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    • 专利摘要:
    The invention relates to substituted heterocyclic substances, in particular, the synergistin derivatives of the total f-ly 0 -N sn2CHNZ NG sn about 3 o n where YH, Y (CH3) g, R-piperidylamino or piperidylthio group, which are in position 3 or 4 and are substituted in some cases, the nitrogen in the cycle is alkyl, or alkylamino, alkyloxy or alkylthio, monosubstituted by S (0), alkylamino, one or two dialkylamino groups, in some cases substituted by dialkylamino, trialkylammonium or 4- or 5-imidazolyl or one cycle selected from piperazino- (in In some cases substituted by alkyl), piperidino, 2-, 3- or 4-pteridine or 1- or 2-pyrrolidinyl (in some cases substituted for the cycle nitrogen by alkyl) when using, the 5-C4 papkil, branched or branched, or pharmaceutically acceptable salts thereof, exhibiting pharmacological activity. The goal is to create .new, active and water-soluble substances of the specified class. The synthesis of new compounds is carried out by reacting a compound of the total f-ly R-H with a compound of the total f-ly Oy-N O T CH3 o. O,., D t 0 .-.;, - H 0 where R has the meanings indicated for R; Y has the indicated meanings; Z is halogen, dialkylphosphoryloxygroup or -0-5 (0) 2 R O – C (O) R. , R-phenyl substituted by lower alkyl; R is lower alkyl. The distribution of the target product is carried out in a free form or in the form of the required salt. New substances exhibit activity against Staphylococcus aureus with a minimum inhibitory concentration of 1–30 µg / cm, a therapeutic dose of DM-4–180 mg / kg, and an LDjo toxicity of 340–1000 mg / kg. 2 tab. I WITH "4:
    公开号:SU1445560A3
    申请号:SU853984289
    申请日:1985-12-06
    公开日:1988-12-15
    发明作者:Корбе Жан-Пьер；Котрель Клод；Фарж Даниель；Пари Жан-Марк
    申请人:Рон-Пуленк Санте (Фирма)；
    IPC主号:
    专利说明:

    where Y is hydrogen or dimethylamino;
    R is 3- or 4-piperidylamino or 3-OR 4-piperidyltyo, in some cases substituted on the nitrogen atom of the ring by an alkyl radical, alkylamino, alkylrxyl or alkylthio group substituted by one hydroxy-sulfonyl, alkylamino, one or two dialkyl amino groups, in some cases by a substituted dialkyl amino group, by trialkylammonium or 4- or 5-imidazolyl or by one cycle selected among piperazino, in some cases substituted by alkyl, piperidino, 1-pyrrho lidinyl, 2-, 3- or 4 -piperidyl and 2-pyrrolidine, in some cases substituted g at the nitrogen atom PA- dicalite alkyl, with the proviso that the alkyl radical contains 1-4 carbon atoms in a straight or branched chain,
    or their pharmaceutically acceptable
    salts.
    The compounds of the formula exhibit pharmacological activity.
    The aim of the invention is to obtain new synergistin derivatives, which have the advantage that they are soluble in water in the form of salts in the therapeutic doses used, while retaining the main spectrum of activity.
    The following examples, not intended to be limiting, show how the invention can be practiced. NMR spectra of products.
    BEHIND
    31f
    W 4
    2NH HN


    All spectra were taken at 250 MHz in deuterochloroform, and the chemical shifts are expressed in parts per million (PLM) with respect to the tetramethylsilane signal. Abbreviations used: with a single T, d doublet5 t triplet; mt multiplet; m array, dd double doublet; for double double doublet doubled double double doublet.
    In examples 2-7, the parentheses are given respectively: chemical shift, waveform, integration (the number of pro; tones, in some cases with a percentage, the volume of isomers) and the assignment of protons,
    In the examples, pulse chromatography is understood as a purification technique, characterized: (due to the fact that the IC uses a short chromatographic column and operates at an average pressure (50 kPa), using silica with a particle size of μm).
    Usually, the reaction is carried out in an organic solvent, such as a stable ester, for example, tetrahydrofuran, an alcohol, for example ethanol, or a chlorinated solvent (for example, methylene chloride or chloroform) at a temperature of about 20 ° C. The reaction is carried out in an alkaline medium. for example, in the presence of an alkaline hydride or an alkaline alkoxide (e.g. sodium ethoxide or tertiary potassium butoxide).
    When R is not substituted with alkoxy or heterocycloxy, it is also possible to work in a neutral medium at 0-50 ° C, in one of the indicated solvents or in an acidic medium (for example, in acetic acid or in a Mixture of acetic acid and catalytic amounts of trifluoroacetic acid) in the presence of or in the absence of a solvent at 0-50 ° C, preferably about 20 ° C.
    When R contains an alkylamino group of 5 1- (2-mercaptopropyl) 4-methylpiperazine in 50 cm of ethanol containing 0.34 g of sodium ethoxide, a solution of 5.2 g of (4-methylphenyl) sullyloxymethylene with pristinamycin 1d in 50 cm of methylene chloride is added. . The reaction mixture was stirred for 16 hours at a temperature of about 20 ° C, then diluted with 500 cm of methylene chloride and 100 cm of distilled water. After re 20
    pu capable of reacting, it is preferable to protect the latter by any known method that does not affect the rest of the molecule
    In addition, when the starting material contains a secondary amino group, in some cases it may be necessary to protect it before the reaction. The protecting radical is removed after the reaction. In this case, the aqueous phase is agitated by stirring. 2 times, an extra means of protection is used, and 50 cm of the total methylene chloride is used to glue.
     Based on an aqueous solution of the corresponding acid to the compound.
    Compounds in which R is a radical substituted with one or two oxysul-1-.4) onc radicals can be converted into salts of metals, catches or salts of addition of nitrogenous bases according to the method described for salts of addition of acids, but when replacing the acid with a metal hydroxide or nitric base.
    Example 1. To a solution of 0.87 g
    5 1- (2-mercaptopropyl) 4-methylpiperazine in 50 cm of ethanol containing 0.34 g of sodium ethylate was added a solution of 5.2 g of (4-methylphenyl) sulfonyloxymethylene pristinamycin 1d in 50 cm of methylene chloride. The reaction mixture is stirred for 16 hours at a temperature of about 20 ° C, then diluted with 500 cm of methylene chloride and 100 cm of distilled water. After re 0
    After 5 stirring, the aqueous phase is extracted 2 times with 50 cm of total methylene chloride.
    to protect the secondary amine function which does not affect the rest of the molecule and can be easily removed. It is especially advantageous to use trifluoroacetyl as a protecting radical, and then it can be removed with an aqueous solution of an alkaline bicarbonate, such as sodium bicarbonate or potassium bicarbonate. .
    The compounds can be purified by known techniques — crystallization, chromatography, or successive extractions in acidic and basic media. Due to the sensitivity of synergistins to an alkaline medium, it is obvious that under an alkaline medium they pick up an environment capable of releasing the base substance from its salt obtained by addition of an acid, i.e. whose pH does not exceed 7.5-8 Compounds in which R is a radical containing an amine function can be converted to an acid addition salt using acid in an organic solvent such as an alcohol, ketone, ester or chlorinated acid. solvent. The salt precipitates, in some cases after concentration of the solution, it is filtered or decanted. Acid addition salts can also be obtained in the form of aqueous solutions at up to
    Combine the organic phases, dry over magnesium sulfate, filter, then concentrate to dryness under reduced pressure (2.7 kPa) at 30 ° C. The residue is purified by flash chromatography (eluent: chloroform-methanol 97.5-2.5 in volume). Combine fractions. 33-80 and concentrate them to dryness under reduced pressure (2.7kPa at. In this way, 1.25 g of 55 1-methyl-3- (4-methylpiperidazinyl) -propyl-thiomethylenepristinamine chromium 1d is obtained in the form of a beige powder, melt Shagos at 195 C.
    1. maybe
    A 10% aqueous solution of 55 3- (4-methyl-1-piperazish) -2-propyl -thiomethylenepristinamine 1d (product AAN) in the form of hydrochloride is prepared: AAL product 0.03 g, 0.1N. hydrochloric acid 0.3 cm.
    1 - 2-Mercaptopropyl-4-methylpipe Razin can be obtained by heating at 100 ° C for 16 h of the mixture
    19 cm of propylene sulfide and 29 cm of N-methylpiperazine. In this way, 32 g of a colorless oil distilled at 1.3 kPa ,, are obtained.
    5- 4-Methylphensht sulfonic 1-methylene methylenpristinamycin Obtained according to the following procedure.
    To a solution of 2.7 g of 5-oxymethyl-pristinamycin 1d in 30 cm of methylene chloride is added at a temperature of about 0.42 cm of triethylshamine, then of 0.57 g of n-toluene sulfonyl chloride. Then the reaction mixture is stirred for 2 hours at a temperature of about
    20C, concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C. The resulting residue was purified by flash chromatography (eluent: methylene chloride - methanol 96.- 4 by volume). After concentrating to dryness of fractions 4-6 under reduced pressure (2.7 kPa) at 30 °, 2.2 g of 58- (4-methylphenyl) sulfonyloxymethylene prystinamine 1d are obtained in a white powder, melting at 265 C, NMR spectrum: 0 , 50 (dd, sh, 5g), 2.35
    (s, F, -502- (3) -Schchz, 30 (dd, Sh,
    ; 5Si) i 5.25 (d, 1H, 5oi), 5.30 (dd, W, 56.7.35-7.90 (system AB + M, NN
    8H, 4 +46. . 7.85 (dd, 1H,
    Nb).
    5 | -Oxymethylene pryspinodamycin 1d can be obtained as follows. .
    With stirring, add 420 cm of an aqueous solution of 0.1 n. hydrochloric acid 10.6 g of 5o-dimethylaminophenyl methacrylamide 1d. The resulting solution is stirred for 3 hours at a temperature of about 20 ° C. Then 30 cm of a saturated aqueous sodium bicarbonate solution is added dropwise in such a way as to obtain a pH of about 4,
    5 O. filtered the precipitated product, washed 3 times with 30 cm of distilled water. After drying under reduced pressure, (2.7 kPa) at a temperature of about
    0 to 20 ° С 9.5 g of 5-oxymethylene-pristinamycin 1d in the form of a beige powder. This product is of sufficient quality so that it can be used in subsequent herds. However, it can be cleaned as follows.
    9.5 g of 55 crude hydroxymethylenepristinamine 1d is dissolved in 50 cm
    0 ethyl acetate, the resulting solution is poured onto 100 g of silica gel in a 2.8 cm column. First 400 cm of ethyl acetate are eluted and the corresponding eluate is removed,
    5 is then eluted with 1600 cm of ethyl acetate and the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at. Thus, 6.35 i-oxymethylene g of pristinamycin 1d is obtained in the form of white crystals, melting at 220 C.
    NMR spectrum: 0.69 (dd, III,,); 2.43 (d, W, 5,), 3.40 (d, 1H ,,), 4.0–4.2 (m, 3N, 4VC + 5, + 5ob); 8, 55 (s,
    5 1H, .CH-OH); 11.63 (s, broad, - 1H, -CH-OH).
    Example 2. Work according to the method of example 1, but starting from 5.2 g of 5 S - (4-methylphenyl) -sulfonyloxime71445560
    tylenpristinamicin 1d, 0.6 g 1-dimethaminophenol-2 and 0.34 sodium ethyl acetate, after purification by flash chromatography (eluent: chloroform - methanol 95-5 by volume) and concentration to dryness of fractions 16-38
    eight
    N, N-Diethyl-4-acethlthiopentane-min-1 can be obtained by the method of example 32 to obtain N, N-dime-tyl-3-acetylthio-2-methylpropylamine, but starting from 32 g N, N-diethyl-4 -chloro-pentane-1 and 15.2 g of thioacetic acid. Thus, 4.31 g of product is obtained in the form of a yellow oil,
    PRI me R 4. A solution of 7.6 g
    under reduced pressure (2.7 kPa), 1 g of 5g- (3-dimersh1amine-2-propyl) thiomethyu-lennopystinamine 1d is obtained in the form of a yellow powder, melting at 172 ° C. . NMR spectrum: 0.65 (dd, 1H, 5),
    1.10 (d, sd, ddn); 2.30 (s, 6H-N
    (CH5) j), 7.60 (with broad, 1H, -CH-S-), 15, is added at this temperature, grown to 7.85 (dd, 1H, 1 Hg).
    Prepare a 5% aqueous solution of 5 S - (3-dimethylamino-2-propyl) -thiome 5 S (4-methylphensh1) -sulfonic shtoximethylene j-pristinamycin 1d in 60 cm of tetrahydrofzfan cooled to the tag-teratura near - 10 C. There slowly
    Thief 0.65 g of 2-dimethylaminoethanol in 60 cm of tetrahydrofuran containing 0.35 g of 50% sodium hydride dispersion in mineral oil. At the end of the addition, the mixture is slowly heated to a temperature of about 20 ° C. The reaction mixture is stirred for 24 hours at this temperature , then diluted with 500 cm of methylene chloride and washed 2 times with 50 cm of the complete solution of ammonium chloride. Or- The phase is dried over magnesium sulphate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue obtained is purified by flash chromatography (eluant: chloroform-methanol 95-5 by volume). Combine fractions 12-17 and concentrate to dryness under reduced pressure (2.7 kPa) at
    20
    tylenpristinamycin 1d (product AAO) as hydrochloride: product AAO 0.03 g 0.1 n. hydrochloric acid 0.3 cm distilled water to 0.6 cm.
    Example 3. The procedure is as in Example 1, but starting from 6.3 g of 58 - (4-methylphenyl) sulfonoxoximethy-5 lenpristinamycin 1d, 1.05 g of 5-diethylaminopentathol-2 and, 0.408 g of sodium ethoxide, after cleaning it with a pulse chromatography (eluent: chloroform - methanol 97.5 - 2.5 by volume) and concentrating to dryness, fractions 47-65 under reduced pressure (2.7 kPa) at 30 ° С to obtain 1.32 g of 5- (5 -di-e-tilamino-2-pentsh1) -thiomethylene prystinamycin 1 melted at
    NMR spectrum: 0.65 (dd, 1H,) 1.20 (t, 6H, -N (CH2CHj) 2). (d, 3H, .- qH-CH5); 1.70 (with broad, 4H, CH / CH) 2. -CHjHpi 2.65 (q, 4H, -N (CH2-CHj) i) -, 3.50 (dd, 1H, 5y G) 7.65 (with broad, 1H, -CH-S-), 7.85 (dd, 1H, I Hg).
    Prepare 10% water solution
    1d in the form of a beige powder, 185 C.
    A thief is 0.65 g of 2-dimethylaminoethanol 60 cm of tetrahydrofuran, containing 0.35 g of a 50% dispersion of hydra sodium in mineral oil. Upon addition, the mixture is allowed to warm to about 20 ° C. The reaction mixture is stirred 24 hours at this temperature, methylene chloride is diluted with 500 cm and washed 2 times with 50 cm of saturated ammonium chloride solution, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue obtained is purified by flash chromatography (eluant: chloroform-methano 95-5 by volume). Combine fractions 12-17 and concentrate to dryness at 35 lower pressure (2.7 kPa) at
    25 C. Thus, 1.5 5 ° - (2-dimethylaminoethoxymethylene) -pristinamycin 1d is obtained in the form of a beige powder, melting at.
    NMR spectrum: 0.65 (dd, 1H, 5 / Jj) 2.3 (s, 6H, -N (CH,) 2); 2.65 (m, 2H); 3.42 (dd, W, 56); 4.15 (t, 2H, -OCH, -), 5.15 (d, W, 5e 7.45 (under aromatics, 1H, C-CHO40
    5§- (5-diethylamino-2-pentsh1) -thiomethi-45 7.80 (dd, 1H, GN). Lenpristinamycin 1d (APP product) Prepare a 1% aqueous solution in the form of hydrochloride; .prod; uk AAR
    5S - (2-dimethylaminoethoxymethyl) cristinamycin 1d (product AAO) as hydrochloride: product AAO 0.03 g, 0.1 n. hydrochloric acid 0.3 distilled water up to 3 cm.
    0.05 rj 0.1 n. hydrochloric acid 0.5 cm
    5-Diethylaminopentanethiol-2 can be prepared according to the procedure of Example 32 to obtain 3-dimethylamino-2-methyl propanethiol, but starting from 4.0 g of N, N-diethyl-4-acetylthiopentanamine-1 and 0.046 g of sodium. After purification by flash chromatography (eluent: ethyl acetate-methanol 70-30 by volume) and concentration of fractions 16-24 to dryness, 2.0 g of 5-diethylaminopentanethiol-2 is obtained as a yellow oil.
    eight
    N, N-Diethyl-4-acethlthiopentane-min-1 can be obtained by the method of example 32 to obtain N, N-dime-tyl-3-acetylthio-2-methylpropylamine, but starting from 32 g N, N-diethyl-4 -chloro-pentane-1 and 15.2 g of thioacetic acid. Thus, 4.31 g of product is obtained in the form of a yellow oil,
    PRI me R 4. A solution of 7.6 g
    5 S (4-methylfensh1) -sulfonsthoximethylen-j-pristinamycin 1d in 60 cm of tetrahydrofzfan is cooled to a tag temperature of about -10 C.
    added at this temperature

    Thief 0.65 g of 2-dimethylaminoethanol in 60 cm of tetrahydrofuran containing 0.35 g of 50% sodium hydride dispersion in mineral oil. At the end of the addition, the mixture is slowly heated to a temperature of about 20 ° C. The reaction mixture is stirred for 24 hours at this temperature , then diluted with 500 cm of methylene chloride and washed 2 times with 50 cm of the complete solution of ammonium chloride. Or- The phase is dried over magnesium sulphate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. The residue obtained is purified by flash chromatography (eluent: chloroform-methanol 95-5 by volume). Combine fractions 12-17 and concentrate to dryness under reduced pressure (2.7 kPa) at
    25 C. Thus, 1.5 g of 5 ° - (2-dimethylamino-ethoxymethylene) - -pristinamycin 1d is obtained in the form of a beige powder, melted at.
    NMR spectrum: 0.65 (dd, 1H, 5 / Jj) i 2.3 (s, 6H, -N (CH,) 2); 2.65 (m, 2H.); 3.42 (dd, W, 56); 4.15 (t, 2H, -OCH, -), 5.15 (d, III, 5e); 7.45 (under the aromatics, 1H, C-CHO),
    7.80 (dd, 1H, GN). Ready t 1% aqueous solution
    7.80 (dd, 1H, GN). Ready t 1% aqueous solution
    5S - (2-dimethylaminoethoxymethyl) - crisristinamine 1d (product AAO) as hydrochloride: product AAO 0.03 g, 0.1 n. hydrochloric acid 0.3 cm, distilled water up to 3 cm.
    Example 5. To a solution of 0.5 g of 5 - (4-methylphenyl) sulfonyloxymeti-1
    flax pristinamycin
    t
    1 d 25 cm of ethanol, 0.12 g of 4-amino-1-methylpiperidine is added at a temperature of about. After stirring for 16 hours at this temperature, the reaction mixture is diluted with 100 cm of methylene chloride.
    twice washed with 100 cm of distilled water. The organic phase is dried over sodium sulfate, then concentrated under reduced pressure (2.7 kPa) at 30 s. The residue is stirred with 15 cm. After filtration, it is obtained.
    ethyl ether. 0.42 g
    The source product ((CH,) 2) Z -OCOCH,
    (OC., Hy)
    Reaction conditions
    CHjCOOH 20 C, 6 h
    CHjCOOH, 20 h
    Products used can NMR spectrum: 0.55 (dd, 1H: 5 (3),
    be obtained as follows; . . 1.30 (td, 6H: —PO () -); -55-adetoxymethylene cryptamine 1.2,40 (d, 1I: 5fi,); 3.40 (dd, 1H: 56)
    To a solution of 1.8 g of 5-oxymethyl-204.25 (ddd, 4H: —PO / O-CH CH) | 5, 25 (d, 1H, pristinamycin 1d in 20 cm of methylene chloride, containing 0.2 g of triethyl amine, are added at a temperature of about -20 ° C with 0.14 cm of acetyl chloroform; a, then left at a temperature of about 20 WITH.
    The reaction mixture is stirred for 20 hours at this temperature, then concentrated to dryness under reduced pressure (2.7 kPa) at 30 ° C, the resulting residue is purified by flash chromatography (eluent: ethyl acetate). After concentrating to dryness of fractions 4-7 under reduced pressure (2.7 kPa) at 30 ° C, 0.7 g of 5-acetoxymethylenepristinamine 1d is obtained in the form of a yellow powder, melting at HO ° C
    NMR spectrum: 0.60 (dd, 1H ,,) -, 2.25 (s, 3N: -CO-CHu, 2.45 (d, 1H: 5 And,) 3.45 (dd, 1H: 5E. ,); 5.25 (dd, 1H,: 5ft :,); 5.45 (d, 1Ht 56,), 7.10 - 7.45 (m, 8H: 6f + b5 + b + I Hi, + I Hj + -CH-0) 5 7.85 (dd, H,: 1 Nb).
    5-Diethoxyphosphoryloxymethylene pristinamycin 1d.
    Work according to the same procedure, but proceeding from 1.8 g of 55-hydroxymethylene strythamine 11cin 1D and 0.34 g of diethyl chlorophosphate, after purification by flash chromatography (eluent: ethyl acetate-methanol) (90-10 by volume) and concentration fractions 6-14 under reduced pressure (2.7 kPa) at 0.8 g of b8-diethoxyphosphoryloxymethylene pristinami 1D1a 1p are obtained in the form of a yellow powder, melting at 150 ° C.
    5B.) 5.40 (d, 1H: 5,), - 7.10- 7.55 (m, 8H: 6J + 6i + 6E + CH-0 + 1 H5 +. GN,), 7.85 ( dd, 1H X 0.85 LH / H 1 st isoc., measures); 8 (dd, 1H X 0.15: GN 2th isomer).
    5 O - oximeshhenpristinamycin 1 can be obtained as in example 1.
    Example 7. Work according to the method of analogous to example 5, but stirred for 20. h, starting from 55 chloromethylene priistinamycin 1d, 5 o - (3-dimethylaminopropyl) - thiomethylene pristinamycin 1d is obtained in the form of a powder, melting powder at 170 C.
    NMR spectrum: 0.70 (dd, 1H: 5p2.), 1.90 (m, 2H: -S-CHiCHjCHiNO; 2.20 (s, 6H: S (CH3)), 2.40 (d, 1H: 5 V,), (m, 2H:) V 3.45 (dd, 1H: 40) 5 7.65 (broad s, 1H: CH-S-).
    A 1% aqueous solution of 5 ° (3-dimethylaminopropyl) thiomethylene-pristinamycin 1 (product AZ) in the form of hydrochloride is prepared: product AZ 0.03 g 45 Oj 1 n. hydrochloric acid 0.3 cm. distilled water up to 3 cm.
    The original product can be obtained as follows.
    A stream of gaseous chlorine is passed through a solution of 1.3 cm of triphenylphosphite in 25 cm of methylene chloride until a stable green color is obtained at a temperature of from -20 to -15 ° C. Then 6 drops of triphenylphosphite are added to decolorize the solution, then 4.1 g oximetsch 5-pristinaschina 1d while maintaining temperature
    between -20 ° C and -15 ° C. Mix the resulting solution for 1 h.
    50
    55
    (1-methyl-4-piperidyl) -aminomethylenphenistinamine 1d as a white powder, melting at 208 ° C,
    Example 6. Work according to the specified method, the following derivatives of synergistine:
    The product is defined previously in example 5
     4.25 (ddd, 4H: PO / O-CH CH) | 5, 25 (d, 1H,
    5B.) 5.40 (d, 1H: 5,), - 7.10- 7.55 (m, 8H: 6J + 6i + 6E + CH-0 + 1 H5 +. GN,), 7.85 ( dd, 1H X 0.85 LH / H 1 st isoc., measures); 8 (dd, 1H X 0.15: GN 2th isomer).
    5 O - oximeshhenpristinamycin 1 can be obtained as in example 1.
    Example 7. Work according to the method similar to example 5, but stirred for 20. h, starting from 55 chloromethylene pristinamycin 1d, 5 o - (3-dimethylaminopropyl) - thiomethylene pristinamycin 1d is obtained in the form of a tan powder melting at 170 WITH..
    NMR spectrum: 0.70 (dd, 1H: 5p2.), 1.90 (m, 2H: -S-CHiCHjCHiNO; 2.20 (s, 6H: S (CH3)), 2.40 (d, 1H: 5 V,), (m, 2H:) V 3.45 (dd, 1H:) 5 7.65 (broad s, 1H: CH-S-).
    A 1% aqueous solution of 5 ° (3-dimethylaminopropyl) thiomethylene-pristinamycin 1 (product AZ) in the form of hydrochloride is prepared: product AZ 0.03 g Oj 1 n. hydrochloric acid 0.3 cm. distilled water up to 3 cm.
    The original product can be obtained as follows.
    A stream of gaseous chlorine is passed through a solution of 1.3 cm of triphenylphosphite in 25 cm of methylene chloride until a stable green color is obtained at a temperature of from -20 to -15 ° C. Then 6 drops of triphenylphosphite are added to decolorize the solution, then 4.1 g oximetsch 5-pristinaschina 1d while maintaining temperature
    between -20 ° C and -15 ° C. Mix the resulting solution for 1 h.
    111445560
    at -15 ° C, then a solution of 0.4 cm of pyridine in 25 cm of methylene chloride is added dropwise. Stir the reaction mixture for 30 minutes at a temperature of
    about 20 seconds, then 0.46 cm of concentrated hydrochloric acid (ot. 1.19) and 50 cm of methylene chloride are added.
    The mixture is washed 4 times with a total of 100 cm of distilled water, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 30 C. The residue is purified by flash chromatography (eluant: ethyl acetate), after concentration to dryness 7 and 9 fractions under reduced pressure (2.7 kPa) with, get 1,2 chlorine methylene-5-pristinamycin 1d in the form of a beige powder with so pl. 190 ° C.
    NMR spectrum: 0.55 (dd; 1H: 5/32), 2.45 (d-, 1H, 5,), 3.45 (ds, 1H,) 5.30 (d, 1H, ZoS); 5.45, (d, 1H, 55,) 7.15 a 7.60 (m; 8H: 6 + 6 + 65 + + 1 H5 + CH-C1); 7.85 (dd5 1H; r-Hg).
    Working by the same method, volatile products can be obtained (see Table 1). In the following tables.
    Unless otherwise specified, a radiologically acceptable salt can also be attached. Y is a dimethylamino group. . these quaternary ammonium salts,
    when R is trialkylammonium. It is known that synergistins having a full radical, these salts corresponding to fermentation represent the anions of the salts described. Pharmaceutically acceptable products for the treatment of many diseases that are very valuable for medicine, such as gram-positive (staphylococci, streptococci, pneumococcal), can also be mentioned alkali metal salts, such as lithium, sodium, potassium salts, alkaline earth metal salts. , such calcium or magnesium salts, ammonium salts, and salts of addition of organic nitrogenous bases: ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropyl AU amine, N, N-dimethylethanolamine, benzyl ina, gew enzilamina, ditsiklogeksilben- zilamina, N-benzyl- / 5-phenethylamine, N, N -dibenzshIetilendiamina, benzgid- rilamyna, arginine, leucine, lysine or N-metsh1Glyukamina.
    ki, enterococci) and gram-negative (in the form of hemophilus, gonococci, meningococci) bacteria. However, these products have the disadvantage that they are insoluble in the aquatic environment and can only be administered by oral route, usually in the form of tablets, pills or pills . Taking into account this insolubility, it is impossible to use well-known synergistines when it is not painful to swallow, namely in pediatrics and resuscitation, whereas the activity spectrum of these products gives a clear indication of this in a large number of cases, for example, with comatose sepsis.
    The new products according to the invention have a significant advantage due to their solubility in water in the form of salts in the therapeutic doses used, which is mainly
     2
    0
    five
    the synergistin's avidity spectrum, namely, they are active in vitro against Smith Staphylococcus aureus at concentrations (7.1-125 µg / ml,
    Usually they are low toxic. but surpasses 300 mg / kg on mnpah with P. LE.
    New products can be used as such for teperaptic use, i.e. as a base, but for use as an aqueous solution, which is their main advantage, it is particularly advantageous to use their pharmaceutically acceptable salts, i.e. non-toxic when used doses.
    As pharmaceutically acceptable salts, salts, additions of mineral acids, such as hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, or organic acids, such as acetates, propionates, succinates, maleates, fumarates, methanesulfonates, para- toluensulfonate, isetinate or substituted derivatives of these compounds. As a pharmaceutically
    five
    radical, these salts correspond to the anions of the above salts. As a pharmaceutically acceptable
    0
    salts may also be mentioned alkali metal salts, such as lithium, sodium, potassium salts, alkaline earth metal salts, such calcium or magnesium salts, ammonium salts, and salts of addition of organic nitrogenous bases: ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine , propylamine, C diisopropyl- amine, N, N-dimethyl ethanol amine, benzyl amine, gew enzilamina, ditsiklogeksilben- zilamina, N-benzyl- / 5-phenethylamine, N, N -dibenzshIetilendiamina, benzgid- rilamyna, arginine, leucine, lysine or Y-Metsh1Glukamina.
    Pharmacological studies.
    In vitro bacteriostatic activity.
    To a series of plates containing a known volume (20 cm) of a suitable culture medium (Miller-Hinton agar), 1/10 of this volume of geometrically progressive (ratio-2) dilutions are added to the test subject.
    0
    five
    13
    144
    th product. Plates are inoculated with a multipoint inoculum, which releases a spot of 10 colony-forming units of the microorganism in three blue axial broth incubated for 18 hours at 37-C and diluted 1/100 of the same medium. After inoculation, the plates are incubated for 24 hours at.
    The minimum inhibitory concept is the actual concentration at which the growth of the microorganism is inhibited.
    Activity against intraderitoneal infection on a mouse.
    Mice are given an intraperithoidal injection of a 0.5 cm approach of 1 of 1 L of culture at 18 h of the test subject. Microorganism in Brain Heartr Infusion (Difco), respectively, diluted with hog mucin. Such an inoculation of pysyas kills control animals within 24 to 48 hours. Test compound enter g subcutaneously twice with an interval of 5 hours per day of inoculation, the first dose is given one hour after the inoculation of the microorganism. A single dose used in a volume of 50 cm / kg.
    The 50% therapeutic dose (DM, e) is the dose of compound applied in a test which, when administered at any given time, allows him to be treated with the correct dose, the test dose during the test period (8 / ton). Table 2 Ilgük.
    about p
    y l
    about b
    e 1 e
    The way luchuchenn p derivatives, synergies1 av oOdey fg.rmuly
    SI
    3
    . -L Ny .-- -Y
    1. about i - i sn, -o sh,
    - - (I 1
    sn ™ ()
    where y
    - in, p; town: -ti d nmetilimde- group;
    5601
    R is 3- or 4-piperidyl.al No. 1no or 3- or., 4-piperidylthio, in some cases substituted on the nitrogen atom of the al- cycle. kel radical, alkylamino ,. alkyloxy or alkylthio group, substituted with one gcdroxysulfonyl, alkyl-oamine one or dum di
    alkylamino groups, in some cases substituted di-alkylamino groups, trialkyl-. ammonium or 4- or 5-imidazolyl or one cycle,
    Selected among piperazny, in some cases x substituted by Alkix, pnperndnno, 1-pyrrole x 5 5- 3 0 or 4-piperidol and 2-pyrrolidin-pa, in some cases, substituted on the atom azo-. that alkyl radical, provided that the Alkyl radical — 5-cal contains 1-4 atoms of hydrogen chloride in a straight or branched chain,
    or their pharmaceutically acceptable salts, of which they are, so that they are reacted with the co-D1p; enH8. general formulas
    R, -H
    where K / has the meanings indicated by -d R,
    with s.oediyennhzm obishy formula1l
    w
    -, i
     .
     JcH, cH4 I
     “I3 o
     iNl t
    about
    about
    . HE
    where i ,. - hydrogen or dimethylmino group:
    , Z - halogen, dialkyl / 3 Ospheryl-CKrpyinia 1SH11 group of the formula OSOiRgH / nj OCOKf, where R is fett-t., Replaced by low-StJ.M alkshyum,. - low
    ali.g1
    ; the subsequent vyielennym target -boduhta in free form or in vgshche 1) armatsevticheskoj reception salt.
    -NH (CH2) 2N (CH,) -NH (CH2,), 2, N (CjHy) 2
    ten
    —NH (CH2) NHCH,
    eleven
    -MCCH), N (CHj) 2
    12
    -NH-CH-CH2N (CH j) 2 CH.
    13
    -NHCH CH-NlCHj CHa
    14
    - IJH-CH- (CH2) HC (C 2H5) 2 CH
    15
    sixteen
    -NH- (CH2) 2 - NQ -1SJH (CH2) 3-NQ
    17-1 H (CH2) 2-N (
    Table 1
    Beige powder melting at 180 with 1% water solution Yellow powder melting at 150 ° C
    5% aqueous solution in hydrochloride species
    Yellow powder melting at 174 ° C
    1% water solution in hydrochloride species
    Yellow powder, so pl. 155 С
    6, an aqueous solution in the form of hydrochloride
    Yellow powder melting at 160 ° C
    1% water solution in the form of hydrochloride
    Orange powder melting at C
    10% water solution in the form of hydrochloride
    Beige powder melting at --TbO C
    1% water solution in the form of hydr ohl orida
    Yellow powder, so pl. 183 С
    1% aqueous solution in the form of hydrochloride.
    Yellow powder, mp. - 170 C 1% water solution
    } {Yelti powder melting at L 16 2 ° C
    one
    18-iJHCcHiViiQ
    one
    pH2CH3-NH-Cli, N
    -NH

    Shz -KN - (- Shz
    -K (CH3) 2-Shch (CH2)
    23
    24
    25
    26
    N (CH3) (CH2) 2li Yellow powder, so pl. 138 seconds
     .
    -NH
    -N (CH,) - S- (CH ,,) N (CHp
    z
    10% water solution in the form of hydrochloride
    Yellow powder melting at 150 ° C
    1% water solution in the form of hydrochloride
    -Y (CH3) (CH2) K (C2Hd) 2 Beige powder, melting
    at 192 C
    1% aqueous solution as hydrochloride
    -H- -S- (CH) jN (CH) 2 Beige powder. Floating
    at 140 ° C
    Continued table. one
    ..one
    3
    1% water solution in the form of hydrochloride
    Beige Powder melting PRYA 172 s
    1% aqueous solution as hydrochloride
    Beige powder melting at
    1% water solution in the form of hydrochloride
    Beige powder, so pl.
    1% water solution in the form of hydrochloride
    Beige powder melting
    at
    5% water solution in the form of hydrochloride
    Yellow powder, so pl. 150 С
    10% water solution in the form of hydrochloride

    KiH.
    -NH
    27
    -KlCHsVS-CHe-CH-CH NtCH l CH3
    28
    -H (CH3) 2-8-CH2-CK (CH3) 2 CH3 CH3
     29
    m I Ltifi 11
    -TS (CH3VS- (CH2) 2- N (J at 180 ° C
    Beige n
    -S- (CH)
    CH, I
    N
    T
    31
    sn.
    32
    -S
    CH2CHj
    33
    S- (CH2) 2N- (CH2) 2-N (CH3) 3
    CHi
    34
    -S-CH / CH NCCHj), / 2
    35- S (CH9) N-GN Beige powder, melting.
     2 - /. „„ „17П ° g
    at 170 C
    and Ltifi 11
    at 180 ° C
    10% aqueous solution in the form of hydrochloride
    ABOUT
     Beige powder, so pl. 234 С
    1% aqueous solution as hydrochloride
    Beige powder, water lookup
    1% aqueous solution in the form of hydrochloride
    Beige powder melting
    1% water solution in hydrochloride species
    Beige powder, melted at 215 ° C
    /
    0.6% aqueous solution in the form of hydrochloride
    Yellow powder melting at 170 ° C
    1% aqueous solution in hydrochloride species
    Beige powder melting at
    1% aqueous solution as hydrochloride
    Yellow powder melting at 160 ° C
    1% aqueous solution
    Beige powder melting at 190 ° C
    T% aqueous solution in the form of hydrochloride
    Beige powder melting
    „„ „17П ° g
    at 170 C
    1% aqueous solution as hydrochloride
    36
    8 (CH2) / N-CH2 Beige powder, melting
    3,
    . at 190 C
    37
    8-CH2-CH-CH2-K (CH3) h. Шз ®
    38
    -S (CH2) 2S05H
    Compound
    for comparison
    Pristinamycin 1.
    Beige powder melting
    . at 190 C
    10% aqueous solution in the form of hydrochloride
    Ocher powder melting at
    1% aqueous solution as hydrochloride
    Yellow powder, t, pl. 280 WITH 5% aqueous solution
    table 2
    thirty
    权利要求:
    Claims (5)
    [1]
    1% aqueous hydrochloride solution
    38 -S (CH 2 ) 2 S0jH Yellow powder, mp. 280 ° C
    1% aqueous solution in the form of hydrochloride "
    Continuation of table 1 < 2
    36 S (CH 2 ) j N ^ N — CH3
    Beige powder, melting at 190 ° C
    10% aqueous hydrochloride solution
    37 ' _ 8-CH2 “CH _ CH2 _ K (CH3) s.
    Ocher powder, melting СНа θ At 150 ° С
    1% aqueous hydrochloride solution
    Beige powder, melting at 170 ° С
    1% aqueous solution
    Beige powder, melting at 19 ° C
    1% aqueous hydrochloride solution
    Yellow powder, melting at 160 ° C
    1% aqueous hydrochloride solution
    Beige powder, melting at 175 ° C
    1% aqueous hydrochloride solution
    Beige powder, melting at 215 ° C /
    0.6% aqueous hydrochloride solution
    Yellow powder, melting at 170 ° C
    1% aqueous hydrochloride solution
    Beige powder, melting at 180 ° C
    1% aqueous solution in the form of hydrochloride ~ N (CH 3 ) 2 —S — CH 2 ~ C ~ N (CH 3 ) 2 sn 3 sn 3
    -N (CH 3 - S- (sn 2 ) sn h 1
    - S- (CH 2 ) 2 γη
    I sn 2 sn 3
    - S- (CH 2 ) 2 N4CH 2 ) 2 -N (CH 3 ) 3 cn 3
    -S-CH / CH 2 N (CHj) 2/2
    - 5 (CH 2 ) 2 -B1 ^ 2> -CH 3
    Beige powder, melting at 200 ° C
    1 9 144 5560
    T s
    Continuation of the table. 1
    CH g —CH — CH 2 K (CH 3 ) 2 cn 3
    10% aqueous solution in the form of hydrochloride • a
    Beige powder, mp 234 C
    1% aqueous hydrochloride solution
    -H- -S- (CH 2 ) jN (CH 3 ) 2
    Beige powder, melting at 140 ° C
    1% aqueous solution in the form of hydrochloride
    -N (CH 3 ) 2 -S- (CH 2 ) N (C 2 H 5 ) 2
    Beige powder, melting at 19
    [2]
    2 ° C
    1% aqueous solution in the form of hydrochloride
    Beige powder, melting at 195 ° C
    -N (CHj) r NH (CH 2 ) r N0N-CH3
    5% aqueous hydrochloride solution
    Yellow powder, mp 150 ° C
    10% aqueous hydrochloride solution
    Yellow powder, mp 138 ° C
    10% aqueous hydrochloride solution
    -N (CH 3 ) 2 -S- (CH 2 ) 4 N (CH,) 2
    Yellow powder, melting at 150 ° C
    1% aqueous solution in the form of hydrochloride. 20
    Beige powder, mp 177 ° C
    1% aqueous solution in vvda hydrochloride pH 2 sn 3 ^ N ~ CH 2 N
    Beige powder, melting at 160 ° C
    fifteen
    I 6
    Table 1
    Example R Melting point solubility 1 g θ 89 -nh (ch 2 ) 2 n (ch 9 ) 2 -νη (οη 2 ) 2 ν (ο 2 η 5 ) 2Beige powder, melting at ^ 180 °1% aqueous solutionYellow powder, melting at ~ 150 ° C5% aqueous hydrochloride solution 10 -NH (CH 2 ) NHCH, Yellow powder, melting at 174 ° C1% aqueous hydrochloride solution eleven -nh (ch 2 ) 9 n (ch 3 ) 2Yellow powder, mp 155 ° C6.6% aqueous hydrochloride solution 12 -NH- CH-CH 2 N (CH 3 ) 2 CH 3Yellow powder, melting at 160 ° C1% aqueous hydrochloride solution thirteen -nhch 2 ch-n (ch 3 ch 3Orange powder, meltingat -1 75 С10% aqueous hydrochloride solution 14 - W-CH- (CH 2 ) jN (C 2 H 5 ) 2 'CH 3Beige powder, melting at 160 ° C1% aqueous hydrochloride solution fifteen -nh- (ch 2 i 2 --nQ Yellow powder, mp 183 ° C1% aqueous hydrochloride solution 16 -nh (ch 2 ) 3 -nQ Yellow powder, mp 170 ° С1% aqueous solution 17 -1ίΗ (0Η 2 ) 2 -Νθ Yellow powder, melting at v162 ° C
    1445560 :
    Continuation of the table. 1 + '. 1% aqueous hydrochloride solution
    -ΝΗ (ςΗ 2 ) 2 “Νθ
    Beige powder, melting at -V 1 72 in C
    1 7 where d. <Has the meanings indicated for R, with the addition of the general formula
    5G where Y is hydrogen or dimethylamino group;
    where Y .. is hydrogen or dimethylamino group;
    .7, is a halogen, dialkylphosphoryloxy group or a group of the formula OSOiRjMnn OCORq., Where HZ is phenyl substituted by lower alkyn, TC is lower alkyl,
    d. subsequent isolation of the target product in free form or in the form of a Pharmaceutically acceptable salt.
    [3]
    3- or .L-piperidylthio, in some cases substituted on the nitrogen atom of the al. quilted radical, alkylamino ,. alkyloxy or alkylthio group substituted with one hydroxysulfonyl, alkylamino, one or two dialkylamino groups; in some cases, a substituted dialkylamino group, trialkyl. ammonium or
    [4]
    4- or 5-imidazolyl or one ring selected from piperazino, in some cases substituted with alkyl, piperidine, 1-pyrrolidinyl, 2-, 3 or 4-piperidyl and 2-pyrrolidinyl, in some cases substituted at azo atom. with an alkyl radical, provided that the alkyl radical contains 1-4 carbon atoms in a straight or branched chain, or their pharmaceutically acceptable salts, excluding the fact that the compound of the general formula is reacted
    R .-- H
    [5]
    5% aqueous solution
    table 2
    Example In vitro activity Staphylococcus aureus, MIC µg / cm ’. In vitro activity, Staphylococcus aureus Smith (mouse),DM ^ mg / kg subcutaneously 3 fifteen 18.5 4 thirty 180 5 4 4 6 4 4 7 1 19 . Comparison CompoundPristinamycin 2 thirty
    Example Toxicity (mice), DLmg / kg subcutaneous 3 1000 5 and 6 750
    340
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    同族专利:
    公开号 | 公开日
    SU1456019A3|1989-01-30|
    GR81555B|1984-12-11|
    FR2549063B1|1985-10-25|
    DK169258B1|1994-09-26|
    FI842812A|1985-01-14|
    KR850001212A|1985-03-16|
    ES534313A0|1985-04-01|
    JPS6038386A|1985-02-27|
    FI78105C|1989-06-12|
    IL72397D0|1984-11-30|
    EP0133097B1|1987-03-04|
    SU1421260A3|1988-08-30|
    US4618599A|1986-10-21|
    AU3047284A|1985-01-17|
    ES537180A0|1985-10-16|
    IL72397A|1987-10-30|
    ES8601210A1|1985-10-16|
    FI842812A0|1984-07-12|
    DK342584A|1985-01-14|
    CA1213583A|1986-11-04|
    FR2549063A1|1985-01-18|
    FI874654A0|1987-10-22|
    PT78894B|1986-08-08|
    ES537179A0|1985-10-16|
    DE3462507D1|1987-04-09|
    DK342584D0|1984-07-12|
    PT78894A|1984-08-01|
    KR910005848B1|1991-08-05|
    ZA845316B|1985-02-27|
    EP0133097A1|1985-02-13|
    ES8601211A1|1985-10-16|
    ES8504201A1|1985-04-01|
    JPH0522718B2|1993-03-30|
    FI874654A|1987-10-22|
    FI78105B|1989-02-28|
    AT25691T|1987-03-15|
    FI80456C|1990-06-11|
    FI80456B|1990-02-28|
    AU567570B2|1987-11-26|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4355112A|1977-06-06|1982-10-19|Sanraku-Ocean Co., Ltd.|Streptomyces culture|FR2549065B1|1983-07-13|1985-10-25|Rhone Poulenc Sante|NOVEL SYNERGISTIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|
    FR2599036B1|1986-05-22|1988-09-09|Rhone Poulenc Sante|NOVEL SYNERGISTIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|
    FR2655343B1|1989-12-05|1992-05-07|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF SYNERGISTINE.|
    FR2664894B1|1990-07-19|1994-08-19|Rhone Poulenc Sante|
    IL121821A|1993-02-17|2000-02-17|Rhone Poulenc Rorer Sa|Process for purifying a group A minority component of streptogramin some such purified components and their uses|
    FR2723373B1|1994-08-02|1996-09-13|Rhone Poulenc Rorer Sa|PURIFIED FORM OF STREPTOGRAMINS, ITS PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|
    FR2796949B1|1999-07-27|2001-09-21|Aventis Pharma Sa|STREPTOGRAMIN DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM|
    JP2008057849A|2006-08-31|2008-03-13|Denso Corp|Manufacturing method of heat exchanger|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8311705A|FR2549063B1|1983-07-13|1983-07-13|NOVEL SYNERGISTIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|
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