Method of producing derivatives of pristinamycin as isomersor their mixtures, or acid-additive salts

专利摘要:
The invention relates to heterocyclic compounds, in particular to the production of substituted at position 26, a group SR pristinamycin II in which R - methylpiperidinyl, / 1-methyl-2-pyrrolidinyl / -methyl, 2-piperidinoethyl, / 4-methyl-1-piperazinyl / carbonyloxyethyl or a group of C 2 -C 4 -alkyl-NR 2 R 3 (it can be substituted with methyl, ethyl or benzyl) R 2 and R 3 - (identical or different) H, C 1 -C 10 -alkyl, cyclopentyl, cyclohexyl or NR 2 R 3 -pyrrolidine, imidazole or morpholine ring, N = 1 or 2, as isomers, or mixtures , or additive salts with acids that can be used in medicine. The goal is to create a new active connection of the specified class. Synthesis is carried out by oxidation of pristinamycin P in m-chlorobenzoic acid or selenium dioxide, followed by isolation of the target product in free form, if necessary, by separation into isomers or by isolation in the form of acid addition salts. 1 tab.
公开号:SU1540655A3
申请号:SU864010148
申请日:1986-01-10
公开日:1990-01-30
发明作者:Баррьер Жан-Клод；Котрель Клод；Пари Жан-Марк
申请人:Рон-Пуленк Санте (Фирма)；
IPC主号:

专利说明:

to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C, a light yellow solid is obtained, which is mixed with 10 cm3 of ethyl ether. The resulting solid
The volume is dried under reduced pressure (90 Pa) and a temperature of 40 ° C. 33.6 g of 26- (2-diisopropylaminoethyl) thiopristinamycin Pb are thus obtained.
(isomer A) in the form of white crystals with
the substance is separated by filtration and after 15 mp. about 122 ° C.
0.62 g of 26- (2-diisopropylamino-NMR spectrum: 1-1.15 (rat, -CH-isoethyl) sulfinylprystinamycin PD (isomer A)) are obtained in the form of a yellow powder with a mp of ca. 155 ° C.
NMR spectrum: 0.90-1.15 (mt, -CH5
/ CH5 at 32, 31, 30 N - (CHC) 1.76
(s, -CHO, at 33); 2.75-3.15 (mt, 7CH2v
sn-15, -H4 and -S-CHz-CHj 5 3.81
 sp-
eight
(i, CH2b 17); 4.76 (d, 5.51 (d, -H0); 6.20 (d, -H „); 6.48 (m, NH in 8); 8.13 (s, -H 40).
Fractions 35-45 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C to obtain a light yellow solid, which is stirred in 15 cm of ethyl ether. The resulting solid is collected by filtration to give 1.07 g of 26- (2-diisopropylaminoethyl) sulfinylpristinpropyl); 1.72 (s, -CH3 at 33); 1.80-, 2.20 (mt, -Has, -H "g); 2.50-3 (mt,
CH x -SCHUCH4- NCcfl J (d wide,
-Na); 4.74 (s broad, -H 57); 6.32 (m, -№j); 8.15 (s, -HQO).
2-Diisopropylaminoethanoltiol can be obtained by a known method.
25 Example 2. To a solution of 10 g of 26- (2-diisopropylaminoethyl) thiopristin amine P & (isomer A) in 300 cm- of chloroform 1.22 g of sodium bicarbonate was added. The solution is cooled to -50 ° C and up to 30 Bpl drop by drop of a solution of 2.98 g of 98% non-chloroperbenzoic acid in 100 cmE of chloroform. The mixture is stirred for 2 hours and 15 minutes at -50 ° C, then a saturated aqueous solution of sodium bicarbonate is added to it. After stirring for 15 minutes at 25 ° C, the mixture is decanted, then the aqueous phase is washed three times with 200 cm3 of dichloromethane. Organic phases
cin P & (isomer Ax 80%, isomer A2.20%) dd, dried over magnesium sulphate, filtered as a light yellow powder, then concentrated until dos T. pl. about 145 ° C. ha under reduced pressure (2.7 kPa)
NMR spectrum (isomer): 1.72 (s ,, and a temperature of 30 ° C and get 10.62 g
—CH3 at 33); 2.70-3.15 (mt, CH2 in 15, -H4, -S-CH -N-CP); 3.81 (s, iCH 5c
itI
DOS
17); 5.26 (d, -Hb7); 6.46 (d,); 6.15 (d, -nm); 8.11 (s, -Heo).
26- (2-Diisopropylaminoethyl) thio pristinamycin Pv can be obtained as follows.
To a solution of 52 g of pristinamycin PD in a mixture of 260 cm of dichloromethane and 520 CNT
methanol is added dropwise to the atmo-, -, After decanting the RP of the aqueous phase, add
a sphere of nitrogen at a temperature of -30 ° C 16 g of 2-diisopropylaminoethanethiol dissolved in 30 cmE of dichloromethane. The solution is stirred for 20 h.
d to 7-8 by adding sodium bicarbonate, then washing with 300 cm of dichloromethane. The organic phases are combined, washed twice.
propyl); 1.72 (s, -CH3 at 33); 1.80-2.20 (mt, -Has, -H "g); 2.50-3 (mt,
CH -SCHUCH4- NCcfl J (d wide,
-Na); 4.74 (s broad, -H 57); 6.32 (m, -№j); 8.15 (s, -HQO).
2-Diisopropylaminoethanoltiol can be obtained by a known method.
Example 2. To a solution of 10 g of 26- (2-diisopropylaminoethyl) thiopristin amine P & (isomer A) in 300 cm- of chloroform 1.22 g of sodium bicarbonate was added. The mixture is cooled to -50 ° C and a solution of 2.98 g of 98% non-m-chloroperbenzoic acid in 100 cmE of chloroform is added dropwise to the PT. The mixture is stirred for 2 hours and 15 minutes at -50 ° C, then a saturated aqueous solution of sodium bicarbonate is added to it. After stirring for 15 minutes at 25 ° C, the mixture is decanted, then the aqueous phase is washed three times with 200 cm3 of dichloromethane. Organic phases
product in the form of whitish meringues. It is dissolved in 400 cm of ethyl acetate.
then treated with 140 cm1 of a 0.1N aqueous solution of hydrochloric acid. After that, the pH of the aqueous solution was adjusted to 4.2 by adding 400 buffer solution with a pH of 4.2. The aqueous phase is decanted, the organic phase is washed with 400 cm of buffer solution with a pH of 4.2. The aqueous phases are combined and washed twice with 150 cm1 of ethyl acetate.
d to 7-8 by adding sodium bicarbonate, then washing with 300 cm of dichloromethane. The organic phases are combined, washed twice.
200 cm of buffer solution with a pH of 7.5. The aqueous phase is washed with 50 cm of dichloromethane, then the organic phases are combined, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C, to obtain 8.04 g of a light yellow solid, which is stirred in 100 cmg of ethyl ether, separated by filtration, then dried under reduced pressure (90 Pa) and a temperature of 40 s. 7.5 g of 2b- (2-diisopropylaminoethyl) sulfinylprythinamicin PE (isomer A) are thus obtained in the form of a yellow powder with mp. about NMR characteristics are identical to the characteristics shown in example 1.
Example 3. The reaction was carried out according to the procedure described in the example, but starting from 53.2 g of 26- (2 diethylamino-ethyl) thiopristinamicin Pv, 6.25 cm of trifluoroacetic acid, 16.4 g / h of chlorobenzoic acid. Three consecutive purifications were performed by flash chromatography (eluent: chloroform-methanol, 90-10 by volume) and fractions of 40 cm were collected according to the following scheme.
Cleaning circuit
Part A (68 g)
Pulsed chromatography 35 part B 55 g (fractions 21-60) pulse chromatography, part C part C &
(fractions 25-35) (fractions 36-60)
10 g 18,8 g 40
pulse chromapulta, chromatograph
part D part E
(5.58 g) (11.5 g)
amycin pe can be obtained as follows.
To a suspension of 13.1 g of Pristnamicin PD in 150 cm of methanol was added a solution of 3.7 g of diethylaminoethiol in 15 cm of methylene chloride. The resulting solution is stirred for 18 hours at a temperature of about 20 ° C, then poured into 1500 cm of distilled water; the resulting mixture was extracted three times with 1000 cm3 (total amount) of methylene chloride. Organic phases of co (fraction 18-30)
(fractions 18-45) 45 are combined, dried over magnesium sulphate,
filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 C. The resulting residue is considered by the method of pulse chromatography (eluenthporoform-methanol, 90-10 by volume); fractions 5-23 are concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C, and 12.4 g of 26- (2-diethylamino-ethyl) thiopristinamycin P & in the form of a yellow powder with So pl. about 105 ° C.
In all cases, the fractions obtained are concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. Part D is stirred in 60 cmE of ethyl ether. The resulting solid is separated by filtration. 5 g of 2.6- (2-diethylaminoethyl) sulphinylprystinamycin Py (AQ isomer) are obtained in the form of a yellow powder with m.p. about .55
NMR spectrum: 1.00-1.14 (mt, -CH3 in 32 + SNE chain); 1.75 (s, -СНъеЗЗ); 2.55-3.20 (пЈ, СНг в 15, -К4,
yu 15
0655
-CH0 Oh

 ); 3.82 (17);
CH.2
0
4.81 (d, -H, 7); 5.51 (d, -H, b); 6.19 (d, -H4); 6.46 (dd, iNH at 8); 8.13 (s, -H.
Part E is stirred in 10 cm 5 of ethyl ether. The resulting solid was collected by filtration. 10.9 g of 26- (2-diethylaminoethyl) sulfinylprythinamine Pa are obtained (A2 isomer 60%, AI isomer 15%, Isomer В „12%, Isomer B 13%).
NMR spectrum: 1.00-1.14 (mt, -CF b in
32i. GSISA ,, and Ae); 1.54 (s, -CH ", at 33 B, and B-d); 1, 68 (s, -CH 3 in
33A4); 1.75 (s, -CH3 at 33 Aa); 2.65-2.95 (rat, -5 (0) SP2SNeX and NFA ”); 2.55-3.20 (mtjT-CH B 15, -H, and
-8 (0) CHENCHK A “); 3.77 (AB limit, SPChV 17 AO; 3.82 (s, in 17 Aa); 4.81 (d, -H / i7 A%); 5.24 and 5.25 (2d,
5 -H27 A and B,); 5.41 (d, 3 A,); 5.51 (d, -Hrt A2); 5.99 and 6 (2d, -H6 B, and Hfe Eg); 6.11 (d, -H „A,); 6.19 (d, HN A); 6.46 (dd, NH in 8 A2); 6.79 (dd, NH in 8 A,); 7.82 (s, -H2Q
0 V, and Br) 5 8.12 (s, -Hjp A,); 8.13 (s, -% o Ar).
26- (2-Diethylaminoethyl) thiopristinamycin Pe can be obtained by the following procedure.
To a suspension of 13.1 g of Pristnamicin PD in 150 cm of methanol was added a solution of 3.7 g of diethylaminoethiol in 15 cm of methylene chloride. The resulting solution is stirred for 18 hours at a temperature of about 20 ° C, then poured into 1500 cm of distilled water; the resulting mixture was extracted three times with 1000 cm3 (total amount) of methylene chloride. The organic phases are combined, dried over magnesium sulphate,
filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 C. The resulting residue is considered by the method of pulse chromatography (eluenthporoform-methanol, 90-10 by volume); fractions 5-23 are concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C, and 12.4 g of 26- (2-diethylamino-ethyl) thiopristinamycin P & in the form of a yellow powder with So pl. about 105 ° C.
NMR spectrum: 1.05 O, -N (CHЈH3) Z + + -H #); 1.70 (s; -HH) 5 1.85-2.15 (w,
-H25, -P2); 2.60 (q, -N (CH2CH $) 2);
2.75 (s, -S-CH2CH2-); 2.9 (dd, LVH, -H, 5); 3.10 (dd, AVH system, -Hi5); 3.40 (ddd, -Hae); 3.80 (s, -H, 7); 4.75 (d, -H21); 5.50 (d, -H); 6.15 (d, -Ni); 6.60 (s wide, / NH at 8); 8.10 (s, -H4C).
Example 4. According to a procedure similar to that described in Example 1, but starting from 5.5 g of 26- (2-dimethylaminoethyl) thiopristinamycin Pv, 0.67 cm3 of trifluoroacetic acid, 1.8 g (U-chloroperbenzoic acid, - {After purification by pulsed chroma tography (eluent: chloroform-methanol, 90-10 by volume), selection of fractions 30 cm and concentration of fractions 23-40 to dryness under reduced pressure (2.7 kPa) and temperature 30 ° С are obtained 0.4 g of 26- (2-methylaminoethyl) sulfinylpristinamycin P (A2 isomer 70%, isomer L (15%, isomer B, 77, isomer B 8%) as a yellow powder with mp around 150 ° WITH.
HPP spectrum (isomer A2): 1.77 (s, -CH3 at 33); 2.41 (s, -M (CH, a) g); 2.703, 20 (mf, -SCH2CH2N, CH2 at 15 and O
); 3.82 (s,; cis in 17); 4.84 (mt, -H, and -Hg7); 5.52 (d, -H,%); 6.19 (d, -H „); 6.42 (m, W in 8); 8.14 (s, H20).
26- (2-Dlmethylaminoethyl) thiopristin-amycin P "can be prepared as follows.
According to the method similar to the method described in example 3, based on 2.7 g of pristinamycin PD and 0.58 g of 2-dimethylaminoethanoltiol after purification by pulse chromatography (eluent: chloroform-methanol, 90-10 by volume) and concentration to dryness of fractions 11-17 under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 1.1 g of 26- (2-dimethylamio-ethyl) thioastinamycin P are obtained in the form of a yellow powder with m.p. about 100 ° C.
NMR spectrum: 2.35 (s, 6H: -N (CH,) g) 2.80 (and, 4I: -S-CH CIl -N); 3.40 (ddd, 1H: -HЈfc); 4.75 (d, 1H: -H); 8.10 (s, in: -HM).
Example 5 According to the procedure similar to that described in Example 2, but starting from 4.7 g of 26- (thyl-1-ethyl-2-aminoethyl) thiopristin-amycin nfr (isomers L 90%, B 10%), 1, 22 g sodium bicarbonate, 1.41 g M-chloroperbenoic acid (98%),
50
five
0
0
five
after purification by flash chromatography (eluent: dichloromethane-methanol, 90-10 by volume), selection of fractions of 20 cm and concentration of fractions 44-52 to dryness under reduced pressure (2.7 kPa) and temperature of 30 ° C, 2.47 are obtained g of a yellow solid, which is stirred in 50 cm3 of ethyl ether, separated by filtration, dried under reduced pressure (90 Pa) and a temperature of 40 ° C. Thus, 2.3 g of 26- (N- -methyl-K-ethyl -2-aminoethyl) sulfinyl-pristinamycin P $ (isomer A) as a yellow powder with m.p. about 145 ° C.
NMR spectrum: 1.09 (t, N-CH2 CH,); 1.76 (s, -SI, at 33); 2.31 (s, 2.54 (mf,,); 2.80 (mf, -H4); 2.70-3.10 (mf, -S-CH2-CH2NQ;
0
2.92-3.12 (2dd, CF2 in 15); 3.24 (mf, -H26); 3.82 (s, -C% at 17); 4.82 (s, -P2r); 5.51 (d, -H ,,); 6.40 (dd, -NH at 8); 8.13 (s, -Fao).
26- (N-Methyl-N-ethyl-2-aminoethyl) thiopristinamycin P (isomers A 90%, B 10%) can be obtained by a procedure similar to that described in Example 1, but starting from D, 11 g pristinamycin PA n 3.2 g of N-methyl-P-ethyl-2-aminoethanethiol. After stirring for 4 days at -20 ° C and purification by flash chromatography (eluent: chloroform-methanol, 90-1 O by volume), selection of fractions 80 cm and concentration of dry fractions 25-48 under reduced pressure (2.7 kP) and a temperature of 30 ° C. 4.75 g of a yellow solid are obtained, which is dried under reduced pressure (90 kPa) and at a temperature of 40 ° C. thus, 4.7 g of 26- (K-methyl-Hl-ethyl-2-aminoethyl) are peptidine P & (A isomers A 90%, B 10%) as a yellow powder with m.p. about 140 ° C.
NMR spectrum: 1.1 (mf,,); 1.73 (s, CH at 33); 2.30 (s, N-CH,); 2.45-2.6 (mf, N-CH2CHj); 2.68-2.78 (2mf, -S-CH2CH2NC); 2.78 (mf, -H +); 2.90 n 3.12 (2dd, -CH4- in 15); 3.40 (d, -Hzj 3.83 (s, -CH2- in 17); 4.76 (s, -ts2,); 5.48 (d, -Fn); 6.14 (d, -Hu ); b, V (mf, NH in 8); 8.11 (s, -H20).
N-Methyl-K-ethyl-2-aminoethylnol can be obtained in a known mego, starting from 25 g of M-metpl-C-ethyl-h -; - per and 43.7 g of ethylene-Thiocarbonate. Poscho
111540655
distillation get 1.3 g of N-methyl-
12
Distillations of 1, J g N-methyl- 7,801 are obtained.
-N-ethyl-2-amino-ethanethiol as a besng of each isomer); Q JQJ (2 s,
colored liquid, t.kip, (6.7 kPa), n. . each isomer).
52 ° C.
WITH
Example 6. According to the procedure, anaExample 7. According to the procedure similar to that described in the application procedure described in the example based on p (26-2-dimer 1, but starting from 9.8 g - (3-diethylaminopropyl) thiopristinamycin P „, 0.72 cm trifluoroacetic acid and
Ethylaminopropyl) thiopristinamycin Pn, 0.72 cm of trifluoroacetic acid and
methylaminopropyl) thiopristinamycin PD
(A / B isomers 50:50), 1.18 cm3 of tri-, 0.9 g of u-x-perperbenzoic acid on fluorofluoroacetic acid, 3.1 g of gy-chloroperbenzoic acid, after cleaning
pulse chromatography method
(eluent: chloroform-methanol, 80-20
2
barely cleaning by the method of pulse chromatography (eluent: chloroform-methanol, 90-10 by volume), selection of fractions
. „260 cm and concentration of dry fractions
volume), the selection of the fraction of 15 cm and con-15 d under reduced pressure (2.7 kPa)
concentration to dryness of fraction 53-75 at a temperature of 0.99 g receive
Under reduced pressure (2.7 kPa) and that 26- (2-diethylaminopropyl) sulfinyl 30 C, 1.6 g of 26- (3-styminacin Py (isomer Aa)) is obtained in the form of dimethylaminopropyl sulfone crystalline yellow powder with m.p. . about 150QC.
Ilg mycina (mixture of isomers) as yellow-20 i
of powder with m.p. about 165 ° C. NMR spectrum: 1.03-1.20 (mf,
NMR spectrum (mixture of isomers of type CH2-CH (CH) N (CH2CH3) and CH3 in 32);
, B2 35% and B a 1.53 (a, -CH3 at 33 B4 and B,); 1.75 (s, -CP at 33 Ae) | 2.26, 2.28 and 2.32 (3 s, NCH3 3 isomers); 3.82 (s, CF2 in 17 Ar); 3.70 and 3.88 (2d, CH2 at 17 V,); 3.69 and 3.91 (2 d, CH4 in 17 B2); 4.76 (d,); 5.25 (dy -H27 B,);
1.76 (s, -CF in 33); 3.82 (s,
; sn „
in 17); 4.79 (m -H27); 5.53 (d, -H4-); 25 6.20 (d, -H „); 6.42 (m, NH at 8); 8.13 (s,).
After concentration to dryness of fractions 23–25 under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 5, 50 (d, -H, Ar) were obtained; 7.63 (mf, NH in 30 and 0.64 g of 26- (2-diethylaminopropyl) 8 V); 7.74 (mf, Ш В 8 В); 7,82 sulfinylprythinamine H8 (isomer
(s, -Hgo Br and B,); 8.14 (s, -go A4). 26- (3-Dimethylaminopropyl) thiopri) as a yellow powder with m.p. about 160-170 ° C.
NMR spectrum: 1.14 (mf, -N (CH4CF); as follows: 1.24 (d broad, CH —CH-tO; 1.73
According to the method similar to the method, i (s, -CF5 in 33); 3.81 (AI limit described in Example 3, but the outcome is from CHP at 17); 5.28 (d, 5.43
5.25 g of pristinamycin PD and 1.3 r (d, -H); 6.15 (d, -H „); 6.88 (t,
3-dimethylaminopropan-thiol, after purifying o); 8.10 (and, H-0). using the method of pulse chromatography 4Q26- (2-Diethylaminopropsh) thiopri (eluent: chloroform-methanol, 90-10 by the styminamine P0 can be obtained following the volume) and concentration to dryness in a blowing manner, 6-29 under reduced pressure (2.7 kPa) According to the method similar to the method
Stynamycin Pr can be obtained at a temperature of 30 ° C. 3.3 g are obtained.
given in example 3 but the outcome
2b- (3-dimethylaminopropyl) thiopristine- 4j from 3.15 g of pristinamycin P. and 1.8 g of mycin P in the form of a yellow powder of c2-diethylaminopropanthiol, after clearing. Pl. about 100 ° C, using flash chromatography (eluSNR NMR: 1.50 (s, PCA, 5: -H ent: methylene chloride-methacol, 90-10 by
1st isomer); 1.70 (s, 3HxO, 5: -H volume), selection of fractions 20 cm and the end of the isomer) 1.80 (m, 2H: -5CHfCH2- 50 dryness concentration of fractions 3-5 with by: 2.20 (s, 6HxO, 5: in situ pressure (2.7 kPa) and tempe N (CH) 1st isomer); 2.25 (s, 6HxO, 5: at 30 ° C, 1.4 g of 26- is obtained ( 2-di- -N (CH) 2nd isomer); 2.40 (m, 2H: ethylaminopropyl) thiopristine-Mlycin P
in the form of a yellow powder with So pl. about
-CHЈ-CH2-SN.Yu; 2.70 (m, 2H: in
. p g-155
3 35 -CHN-CH-CHNCO; 3 45J 2 t Hs And
kazt dog isomer); /, 7GP (2 d, 1H:
26
9H; -H „NMR spectrum: 1 (n, -N (CF2CHj) 2); 2.50 (m, 6F: -S-CЈ1. -CH-N (Q42CH) i); 3.30 (m, IH:
12
Example 7. According to the method similar to the method described in the example, based on p (26-2-di
Ethylaminopropyl) thiopristinamycin Pn, 0.72 cm of trifluoroacetic acid and
, 9 g of u-xyperperbenzoic acid for CH2-CH (CH) N (CH2CH3) and CH3 in 32);
1.76 (s, -CF in 33); 3.82 (s,
; sn „
in 17); 4.79 (m -H27); 5.53 (d, -H4-); 6.20 (d, -H „); 6.42 (m, NH at 8); 8.13 (s,).
After concentrating the fractions 23-25 to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 0.64 g of 26- (2-diethylaminopropyl) sulfinylprythinamine H8 (isomer
given in example 3 but the outcome
9H; -H „NMR spectrum: 1 (n, -N (CF2CHj) 2); 2.50 (m, 6F: -S-CЈ1. -CH-N (Q42CH) i); 3.30 (m, IH:
-H24); 4.70 (d, 1H: —I27); 8.12 (s, 1I: -Hto.
2-Diethylaminopropanethiol can be obtained as follows.
To a solution of 29.5 g of β-3-isothioureido-2-diethylaminopropane dichlorohydrate in 150 cm of distilled water is added 25 cm of 10N aqueous sodium hydroxide solution. The mixture is heated at 100 ° C for 1 hour, cooled to 20 ° C, the pH is adjusted to 9 by the addition of 8 cm 12 N. aqueous hydrochloric acid solution, then extracted
at 200 ° C a solution of 66 g of ethyl 2-di-ethylaminopropionate in 330 cm of ethyl ether. The reaction is maintained at 35 ° C for 5 hours, then the temperature is lowered to 0 ° C. After this, 12.4 cm of water is added dropwise at OC, stirred for 30 minutes, then the mixture is filtered through porous glass and washed with ethyl ether the phase is dried over potassium carbonate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 C. Semi
three times 100 cmE of ethyl ether. Ether (5 are 43.8 g of yellow liquid, which
The combined phases are combined, dried over potassium carbonate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. The mixture is purified by distillation. 5.8 g of 2-diethylamino-1-propanethiol are obtained in the form of a colorless liquid. Bp (2.7 kPa) 78 ° C.
The s-1-isothiureido-2-diethylaminopropane dihydrochloride can be prepared as follows.
To a solution of 41 g of 1- -chloro-2-diethylaminopropane hydrochloride in 200 cm of dimethylformamide was added 16.7 g of thiourea. The mixture is heated at 100 ° C for 30 minutes, then cooled to 20 ° C. The white precipitate formed is separated by filtration, washed three times with 20 cm of dimethylformamide, then three times with 20 cm of ethyl ether. 29.6 g of a-1-isothioureido-2-diethylaminopropane dichlorohydrate are obtained in the form of white crystals with m.p. 247 - 249 ° C.
20
25
thirty
35
dissolved in 200 cmu of acetone, 78 ml of a 4.5 N solution of hydrochloric acid in ethyl ether are added. Chlorine 2-diethylaminopropanol crystallizes. After filtration, 45.2 g of white crystals are obtained with a m.p. 97-100 C.
Example 8. According to the method, and the logical method described in at re 2, but starting from 4 g of 26- (2-diethyl aminopropyl) thiopristinamycin Pn (and measure A, 1.16 g of 98% W-chloroperbozoic acid and 1 g of solid sodium biconate, after purification by pulse chromatography (eluentkh form-methanol 93-7 by volume), to a dry concentration (2.7 kPa) under reduced pressure (2.7 kPa) and temperature and selection of fractions 25 get 2 , 69 g of 26- (2-diethylaminopopyl) sulfinylprythinamycin P (from measure Lg) in the form of a yellow powder with characteristics identical to those of the product obtained About in 7.
The 1-chloro-2-diethylaminopropane hydrochloride can be prepared as follows.
45.2 g of 2-diethyl-aminopropanol hydrochloride is added to 100 cm of thionyl chloride over 15 minutes, then heated to 80 ° C. After stirring for 2 hours, the excess of thionyl chloride is distilled off and the residue is dissolved in 200 cm of ethyl ether. 1-Chloro-2-diethylaminopropane hydrochloride crystallizes. After filtering, 48.2 g of white crystals with a m.p. П2 ° С.
The 2-diethylaminopropanol hydrochloride - can be prepared as follows.
Under nitrogen atmosphere, a suspension of 10.6 g of lithium aluminum hydrate in 1 liter of ethyl ether was slowly added
at 200 ° C, a solution of 66 g of ethyl-2-diethylaminopropionate in 330 cm of ethyl ether. The reaction is maintained at 35 ° C for 5 hours, then the temperature is lowered to 0 ° C. After this, 12.5 cm of water is added dropwise at OC, stirred for 30 minutes, then the mixture is filtered through a porous glass and washed with ethyl ether. The ether phase is dried over potassium carbonate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. 43.8 g of a yellow liquid are obtained, which
5 are 43.8 g of yellow liquid, which
0
five
0
five
0
d
five
dissolved in 200 cmu of acetone, then 78 cm of a 4.5 N solution of gaseous hydrogen chloride in ethyl ether are added. The 2-diethylaminopropanol hydrochloride crystallizes. After filtration, 45.2 g of white crystals are obtained with a m.p. 97-100 C.
Example 8. By the method similar to the method described in example 2, but starting from 4 g of 26- (2-diethyl-aminopropyl) thiopristinamine P „(isomer A, 1.16 g of 98%% chloroperbenzoic acid and 1 g of solid sodium bicarbonate, after purification by flash chromatography (eluent chloroform-methanol 93-7 by volume), the concentration of dryness of fractions 21-48 under reduced pressure (2.7 kPa) and temperature, and the selection of fractions of 25 cm is obtained 2.69 g 26- (2-diethylaminopropyl) sulfinylprythinamycin P (Lg isomers) in the form of a yellow powder with characteristics identical to sticks of the product obtained in example 7.
26- (2-Diethylaminopropyl) thiopristinomycin P (isomer A) can be obtained by a method similar to that described in Example 1, which is 5 d from 15 g of pristinamycin Nd and 4.62 g of 2-diethylaminopropanthiol . After purification by flash chromatography (eluent: chloroform-methanol, 90-10 by volume), dry concentration of fractions 27-52 under reduced pressure (2.7 kPa) and temperature 30 ° С and selection
40 cm3 fractions get 60 cm of ethyl ether, filtered, then dried. Obtain 8.2 g of 26- (2-diethylaminopropyl) thiopristinamycin P & (isomer A) in the form of a light yellow powder with m.p. about 122 ° C
NMR spectrum: .1-1.15 (mf, -CH3 ethyl + + CHS-pK-N (CftHe) i); 5.70 (s, -SI, in
-CH & -CHE 33); 2.35-2.60 (mf, - N

2.50-3.10 (mf, -SCR4CH-); 2.75 (mf, -H4); 2.89 and 3.05 (2 dd1
2.92 and 3.08 (2 ddj: CHg in 15) 3.30 (mf
3.37 (mf
4.69
4.71
6.13
6J4
t ji
t.
d d) H
(dj
H ,.); 3.80 (s, -CH2 in 17
hch); 5.45 (d, -H, $); 6.4-6.0 (mf, NH
(dd | -V (S
}
2-Diethylaminopropanethiol can be obtained by the method described in example 7.
Example 9. According to the method, ana-crystallized is crystallized from 30 cm of acetonitrile. After filtering and drying, 5.91 g of 26- (I-diethylamino-2- -propyl) thiopristinamycin P. (isomers A) are obtained in the form of white crystals with mp.
logical method described in the example- j $ 1Чб ° г
re 2, starting from 4.58 g of 26- (1-diethyl-amino-2-propyl) thiopristinamicin P (isomers A), 1.29 g of ft-chloroperbenzoic acid (98% NaI) and 1.14 g solid sodium bicarbonate after purification
NMR spectrum: -K (SNGCH,) g);
sn3-sn-sn21O;
0.9-1.10 (mf, 1.33-1.37 (2 d,
using pulsed chromatography (eluent: chloroform-methanol, 97-3 by volume), selection of fractions 20 cm8 and concentration of dryness under reduced pressure (2.7 kPa) and temperature 30 ° C, respectively, fractions 59-77 and 79-97 are obtained from fractions 79 -97 1.47 g of 26- (1-diethylamino-2-propyl) sulfonyl-pristinamycin P first isomer) as a light yellow solid with m.p. about 132 ° C.
NMR spectrum: 1.02 (t, -OTZ ethyl); 1.34 (d, CH3-CH-CH2N (C2HS) 4); 1.72 (at, -CHS at 33); 2.5-2.7 (mf,
CH4-CHa-N); 2.77 (mf, -H4);
thirty
2.4-2.65 (mf,
1.7 (s, -CH in 33);
) J 2.76
-CHt-cng40
w2, 97
2.87 and 3.09 (2 dd, CH2 in 15); (mf, -S-CHO; 3.72 (mf, -Hw) j
ABOUT
3.80 (s, CH2 at 17); 4.92 (mf,); 5.43 (d, -H „); 6.15 (d, -H „); 6.72 (dd, NH at 8); 8.06 (s, -go).
From fractions 59-77, 1.07 g of 26- (1-diethylamino-2-propyl) sulfinyl-pristinamycin P (second isomer) is obtained in the form of a light yellow solid with m.p. 128 ° C.
(mf, -1C); 3 (mf, -S-CHi); 2.9 and 3.1
(2 dd, tsCHj, in 15); 3.52 (mf, -HM);
3.81 (s. 17); 4.78 (d, -Ht7);
35 5.46 (d, -H2,); 6.14 (d, -HH); 6.40
(mf, NH at 8); 8.09 and 8.10 (2 s, -H-J. I
1-Diethylamino-2-propanthiol can be obtained by a known method.
IO example According to a procedure similar to that described in Example 2, but starting from 1.7 g of -dimethylaminobutyl-2 (R) J of thiopristimycin Pa (isomer A), 0.50 g of bi- .g sodium carbonate, and 0.45 g 98% (ll-chloroperbenzoic acid, after purification by flash chromatography (eluent: ethyl acetate-methanol} 85-15 by volume) and concentration of dry fraction 35-58 under reduced pressure (2.7 kPa) and temperature 30 C, i, 1 g of a white solid which is stirred in 30 cm of ethyl ether is obtained. After filtering and drying, 0.95 g of 26- - 2-dimethylaminobutyl-2 (E) sulfinyl- is obtained. pristinamycin P. (isomer A2) in the form of a solid of a white color with a melting point of about 126 C.
:
NMR spectrum: 1.72 (s, SI, at 33); 3.4 (mf, -H); 3.79 (s.CH at 17); 4.74 (mf, -H21); 5.48 (d, -H «); 6.18,
5 (d, -Ni); 6.80 (mf, in 8); 8.09 (s, -HM).
26- (1-Diethylamino-2-propyl) thiopristine I P (isomers A) can be obtained by a method similar to that described in Example 1, but starting from 13 g of Pristinamycin P. and 4 g of 1-diethylamino 2-propanethiol. After purification by flash chromatography (eluent: chloroform-methanol,
15 90-10 by volume) and concentration to dryness of the fractions 46-55 under reduced pressure (2.7 kPa) and a temperature of 30 ° C with the selection of fractions of 50 cm, 8 g of a pale yellow solid are obtained, which crystallize from 30 cm of the NMR NMR spectrum: - K (SNGCH,) g);
sn3-sn-sn21O;
0.9-1.10 (mf, 1.33-1.37 (2 d,
2.4-2.65 (mf,
1.7 (s, -CH in 33);
) J 2.76
-CHt-cng0
(mf, -1C); 3 (mf, -S-CHi); 2.9 and 3.1
(2 dd, tsCHj, in 15); 3.52 (mf, -HM);
3.81 (s. 17); 4.78 (d, -Ht7);
5 5.46 (d, -H2,); 6.14 (d, -HH); 6.40
(mf, NH at 8); 8.09 and 8.10 (2 s, -H-J. I
1-Diethylamino-2-propanthiol can be obtained by a known method.
IO example According to a procedure similar to that described in Example 2, but starting from 1.7 g of -dimethylaminobutyl-2 (R) J thiopristhytycin Pa (isomer A), 0.50 g of bi-g sodium carbonate, and 0.45 g 98 % (ll-chloroperbenzoic acid, after purification by flash chromatography (eluent: ethyl acetate-methanol} 85-15 by volume) and concentration of the dry fraction 35-58 under reduced pressure (2.7 kPa) and temperature 30 С i, 1 g of a white solid is obtained which is stirred in 30 cm of ethyl ether. After filtering and drying, 0.95 g of 26- - 2-dimethylaminobutyl-2 (E) sulfinyl is obtained. ristinamycin P. (isomer A2) in the form of a solid of a white color with a melting point of about 126 C.
NMR spectrum: 1 (mf, N-pH-CH2-CH,) 5 1.45-1.75 (mf, N-CH-CHjiCH,); 1.78 (s, -CH, in 33); 2.50-3.05 (mf, -S-CP2-CHC and -H4); 2.93 and 3.14
ABOUT
(2 dd, CH2 15); 3.31 (mf, -Htt); 3.84 (s, CH2 at 17); 4.84 (d, -H2,); 5.51 (d, -H „); 6.19 (d, -n „); 6.30 (dd, NH at 8); 8.15 (s, -and).
26-2-Dimethylaminobutyl-2- (K) 1 thio-isostinamycin P (, (isomer A) can be obtained by a procedure similar to that described in Example 1, but starting from 8 g of pristinamycin PD and 2.3 g of 2- dimethylaminobutanethiol-2 (R). After purification by flash chromatography (eluent: dichloromethane-methanol, 90-10 by volume) and concentration of dry fractions 36-55 under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 3 g are obtained. -Ј2-dimethylaminobutyl -2 (K)} thiopristinamycin P (isomer A) in the form of a light yellow substance with m.p.
After crystallization of 0.9 g of this product from 5 cm of acetonitrile, after separation by filtration, 0.2 g of 26-2-dimethylaminobutyl-2 (P) thiopristipamycin Pv (isomer A) in the form of white crystals with m.p. 122 ° C.
NMR spectrum: 1 (nf, N-CH-CHj-CF,); 1.4-1.7 (mf, N — CH — CFgCITj); 1.72 (s, -CH3 at 33); 3.20 (s, -N (CH,) t); 2.5-2.85 (mf, -5-CH2-SNP and H4); 2.93 and 3.10 (2 dd, CF2 in 15); 3.34 (d wide, -Ngb); 3.83 (s, CP2 of 17); 4.76 (s pyro, -Ngt); 5.48 (d, -I „); 6.14 (d, -n „); 6.26 (dd, NH in 3); 8.13 (s, -Nm).
2-Dimethylaminobutanediol (K) can be obtained by a procedure similar to that described in Example 11 below, starting from 52.4 g of triphenylphosphine, 40 cm of diisopropylzodicarboxylate, 12 g of 2-dimethylaminobutanol (R) and 15.2 cm of thioluacetic acid (in In this case, the intermediate triester is hydrolyzed directly during silica gel chromatography).
After purification by pulse chromatography (eluent: dichloromethane - 1000 cm, then dichloromethane-methanol, 85-15 by volume - 2000 cm, then dichloromethane-methanol, 80-20 by volume - 4000 cme), selection of fractions 100 cm and concentration dry 14 g are obtained under reduced pressure of fractions 42-60
,ten
15
20
five
- th -) .25
;
one,
thirty
35
40
45
50
55
oily oil that is distilled. 2.4 g of 2-dimethylaminobutanediol (R) are thus obtained in the form of a colorless liquid. Bp (4 kPa) 70-75 ° C.
Example 11. According to a procedure similar to that described in Example 2, but using 2.67 g dimethylamino-3 phenylpropyl-2- (memory thioistinamine Pr (isomer A), 0.7 g sodium bicarbonate and 0.7 g 98% M-chloroperbenzoic acid, after purification by flash chromatography (eluent: chloroform-methanol, 90-10 by volume), selection of fractions 20 cm and concentration of dry fractions 19-23 under reduced pressure (2.7 kPa) and At a temperature of 30 ° C, 1.3 g of a light yellow solid are obtained, which is stirred in 50 cm of ethyl ether, separated by filtration, and 1.18 g are obtained. 26 - 2-dimethylamino-3-phenylpropyl-2 (h) sulfinylprythinamycin P (isomer A.) in the form of light yellow
ABOUT
solids with m.p. about 150 C. NMR spectrum (400 MHz, CDC1,): 1.73
(s, -SI, in 33); 2.4-2.6 (mfl 2.8-3.15 (mfj
- S - CRjC); 2.44 (s, -N (CH,)
Oh ng
2.77 (mf, -H4); 2.89 and 3.1 (2 dd, CH2 in 15); 3.18 (mf, -H2S); 3.82
(s, CHaB 17); 4.68 (d, -H2t); 5.51
(d, -Ho); 6.19 (d, -HM); 6.50 (dd, NH at 8); 7.18 (d, -H to 0-phenyl); 7.23 (t, -H in L-phenyl); 7.3 (t, -H
in | Vi-phenyl); 8.13 (s, -Ht.0).
A 1% aqueous solution of 26-2-dimethylamino-3-phenylpropyl-2 (8) sulfinylprynnamycin P (isomer A) is obtained from the following ingredients: product 30 mg; 0.1 ns salt per acid 0.45 cm, distilled water up to 3 cm.
26-2-dimethylamino-3-6enylpropyl -2 (s) J thiopristinamycin P & (isomer A) can be obtained according to the procedure similar to that described in example 1 for the preparation of starting material from 7.13 g of pristinamycin Pd and 2.65 g of 2-dimethylamino-3-phenylpropanthiol (s), and after purification method. pulse chromatography (eluent: ethyl-, acetate-methanol, 80-20 by volume), selection of fractions of 60 cm and concentration of dry fractions 33-43 under reduced pressure (2.7 kPa) and a temperature of 30 ° C
4.6 g of a light yellow solid are obtained, which is stirred in 50 cm of ethyl ether, filtered, then dried under reduced pressure (90 Pa) and a temperature of 45 ° C. Thus obtained 3.6 g of 26- |, 2-dimethyl- amino-3-phenylpropane 2 (8)} thiopristinamycin P in (isomer A) in the form of a pale yellow powder with m.p. about I ° C. NMR spectrum: 1.69 (s, -CH, at 33); 2.38 (g, MCH,); 2.35-3.05 (mf,
H -8CHNg-C-C%); 2.73 (mt, -H4); 2.89
I
and 3.10 (2 dd, in 15); 3.26 (broad, -H); 3.81 (d, CHg at 17); 4.68 (s wide, -Nat); 5.47 (d, -Hb); 6.12 (d, -H4,); 6.27 (mf, NH at 8); 7.18 (d, -H in 0-phenyl); 7.21 (t, -H in p-phenyl); 7.30 (t, -H in M-phenyl); 8.11 (s, -Hto)
2-Dimethylamino-2-phenylpropanethiol (s) can be prepared as follows.
To a solution of 20 g of 2-dimethylamino-3-α-phenylpropanethiol acetate (s) (unpurified) in 50 cm of methanol was added, under nitrogen, 0.2 g of sodium methoxide and heated with reflux for 2 hours. The mixture was then concentrated to dryness under reduced pressure. pressure (2.7 kPa) and a temperature of 30 ° C, and a liquid is obtained which is purified by distillation. 2.4 g of 2-dimethylamino-3-phenylpropanethiol (s) are obtained in the form of a colorless liquid, b.p. (14 Pa) 95 C which is used as such for the next reaction.
2-Dimethylamino-3-phenylpropanethiol acetate (s) can be prepared as follows.
Under nitrogen at 0 ° C, 41.97 g of triphenylphosphine is added to 310 cm of tetrahydrofuran, then 31.5 cm of diisopropyl eodicarboxylate are added dropwise and stirred for 30 minutes at 0 ° C. To the resulting white suspension is added dropwise a mixture of 15 g of 2-dimethylamino-3-phenylpropanol (3) and 11.44 cm of thioacetic acid, dissolved in 160 cm of tetrahydrofuran. After stirring for 1 hour at 0 ° C and for 1 hour 30 minutes at 25 ° C, the mixture is concentrated to dryness under reduced pressure (2.7 kPa) and
0
five
five
about 5
0 Q
five
temperature 190 cm of methanol are added to the resulting oil, a white solid is precipitated by filtration, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. The residue is then mixed with 200 cm of isopropidoxide, a precipitated solid the white color is separated again by filtration and the filtrate is concentrated, 45 g of a yellow oil are obtained, which is purified by means of flash chromatography (eluent: dichloromethane-methanol, 90-10 by volume), and 100 cm fractions are collected. After concentration of the 37-55 fractions to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 10.4 g of 2-dimethylamino-3-phenylpro-panthiol acetate (s) are obtained in the form of a yellow-orange oil (containing triphenylphosphine oxide).
Example 12. Apply a procedure similar to that described in Example 1, but starting from 12.5 g of 26- (1-pyrrolidinyl) ethyl thiopristinamycin Py (isomer A 90%), 1.47 cm of trifluoroacetic acid, 3.86 gee-chloroperbenzoic acid, after purification by pulse chromatography (eluent: chloroform-methanol, 85-15 by volume), selection of fractions 30 cm and concentration of dry fractions 18-25 under reduced pressure (2.7 kPa) and temperature 30 ° С 3.9 g - (1-pyrrolidinyl ethyl sulfinylpresti - namycin P & (isomers A 60%, Ar 25%, B 15%) in the form of a yellow powder with mp about 175 ° C. NMR spectrum ( isomer A): 1.74 (s,
CH20
five
—CH, at 33); 2.62 (mf, -N
);
-CH42, 70-3.20 (mf,: sCHa at 15, -S-CHaCHtN: T, -H4); 3.81 (8 CHav17);
ABOUT
5.28 (s wide, -H27); 5.45 (d, - -H); 6.14 (d, -H (,); 6.58 (mf.NH in 8); 8.12 (s, -Htt).
After concentration of the fractions 26-43 to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 4.36 g of (1-pyrrolidinyl) ethyl sulfinylprythinamine P6 is obtained (A4 isomer
75%, isomer A, 5%, isomer B, isomer Bg 10%) with m.p. about
at
as yellow 45 ° C.
10% powder
Nuclear Magnetic Resonance Spectrum (isomer Hg): 1.76 (s, -CH, at 33); 1.82 (m, CH2 in -3 and -4 pyrrolidinyl); 3.63 (mf -N-CH2-)

CH2-
2.85-3.20 (mt, -S-CU -CH and CHg in 15); 3.82 (s, in 17); 4.84 (dd, -H3 + d, -H27); 5.51 (d, -H13); 6.18 (d, -H „); 6.47 (nf.HH in 8); 8.13 O, -Nm).
(1-Pyrrolidinyl) ethyl thiopsystomyucine Pv can be prepared as follows.
Using a technique similar to that described in Example 3, but starting from 5.25 g of pristinamycin PD and 1.7 g of 2- (1-pyrrolidinyl ethanethiol), after purification by flash chromatography (eluent: chloroform-methanol, 95-5 by volume) and concentration to dryness of fractions 19-60 under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 3.9 g of 26-2- (1-pyrrolidi-yl) ethyl thiopristinamycin P. are obtained as a yellow powder with T. square about .
NMR spectrum: 1.90 (mf, 4H:
-tf
cis
CH,
2.50-2.80 (n, 611:
n c
-s-cH2cH2n jg);
3.40 (d, 1H: -H); 4.75 (d, 1H: —NHT); 8.10 (s, 1H: H2o).
Example 13. Apply a procedure similar to that described in Example 1, but starting from 6 g of 26- (2- -piperidinoethyl) thioghystinamycin P (isomer L), 0.69 cm of tris-to-acetic acid and 1.82 g of 85% C | - chloroperbenzoic acid, after purification by pulse chromatography (eluent: chloroform - methanol, 85-15 by volume), selection of fractions 20 cm and concentration of dry fractions 52-105 under reduced pressure (2.7 kPa) and temperature 30 C, 4.7 g of a yellow solid are obtained, which is again purified by flash chromatography (eluent: chloroformmetol, 85-15 by volume) and fractions are collected.
5 cm After concentration of fractions 9299 under reduced pressure (2.7 kPa and a temperature of 30 ° C, 1.83 g of a yellow solid is obtained, which is transferred to 20 cm 3 of ethyl
22
ether, separated by filtration, then dried under reduced pressure (90 Pa) and a temperature of 30 ° C. 1.51 g of 26- (2-piperidinoethyl) thiopristinnamicine P. is thus obtained (A4 isomers 90%, A 10%) as yellow powder with m.p. about 162 ° C.
Nuclear Magnetic Resonance Spectrum (400 MHz, CDC1,): 1.52
(tnf.);
/ -CH2 v -V)
h-w /
CH2 h 1.78
sn.
2.64 (mf, -N
; 2.80 (mf,
CH
20 25

thirty
35
40
4j
50
55
-H4); 2.85-3.25 (mf: -S-CI -CH -N -);
ABOUT
2, and 3.15 (2 dd, CH2 in 15); 3.20 (mf, -Hg6); 3.83 (in, CHg in 17); 4.92 (d, -H „); 5.54 (d, -Hn); 6.24 (d, -H „); 6.70 (mf.NH at 8); 8, 14 (s, -H2 (j) "
After concentration of Lractions 100-140 to dryness under reduced pressure (2.7 kPa) and a temperature of 309 ° C, 2.11 g of a yellow solid are obtained, which is stirred in 20 cm of ethyl ether, separated by filtration, then dried under reduced pressure (90 Pa) and a temperature of 30 C. Obtain 1.75 g of 26- (2-pyperidinoethyl) iopristinamine P (isomers A 50%, A 50%) in the form of a yellow powder with So pl. about 152 C.
Nuclear Magnetic Resonance Spectrum: 1.74 (s, -CH in 33 isomer A ,,); 1.78 (s, -Cl in 33 isomer A); 3.20 (mf, H24 isomer A); 3.46- (mf, HjЈ isomer A.); 3.82 (AB limit,: CHg in 17 isomer A,); 3.83 (s, Seg in 17 isomer A4); 4.90 (d, -H isomer Ar); 5.30 (s, -H47 isomer A,); 5.52 (d, -H,} isomer A «); 5.54 (d, -Hw isomer A); 6.60 (dd, -H5 isomer A4); 6.70 (dd, -Es isomer A (); 8.14 (s, -Hjo isomers Ag and A.).
26- (2-Piperidinoethyl) thiopristinnamine P (isomer A) can be obtained as follows.
fleficTBvn according to the procedure similar to that described in Example 1, but proceeding from 11.8 g of pristinamycin P and 3.58 g of 2-piperndino ethanethiol, after purification using the pulse chromate method 23154065524
screening (eluent: chloroform-methanol, 2CH2 at 17); 4.53 (dd, - CF4);
, 4.77 (d, -H „); 5.52 (d, -H, 3) 5 6.16
(d, -H, (); 6.46 (dd.SKH in 8); 7.12 5 (s, -y - - N); 7.69 (s, - CH N-); 8.16 ( s, -H,).
85–15 by volume), selection of fractions of 60 cm and concentration of the fractions 24–31 to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C give 8.3 g of 26- (2-piperidinoethyl) thiopristiminacin Ilg (isomer A) in the form of a light yellow powder with TPEGE, about 120 ° C. k NMR spectrum: 1.08 (d, -C1I., at 32);
1.40-1.60 (mf, 1.60ftfO i
26-12- (1-Imidazolyl) ethyl thiopristinamycin PC can be obtained by a method similar to that described in Example 3, but starting from 14.35 g of pristinamycin PD and 3.5 g of 2- (I- imide zolyl) ethanethiol. After stirring for 18 hours at 20 ° C, purification by flash chromatography (eluent- $ 15: ethyl acetate-methanol, 80-20 by volume) and concentration of dry fractions 34-59 under reduced pressure (2.7 kPa) and temperature 30 ° C get a solid yellow color, koto (mf, N
Cll

u); 1.73 (s, -CH
Clb
in 33); 2.45-2.90 (mf, -8-CHg-CH, cis-N,); 3.43 (mf, -H26) 5
si
g
26-12- (1-Imidazolyl) ethyl thiopristinamycin PC can be obtained by a method similar to the method described in Example 3, but starting from 14.35 g of pristinamycin PD and 3.5 g of 2- (I-imidazolyl ) ethanethiol. After stirring for 18 hours at 20 ° C, purification by flash chromatography (eluent- $ 15: ethyl acetate-methanol, 80-20 by volume) and concentration of dry fractions 34-59 under reduced pressure (2.7 kPa) and temperature 30 ° C get a yellow solid, koto3, 82 (s, .CH in 17) 5 4.71 (s wide, 20 swarm mixed in 60 cm3 ethyl Hi) t 5.50 (d, -Hij) (d,) . ether, then separated by ailtration
Example 14. I act according to the method similar to the method described in example 2, but based on 3.2 g
and get 10.9 g of 26- 2- (1-imidazolyl) ethyl thiopristinamine P (isomer ..., - A 85%, B 15%) as a solid substance t26-2- (1-imidazolyl) ethyl thiopristine- 25 WA yellow with m.pl. about 160 ° C.
Mycin P (A isomers 85%, B 15%), 1 g NMR spectrum: 1.53 (s, -CHg in 33 V);
sodium bicarbonate and 0.93 g Sch-chlorper-1.73 (s, -CH, 33 A); 2.74 (mf,
benzoic acid (98%) ,. after -H4 A); 2, 86 and 3, 14 (2 dd-CH4 in 15 A);
purification using pulse chromatography
2.85-3.05 (mf, -CH, -);
lg 3.11
(mf,
fii {eluent: chloroform-methanol, 90-10 30 -H4 A); 3 S32 (mf, -H46 B); 3.82 (limit
AB, CH2 at 17 A); 4.15 - 4.30 (mf, -CiyiO; 4.58 (d, -H "B); 4.68 (d narrowed down, -H47 A); 5.44 (d, -H A); 6, 16 (d, -HH A); 6.83 (dd, in 8 A); 6.97 and 7.08 (2 s, B); 7.01 and 7.10 (2 s, N-CH CNHCA) ; 7.54 (s,); 7.61 (s,); 7.64 (mf, in 8 7.82 (s, -Hgo B); 8.09 (s, -H2o L).
2- (1-Imidazolyl) ethanethiol can be obtained by a method similar to that described in Example 11 for preparing the starting material, but starting from 21 g of 2- (1-imidazolyl) ethan-d5 diol acetate and 0.5 g of sodium methoxide. After purification of distillations, 2.3 g of 2- (1-imidazolyl) ethanethiol are obtained in the form of an oil (eg, boiling point (20 Pa) 99,).
by volume), selection of fractions of 25 cm and concentration of dry fractions 29-49 under reduced pressure (2.7 kPa) and temperature 30 ° C to obtain 1.4 g of a yellow solid. The obtained solid is again purified by flash chromatography (eluent: chloroform-methanol, 90-10 by volume), the fractions selected are 10 cm each. After concentration to dryness of the fractions 47-55. Under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 0.62 g of a light yellow solid is obtained, which is stirred in 20 cm of ethyl ether, separated by filtration, then dried under reduced pressure ( 90 Pa) and temperature. Thus, 0.6 g (1-imidazolyl) ethyl sulfinylpristinamine P. (isomer A ′) is obtained in the form of a yellow solid with m.p. about 170 C.
Nuclear Magnetic Resonance Spectrum (400 MHz, CDC1) s 1.80 (s, –C3 to 33); 2.72 (mf, H4); 2.97-3.09 (2 dd, CH4 in 15); 3.0 (mf, -H2 & and one H -S-CHg-); 3.48 (mf,
About other N -S-SNG-); 3.82 (AB limit,
ABOUT
35
40
50
55
2- (1-Nmidazolyl) ethanethiol acetate can be obtained by a method similar to that described in Example 11 for the preparation of an intermediate, but starting from 15 g of 2- (1-imide olyl) ethanol, 70.2 g of triphenylphosphine, 55.8 cm diisopropyl azodicarboxylate and 21 cm of thiol acetic acid. After purification by flash chromatography (eluent: methylene chloride
(d, -H, (); 6.46 (dd.SKH in 8); 7.12 5 (s, -y - - N); 7.69 (s, - CH N-); 8.16 ( s, -H,).
ftfO i
26-12- (1-Imidazolyl) ethyl thiopristinamycin PC can be obtained by a method similar to the method described in Example 3, but starting from 14.35 g of pristinamycin PD and 3.5 g of 2- (I-imidazolyl ) ethanethiol. After stirring for 18 hours at 20 ° C, purification by flash chromatography (eluent: ethyl acetate-methanol, 80-20 by volume) and concentration to dryness of fractions 34-59 under reduced pressure (2.7 kPa) and temperature 30 ° C, a yellow solid is obtained which is stirred in 60 cm 3 of ethyl ether, then separated by Ailtration
-H4 A); 2, 86 and 3, 14 (2 dd-CH4 in 15 A);
2.85-3.05 (mf, -CH, -);
lg 3.11
(mf,
-H4 A); 3 S32 (mf, -H46 B); 3,82 (previous
2- (1-Nmidazolyl) ethanethiol acetate can be obtained by a method similar to that described in Example 11 for the preparation of an intermediate, but starting from 15 g of 2- (1-imide olyl) ethanol, 70.2 g of triphenylphosphine, 55.8 cm diisopropyl azodicarboxylate and 21 cm of thiol acetic acid. After purification by flash chromatography (eluent: methylene chloride
25
1500 cm, then ethyl acetate-methanol, 80-20 by volume), selection of fractions 100 cm and concentration to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C from fractions 21-35 gives 21.14 g of 2- (1- imidazolyl) ethylthioacetate as a yellow-orange oil, which is used without further purification.
Example 15. Operating according to the procedure similar to that described in Example 2, but starting from 5.5 g of 26- (2-morpholinoethyl) thiopristinamine Pc (isomer L), 1.3 g of sodium bicarbonate, 1.4 g of fM -chloroperbenzoic acid (98%) is obtained after extraction of the reaction mixture, the organic residue sugaki over magnesium sulfate, filtration and concentration to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C, a light yellow solid, which alternates
colors,
stitched in 100 cm nsopronyloxide, separated by filtration, then dried under reduced pressure (00 Pa) and a temperature of 35 ° C. 4.8 g of 26- (2-morochoshnoethyl) sulphinylprystinamycin P (isomer A) is thus obtained in the form of a solid substances light of a yellow-yellow color with So pl. about .
NMR spectrum: 1.77 (s, –Cll to 33);
cnt
2.6-3.1 (mf, -S-CH, -CH, N
 -AND); 2.85 and 3.13 (2 in 15); 3.20 (mf, -Hw); 3.78 (mf, -CP O-CHf
3.81 (s,; gSNg at 17); 4.85 (mf, -H „); 5.53 (d, -H „); 6.20 (d, -H „); 6.53 (mf, NH in 8); 8.14 (s, -HM).
26- (2-Morpholinoethyl) thiopristinamine Pg (isomer A) can be obtained by a method similar to the method described in Example 1, but starting from 15 g of pristinamycin IId and 6.3 g of 2-morpholi- (noethanethiol. After purification by pulse chromatography (eluent: ethyl 75-25 by volume) with
acetate-methanol
selection of fractions of 30 cm and concentration of dry fractions of 35-49 under reduced pressure (2.7 kPa) and temperature of 30 ° C gives 11 g of a solid beige color, which is crystallized from 120 cm of acetonitrile. Get
CH,
17); 5.26 (d, -H, 7); 5.44
- - -
thus 5.7 g 26- (2-marine lipino ":" I, D, G
ethyl) thiopristinamycin Hi (isomer b u td) ° 0 / ipg
in the form of white crystals with m. 132 S., in 8); 8.10 (s, -go).
NMR spectrum: 2.50 (mf, -N
26
1.73 (s, -SI, at 33); -CҐt); 2.6-2.9 (mf,
CIS-H4); 2.64 (mf, N-CH4-); 2.79 (mf, -SCfy-); 2.91 and 3.11 (2 dd, CH2B 15); 3.37 (d wide, HU); 3.74
-sng CR); 3.83 (s, chft in
10 (mf, 0
17); 4.74 (s wide,); 5.45 (d-H „); 6.13 (d, -H, 4); 6.28 (mf, NH at 8); 8.13 (s, -Hw).
Example 16, Operating according to the procedure similar to that described in Example 1, but starting from 5.8 g of 26- (2-butylamino-ethyl) thiopretinamine P (isomer A 80%, isomer B 20%), 0.68 cm tfluoroacetic acid, 1.8 g / U-chloroperbenzoic acid, after purification by flash chromatography (eluent: chloroform-methanol, 90-10 by volume), selection of fractions 5–15 cm and concentration of dry fractions 9–15 under reduced pressure (2.7 kPa) and a temperature of 30 ° C., 1.7 g of 26- (2-butylamino-ethyl) sulfinyl pristinamycin Hg (isomer A $ 70%, isomer B
five
0
0
15%, isomer B 15%) as a yellow powder with m.p. about 140s C.
Nuclear Magnetic Resonance Spectrum (isomer A): 0.85-1.00 (mf, -SI, 31 and 30 + -CHj chains); 1.34 (mf, -CHjCT,); 1.48 (mf, -CHjCHjCHjC); 1.75 (s, -CH, in 33); 5 2.50-3.30 (mf, -H16, in 2, -S-CH4-CH2-CH-H4); 3.80 (s,
0 -SI /
 „17); 4.80 (d, -H.,); 5.50 o (d, -H „); 6.17 (d, -H „); 6.40 (dd, NH in G); 8.12 (s, -HM).
After the end of termination of the 18-2A fractions to dryness under reduced pressure (2.7 kPa) and temperature, 5 0.5 g of 26- (2-butylamino-ethyl) sulfinyl-prinnamicin Pv are obtained (isomer A 85%,

as yellow 1704.
powder
0
NMR spectrum (mf, -CHj in 3
(isomer A): 0.85-, 00 30 and -CH, chains); 1.33
(mf, -CH2CH3); 1.47 (mt, -SNgSR-CH2CH) 1.71 (s7 -CH, 33); 2.50-3.25 (mf, -S-CHtCHjN-i. And -H4), 3.79 (AB limit,
five
 ABOUT
CH,
17); 5.26 (d, -H, 7); 5.44 (d,
- - -; MN
„:„ I, D, G
 b u td) ° 0 / ipg
2.35 g (for -chloroperbenoic acid, after purification by flash chromatography (eluent: chloroform-methanol, 90-10 by volume); selection of fractions 40 cm and concentration of dry fractions 12-15 under reduced pressure (2.7 kPa) and at a temperature of 30 ° C, 1.5 g of 26- (2-decylaminoethyl) sul26- (2-butylaminoethyl) thiopristinamycin P is obtained (isomer A 80%, isomer B 20% can be prepared as described below in Example 17.
Example 17. I act according to the mea- sured method similar to that described in Example 1, but starting from 3.15 g of 26- (2-butylamino-ethyl) thiopristinamicin Pv (isomer B), 0.37 cm trifluoroalk of finilpristinamycin P8 (isomer) / hydrochloric acid, after purification by flash chromatography (eluent: chloroform-methanol, 90-10 by volume), selection of fractions 15 cm and concentration of dry fractions 18-35 under reduced 15 pressure (2.7 kPa) and at a temperature of 30 ° C., 1.18 g of 26- (2-butylamino-ethyl) sulfinylprythinamicin P (isomer B 65%, isomer B4 35%) are obtained as a yellow powder with m.p. about 140 ° C. 20
NMR spectrum: .0.90-1.05 (inf, -CHj at 30 and 31 and -CH, chains B, and Br); 1.40 (mf, -CHZCH B, and B2); 1.50 (mf, -СНаСНг.СНгСНэ В, and Ве); 1.57 (s, -С1Ц at 33 V, and Br); 2.63 (t ,: 25 B1 and Br); 2.65-3.30 (mf, -S-CHjjCHjN
O mind B- 15, -N4 B and B4); 3.74 and 3.92
(2 d, -CH4 at 17 B,); 3.73 and 3.94 (2 d,: CH2 at 17 V); 4.78 (d, -H4TH2); 4.75-4.90 (mf, -H j, and -11 V, and Br); 5.27 (mf, -Hg1 B,); 5.70 (2 d, -H, 4 B, and Be); 7.69 (dd, W in 8 B z); 7.69 (dd, NH in 8 V,); 7.84 (s, - -Hgo Br); 6.85 (s, -ng „B4).
I work according to the method s similar to the method described in example 3, but starting from 25 g of pristinamycin PD and 6.34 g of 2-butylaminoethiol, after purification by pulse chromatography (eluent: chloroform-methanol 90-U by volume), selection of fractions of 60 cm and concentration of the fractions 12–15 to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. gives 3.15 g of 26- (2-butylaminoethyl) thioistaminacin L in the form of a yellow powder with m.p. about PO C. After concentration to dryness of fractions 15-25 under reduced pressure (2.7 kPa) and a temperature of 30 ° C, 5.89 g of 26- (2- -butylaminoethyl) thiopristinamycin P are obtained (isomer A 80%, isomer B 20%) .
Example 18. Acting on the method, measure
thirty
35
40
45
50
similar to that described in pri- 1, but starting from 8.6 g 26- (2-de55
in the form of a yellow powder with So pl. about 128 ° C.
NMR spectrum: 0.88 (s, - (CH4), - CH); 1.30 (t, (CH4) E); 1.50 (t,). ); 1.77 (d, -CP, at 33); 4.81 d, -and "); 5.51 (d, -Hf); 6.19 (d, -H (,); 6.53 (mf, NH in 8); 8.13 (s, -H40).
After concentration of the 15-15 fractions to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C., 2.51 g of 26- (2-decylaminoethyl) sulfinannistrythinamine Pa (isomers) are obtained in the form of a yellow powder with m.p. about 124 ° C.
NMR spectrum (mixture of isomers of type At 50%, A, 15%, B, 20% and Br 15%); 1.54 (s, -CHj at 33 V and Br); 3.72 and 3.88 (2 d.CH at 17 V,); 3.70 and 3.92 (2 d, in 17 Vg); 4.75 (o, —H cr); 5.25 (o, -Hg7 B,); 7.67 (dd, at 8 vg); 7.77 (dd, NH in 8 V); 7.81 (s, -Hy B and B) (the characteristic peaks of the isomers A4 and A are identical to the peaks mentioned above and below).
A 1% aqueous solution of 26- (2-decylaminoethyl) sulfinylprystinamycin II is obtained in the form of hydrochloride from the following ingredients: 26 - (- decylamino-methyl) sulfinylprythinamycin DJ 15 mg 0.1N hydrochloric acid 0.20 distilled water up to 1.5 cm
After concentrating the fractions 20-24 to dryness under reduced pressure (2.7 kPa) and temperature, 1.12 g of 26- (2-decylaminoethyl) sulPhenylpristinamycin P are obtained (A isomers 60%, A 20%, B 20%) yellow powder with So pl. about 136 ° C.
Nuclear Magnetic Resonance Spectrum (isomer A): 2.50-3.20 (in 15, -H4 and 8-C} 12CHG-K-CH4-);
D)
3.82 (AB limit, CH. 17); 5.27 (d, -Ht7); 5.46 (d,); 6.15 (ds -H ,,); 6.62 (mf, zm at 8); 8.12 (a, -Hja).
26- (2-Decylaminoethyl) thiopristinamine P $ can be obtained as follows.
, cylaminoethyl) thiopristinamycin P, 0.9 cmg of trifluoroacetic acid,
2.35 g (for -chloroperbenoic acid, after purification by flash chromatography (eluent: chloroform-methanol, 90-10 by volume); selection of fractions 40 cm and concentration of dry fractions 12-15 under reduced pressure (2.7 kPa) and the temperature of 30 ° C. get 1.5 g of 26- (2-decylaminoethyl) sulfate -
finilpristinamycin P8 (isomer) /
Finilpristinamycin P8 (isomer) / 5 0
five
0
five
0
five
0
five
in the form of a yellow powder with So pl. about 128 ° C.
NMR spectrum: 0.88 (s, - (CH4), - CH); 1.30 (t, (CH4) E); 1.50 (t,). ); 1.77 (d, -CP, at 33); 4.81 d, -and "); 5.51 (d, -Hf); 6.19 (d, -H (,); 6.53 (mf, NH in 8); 8.13 (s, -H40).
After concentration of the 15-15 fractions to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C., 2.51 g of 26- (2-decylaminoethyl) sulfinannistrythinamine Pa (isomers) are obtained in the form of a yellow powder with m.p. about 124 ° C.
NMR spectrum (mixture of isomers of type At 50%, A, 15%, B, 20% and Br 15%); 1.54 (s, -CHj at 33 V and Br); 3.72 and 3.88 (2 d.CH at 17 V,); 3.70 and 3.92 (2 d, in 17 Vg); 4.75 (o, —H cr); 5.25 (o, -Hg7 B,); 7.67 (dd, at 8 vg); 7.77 (dd, NH in 8 V); 7.81 (s, -Hy B and B) (the characteristic peaks of the isomers A4 and A are identical to the peaks mentioned above and below).
A 1% aqueous solution of 26- (2-decylaminoethyl) sulfinylprystinamycin II is obtained in the form of hydrochloride from the following ingredients: 26 - (- decylamino-methyl) sulfinylprythinamycin DJ 15 mg 0.1N hydrochloric acid 0.20 distilled water up to 1.5 cm
After concentrating the fractions 20-24 to dryness under reduced pressure (2.7 kPa) and temperature, 1.12 g of 26- (2-decylaminoethyl) sul-1-nylpristinamycin P are obtained (A isomers 60%, A 20%, B 20%) in a yellow powder with m.p. about 136 ° C.
Nuclear Magnetic Resonance Spectrum (isomer A): 2.50-3.20 (in 15, -H4 and 8-C} 12CHG-K-CH4-);
D)
3.82 (AB limit, CH. 17); 5.27 (d, -Ht7); 5.46 (d,); 6.15 (ds -H ,,); 6.62 (mf, zm at 8); 8.12 (a, -Hja).
26- (2-Decylaminoethyl) thiopristinamine P $ can be obtained as follows.
I act according to the method similar to the method described in example 3, but starting from 5.25 g of pristinamycin P and 3.26 g of 2-decylaminoethanol after purification using pulse chromatography (eluent: methylene chloride-methanol, 95-5 by volume) and concentration dry fractions 20-43 under reduced pressure (2.7 kPa) and a temperature of 30 ° C 10 to obtain 1.2 g of 26- (2-decylaminoethyl) thiopristinamicin L in the form of a yellow powder with m.p. about .
NMR spectrum (mixture of isomers 70-30 A
93-7 by volume) and concentration to dryness of fractions 7-18 under reduced pressure (2.7 kPa) and a temperature of 30 ° C. 1.7 g of 26- (2-cyclohexylaminoethyl) thiopristinamycin P are obtained in the form of a beige-colored powder with m.p. about 120 C.
NMR spectrum: 1-1.4 (mf, cyclohexyl (partially)); 1.54 (s, -С1Ц in 33 isomers B); 1.73 (s, -CH in 33 isomers A); 1.6-2 (tЈ, CH4 cyclohec; KCH .-);
strength (in part)); 2.80 (mf, 2.93 (t, -SCHZ-); 3.36 (d, -H yzome-Npa B); 4.64 (d, J 3 Hz, -H27 Isomes B): 0.88 (t, -CHO; 1 30 -GOS -1 -15 ras B) J 472 (s H2T isomev, btij; 53jimt, (CH2) 8), p A); 6.50 (mf, -NH isomer L);
1.54 (s, -SI, to 33 V); 1.72 (s, -CH, /,-,.,,-,. „H,„, in 33 A); 2.6-3 (mf, -CH2CH2-N-CH4-); 3.38 (d wide, -Na L); 3.50 (mf, -H20 V); 4.64 (d, J - 3.5 Hz, -n,., B); 20 4.72 (s wide, -Ngt A); 7.80
 (mf, -NHe isomer B); 7.80 (s,
-NgP isomer B); 8.12 (s, of ° ie ra A).
(s, -go B); 8.12 (s, -Hfto A).
Example 19. I act according to the method of Example 20. I act according to the procedure similar to that described in Example 2, but starting from 5 g of 26- (L-cyclohexyl-L-methyl-2-amino-procedure, similar to that described by ethyl) thiopristinamycin Pv (isomers BUT
thirty
in Example 1, but starting from 4.4 g of 26- (2-β-cyclohexylaminoethyl) sulfinylpristilamipine P. (A isomers 80%, B 20 0.5 cm trifluoroacetic acid, 1.15 g (U-perbenzoic acid after purification using pulsed chromatography (elp: chloroform-methanol, 90-10 by volume) and selection of aractions 40 cm and concentration of dry aractions 24 - 29 under reduced pressure (2.7 kPa) and a temperature of 30 ° C get 35 0.39 g 26- ( 2-cyclohexnlaminoethyl) sulfinylprythinamycin P (isomer Ag 902) in the form of a light, yellow powder with a melting point of about 166 C.
NMR spectrum: 1.05-1.35 (mf, CNg cyclohexyl (partially)); 1.77 (s, -CH,
33); 1.55-2.25 (mf, CH4 to
25, Ng, and: CH2 cyclohexyl (partially); 2.45-J, 35 (mf, llu, CH2 at 15,
: CH „
—H4 and —S — CH CI — N — CH); 3.32 (s,
ABOUT
in 17); 4.82 (d, -Nm); 5.52 (d, -H „); b, 19 (d, -H „); b, 38 (dd, OT at 8); 8.14 (s, -HЈD), 50
26- (2-Cyclohexylaminoethyl) thiopripostinshi P & The model can be obtained as follows.
I act according to the method similar to that described in Example 3, but starting from 5.25 g of pristinamycin P and 3.6 g of 2-cyclohexylaminoethanol after purification by flash chromatography (eluent: chloroform-methanol,
80%, B 20%), 1.17 g of sodium bicarbonate, 1.2 g (and -chloroperbenzoic acid (98%) after purification by flash chromatography (eluent: dichloromethane-methanol, 80-20 by volume) and selecting fractions of 30 cm and concentration of dry fractions 40-60 under reduced pressure (2.7 kPa) and a temperature of 30 ° C to obtain 3.5 g of solid of 7-celite color, which is again purified by pulse chromatography (eluent: ethyl acetate-methanol , 80–20 by volume) and take fractions of 25 cm. After concentration to dryness of fractions 11–18 under reduced pressure (2.7 kPa 40 and temperature, 1.2 g of solid are obtained The yellow colored substance, which was stirred in 30 cm of ethyl alcohol, was separated by filtration, then dried under reduced pressure (90 Pa and a temperature of 35 ° C. Thus obtained 1.1 g of 26- (H-cyclohexyl-H-methyl-2 -achinoethyl) sulfiniprinistinamycin Pd (isomer A) in the form of an X-ray powder with a melting point of about 126 C.
Spectrum 1.10-2 (nf.CH cyclohexyl); 1.76 (s, -CH in 33); 2.34 (s, - CH,); 2.45 (mf, 2.7-3.15 (mf, - S - C% -CHaN -H4);
ABOUT
2.93 and 3.14 (2 dd.Clij, in 15); 3.25 (ddd, CH2 at 17); 4.82 (d, -Ha7 5.52 (d, -K, -); 6.18 (d, -H, 4); 6.43 (in 8); 8.13 (s,).
45
93-7 by volume) and concentration to dryness of fractions 7-18 under reduced pressure (2.7 kPa) and a temperature of 30 ° C. 1.7 g of 26- (2-cyclohexylaminoethyl) thiopristinamycin P are obtained in the form of a beige-colored powder with m.p. about 120 C.
NMR spectrum: 1-1.4 (mf, cyclohexyl (partially)); 1.54 (s, -С1Ц in 33 isomers B); 1.73 (s, -CH in 33 isomers A); 1.6-2 (tЈ, CH4 cyclohec; KCH .-);
strength (in part)); 2.80 (mf, 2.93 (t, -SCHZ-); 3.36 (d, -H isomer B); 4.64 (d, J 3 Hz, -H27 isomer B) J 472 (s H2T isomer A); 6.50 (mf, -NH isomer L);
, -,., -,. „H , „,
 (mf, -NHe isomer B); 7.80 (s,
-NgP isomer B); 8.12 (s, of ° ie ra A).
, -,., -,. „H , „,
Example 20. Operating according to the method similar to that described in Example 2, but starting from 5 g of 26- (L-cyclohexyl-L-methyl-2-aminoethyl) thiopristinamicin Pv (isomers A
0
five
0
80%, B 20%), 1.17 g of sodium bicarbonate, 1.2 g (and -chloroperbenzoic acid (98%) after purification by flash chromatography (eluent: dichloromethane-methanol, 80-20 by volume) and selecting fractions of 30 cm and concentration of dry fractions 40-60 under reduced pressure (2.7 kPa) and a temperature of 30 ° C to obtain 3.5 g of solid of 7-celite color, which is again purified by pulse chromatography (eluent: ethyl acetate-methanol , 80–20 by volume) and take fractions of 25 cm. After concentration to dryness of fractions 11–18 under reduced pressure (2.7 kPa 0 and temperature, 1.2 g of solid are obtained A yellow colored substance, which was stirred in 30 cm of ethyl eLira, was separated by filtration, then dried under reduced pressure (90 Pa) and a temperature of 35 ° C. Thus obtained 1.1 g of 26- (H-cyclohexyl-H-methyl -2-acinoethyl) sulfinylpristinamycin Pd (isomer A) in the form of an X-ray powder with a mp of about 126 C.
Spectrum 1.10-2 (nf.CH cyclohexyl); 1.76 (s, -CH in 33); 2.34 (s, - CH,); 2.45 (mf, 2.7-3.15 (mf, - S - C% -CHaN -H4);
ABOUT
2.93 and 3.14 (2 dd.Clij, in 15); , 3.25 (ddd, CH2 at 17); 4.82 (d, -Ha7); 5.52 (d, -K, -); 6.18 (d, -H, 4); 6.43 (at 8); 8.13 (s,).
five
26- (H-Cyclohexyl-M-methyl-2-aminoethyl) thiopristinamicin Ilg (isomer A 80%, B 20%) can be obtained by a method similar to the method described in Example 3 for the preparation of a semi-product, but starting from 10, 5 g of pristinamisin PD and 4 g of cyclohexyl-K-methyl-2-amino etanethiol. After purification by flash chromatography (eluent: ethyl acetate-methanol, 80–20 by volume), selection of fractions 30 cm3 and concentration of fractions 42-96 to dryness under reduced pressure (2.7 kPa) and temperature 30 ° C, a yellow solid is obtained, which is stirred in 80 cm of isopropyl oxide, separated by filtration, then dried under reduced pressure (90 Pa) and a temperature of 35 ° C. Thus, 7.9 g of 26- (N-β-cyclohexyl-1T-methyl-2-aminoethyl) thioistinamine Hg (isomers L 80% and B 20%) are obtained in the form of a yellow powder with m.p. about 1 I 6 ° C.
NMR spectrum (a mixture of 80/20 two isomers A and B); 1.25 and 1.6-1.9 (mf, 11GCHH cyclohexyl for A and B); 1.56 (s, -CH in 33 V); 1.73 (s, -CH3 at 33 A); 2.25-2.5 (mf, CH-cyclohexyl for A and B); 2.32 (в, №-СН, В); 2.35 (s, N-CH, A); 2.6-2.8 (mf, -H4 A and B); 2.78 (LV limit, A and B); 2.9 and.3.14 (2 dd, CH2 in 15 A); 3.41 (d wide, -Hg6 A); 3.73 and 3.91 (2 d,: CH2 at 15 A); 3.83 (s, CH2 in 17 A); 4.65 (d, -II „В); 4.76 (s wide, A); 5.49 (d, -Hf} A); 6.16 (d, -Н „A); 6.3b (mf, p: NH in 8 A); 7.73 (mf. In 8 V); 7.82 (s, -Nm B); 8.13 (s, -H20 A).
The N-cyclohexane n-methyl-2-aminoethanethiol can be prepared as follows.
To 20 g of d- (n-cyclohexyl-K-methyl-2-aminoethyl) isothiouronium dichlorohydrate, isothiouronium is added, under a nitrogen atmosphere, to 23 cm of a 6N aqueous sodium hydroxide solution. After stirring for 2 hours at 100 ° C, the mixture is cooled to, then concentrated hydrochloric acid is added to it to pH 9. The solution is washed three times with 50 cm of dichloromethane, then the organic phases are combined, dried over magnesium sulfate, filtered , then it is concentrated to dryness under reduced pressure (2.7 kPa) and the temperature of HOC, and an oil is obtained, which is purified by distillation under reduced pressure (130 Pa).
4.3 g of M-cyclohexyl-N-methyl--2-aminoethanethiol are obtained in the form of a colorless liquid, b.p. (130 Pa) 68 ° C.
N-cyclohexyl-K-methyl-2-amino-ethanethiouronium dihydrochloride can be prepared as follows.
To 30 g of N-cyclohekeyl-1-methyl-2-amino-chloroethane hydrochloride in 300 cm of ethanol was added 10.7 g of thiourea. The resulting solution is heated at 78 ° C for 18 hours. After cooling, the resulting white substance is filtered, then washed with ethanol. Thus, 21.5 g of K-cyclohexyl-No-methyl-2-amino-ethanethiouroni dichlorohydrate is obtained in the form of a white solid with mp. 24 C.
2- (K-cyclohexyl-M-methylamino) - chloroethane hydrochloride can be prepared as follows.
25 g of 1-cyclohexyl-M-methyl-2-α-amino ethanol is added dropwise to I20 g of thionyl chloride, then the mixture is heated at 70 ° C for 24 hours. After distillation of the excess thionyl chloride, the resulting orange oil is stirred in 200 cm of ethyl ether and a white solid is obtained which is separated by filtration, then washed with ether. 30 g of 2- (11-cyclohexyl-N-methylamino--1-chloroethane) hydrochloride are obtained in the form of a white solid with m.p. .
Example 21. Operating according to the procedure similar to that described in Example 1, but starting from 4.3 g of 26- (4-methyl-1-piperazinyl) -2-carbonyloxyethyl thiopristinamycin P (isomer A), 0.45 cm tristoacetic acid, 1.2 g of m-chloroperbenzoic acid after purification by flash chromatography (eluent: chloroform-methanol, 90-10 by volume), selection of fractions 30 cm and concentration of dry fractions 42-56 under reduced pressure (2.7 kPa ) and a temperature of 30 ° C, 1.2 g of 26-G (4-methyl-1-piperaeinyl) -2-β-carbonyloxyethyl sulfinylpristine- | mycinol (Ac isomer) is obtained in the form of light yellow of powder with m.p. about 135 C.
NMR spectrum: 1.78 (s, -CH in 33); 2.32 (s, 7: M-C1C); 2.42 (t,
/ CH h
  ; , 8 (2mf, CIS
im,
- $ - CH2-); 3.54 (r
0
CHS-CO-N.
ICH- /
3.82 (s, CH4 at 17); 4.58 (mf, -CHt-0-C-Ni); 4.82 (d, -H); 5.50
.0
(d, -H41); 6.20 (d, -HI (); 6.39 (dd,
NH at 8); 8.14 (s, -H).
After concentration to dryness of fractions 65-95 under reduced pressure
15 using the method of pulse chromatography (eluent: chloroform-methanol, 90-1 by volume), selection of fractions 60 cm and concentration of fractions 26-36 to dryness under reduced pressure (2.7 kPa) and
(2.7 kPa) and a temperature of 30 ° C., 0.65 g (4-methyl-1-piperazinyl) carbonyloxyethyl sulphinyl pristy-2 () temperature is obtained; 2.3 g of Namysine Pv (isomer A) are obtained in the form of light 26- 1-methyl-2 (5) pyrrolidinyl methyl yellow powder with m.p. about 140 S. LJ
Sulfinylprystaminacin P "(isomer A in the form of a light yellow powder with Tpl at about 140 ° C.
NMR spectrum: 1.75 (s, -CH, at 33); 2.34 (s ,; N-CW}); 2.44 (gp,
CH2
—CO-N N-); 2.90-3.15 (mf. -G.G
-SN
-S-CH -); 3.55 (m, -CO-N
N-);
 H;
3.83 (, B 17); 4.51-4.65 (2 ddd, -CH-O-C-N); 5.28 (d, -H2); 6.19 (d,
K Oh
-N.,); b, 55 (dd.NH at 8); 8.14 (s, (s, SND. In 17); 4.81 (d, -11t7);
-N "). 5.52 (d, -n"); 6.20 (d, -n „);
(4-Methyl-1-piperaeinyl) car-6,42 (dd.NH in 8); 8.14 (s, -H20). bonyloxyethylthiopristinamycin P, mo- After concentration to dryness of fractions
It can be obtained as follows.46 - 59 with
Under reduced pressure I act in a manner analogous to SPO-40 (2.7 kPa) and a temperature of 30 ° C to obtain 1.1 g of 26-methyl-2 (5) pmrropidine G methylsulfinylprythinamycin P (isomer AL in the form of a light powder with m.p. about 1489C.
NMR spectrum: 1.73 (s, -CH, at 33);
as described in Example 3, but starting from 5.25 g of pristinamycin PD and from 3.76 g of 2- (4-methyl-1-piperazinyl) carbonyloxyethanethiol, after purification by flash chromatography (eluent: chlorosorm-methanol, 90-10 by volume) and concentration of the fractions 10–18 to dryness under reduced pressure (2.7 kPa; and a temperature of 30 ° C; 2.55 g of (4-methyl-1-piperazinyl) carbonyloxy thiopristinamycin P. are obtained in the form of a beige powder with Mp approx.
NMR spectrum: 1.54 (s, -CH, 33 isomers B); 1.73 (s, -CHj in 33 isomers A); 2.3 (s.N-CHj); 2.4 (m,
  (m - ™ C-N C -);
-cjii- cng-;
45
N
1.70-2.50 (mf,
CH
G, Shg -HZ,):
CH2-CH2
50
2.41 (s.N-CHj); 2.65-3.25 (mf, CH, in 15, -H in 4, - S —CHNg — CHC);
0
3.82 (AB limit, CHZ at 17); 5.45 (d.) 5); 6.17 (d, -H ,,); 8.11 (s, -HM).
26- (1-Methyl-2-pyrrolidinyl) MPT and p-thiopristinamycin P may be norn as follows.
3.98 (mf, -CHN-OCO-); 4.59 (d, J 4 Hz, Hg7 of isomer B); 4.69 (s broad, —Ng of isomer A); 7.05 (t.NH
in 8 isomer A); 7.7 (m, NH in 8 isomer B); 7.80 (s, -H isomer B); 8.10 (s, -Hj.0 isomer A).
Example 22. According to the method similar to the method described in
O of example 1, but starting from 7.8 g of 26-JJ-methyl-2 (8) pyrrolidinyl methylthiopristinamine P (isomer A), 0.91 cm of trifluoroacetic acid and 2.4 g / C - chloroperbenzene acid, pulp chromatography (eluent: chloroform-methanol, 90-10 by volume), selection of fractions 60 cm and concentration of dry fractions 26-36 under reduced pressure (2.7 kPa) and
() to a temperature of 2.3 g of 26-1-methyl-2 (5) pyrrolidinyl methyl LJ
temperature, 2.3 g of 26-1-methyl-2 (5) pyrrolidinyl methyl-LJ are obtained.
Sulfinylprystaminacin P (isomer A) in the form of a light yellow powder with m.p. about 140 ° C.
NMR spectrum: 1.76 (s, -CH3 at 33); 2.48 (s, NCH); 1.70-2.60 (mf, -Nm
 at 25 and
thirty
SNISN2
2.75-3.25 (mf,,
S-CH2-CH);
about
N
(mf,
CH
G, Shg -HZ,):
CH2-CH2
50
2.41 (s.N-CHj); 2.65-3.25 (mf, CH, in 15, -H in 4, - S —CHNg — CHC);
0
3.82 (AB limit, CHZ at 17); 5.45 (d.) 5); 6.17 (d, -H ,,); 8.11 (s, -HM).
26- (1-Methyl-2-pyrrolidinyl) MPT and p-thiopristinamycin P may be norn as follows.
35
I act according to the procedure similar to that described in Example 3, but starting from 10.5 g of pristinamycin PA and 3.14 g of 1-methyl-2- (8) pyrrolidinyl methanethiol after purification by flash chromatography (eluant: chloroform-methanol , 90-10 by volume) and concentration to dryness of fractions 20-35 under reduced pressure (2.7 kPa) and a temperature of 30 ° C. 7.8 g of isomer L are obtained in the form of a yellow powder with m.p. approximately 20 ° C.
Nuclear Magnetic Resonance Spectrum: 1.70 (s, -CH, 33); 2.38 (s, N-CH,); 1.70-2.50 (mf, -H4Ch, - ° c -C
CH2
: HfCH2) J
L at 25 and
/and
2.6-3.20 mf, - S-SIL-CHO 5 3.82 (s, CRj at 17); 4.73 (d, -Hg1); 5.45 (d, -H1}); 6.15 (d, -Ni); 6.41 (dd, 5NH at 8); 8.11 (s, -Ni).
To 25 g of crude s- | 1-methyl-2 (8) pyrrolidinylmethyl-zyothiourony dichlorohydrate, dissolved in 100 cm of distilled water, add 100 cm of 4N aqueous sodium hydroxide solution, then the mixture is stirred under a nitrogen atmosphere for 2 hours The reaction mixture is cooled to 0 ° C., 25 cm of a 12N aqueous hydrochloric acid solution are added to it, then extracted twice with 200 cm of methylene chloride. The organic phase is dried over sodium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. Thus obtained 5.9 g of P-methyl-2 (5) pyrrolidine Methane thiol in the form of a light yellow oil, which used for the next reaction without further purification.
Rf 0.15, chromatographic plate with silica gel. Eluent: chloroform-methanol, 90-10 by volume ,.
To 11.9 g of 1-methyl-2 (8) pyrrolidinyl chloromethane hydrochloride dissolved in 50 cm of ethanol, 10.7 g of thiourea are added, then stirred with reflux for 48 hours. The mixture is concentrated to dryness under reduced pressure (2.7 kPa ). and a temperature of 40 ° C. The residue is dissolved in 100 cm of hot ethanol, then filtered through activated charcoal. After concentration of the filtrate to dryness under reduced pressure (2.7 kPa) and temp 1540655
36
25 g of a light yellow oil consisting of s- Јl-methyl- 2 (8) pyrro-lidinylmethyl} isothiouronium dichlorohydrate and isothiouronium and an excess of urea is obtained.
Rf 0.1; silica gel chromatographic plate; eluent: chloroform-methanol, 90-10 by volume.
Example 23. Operating according to the procedure similar to that described in Example 1, but starting from 2.6 g of 26- (1 methyl 4-piperidine) thiopristinamycin II, 0.3 cm of trifluoroacetic acid and 0.8 g (U- chloroperbenzoic
acid, after purification by pulse chromatography (eluent: chloro-form-methanol, 90-10 by volume), selection of fractions 40 cm and concentration to dryness of fractions 20-35 with reduced
pressure (2.7 kPa) and a temperature of 30 ° C., 0.33 g of 26- (1-methyl-4-β-piperidinyl) sulfinylprythinamycin P (isomer AJ) is obtained as a yellow powder with m.p. about 170 C.
, NMR spectrum: 1.76 (s, -Cllj. At 33);
(mf, -CH

, sn2-sn2x
SI 2 SI 2
-)
2.32 (s,: N-CH); 3.82 (s, CH2 at 17); 4.85 (d, -H „); 5.50 (d, -N "); 6.19 (d, -H „); 6.37 (dd.NH at 8); 8.15 (s, -H-jjj).
26- (1-Methyl-4-piperidinyl) thiopristinamycin P can be obtained as follows.
I act according to the method similar to the method described in example 3, but based on 3.15 g of pristinamycin P and
1.6 g of 2-methyl-4-piperidintiol, after adding 0.6 g of triethylamine to the reaction mixture, purification by flash chromatography (eluent: methylene chloride-methanol, 92-8 by volume) and
concentrations of 4-20 fractions to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C give 0.9 g of 26- (1-methyl-4-piperidinyl) thiopristinamide P as a yellow powder with m.p.
about .
NMR spectrum: 2.10 (m, 4H:
sn
2L
- $ - (N-); 2.25 (at, DI: T
-З Н-СНз); 2.80 (t, 4n:
CH
AND,
; N-); 3.55 (ha, W: -H);
, 4.62 (t, 1H: -H); 7.70 (t, 1H: -H 8.10 (s, IH: -I).
Example 24. To 7.8 g of 26- (2- -diethylaminoethyl) thiopristinamycin II dissolved in 60 cm3 of methanol, is added at 0 ° C under a nitrogen atmosphere. 0.92 cm trifluoroacetic acid. After holding at 0 ° C for 15 minutes, the temperature is raised to then 1.7 g of selenium dioxide is added. After the dissolution of the whole selenium dioxide is completed, it is slowly added at a temperature below 25 ° C with 7 cm of a 30% aqueous solution of hydrogen peroxide. After stirring for 1 hour at 25 ° C, the reaction mixture is cooled to 10 ° C, 50 cm of a saturated aqueous solution of sodium bicarbonate are added, then extracted four times with 50 cm of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 k11a) and a temperature of 30 ° C. The resulting yellow solid is purified by flash chromatography (eluent: chloroform-methanol, 90-10 by volume) with a fraction of 40 cm. After concentration to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C in fractions 31-38, a white solid is obtained, which is purified by flash chromatography (eluent: ethyl acetate-methanol, 80–20 by volume) with the selection of fractions 40 cm . After concentration to dryness under reduced pressure of fractions 27-33, a white solid is obtained, which is stirred in 50 cm of ethyl ether, separated by pouring, then dried under reduced pressure (90 Pa) and temperatures of 30 ° C. 0.5 g of 26- (2-diethylaminoethyl) sulfinylprystinamycin P- (isomer A) is thus obtained in the form of a white solid with m.p. about 150 ° C.
Nuclear Magnetic Resonance Spectrum: 0.97 (d, -SЩCH at 30 and 31 and -CH ethyl); 1.75 (s,)
2.62 (d,); 3.00 - 3.40
 CHg (mt, -S02CH2CH2NO; 3.82 (s, CHg in 17); 5.34 (d, -H "); 5.43 (d, -H
five
0
five
0
five
five
0
five
0
6.16 (d5 -HH); 6.54 (dd, NH at 8); 8.10 (s, -Nm).
By proceeding in the same manner as in Example 24, the following compounds were prepared:
26- (2-Dimethylaminoethyl) sulfinyl-pristinamycin P, So pl. 120-122 C.
NMR spectrum: 2.7 - 3.4 (mt-Hff and -S02CF4CP N3; 5.40 (d, -H ");
5.46 (d, -n „); 6.15 (d, -n „);
6.45 (dd broad, -He); 8.12 (s, -H20). 26- (2-Dipropylaminoethyl) sulfinyl-pristinamycin Pv, So pl. 129-131E.C.
NMR spectrum: 1.50 (sextet, NCHtCH4CHj); 1.75 (s, -SI, in the position ZZU; 2.46 (tj NCRjCPjCH,); 3.07 (mt, -SOaCH4CHzNЈ); 3.27 (t, -SOaGF2CH, NO; 3.57 (mt, - H,); 5.31 (d, -Hr); 5.47 (d, -H,); 6.16 (d, -H ()); fe, 47 (t, with, HB); 8.12
(s, -Ny).
26- (2-Dibutylaminoethyl) sulfinyl-pristinamycin P, m.p. about 90 ° C.
Spectrum LOT: 0.96 (t, -N (); 1.2 - 1.6 (mt, -NlCH CF CH SI,)) 1.76 (s, -CH-j at position 33); 2.48 (t, (CH1) rCH, 3.08 (nt, -SOgCI CH NO; 3.14 (mt, -saCtLCHjNC) 5.31 (d, -Ht7); 6.16 (d, -H0) ;
6.47 (dd wide, -He); 8, Yu (s, -Hzo). 26-p- (N-Methyl-C-butylamino) ethyl
sulfinylprystaminacin P., m.p. about 11 8 ° C.
NMR spectrum: 0.98 (t, (CH2) CHj); 1.35 (rat, N (CF4) 2 SNgCH); 1.47 (mt, .jCHj); 1.78 (s, -CH, at position 33); 2.31 (s, rNCH3); 2.44 (t, NCHa () CHJ); 2.98 (t, -SOfeCH2CHzN-); 3.31 (t, -SOfcCF CHjNC); 5.37 (d, -H27); 5.45 (d,); 6.17 (d, -HH); 6.62 (t, broad, -Ng); 8.10 (s, -H40).
(K-Egil-i-isopropichamino) ethyl sulfinylprythinamycin P, T.pp. 108-110 ° C.
NMR spectrum: 0.9 - 1.1 (d, t, -CFj at position 30, STC at position 31, N (CH4) 2 - NCH2CHj); 1.73 (s, CF at position 33); 2.54 (q, NCFzCF,); 2.98 (t, -SOaCHaCHzN); 3.23 (t, -SOjCHjCFjNi); 5.32 (d, H2-); 5.44
(d, -n „); 6.16 (d, -n „); 6.58 (t,
wide -H8); 8.08 (s, -Hift).
26- (2-Morpholinoethyl) sulfinylprythinamycin Hg, m.p. about 108 g.
NMR: 1.77 (s, -C% polo .2
/
 five
mon - 7
2.57 (m, -N
:about)
2.97 (t,); 3.37 Tt,
-OB
-SO, CHtCHtNO; 3.74 (t, -flf
-ABOUT
5.38 (d, -H4r) 5 5.43 (d, -H,});
6.16 (d, -H ,,); 6.60 (t, wide, -lig)
8.11 (s, -HZC) ..
26- (2-Piperidinyl ethyl) sulfinyl-pristinamycin P |, So pl. 125-127 C.
NMR spectrum: 1.48 and 1.61 (mt,
.Shh-h
-n2cC; and -); 1 75s-CHSB 2
uh
position 33); 2.48 (mt,
SNG- .
)); 2.94 (t,
CH2
3.34 (t, -soa, n); 5.36 (a, -ng7); 5.44 (d, -n „); 6.17 (d, -ni);
6.60 (t, broad, -Ht); 8.10 (s, -nga). s
(1 - Pierre roll) ethyl sulphinylpristinamycin P, m.p. 117 ° C.
NMR spectrum: 1.73 (s, -C1C at position 33); 1.82 (rat wide,
-1C
 2.60 (mt wide,
v; 3.06 (t, h
 -SOfcCHfcCHaNO; 3.33 (t, -S02CJaCH2NC); 5.38 (d, -Hl7); 5.45 (d, -H4f); 45
6.16 (d, -HH); 6.58 (t, wide, - Not)
6.08 (s, -Hto).
26- (2-Diethylaminostil) sulfinyl-pristinamycin P (isomer B), m.p. about 98 ° C.50
NMR spectrum: 1.07 (t, -I (CH "CH-) 4); 1.56 (s, -CH3 at position 33); 2.4 - 2.8 (mt, -S02CHzCHaN (CF4CH) z); 3.14 (tnt, -502CHNg-); 4.07 (mt, -H); 4.87 (d, -Hi6); 4.87 (d, -I,) 5 55
5.28 (dj –n „) ;; 5.68 (d, -H (f);
7.71 (t, broad, -He); 7.89 (s, -H2ff). Example 25. Operate according to the method similar to the method described 5
)
about);
.ten
-lig)
.
-
B 20
25
ng7);
ha) zo
-.
about ,
35
40
C); 45
-Not)
l- 50
four); ,four - ); 55
H2ff). in the example 24, but starting from 6.86 g of 26- (2-diieopropylaminoethyl) thiopristinamine Pr (isomer A), 0.77 cm of trifluoroacetic acid, 1.15 g of selenium dioxide and 6.33 cm3 of a 30% aqueous solution hydrogen peroxide. After purification by flash chromatography (eluent: ethyl acetate-methanol, 85-15 by volume) with a selection of fractions of 30 cm, concentration to dryness under reduced pressure of fractions 26-33, a solid yellowish solid is obtained, which is stirred in 30 cm of ethyl ether, section are filtered, then dried under reduced pressure (90 Pa) and a temperature of 30 ° C. 0.7 g of 26- (2-di-isopropylaminoethyl) sulfinylprystinamycin D (isomer A) is obtained in the form of a yellow solid with m.p. about 140 ° C.
NMR spectrum: 1.06 (d, -CHj isopropyl); 1.75 (s, -CH3 at 33); 2.79 (mf, -H4); 2.92 and 3.1 U (2 dd, CH2 in 15); 2.7-3.30 (mf, -S-CH-CH N (CH) J;
BUT
oh oh
3.52 (d wide, -H); 3.82 (s, CHt at 17); 5.27 (d butted, -H2T); 5.47 (d, -n “); 6.17 (d, -H „); 6.42 (mf.Nll to 8); 8.12 (s, -ng „).
Example 26. Carried out according to the method described in Example 2, but starting from 2.9 g (2-cyclopentylamino-ethyl) -26-thiopristinamycin P (isomer A), 0.72 g sodium bicarbonate and 0.75 g 98% -with fW-chloroperbenzoic acid, at -30 C. After purification using flash chromatography (eluent: methylene chloride-methanol, 90:10 by volume), fractions of 30 cm are collected and the fractions 25-31 are concentrated to dryness under reduced pressure (2, 7 kPa) at 30 ° C, obtain 0.7 g of solid yellow, which is again purified using flash chromatography (eluent: meth Lenchloride-methanol in a ratio of 95: 5 by volume), collecting fractions of 20 cm each. After concentrating to dryness, Fractions 78-95 at a lower pressure (2.7 kPa) at 30 ° C, 0.4 g (2- cyclopentylamino-ethyl) -26-sulphiiylpristinamycin P (A2 isomer) in the form of a solid light yellow color, melting at.
41
NMR spectrum; $ 1.76 (s, CH. In position 33); 1.30-2.25 (rat, pC2 cyclopentyl); 2.80 (mt, -Nf); 2.85-3.25 (mt, -80-CH4CHN-H-CHC; CH4 at position 15; —H); 3.82 (s, CHj. At position 17); A, 81 (d, -Hj7); 5.53 (d, -H „); 6.19 (d, -H (); 6.30 (mt, NH in position 8); 8.15 (s, -Heo).
(2-Cyclopentylaminoethyl) -26-thiostomycin P (isomer A) can be obtained by a method similar to that described in Example 1 for the preparation of the starting product, but starting from 15 g of pristinamycin IIg and 4.3 g of 2-cyclopentylamine ethanethiol. After aging for 3 days at -20 ° C, purification using flash chromatography (eluent: methylene chloride-methanol in a ratio of 90:10 by volume), collect fractions of 30 cm, and also after concentrating to dryness fractions 69-91 with reduced under pressure (2.7 kPa) at 30 ° C, 5.2 g of a yellow solid are obtained, which is dissolved in a mixture of 45 cm of acetone and 30 cm of diethyl ether. The resulting precipitate was separated by filtration, then dried under reduced pressure (90 Pa) at 35 ° C to obtain 2.9 g of (2-cyclopentylamine-ethyl) -26-thiopristinamine P (isomer A) as a light yellow solid, melt at 144 C.
NMR spectrum: 5 1.73 (s, -CHj at position 33); 1.50-2 (ton, SNg cyclopentyl); 2.78 (multiplet, -HC) 2.88 and 3.18 (2 d, CH- in position 15
2.85-3.85 (mt, -S-CH2-CH2-Nc); 3.26 (mt, N-CHO; 3.42 (T, u, Hzg); 3.82 (in position 17); 4.70 (d, -H "); 5.48 (d, -n" ); 6.18 (d, -H, (); 6.82 (mt, NH at position 8); 8.15 (s, -Hto).
If the pristinamycin Pp derivative of general formula (II) is used as a salt, salts formed with organic or mineral acids, preferably with trifluoroacetic, tartaric, acetic, benzoic or hydrochloric acids are used.
If the product of the common formula (II) is used in the form of a salt or a protected derivative, the reaction is expediently carried out at a temperature of from -40 to 50 ° C.
If you want to get the product of the general formula (I), in which n 1, then not 1
-);

54065542
It is necessary to carry out the reaction starting from the derivative pristinamycin P of general formula (II) in the presence of bicarbon, that alkali metal (for example, sodium bicarbonate) at a temperature of from -60 to.
If R contains an alkyl-amino or cycloalkylamino substituent,
You can also use a powdered derivative of the general formula (II), the latter can be protected by any amine protecting group, the use and removal of which does not
15 acts on the rest of the molecule; It is advisable to use a trifluoroacetyl group which, after carrying out the reaction, can be removed by treating with an alkali metal bicarbonate (sodium bicarbonate or potassium bicarbonate) in an aqueous solution.
Acceptable salts with mineral acids, for example chlorohydrates, hydrobromides, sulfates, nitrates, phosphates, or with organic acids, for example acetates, propionates, succinates, maleates can be cited as pharmaceutical acceptable salts for products of general formula (I). , fumarates, methanesulfonates, l-toluenesulfonates, isotionates, or substituted derivatives of these compounds. As pharmaceutically acceptable salts, you can also specify
ic salts with alkali metals (for example, sodium and potassium), with alkaline earth metals (for example, magnesium salts), ammonium salt and additive salts with nitrated organic
BEFORE the bases (ethanolamine, dmethanol-amine, trnethanolamine, triethylamine, methylamine, propylamine, di-ychopropylamine, NN-dimethylethanolamine, benchipamine, diphenchylamine, dicyclohekeyl benchyl amine
45 K-benzyl- | 3- & enethylamine, NN-cybenzip- ethylenediapine, benhydrylamine, arginine, leiin, lysine or N-methylglucmin).
The proposed pristiramycin IK derivatives and their pharmaceutically acceptable salts exhibit anti-tommus properties, are of particular interest in vitro and in vivo.
In vitro products of the common formats (I) showed activity with respect to Staphylococcus aureus Smith in daughters 4–100 µg / cm}, besides, rot has a snkergic effect on the antimicrobial effect of pristinamycin 1d in doses of 0.1-10 μg / cm3 .
In vivo, the proposed products showed activity against experimental infections in mice caused by Staphylococcus aureus Smith in doses ranging from 40 mg / kg to doses above 3000 mg / kg when administered subcutaneously. At doses of 8 to 200 mg / kg when administered subcutaneously, they synergize anti-microbial action when combined with pristinamycin 1d in the range of ratios (10-90) - (90-S).
The acute toxicity of the products of general formula (I), expressed in DLff0, is usually in the range of 300 mg / kg to doses in excess of $ g / kg when given subcutaneously to mice.
Bacteriostatic activity.
In a series of flat containers with a volume of 20 cm, containing the appropriate culture medium (Muller-Hinton agar), portions are introduced with a volume of 1/10.
this volume by the method of several times-25 group II. In addition, due to the exponential expiration of the well-known synergy of action for (every 2 times) of the test products of this type, all the derivatives of the substance. The containers inoculated in monostinamycin were tested separately and inoculum inoculum, where it was formed in a compound (60/40 May.) With a permanent spot of 10 units of microorganisms, 30 mycin, which is predominant
a sample of colony, trypsin broth broth incubated for 18 hours at 37 ° C and diluted 1/100 with the same medium.
a product of group I.
From these tests, it follows that the products offered are taken alone or in combination with pristinamycin.
After inoculation, the plates are incubated for 24 hours at 37 C.
The minimum inhibitory concentration (MIC) was the lowest concentration at which the development of microorganisms was inhibited.
Activity against intraperitoneal infections in mice.
Mice were injected intraperitoneally with 0.5 cm of the appropriate culture at the age of 18 hours of the test microorganism in the medium of an extract of the brain and heart (Difco), respectively diluted with 5% bora mucin. The test substance was administered subcutaneously twice with an interval of 5 hours per day of inoculation, while the first dose was administered 1 hour after the inoculation of the microorganism. Used single doses contained in a volume of 50 cm / kg
The 50% therapeutic dose (CDJO) was the dose of the test substance, which with each injection into the animal helped half of the experimental animals.
The survivors survive for a trial period (8 days).
The results are presented in the table.
Natural pristinamycin consists of 5 components belonging to two different groups. Group I: 1D, 1, 1C and group II; Pristinamitsh Pd and P &. Among these
Five components two are predominant - pristinamycin 1d (15-22%) and pristinamycin PD (45-60%), the proportions of the other components are less than 10%. Feature of this
A class of products is the synergistic action of two groups of components.
The proposed products, which are derivatives of pristinamycin P, belong to group II, as a result of which the product must be chosen from group II for comparison, therefore the products were compared with pristinamycin PD, which is the predominant product

a product of group I.
From these tests, it follows that the products offered are taken alone or in combination with pristinamycin.
I have a level of activity equal to the level of activity of pristinamycin Pd or the level of activity of its combination with pristinamipin T. Furthermore, a significant advantage of the products offered is their solubility and the possibility of administering to humans in a parenteral route, which is not characteristic of its compounds with pristinamycin I, which are insoluble. In laboratory tests

权利要求:
Claims (1)
[1]
these products were administered to mice as a suspension, but this can by no means be attributed to humans. The invention The method of obtaining derivatives of pristinamycin P6 total yormula
ch3
J.
Go ™
at
HE
„ONL.
t o gh
SNS with J
li N
de
- methylpiperidinyl, (I-methyl-. -2-pyrrolidinyl) methyl, 2-piperidinoethyl, (4-methyl-1-piperaoinyl) carbonyl-hydroxyethyl, or a group, R,
alk - N
/ lg
XR,
alk - Cr-C4 alkyl, unsubstituted or mixed with methyl, ethyl or benzyl, Ra and PJ are the same or different and mean hydrogen, C -C alkyl, cyclopentyl, cyclohexyl or R2 and R3 together with the adjacent nitrogen form a pyrrolidine, imidazole or morpholine ring; n 1 or 2
Lorme isomers or their mixtures, or dditive salts with acids, about 20

4 6 4 4 4 4 4 15 4 8 4 4 4 8 4 4 4 2
60 15 4 4 8 8 8 8
0.25
0.5
0.25
0.5
0.25
0.25
0.12
one
0.25
0.5
0.25
0.12
0.12
0.5
0.25
0.12
0.12
0.12
2
0.5
0.25
0.12
0.5
0.25
0.5
0.5
Because a compound of the general formula
where R has the indicated values, the fa-chlorobenzoic acid is oxidized with acid or selenium dioxide, followed by isolation of the target product in free form, if necessary, by separation into isomers or by isolation as acid addition salts. I
65 80 65 60 70 90 22
140 44 90 44
130 65
170 65 85 70 70
120
200 40
120
150
300
300
95
8 10
eight
10 12 15
6 30
9 10
9 12 10 26
6.5 20 18 18 22 65
eight
20 44 80 28 16
47

four
thirty
60
four
four
30 8 8 4
0.25 1
four
0.06
0.12
one
0.5 0.25 0.12
154065548
, Table continuation
12
60
24 8.5 6.5
15 8.5
eleven
ten

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引用文献:

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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FR8500377A|FR2576022B1|1985-01-11|1985-01-11|NOVEL DERIVATIVES OF PRISTINAMYCIN II B, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|LV930080A| LV5269A3|1985-01-11|1993-01-29|Pristinamicin P Beta Derivative Pickup Isomers or their Mix Type or Skab-Aditivo|