / KjCO HCl205-206
    TEAObased210-215
    KjCOj Foundation, co.NS1173-175

    Chansoz / Oxalat 176-178
    TEANS1198-201
    DMAC / toluene NaHCO, / Base - - / K, SOZ
    Table 3 That PP., C 219-220 - 144-145 132-133 256-257 243-244 211-212 201-202
    23
    1417796
    24 Tabli.tsa 4
    27
    D18219
    D17555 D17556
    1417796
    28 Continuation of table 5
    Table 6
    19.5 31.6 15.8
    50
    50
    ten
    20
    29
    1417796
    30 Continuation of table 6
    31141779632
    Continued tabLo 7
    权利要求:
    Claims (2)
    [1]
    1 D 16 218 210 4 D 16 277 More 200 5 D 16 903 More 200 6 D 16 904 More 200 8 D 16 938 More 200 9 D 17 002 95 10 D 17 092 More 150 12 D 16 222 75 thirteen D 16 294 180 14 D 16 300 More 200 fifteen D 16 481 More 200 16 D 16 586 142 17 D 17 244 More 200
    Continuation of table 0 7
    2 u ---- 1-----—- y—18 1 D 17 256 More 150 19 D 17,298 More 200 20 IN 17,299 More 200 21 D 17,379 More 200 23 IN 16 949 90 24 D 18 050 More 120 25 D 17 003 More 100 26 IN 16,819 More 100 27 D 17 104 27.0 28 D 17 114 More 100 , thirty D 17 180 175 31 D 17 183 More 150 32 IN 17,240 More 200 33 D 17,242 More 100 34 D 17 243 More 200 ‘ 35 IN 17 251 More 200 36 D 17 254 More 200 37 D 17 255 More 200 38 IN 17 259 More 150 39 D 17,260 More 200 40 IN 17,261 More 200 41 IN 17,295 More 150 42 D 17 348 More 100 44 D 17 356 155 45 D 17 384 More 200 46 IN 17 168 More 120 47 D 17 030 More. 200
    141779-6 p. , * Continuation of taol. 7
    g. T t 3 48 D 17 031 More than 200 49 D 17 007 fifty fifty D 16 818 120 .51 D 16 949 90 52 D 17 097 More than 100 53 D 17 258 160 54 B 17 355 More than 150 56. D 18,086. More than 150 57 D 16 948 More than 150 58 D 17 002 95 59 D 16 924 More than 150
    fox)
    59 In 16 background) 928 (sul- More 150 D 18 219 More 150 D 17 555 More 200 D 17 556 More 100 D 17 562 More 120 ¥D 18 271 More 160 D 18 328 More 150 D 18 414 More 120 D 18 432 More 150 D 18 529 More 180 D 18 5.87 More 170 D 18 604 More 160 D 18 614 Bohlen 200 D 18 616 More 160 D 18 147 More 150 D 18 586 More 200
    Continuation of the table. 7
    1 2 35 sn 2 sn (sn 3 ) -sn 3 36 ch 2 ch 2 ch 2 f 37 sn 2 sn 2 sn 2 n (sn 3 ) 38 - <th> 39 pine 3 40 SOSN 2 CH- ^ n) 41 sn, - <] 42 (CH ^ CH / 0 !: 43 <cn d ) 44 (sc 2 ) g -sc 3 45 Wh> D17555 - (sn 2 ) g- sn 3 D 1755.6 - (cn 2 ) 2 -c <^ | D17562 -sn (sn 3 ) 2
    - - ---—3 r --- 1 6 1DMAC / toluene NaHC0 3Maleate 135-136 DMAC / toluene NaHC0 3HC1 167-169 DMAC / toluene NaHC0 3HC1 273-277 DMAC / toluene NaHCO 3 / K 2С0 3 НС1 205-206 Dioxane Tea Base 210-215 Dioxane to 2 from 3Base - - dmdzh K 2 CO 3HC1 173-175 Toluene NaHCO 3 / / to 2 s 3Oxalate 176-178 Dioxane Tea HC1 198-201 DMAC / toluene NaHC0 3 / / K 2 CO 3Base · Toluene NaHC0 3HC1 208-210 Dioxane Triethylamine Oxalate 148 Toluene / DMA to 2 from 3Oxalate 167-168 Dioxane Triethyl Oxalate 153-155
    amine
    With a sword e: TEA = triethylamine; DMAC = dimethylacetamide,
    Table 3
    Example T '~ t ! 1eleven1 Ieleveneleven1! Salt That pl., ° 49 ' 6-C1 ABOUT HC1 219-220 '' '' fifty 6-C1. S Maleate 144-145 51 6-C1 S HC1 132-133 52 n S • 2НС1 256-257 53 6-CH 3S 2НС1 243-244 54 5-C1 S HC1 211-212 55 3-C1 S HC1 201-202
    R 1 eleveneleven1 1 SO I1 feleveneleveneleven1 ιeleveneleven1_________________J Solvent Cleaning option Salt Table 4 Mp. ° C Exit,% Cipher 3-conh 2-. DMA B Base 172-173 41 D18271 4-CONH 26-C1 Bottom A Oxalate 242-243 thirteen D18328 6-NH-CH 2 -  - . DMA B. 2НС1 193-196 36 D18414 z-sleep (s 2 n ^ 2- DMA B Oxalate 130-132 34 D18432 4-CONH-CH 36-C1 DMA B Maleate 169-171 14 D18529 z-os 2 n 5- • DMA B 2-HC1 159-161 40 D18587 3-cn - DMA B HC1 227-230 26 D18604 5-NO 2- DMA B Maleate 148-153 23 D18614 z-os 2 n 5 6 -Cl DMA B HC1 239-242 75 D18616Ethanol A HC1 237-239 22
    Table 5
    Connection example Electric painDose, mg / kg orally oh test% actionaction Haffner-tesaDose, mg / kg orally % actions D 1126 fifty 0 fifty 0 125 fifteen 100 33 283 fifty 173 fifty 1 fifty 31 8 fifty ' 4 fifty 16 - - 5. '-. · - 71 fifty 6 - - 71 fifty 8 fifty 31. - - 9 - - fifty 20 10 - - fifty 60 12 fifty fifty
    25 1417796 26
    Continuation of the table "5
    Connection example Electric pain test Haffner Test Dose, ng./kg orally X action Dose, mg / hg orally X action thirteen 87 fifty 29th fifty 14 fifty 14 100 fifty fifteen 14 fifty - 16 10 fifty 14 fifty 17 fifty 23 fifty 80 18 fifty 16 fifty 100 19 18 fifty 10 fifty 20 fifty 14 fifty thirty 21 fifty 20 fifty thirty 23 3 fifty 4 fifty 24 fifty 18 fifty 20 25 fifty 19 20 fifty 26 20 43 20 20 27 9 fifty 12 fifty 28 thirteen fifty eleven fifty 29th fifty 10 fifty fifty thirty 5 4 warpfifty 7 fifty 31 fifty 54 fifty 40 32 fifty 25 fifty thirty 33 7 fifty eleven fifty 34. 6 fifty 8 fifty 35 10 fifty 1 ° fifty 36 8 fifty 6 fifty 37 fifty thirty - - 38 8 fifty fifty 70 39 fifty 44 fifty 10
    Continuation of Table 5
    Connection example Electro-test Haf peg test. Dose mg / kg X action Dose mg / kg X d her 3 orally action orally action
    40 fifty 21 fifty 41 32 fifty 9 fifty 42 eleven fifty 17 fifty 44 9 fifty 12 fifty 45 20 fifty 22 fifty 46 25 fifty 33 fifty 47 fifty 22 -  - 48 fifty 18 fifty thirty 49 eleven fifty 7 fifty fifty 7 fifty 7 fifty 51 3 fifty .4 fifty 52 20 thirty 20 67 53 10 fifty fifty 90 54 49 fifty '39 fifty 57 fifty 28 - - 58- fifty 20 59 20 10 20 . 20 (sulfoxide) 20 37 20 20 (sul
    _____
    Table 6
    Cipher Electric pain test Haff peg test From table 2 From table 4______ Dose, mg / kg orally X actionaction Dose, mg / kg orally X action
    D18219 fifty 19.5 fifty 10 D17555fifty 31.6 - -
    D17556
    15.8
    thirty
    Continuation of Table 6
    Cipher Electric pain test Bump test From table 2 From table 4 Dose, mg / kg. Orally X action Dose, mg / kg orally X action D17562Jfifty 56.6 fifty thirty D18271 fifty 20.1 - - D18328 fifty 27.1 10 10 D18414 fifty 52,2 fifty 20
    D18432 fifty fifteen* “ D18529 fifty ' 26 47 fifty D18604 fifty 45.6 fifty 40 D18614 68 fifty 28 fifty D18618- fifty thirty
    Table 7
    Connection example
    Cipher
    CDy 0 , mg / kg (oral administration)
    1 2 3 4 P 6 7 8 G “ 10 16 6-C1 n S2 and2 DMSO in 184-187 17 6-CH, n S - 2 2 DMSO B 216-218 dihydrochloride 18 b-osn 3n S - 2 2 DMSO B 165-167 19 6 — B n S - 2 2 DMSO IN 198-199 20** 5-C1 n S - 2 2 Toluene IN 134-136maleate 21 ** 3-C1 n S - 2 2 DMSO IN 125-126maleate
    Note: DMSO = dimethyl sulfoxide; DMF = dimethylformamide; DMAC = dimethylacetamido The dash (-) in the Alk column means that the Alk group is absent here ”
    Maleates were obtained using an isopropanol solution of maleic acid "
    Maleates were obtained with maleic acid in acetone and recrystallized from ethanol,
    Table and 2ExampleR 3 Solvent Main connection Salt Mp ", ° C l · 1. ' I Ieleveneleveneleveneleveneleveneleveneleveneleveneleven1 №1eleveneleveneleveneleveneleven111111 3 I 1eleveneleveneleven1 4> |eleveneleveneleveneleven 5 - 6 26 (sn 2 ) H§> Dioxane Tea Maleate126-127 27 sn 2 sn = sn 2Dioxane Tea Oxalate134-136 28 sun 2 sun 2 he Xylene to 2 from 3Base 67-70 29th cn 2 cn 2 co ^ H ^ Dioxane Tea HC1169-173 zo C 3 H 7Dioxane Tea HC1172-175 31CH 2- ©> Dioxane Tea Oxalate175-178 32 to - C 6 N AND DMAC / toluene NaHCO 3Oxalate155-156 33C 2 H 5 Dioxane Tea HC1203-205 34 CH (CH 3 ) 2Dioxane Tea Oxalate160
    Continuation of Table 2
    1 6 backgrounds or sulfoxides, remove the amino-protecting group and the resulting compounds are transferred in free form, or 5 in the form of salts, or pyridine-N-oxides.
    2o. A method for producing pyridin-2-ethers or pyridin-2-thioethers of the general formula J_ 0'X- (CH2) p- < ( (™ 2 2} n m> Ν-Β ”carbonylamino group, hydroxyl, C 1 -C 4 alkoxy, carbamoyl group or mono- or di-C ( -C £ - alkylcarbamoyl group;
    R 3 is hydrogen, unbranched or branched, C T -C ^ -alkyl, lower alkyl, substituted by halogen hydroxyphenyl-, Cj-C-cycloalkyl, lower alkoxy-, lower dialkylamino, or 1, 3-dioxolan-2-yl group cyclohexyl, lower alkenyl, lower alkylcarbonyl or cyclohexyl lower alkylcarbonyl;
    X is oxygen, sulfur, SO or SO;
    m = 1, 2, 3, 4; π = 0,1, 2, 3;
    p = 0, 1, 2;
    grouping
    -When R 1 and R, are independently hydrogen, halogen, 15 cyano, nitro, amino or amino group substituted by a halogenbenzyl radical or a phenyl-C 1 -C 4 alkyl radical 20, C., - C 4 - alkaline nails of Uppa, C f -C 4 -alkoxycarbonylamino group, hydroxy, C 1 -C 4 ~ alkoxyl, · carba25 moyl group or mono- or di - ^ - C ^ -alkyl carbamoid group-quinuclidyl or tropanilic residue; or their acid addition salts, or pyridine-H-oxides, characterized in that the compound of the general formula wherein R f and R have the indicated meanings; The halogen, or pyridine-Noxide thereof, is reacted with a compound of general formula pa;
    R 3 is hydrogen, straight or branched, C ^ -C ^ -alkyl, lower alkyl substituted by halogen, hydroxy-, phenyl-, C ^ -C ^ -cycloalkyl-, lower alkoxy-, lower dialkylamino or 1,3-dioxolane- 2-methyl group, cyclo: hexyl, lower alkenyl, lower alkylcarbonyl or cyclohexyl lower alkylcarbonyl;
    X is oxygen, sulfur, SO or / (CH 2 ) P ^ (CH 2 ) P > - (CH 2 ) pY
    so 2•9 m = 1, 2 3 4; n = 0 1, 2 3; P = 0 1" 2j
    where n, w and p have the indicated meanings;
    R 3 has the indicated meanings, with the exception of hydrogen, or means an amino protecting group;
    Y — hydroxy or mercapto grouping V ′ 4CH 2 ) n j ′ z 5 “quinuclide or tropanilic residue;
    Group ;
    and the target product is added or, if necessary, converted into sully of their acid addition salts, or pyridine-N-oxides, characterized in that the compound of the general formula where R and R have the indicated values;
    Z is a hydroxyl or mercapto group, or its pyridine-N-oxide is reacted with a compound of the general formula wherein n, m and p have the indicated meanings;
    R 3 has the indicated meanings, with the exception of hydrogen, or means an amino protecting group;
    Y is halogen, a C 4 -C 4 -alkylsulfonyloxy or arylsulfonyloxy group, and the target product is isolated or, if necessary, converted to sulfones or sulfoxides, the amino protecting group is removed and the resulting compounds are removed in free form, or in the form of salts, or pyridin-N- oxides.
    Table 1
    134-136
    DMSO
    6-C1
    6-C1
    6-C1
    6-C1
    6-C1
    3-NH
    N
    6-C1
    6-C1
    6-C1
    6-C1 s no 2
    DMSO
    DMAC
    DMAC
    DMF
    DMSO
    DMSO
    DMSO
    DMSO
    DMSO
    3-n0
    3-NHCQCH
    Tropanil- (3) residue Hinuclidyl (3) residue
    Dioxane
    Dioxane
    Dioxane
    110-113
    147-148
    168-169
    214-216
    245-250
    240-241
    226-230
    250-251
    241-243
    155-157
    132-134 (maleate)
    G.
    110-112 maleate
    1417796 20
    Continuation of table 1
    1. A method of producing simple pyridin-2-ethers or pyridin-2-thioethers of the general formula where R 1 and R 2 are independently hydrogen, halogen, cyano, nitro, or a dose.
    An electric pain test / electric pain test.
    Guided by the method, individual mice were placed in an arena in which they were irritated through the grate on the floor with electric current. The current type was increased to the amino group or amino group substituted by a h55 logenbenzyl radical or phenyl-C 1 -C + alkyl radical,
    A C 1 -C 4 alkanoylamino group; C 4 -C 4 alkoxy 1,5
    [2]
    2 3 D 17 182 More than 180 D 17 384 More than 200 D 17 451 More than 150 D 17,519 More than 120 D 18 329 More than 150 D 18 433 More than 160 D 17,586 More than 50 D 17 863 . More than 120 D 17 637 More than 140
    D 1126
    1530
    Editor> N. Kishtupinets Compiled by I. BocharovaTehred L., 0lynyk Proofreader M. Demchik
    Order 4081/59 Circulation 370 Subscribed
    VNIIIPI of the USSR State Committee for Inventions and Discoveries
    113035, Moscow; Zh-35, Raushskaya nab., D. 4/5
    Production and printing company, Uzhhorod, st. Project, 4
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1417796A3|1988-08-15|Versions of method of producing pyridine-2-ethers or pyridine-2-thioethers or acid-additive salts thereof,or pyridine-n-oxides
    US5877187A|1999-03-02|Benzimidazole derivatives with antihistaminic activity
    DE69730490T2|2005-09-29|AMINO-ETHEROCYCLIC COMPOUNDS AS ANTITHROMBOTIC OR ANTICOAGULATING AGENT
    SU1375127A3|1988-02-15|Method of producing derivatives of 1.2-diaminocyclobutene-3.4-dion or chlorohydrates thereof
    US5599830A|1997-02-04|Sulphorous derivatives of imidazole and their use as medicaments
    PT91351B|1997-01-31|METHOD FOR THE PREPARATION OF ALCOXY-4- | -PYRIDONE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
    TWI654172B|2019-03-21|Cycloalkyl formic acid derivatives, preparation method thereof and application thereof in medicine
    RU2168508C2|2001-06-10|Benzonitriles and benzofluorides, method of their synthesis, pharmaceutical composition, method of its preparing
    JP2003528046A|2003-09-24|Phenoxypropanolamines, their preparation and therapeutic use
    IL123600A|2001-05-20|2| quinolone derivatives, their preparation and their use in therapy
    EP0722942A1|1996-07-24|Indole piperidine derivatives
    EP0937711A1|1999-08-25|Thiobenzamides, process for their preparation and medicaments containing them
    CZ20014302A3|2002-03-13|Sulfonylamino derivatives, process of their preparation and pharmaceutical preparations in which they are comprised
    JP2004513125A|2004-04-30|N-type calcium channel antagonists for the treatment of pain
    MX2013006974A|2013-10-07|Asymmetric ureas and medical uses thereof.
    DE60215313T2|2007-06-14|INDOIND DERIVATIVES AND THEIR USE AS GNRH ANTAGONISTS
    CA2254974A1|1997-11-27|Antagonists of gonadotropin releasing hormone
    RU2738844C2|2020-12-17|Containing a substitute, which is butane, in the heterocyclic ring a pyridone derivative for treating fibrosis and inflammatory diseases
    EP0206225A2|1986-12-30|Indole derivatives
    EP0203435A2|1986-12-03|Novel pyridine derivatives and process for preparing the same
    DE4324393A1|1995-01-26|4-aryloxy and 4-arylthiopiperidine derivatives
    EP0121716B1|1987-12-09|Indole derivatives
    PL144341B1|1988-05-31|Method of obtaining new heterocyclic compounds
    EP0008652A1|1980-03-19|New intermediates and their use for the preparation of new oxadiazolo-pyrimidine derivatives
    US4124587A|1978-11-07|4-Hydroxy-3-sulfinyl-quinolin-2|-ones
    同族专利:
    公开号 | 公开日
    GB2152048B|1987-11-11|
    PT79736A|1985-01-01|
    NO164237C|1990-09-12|
    DD231354A5|1985-12-24|
    PT79736B|1986-12-30|
    FI845126A0|1984-12-27|
    KR850004755A|1985-07-27|
    FI845126L|1985-06-29|
    IL73608A|1987-12-31|
    GB2152048A|1985-07-31|
    FI84062C|1991-10-10|
    ES539076A0|1986-05-16|
    ZA848275B|1985-08-28|
    EP0149088B1|1989-01-18|
    DK613384A|1985-06-29|
    DE3476205D1|1989-02-23|
    DE3443968A1|1985-10-31|
    ES8607014A1|1986-05-16|
    NO845250L|1985-07-01|
    AU3699684A|1985-07-04|
    KR870000354B1|1987-03-05|
    GB8432162D0|1985-01-30|
    US4643995A|1987-02-17|
    AT40131T|1989-02-15|
    FI84062B|1991-06-28|
    DK613384D0|1984-12-20|
    IL73608D0|1985-02-28|
    HU194209B|1988-01-28|
    CN85101353A|1986-10-15|
    EP0149088A1|1985-07-24|
    JPS60169476A|1985-09-02|
    AU566560B2|1987-10-22|
    HUT36115A|1985-08-28|
    GR82596B|1985-04-29|
    NO164237B|1990-06-05|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    BE630125A|
    GB1041342A|1962-03-27|1966-09-07|Degussa|New pyridine derivatives|
    GB1054338A|1963-07-11|
    FR4674M|1964-06-05|
    GB1306139A|1970-08-06|1973-02-07|
    US3905984A|1971-03-09|1975-09-16|Smith Kline French Lab|Pyridyl substituted thioalkyl-and oxyalkyl-thioureas and ureas|
    FR2187317B2|1972-06-07|1975-06-20|Hexachimie|
    US3947463A|1972-06-22|1976-03-30|Cassella Farbwerke Mainkur Ag|Certain 2-amino-nicotinonitrile derivatives|
    US3956294A|1972-06-22|1976-05-11|Cassella Farbwerke Mainkur Aktiengesellschaft|Substituted pyridine compounds|
    US3980659A|1972-06-22|1976-09-14|Cassella Farbwerke Mainkur Aktiengesellschaft|Certain 6-amino-4-hydrocarbyl-nicotinamides|
    US3954782A|1972-06-22|1976-05-04|Cassella Farbwerke Mainkur Aktiengesellschaft|2,6-Hydrazino-3-pyridine carboxyamides|
    US4061642A|1972-06-22|1977-12-06|Cassella Farbwerke Mainkur Ag|2,4,6-Trisubstituted-3-pyridine carboxamides|
    US3946024A|1972-06-22|1976-03-23|Cassella Farbwerke Mainkur Ag|2-Hydrocarbyloxy-pyridine compounds|
    DE2549999C2|1975-11-07|1989-01-26|Boehringer Mannheim Gmbh, 6800 Mannheim, De|
    DE2905876A1|1979-02-16|1980-08-28|Boehringer Mannheim Gmbh|NEW PIPERIDINOPROPYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    US4203990A|1979-04-30|1980-05-20|G. D. Searle & Co.|Anti-diarrheal 2-substituted quinuclidines|
    FR2459240B1|1979-06-21|1982-10-22|Cm Ind|
    DE3045688A1|1980-12-04|1982-07-08|C.H. Boehringer Sohn, 6507 Ingelheim|NEW 8-ARYLALKYL-3-PHENYL-3-NORTROPANOLE, THE ACID ADDITION SALTS THEREOF, THE MEDICINAL PRODUCTS CONTAINING THE SAME AND METHOD FOR THE PRODUCTION THEREOF|
    IT1190942B|1982-08-04|1988-02-24|Poli Ind Chimica Spa|COMPOUND WITH ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY, ITS PREPARATION PROCEDURE AND RELATED PHARMACEUTICAL COMPOSITIONS|ZA836994B|1982-09-30|1984-05-30|Robins Co Inc A H|Fused aromatic oxazepinones and sulfur analogs thereof|
    DK623586A|1985-12-27|1987-06-28|Eisai Co Ltd|PIPERIDE INGREDIENTS OR SALTS THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE COMPOUNDS|
    US4853027A|1986-09-08|1989-08-01|E. I. Du Pont De Nemours And Company|Phytotoxic 2-alkyl-5--pyrrole-3,4-dicarboxylates|
    EP0287908A3|1987-04-18|1989-12-27|ASTA Medica Aktiengesellschaft|Nitrogen-containing cycloaliphatic compounds having an aminacid radical and a pyridine ring|
    GB8718445D0|1987-08-04|1987-09-09|Wyeth John & Brother Ltd|Pyridyl-ethers|
    CA1307790C|1987-08-04|1992-09-22|Ian Anthony Cliffe|Ethers|
    FR2655649B1|1989-12-12|1994-07-08|Adir|NOVEL PIPERIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|
    MX9100517A|1990-08-06|1992-04-01|Smith Kline French Lab|COMPOUNDS|
    IL107184A|1992-10-09|1997-08-14|Abbott Lab|Heterocyclic ether compounds that enhance cognitive function|
    US5914328A|1992-10-09|1999-06-22|Abbott Laboratories|Heterocyclic ether compounds useful in controlling neurotransmitter release|
    US5948793A|1992-10-09|1999-09-07|Abbott Laboratories|3-pyridyloxymethyl heterocyclic ether compounds useful in controlling neurotransmitter release|
    ZA9610741B|1995-12-22|1997-06-24|Warner Lambert Co|4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists|
    ZA9610736B|1995-12-22|1997-06-27|Warner Lambert Co|2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists|
    ZA9610738B|1995-12-22|1997-06-24|Warner Lambert Co|Subtype selective nmda receptor ligands and the use thereof|
    ZA9610745B|1995-12-22|1997-06-24|Warner Lambert Co|4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists|
    US5629325A|1996-06-06|1997-05-13|Abbott Laboratories|3-pyridyloxymethyl heterocyclic ether compounds useful in controlling chemical synaptic transmission|
    US6437138B1|1996-06-06|2002-08-20|Abbott Laboratories|3-pyridyloxymethyl heterocyclic ether compounds useful in controlling chemical synaptic transmission|
    US6133253A|1996-12-10|2000-10-17|Abbott Laboratories|3-Pyridyl enantiomers and their use as analgesics|
    EP1034174B1|1997-11-05|2003-08-13|Neurosearch A/S|Azaring-ether derivatives and their use as nicotinic ach receptor modulators|
    US6632823B1|1997-12-22|2003-10-14|Merck & Co., Inc.|Substituted pyridine compounds useful as modulators of acetylcholine receptors|
    PE20000728A1|1998-06-26|2000-08-21|Cocensys Inc|HETEROCYCLES 4-BENZYL PIPERIDINE ALKYLSULFOXIDE AND THEIR USE AS SUBTYPE-SELECTIVE NMDA RECEPTOR ANTAGONISTS|
    WO2001019817A2|1999-09-14|2001-03-22|Abbott Laboratories|3-pyrrolidinyloxy-3'-pyridyl ether compounds useful for controlling chemical synaptic transmission|
    DE10000739A1|2000-01-11|2001-07-12|Merck Patent Gmbh|New piperidine and piperazine derivatives which are antagonists of certain serotonin receptors, are useful in treatment of, e.g. eating disorders, stroke, anxiety or Parkinson's disease|
    US6436916B1|2000-10-12|2002-08-20|Alvin Guttag|Ibuprofen-aspirin and hydroxymethylacylfulvene analogs|
    WO2003062224A1|2002-01-17|2003-07-31|Eli Lilly And Company|Aza-cyclic compounds as modulators of acetylcholine receptors|
    GB0220581D0|2002-09-04|2002-10-09|Novartis Ag|Organic Compound|
    MXPA05007485A|2003-01-14|2006-01-30|Arena Pharm Inc|1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia.|
    EP1638965A1|2003-06-24|2006-03-29|NeuroSearch A/S|Novel 8-aza-bicyclo¬3.2.1|octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors|
    AR045047A1|2003-07-11|2005-10-12|Arena Pharm Inc|ARILO AND HETEROARILO DERIVATIVES TRISUSTITUIDOS AS MODULATORS OF METABOLISM AND PROFILAXIS AND TREATMENT OF DISORDERS RELATED TO THEMSELVES|
    AU2005252211A1|2004-06-04|2005-12-22|Arena Pharmaceuticals, Inc.|Substituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto|
    AR049401A1|2004-06-18|2006-07-26|Novartis Ag|AZA-BICICLONONANS|
    GB0415746D0|2004-07-14|2004-08-18|Novartis Ag|Organic compounds|
    DOP2006000010A|2005-01-10|2006-07-31|Arena Pharm Inc|PROCEDURE TO PREPARE AROMATIC ETERES|
    MY148521A|2005-01-10|2013-04-30|Arena Pharm Inc|Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto|
    US7413805B2|2005-02-25|2008-08-19|Fry's Metals, Inc.|Preparation of metallic particles for electrokinetic or electrostatic deposition|
    DK1931654T3|2005-09-16|2009-07-27|Arena Pharm Inc|Metabolic modulators and treatment of disorders related thereto|
    GB0521508D0|2005-10-21|2005-11-30|Novartis Ag|Organic compounds|
    GB0525673D0|2005-12-16|2006-01-25|Novartis Ag|Organic compounds|
    GB0525672D0|2005-12-16|2006-01-25|Novartis Ag|Organic compounds|
    PT2018380E|2006-05-19|2012-01-17|Abbott Lab|Cns active fused bicycloheterocycle substituted azabicyclic alkane derivatives|
    TW200811147A|2006-07-06|2008-03-01|Arena Pharm Inc|Modulators of metabolism and the treatment of disorders related thereto|
    TW200811140A|2006-07-06|2008-03-01|Arena Pharm Inc|Modulators of metabolism and the treatment of disorders related thereto|
    UA99620C2|2007-05-23|2012-09-10|Мерк Шарп Энд Доме Корп.|Pyridyl piperidine orexin receptor antagonists|
    WO2010048013A1|2008-10-21|2010-04-29|Merck Sharp & Dohme Corp.|2,5-disubstituted morpholine orexin receptor antagonists|
    WO2010048010A1|2008-10-21|2010-04-29|Merck Sharp & Dohme Corp.|2,5-disubstituted piperidine orexin receptor antagonists|
    CA2739919A1|2008-10-21|2010-04-29|Merck Sharp & Dohme Corp.|2,4-disubstituted pyrrolidine orexin receptor antagonists|
    CN103539791B|2010-09-22|2017-01-11|艾尼纳制药公司|Modulators of the GPR119 receptor and the treatment of disorders related thereto|
    AR088352A1|2011-10-19|2014-05-28|Merck Sharp & Dohme|ANTAGONISTS OF THE RECEIVER OF 2-PIRIDILOXI-4-NITRILE OREXINE|
    CN107405332A|2015-01-06|2017-11-28|艾尼纳制药公司|Treatment and S1P1The method of receptor related illness|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3347276|1983-12-28|
    [返回顶部]