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    • 专利摘要:
    Imidazolylethoxy derivatives of pyrazolo-[3,4-b]pyridine-5-methanols having the general formula <IMAGE> and their acid addition salts are useful as antifungal and antibacterial agents.
    公开号:SU873884A3
    申请号:SU792782862
    申请日:1979-07-09
    公开日:1981-10-15
    发明作者:Хен Ганс
    申请人:Е.Р.Сквибб Энд Санз Инк.(Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING IMIDAZOZOLYLETHETHYPRYAZOLO SZ DERIVATIVES, 4-. L PYRIDIN-5-METHANOLS
    The invention relates to a hemispirazolo 3,4-Upiriain-5-methanol method for the production of new production imiazapnleto compounds of the formula I, OR THEIR SULIUM 2
    GUE R - hydrogen, lower alkyl, phenyl, phenyl-lower alkyl or cyclone alkyl;
    R-, R., Rc and Rjj- each hydrogen, lower
    alkyl or phenyl;
    I. - voorots, OXI-, lower apcoxy-, lower alkylthio, phenrXI-, or phenyl-lower alkoxygroup, halogen {group-o
    -K:
    Rio
    where Rg and each hydrogen, lower
    alkyl, phenyl ...
    16 or substituted phenyl ,. the phenyl substituent is halogen, hydroxy, lower alkoxy, lower alkyl, mercapto, lower alkylthio, cyano or nitro;
    20H- and R - each vozzoroa, halogen,
    OXI-, lower alkoxy-, lower alknltio-, lower alkyl or nitro-grupa, their salts, which have antifungal or antibacterial activity and can be used in mepicin. 8 In the literature, there is a known method for the alkylation of oxo-mutations with halo-oxychloro- gam compounds with the formation of an ester bond from. The aim of the invention is a process for the preparation of novel imidazolyl ethoxypyrazolo 3,4-b tfnaine-5-methanol or their salts, which have antifungal or antibacterial activity. The proposed method for the preparation of compounds of formula 1, based on a reaction known in organic chemistry, consists in the fact that the compound Formula X, where chlorine, bromine or iodine, is reacted with the compound of Formula L1 Wb I ii-dHz-cI-OH where Ri. Tl have the indicated meanings. The compounds of formula I form salts of non-toxic physiologically acceptable representatives. The bases of formula I form salts by reacting with one or more equivalents of any of a wide variety of common inorganic and organic acids, providing acid addition salts, including, for example, hydroxy halides (especially hydrochloride and gtzbobromid), sulfate, nitrate, borate, phosphate, oxalic acid salt, tartaric acid salt, maleic acid salt, citrate, acetate, aksorbat, succinic acid salt, benzenesulfonate, methane sulfonate, nickel hexanesulfonate and toluene sulfonate. Acid addition salts are often a convenient means for isolating and purifying a product, for example, by forming and precipitating a salt (which are not necessarily non-toxic) in a suitable medium in which the salt is insoluble, then after separating the salt by neutralization with a base, such as barium hydroxide or calcium hydroxide to obtain a free base. Other salts may then be formed from the free base by reaction of g with one or more equivalents of an acid containing the desired acid group. The novel compounds of the formula I and their salts are useful as antifungal agents and can be used to fight infection in various mammalian mammals such as mice, rats, dogs, guinea pigs and the like, especially for organisms such as qtbicans .Tr cViomonas raojinaCis or TH f -Vioph iion mentoc3jrcipt -kes. For example, a compound or a mixture of a scientific research institute of the formula I, or their physiological acceptable acid addition salt, can be administered orally by an infected animal, for example, mice in an amount of about 5 to 25 mg / kg per day, in 2-4 individual doses. They can be converted into preparations in the form of tablets, capsules or elixir containing 10-250 mg per dosage unit, by mixing the active substance or substances with a conventional carrier, binder, protective agent, flavor, etc. It is preferable to apply them, for example, topically by intravaginal (intrauterine) administration, in the form of locen, or in the form of conventional cream and concentrations of 0.01– 3 wt.% In a period of about 3–7 tons from two ao four times daily. Example. 4-Chloro-5- | 1- (2,4-dichlorophenyl) -2- (1H-imvdazol-1-yl) -oxy hydroxy-methyl-1-ethyl-3-methyl-1H-pyraole-3,4-b1 pyridine, hydrochloride. A. 4-Chloro-5-chlorometh-1-e-3-methyl-1H-pyrazolo 3, 4-b} is pyridine. To a three-necked flask with a stirrer, a reflux condenser and an addition funnel, 94.6 g of 4-chloro-1-ethyl-3-methyl-1H-pyrazole C3,4-ti3 pyridine-5-methanol (O, 42 mol) are added. While stirring, 745 ml of gionyl chloride was added by dropping over 45 minutes and the mixture was then heated under reflux for one and a half hours. The excess thionyl chloride is removed with a rotary evaporator and the residue is dissolved in benzene. The solvent is again removed and the remaining solid is triturated with ligrin, filtered and dried at 7 ° C, yielding 91 g of 4-chloro-5-chloromethyl-1-ethyl-1H-chfazolo, 4-6} ridine, which after per-crystallization 83.5 g of pure product is obtained from hexane (melting point 96-97 ° C). Evaporation of the ligroin uterine zhitsk and recrystallization of the residue gives a secondary collection of 5.7 g, a melting point of 95-9 bs, the total yield of 89.2 g (87%). B 4-chloro-5- {I l- (2,4-ai-chlorophenyl) -2 - (1H-imidazol-1 -yl) -ethoxy-methyl -1-ethyl-3-methyl-1H-pyrazolo Gs, 4 -B pyridine, TI hydrochloride 24.4 g of sodium hydroxide (0.61 mol and 23 ml of water) are introduced into a three-necked flask with a stirrer, a phlegmator, and a venting tube. The solution is cooled to 45 ° C while nitrogen is passed through the flask and then added 6.43 g of 1- (2,4-dichro-phenyl) -2- (1H-imidazol-1-yl) -ethanol (0.025 mol), 0.43 g of benzyltrimethylammonium chloride and 25 ml of tetrahydrofuran. To the mixture, which is heated to , a solution of 6.1 g of 4-chloro-5-chloromethyl-1-ethyl-3-methyl-1H-pyrazol GZ, 4-bJ-pyridine (0.025 1) in 10 ml of tetrahydrofuran from a pre-heated dropping funnel for 3 minutes, the mixture is vigorously stirred for 3 hours while using a water bath, then the warm mixture is transferred to a separating funnel, aqueous sodium hydroxide is extracted with 10 ml of tetrahydrofuran. dried with sodium sulfate; after removing the solvent, the residual oil is extracted with ether, treated with charcoal and filtered. To a solution of the free base is added dropwise 5.9 ml of ether with lactic acid (30.9%). Precipitated 4-hlLr-5- | G1- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) -ethoxy-3-methyl-1-ethyl-3-methyl-1H-pyrazolo GZ, 4-b pyricin hydrochloride is filtered off, dried in a vacuum desiccator and recrystallized from acetonitrile, melting point 200-201 0, yield 5.67 g (45%). P p i. m e r 2. 4-Chloro-5- | G1- (4-chloro-phenyl) -2- (1H-imindazol-1-ip -sTOKCHj-methyl -1-ethyl-3-methyl-1 H-Shfazopo 3, 4-pyridine, gitsrohlorvd. Follow the procedure of example 1B, but take 5.6 g (O, O25 Mol) 1- {4-chlorophenip) -2- (1 H-imidazol-1-yl) -3TaBOjja instead of 1- ( 2,4-dichlorofensh1) -2- (1 H-Kmidaaol-1-yl) -ethanopa, In case of example 1B, the cake product is graded. After cooling to room temperature, the slurry is sucked off into a sintered funnel. Then the solid is suspended in 4O ml of water, neutralized with acetic acid, filtered again, washed with water and dried at, recrystallization from acetonitrile gives 5.6 g (52%) of pure product, melting point 176-177c, K 5.4 of the product, 4-chloro-5- 1- - (4-chlorofesh) -2- (1H-imkatsazol-1-yl-ethoxy-methyl -1-ethyl-3-methyl-1Hr {sol-3,4-) pyridine dissolved in 15 ml of absolute alcohol and 5 ml of alcoholic hydrochloric acid (184 g of HCt / l) with weak heating, 120 ml of ether are added. The precipitated hydrochloride is filtered off after it has stood overnight, washed with a mixture of ether and alcohol (5: 1) and dried, yield 6.3 g (10 O%), melting point 184-185 ° C. 4-Chloro-5- - (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl) aTOKCvi -methyl | -1-ethyl-1H-pyrazolo Gz, 4-b pyridine, hydrochloride. A.4-Chlo {-5-chloromethyl-1-ethyl-1H-pyrazoloGs, 4-b3 pyridine. 150 ml of thionyl chloroxy is carefully added to 20 g of 4-chloro-1-ethyl-1H-pyraolo, 4-b pyridine-5-methanol (O, O094 mol) so that heat and moderate evolution of gas take place. The mixture was left overnight, and after the rotated time, the excess thionyl chloride was distilled off using a rotary evaporator and the residue was treated with ice. Crystalline 4-chloro) -5-chloromethyl-1-ethyl-1H-pyrazolo Cz, 4-b} pyridine is sucked off, washed with water and dried in a vacuum desiccator over phosphorus pentoxide, yield 19.7 g (91%), after recrystallization from hexane, melting point 73-74C. B.2-Chloro-5- - (2,4-dichlorophenyl) -2- (1H-imidaz6l-1-yl) -etoxp} -methyl -1-ethyl-1H-11irazolo 3,4-Ь pyridine, hydrochloride. 7.71 g of l- (2,4-dichlorophenyl) -2- (lH-imidazol-1-ShI) ethane (0.03 mol) and 6.9 g of 4-chloro-5-chloromethyl-1-tyl-1H -pyrazolo C3, 4-b pyridine (0.03 mol) was reacted according to the procedure of Example 1B. The combined tetrahydrate layers (ofuran are treated with charcoal and filtered. 25 O ml of ether is added to the tetrahydrofuran solution, the oily mixture is removed, which is removed by deantizing the solution. After the solution containing the free base is clarified by adding HufEO filter media, an excess of ethereal hydrochloric acid is added.The precipitated hydrochloride is allowed to settle for 2 hours, then filtered, washed with ether and dried in a vacuum desiccator, yield 8.3 g (61%). The product is recrystallized with 3N hydrochloride acid with wood coal. Thus obtained -4-.chloro-5 (4-cichlorophenyl) -2- (1H-ima-aoop-1-yl) -ethoxy-3-methyl-1-ethyl-1H-pyrazo o-C3, 4 -1g pyricin, hycrochloresis (1: 1) contains psmols of water; melting point; .1, 166-167 C. Example 4: 5- | 11- (2,4-Dichlorophenyl -2- (1H- imicazol-1-yl) ethoxy-1-methyl} -1-ethyl-3-methyl-1H-pyrazolo 13,4-L-pyriain, hydrochloride A. A. 1-ethyl-3-methyl-1H ethyl ester .pyrazolo 1314 -L PCAIN 5-carboxylic acid. To 8O, 3 g of ethyl 4-chloro-1-znl-3-methyl-1H-pyrazolo 3,4-b pyridine-5-carboxylic acid (, O, 3 mol) dissolved in 270 ml of glacial acetic acid, 33.4 g of triethylamine (0.33 mol) and 7.5 g of palladium on charcoal (10%) are added. The mixture is hydrogenated at room temperature and a pressure of 2.5 atm. After about 19 hours, the theoretical amount of hydrogen is absorbed. The catalyst is then filtered off and the filtrate is evaporated. The residue is treated with 2OO ml of water and extracted with ether. The combined ether extracts are dissolved and the ether is distilled off. The oily ethyl ester of 1-ethyl-3-methyl-1H-III-3-3,4-pyridine-5-carboxylic acid, after a short period of entropy, a yield of 64.5 g (92%) begins, i.e., 144-146 C V. 1 -5til-3-methyl-1H-pyrazolo 3,4-bzpyridin-5-methanol, hydrochloride. 49 g of 1-ethyl-3-methyl-1H-pyrazole GZ, 4-1) 2-carboxylic acid ester is dissolved in 25 O ml of anhydrous tetrahydrofuran. . Nitrogen was passed through a flask while stirring and cooling with tap water. 6 g of lithium aluminum hydride (0.16 mol) was added in small portions to maintain the reaction temperature. Stirring is continued for an additional 3 hours at room temperature. Then 3N hydrochloric acid (380 ml) was added while the flask was cooled with ice water and the turbid solution was evaporated in vacuo. The residue is dissolved in B 95 ml of hot water and the solution is left to stand for 2 days. Zakrio talloviak product (8 g, melting point O7-2O8S) discarded. The aqueous, fine liquid is extracted in 3 portions of 1OO ml x Ip. The combined expr &amp; hlfopho {x4a is dried with sodium sulfate and evaporated in vacuo. The resulting mass of the oily crystalline scatters is removed; washed with an adonitryl and dried at 70 ° C, yield 10 g (21%) of 1-ethyl-3-methyl-1H-pyrazolo 3, 4-b1-pyridine-5-methanol, hydrochloride 1: 1), melting point 169-170 s. A sample recrystallized from acetonitrile is melted at 170-171 ° C. , C.5-Xpormethyl-1-etyp-3-methyl-1H-piraaolo-3,4-pyridine, hyarochlorits (1: 1). To 11 g of 1-9Tyl-3-methyl-1H-pyrazolo 3,4-bzpyridin-5-methanol (0.057 mol) dissolved in 50 ml of anhydrous benzene, 55 ml of thionyl chloride are added dropwise. The white suspension formed by this reaction is further stirred for 3 hours at room temperature. Then the slurry is filtered off with suction, washed with benzene and dried at 7 ° C, yield 6.6 g of 5-chloromethyl-1-methyl-3-methyl-1H-chfazolo C3,4-b3 pyridine, rdr ochloride (1: 1), melting point 154-157 C. Evaporation of the mother liquor, dissolving the residue in chloroform and removing ris1; the solvent gives an additional 7.4 g (melting point 152-154 ° C; total yield 14 g (10 O%), D. 5- {G1- (2,4-Dichlorophenyl ) -2H- (1H-imicyzol-1-yl) -etrxy2-methyl -1-ethyl-3-methyl-1H-pyrazolo-3, 4-b pyridine, hydrochloride, 7.71 g of 1- (2,4- cichlrrphenyl) -2H- (1H-imidazol-1-yl) -ethanol .0.03 mol) and 7.4 g 5-hpor {1-methyl-1-ethyl-3-methyl-1H-pyrazolo-Hz, 4-b pyridine, hydrochloride (O, OZ mol) is reacted according to the procedure of Example 1B. The combined layers of tetrahydrofuran are treated with charcoal, filtered, and dried with sodium sulfate. After adding 300 ml of ether and filtering the charcoal through the charcoal, the filtrate containing the free base is mixed with hydrochloric acid ester (415 g / l, 0.09 mol). Precipitated 5- 1- (2,4-dichlorophenyl-2H- (1H-imidazOL-1-IL-ethoxy methyl-1-ethyl-3-methyl-1H-pyrazoloG, 4-b} pyridine, hydrochloride (14.8 g) treated with ether, filtered off, dried in a vacuum desiccator and recrystallized from acetone, melting point 158-159 ° C with decomposition, yield 8.11 g (58%). The following additional products of formula C are obtained by the method of example 1B by an unsubstituted or substituted 2 - (1H-imidazol-1-yl) -ethanol of formula A with unsubstituted or substituted 5-chloromethyl-1H-pyrazolo C3, 4-b. Pyridine of formula B / The substituents are used in co relevant formulas. (see table.).
    9
    KBA
    P-ng-t
    .
    S73884
    Continued table. Hz R - Naoal, lower alknp, phenyl, fetch-lower alkyl or cyclone alkyl; . each vozorots, lower alkyl or phenyl; R a. - votsorots, oxy-, lower al-COXI-, lower alkylthis, phenoxy or phenyl-lower alkoxy group, halogen or group where Rg and ff voorots, lower alkyl, phenyl or substituted phenyl, where the substituent of phenyl is halogen, oxy-lower alkoxy, lower alkyl, mercap = ° C alkylthio, cyano or nitro; RV and each knots, halogen, oxy-, lower alkoxy, lower alkylthio lower alkyl or nitro, or their salts, characterized in that the formula 4 B C K d 5 -RZ where X is chlorine, bromine; interaction with the compound of the formula d) t-eNg s1- (, L, where 1, have the indicated; meanings. Sources of information taken into account for the examination 1. Wagner C. Alkylation of oxysocenic. with a halium compound — Chemistry of Organic Synthesis, 1953, p. 22,627.
    权利要求:
    Claims (1)
    [1]
    The claims The method of obtaining derivatives of imide.
    where R ^ is hydrogen, lower alkyl, phenyl, phenyl lower alkyl or cyclone lower alkyl;
    b to a * < q, th hydrogen, lower alkyl or phenyl;
    R 3, is wocoroc, hydroxy, lower alkoxy, lower alkylthio, phenoxy or phenyl, lower alkoxy is a group, halogen or a group where Rg and R <( j is wcocyc, lower alkyl, phenyl or substituted phenyl, where the substituent phenyl is halogen, hydroxy lower alkoxy, lower alkyl, mercapto, lower alkylthio, cyano or nitro;
    R 7 and R & are each wotsots, halogen, hydroxy, lower alkoxy, lower alkylthio, lower alkyl or nitro group, or their salts, characterized in that the compound of the formula where X is chloro, bromo or ioc, is reacted with a compound of the formula vg where R & , Ry and Rg have the following: meanings.
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    同族专利:
    公开号 | 公开日
    CS208115B2|1981-08-31|
    DD144774A5|1980-11-05|
    IT1122056B|1986-04-23|
    IT7924171D0|1979-07-06|
    BE877600A|1980-01-10|
    IE48442B1|1985-01-23|
    NO792275L|1980-01-11|
    US4159380A|1979-06-26|
    SE7905987L|1980-01-11|
    DE2927867A1|1980-01-31|
    AU519835B2|1981-12-24|
    AU4800179A|1980-02-07|
    LU81477A1|1979-10-31|
    IE791277L|1980-01-10|
    YU163779A|1983-06-30|
    NL7905242A|1980-01-14|
    ZA792908B|1980-06-25|
    ES482280A1|1980-04-01|
    JPS5513298A|1980-01-30|
    GR73111B|1984-02-02|
    FR2430946A1|1980-02-08|
    GB2024815A|1980-01-16|
    PL216944A1|1980-08-11|
    PH14437A|1981-07-16|
    DK288079A|1980-01-11|
    NZ190698A|1981-10-19|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    SU557755A3|1968-08-19|1977-05-05|Янссен Фармасьютика Н.В. |Method for preparing imidazole derivatives|
    US3658813A|1970-01-13|1972-04-25|Janssen Pharmaceutica Nv|1--ethyl)-imidazoles|
    US3928368A|1973-12-12|1975-12-23|Squibb & Sons Inc|Alcohol derivatives of pyrazolo{8 3,4-b{9 pyridines|
    US3983128A|1973-12-12|1976-09-28|E. R. Squibb & Sons, Inc.|Alcohol derivatives of pyrazolo[3,4-b]pyridines|
    US3991201A|1974-06-27|1976-11-09|Janssen Pharmaceutica N.V.|1-imidazoles as antimicrobial agents|IT1097314B|1978-07-26|1985-08-31|Recordati Chem Pharm|DERIVATIVES OF IMIDAZOLE WITH ANTI-CONVULSIVE ACTIVITY|
    US4234589A|1979-09-24|1980-11-18|E. R. Squibb & Sons, Inc.|Imidazolylethoxymethyl derivatives of 1,3-dioxolo quinolines|
    US4282230A|1979-11-15|1981-08-04|E. R. Squibb & Sons, Inc.|Imidazolylethoxy derivatives of quinoline-2- or 4-methanols, antimicrobial compositions containing them and method for treating bacterial or fungal infections with them|
    US4248881A|1979-12-20|1981-02-03|E. R. Squibb & Sons, Inc.|Imidazolylethoxymethyl derivatives of pyrazole|
    US4260614A|1980-02-08|1981-04-07|E. R. Squibb & Sons, Inc.|4--1,3-dioxolan-4-yl)methoxypyrazolopyridines|
    US4260616A|1980-02-14|1981-04-07|E. R. Squibb & Sons, Inc.|Antimicrobial imidazolylethoxymethyl derivatives of 1,3-dioxolo quinolines|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/923,418|US4159380A|1978-07-10|1978-07-10|Imidazolylethoxy derivatives of pyrazolo[3,4-b]pyridine-5-methanols|
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