Method of producing derivatives of pristinoamycin ii

专利摘要:
The invention relates to heterocyclic compounds, in particular the preparation of the pristinamycin He (PR) derivatives of the general formula I O. OH (CH. ... 1 or a straight chain or branched alkylthio radical substituted by one or two R, ,, or 1-methyl -4-piperidylthio4 R, C, -C-dialkylamino, 1-pyrrolidinyl, 4-piperidyl, 4-methyl-1-1 | iprazinyl, which can be used in medicine. low toxicity. Synthesis of PR is carried out by introducing the radical R into unsubstituted pristinamycin 11, formulas, in the formula of the description with the help of the compound RH, where R. has the indicated values, in methanol or ethanol or a chlorinated solvent, or in an ik mixture at 0-50 ° C (preferably in the presence of tertiary amine-triethylamine, ethanolamine, dimethyl - ethanolamine) followed by, if necessary, the separation of isomers - PR and its conversion into hydrochloride.The solubility of PR 20-50 mg / cm, and pristinamycin 11, 0.0001 mg / cm. OL synergistically increases the biological activity of pristinamycin I or virginiamycin. The toxicity of LDjo is 300-900 mg / kg. 7 tab. i with 00 so a X) O5 cx C / 1
公开号:SU1396968A3
申请号:SU843760753
申请日:1984-07-12
公开日:1988-05-15
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:

This invention relates to a process for the preparation of new derivatives of pristinamycin Tig.
of general formula O
where R is the radical R or a straight chain or branched radical Cj is alkylthio, substituted by one or two radicals R, or 1-methyl-4-piperiltio; and R groups C, - C-dialkylamino,
It is known that synergistines obtained by fermentation methods are products that are very valuable in
15 medicine for the treatment of many diseases caused by gram-positive bacteria (such as staphylococci, streptococci, pneumococci, enterococci) and gram-negative bacterium-pyrrolidinyl, 4-piperidyl, 4-methyl-20 ries (such as hemophilus, gonococci.
meningococci). However, the disadvantage of all these products is that they are insoluble in the aquatic environment and, therefore, can be introduced into the organism only orally, usually in the form of gelatin capsules, pills or tablets. Because of this insolubility, it is not possible to use known synergistines if the patient is not in
-1-PIP Erazinyl,
which can be used in
antimicrobial drugs.
The purpose of the invention is to develop on the basis of (A known method of the method of obtaining new compounds with valuable pharmacological properties with low toxicity.
In accordance with the invention of promeningococci). Alone of all these products they are insoluble, therefore I can. the body is only ora a form of gelatin tablets. Due to immobility, impossible synergistines, e
The products of general formula (I) are obtained by swallowing, the interaction of the product of general formula R - H (III), where K has given values, with the product frmules
O35
A. Vo
SNS 1 „Yal 31. J40
SNS
sn,
(Iii)
is found in pediatric, where the spectrum of products is for admission to many measures in cases of coma
New products with the distinct advantages of vorimy in water, usually in therapeutically, pristinamycin or substance can dissolve synergistins.
those. with pristinamycin Idg
Usually the reaction is carried out without a solvent or in an organic solvent, for example an alcohol, for example methanol or ethanol, or a chlorinated solvent, for example methylene chloride, 1,2-dichloroethane or chloroform, or in a mixture of such solvents (for example, methylene chloride-methanol). -50 ° C;
It is sometimes advisable to carry out the reaction in the presence of a tertiary amine, for example, triethylamine, or .eta-, nolamine (for example, dimethyl methanol / amine).
New products of general formula (I) can be purified by conventional, known methods, for example crystallization,
chromatography or sequential extraction in an acidic or basic medium. The basic medium is understood to be an environment that is alkaline only enough to distinguish uterine
a substance from its acid addition salt, i.e. Wednesday with pH not more than 7.5-8.
It is known that synergistins obtained by fermentation methods are products that are very valuable in
medicine for the treatment of many diseases caused by gram-positive bacteria (such as staphylococci, streptococci, pneumococci, enterococci) and gram-negative bacteria (such as hemophilus, gonococci.
meningococci). However, the disadvantage of all these products is that they are insoluble in the aquatic environment and, therefore, can be introduced into the organism only orally, usually in the form of gelatin capsules, pills or tablets. Because of this insolubility, it is not possible to use known synergistines if the patient is not in
able to swallow
namely it
 able to swallow
five
0
five
0
It is found in pediatrics and resuscitation, where the activity spectrum of these products is an important indication for administration in many cases, for example, in cases of comatose senticemia.
New products have the significant advantage of being soluble in water, usually in the form of salts, in therapeutically applied doses, and can be aroused by the synergistic effect of the bactericidal effect of pristinamycin 1d, virginiamycin S or soluble synergistin derivatives.
The acute toxicity of the products of general formula (I), infused in DLj, is usually 300-900 mg / kg upon subcutaneous administration of the mouse.
For therapeutic purposes, new products can be applied as such, i.e. as bases in combination with known synergistins, but since the main advantage of the products is their solubility in water, it is especially advantageous to use them in the form of pharmaceutically acceptable salts in combination with known synergistins that are themselves converted into soluble forms, or in the form of pharmaceutically acceptable salts, or, if necessary, in the form of bases, if their solubility is sufficient for the resulting solution to contain an amount of product at least equal to the therapeutically active dose.
As pharmaceutically acceptable salts as products of general formula Q (I), salts with mineral acids can be mentioned, for example, chlorohydrates,
The following examples illustrate the practical implementation of the invention. All PMR spectra were obtained at 250 MHz in deuterium chloroform, chemical shifts were measured in ppm relative to the signal of tetramethylsilane. In the following, the following secrets are used: S singlet; d doublet lash; mt multiplet; t massive, dd doublet of doublet; dt doublet triplet; ddd doublet doublet doublet, dddd doublet doublet doublet doublet doublet.
In the examples, the term flash chromatography implies a purification method, characterized in that a short column is used and chromatographed at an average pressure (50 kPa) using silica with a particle size of 40-53 µm.
PRI me R. 1. To a suspension of 13.1 g of pristinamycin 11 in 150 cm of methanol, a solution of 3.7 g of diethylaminoethanethiol in 15 cm of methylene chloride is added. The resulting solution is stirred for 18 hours at a temperature of about 20 ° C, then drunk in 1500 cm of distilled water; the resulting mixture was extracted three times with methylene chloride (total amount 1000 cm). The organic phases are combined, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. The resulting residue is purified by flash chromatography (eluent: chloroform-methanol, 90-10 by volume; after concentration to dryness of fractions 5-23 under reduced pressure (2.7 kPa) and temperature, 12.4 g of 26- (2-diethylamino ethanol) thioistinamycin 11 11 are obtained in the form of a yellow powder, melting at a temperature of about 105 ° C (Table 1 ).
A 2% aqueous solution of 26- (2-diethylaminoethyl) thiopristinamine is obtained30
35
40
45
50
55
Q
about 5
0
five
0
five
0
five
Tsina Ilg (product of overhead lines) in the form of chlorhydrate of the following composition:
Product BA, g
0.05
n, sol on
3 acid cm
Distiller ovanna
water,
P
0.1 3
Up to 5
2. According to the method described, 1, but starting from 2.7 g
cm
In the example of pristinamycin II /, and 0.58 g of 2-dimethyl-aminoethanethiol, after purification using flash chromatography (eluent: chloroformmethanol, 90-10 by volume) and concentrating to dryness of fractions 11-17 with a reduced pressure (2.7, kPa) and a temperature of 30 ° C, 1.1 g of 26- (2-dimethylaminoethyl) thiopristinamine II6 are obtained in the form of a yellow powder melting at a temperature of about 2.35 NMR spectra (8, 6H, -N (CH3)) i 2.80 (m, 4H, -S-CHi.); 3.40 (ddd, 1H, H 26); 4.75 (d, 1H: H 27) -, 8.10 (S, 1H: H 20).
A 2% aqueous solution of 26- (2-dimethylaminoethyl) thiopristinamycin II in (product BB) is obtained in the form of chlorine hydrate of the following composition: Product WB, g O, 1 0.1 n acid salt,, 6
Distilled i
water see
Example
in the example
Up to 5
3. According to the method described, 1, but proceeding from 5.25 g of pristinamycin Id and 1.3 g of 3-dimethyl-aminopropanol, was purified by flash chromatography (eluent: chloroformmethanol, 90-10 by volume) and concentrated to dryness of fractions 6 -29 under reduced pressure (2.7 (2.7 kPa) and temperature, 3.3 g of 26- (3-dimesh1aminopropyl) thioistinamine IIg are obtained in
crucible
.
yellow as temperature
powder, about
NMR spectrum: 1.50 (S, ZN, XO, 5 H 33 first isomer); 1.70 (S, 3N xO, 5: H 33 second isomer); 1.80 (t, 2H: -S CHi-CHi-CH Nv); 20 (S, 6H X 0.5, -N (CHj) first isomer); 2.25 (S, 6H X 0.5, -K (CH3), g second isomer); 4.40 (t, 2H: - S); 2.70 (ha, 2H: - CH-j-CH ,, - -CHiNC)
3 35 1
“. | (2 m, IHi H 26 of each isomer);
,, jj (2 d, 1H; H 27 of each ischemer).
513969686
(2 S, 1 H: H 20 of each isomer),.,, „„.
,.-S Crl2Cll2jN N-j,
A 3.3% aqueous solution of CH 2 CH 2 is obtained.
26- (3-dimethylaminopropyl) thiopristine- g
mycin 118 (product BC) of the following 3.33 (d, 1H: H 26), 4.75 (d, 1H: H 27) J
composition: 8,10 (S, 1H: H 20).
Product Sun, g0,1 Get a 2% aqueous solution
0.1 and. salt on 26-2- (4-methyl-1-piperazinyl) -ethyl
acid,, 5510thiopristinamycin II in (product of BE) in
Distilled water, in the form of hydrochloride of the following composition: cm Up to 3Product BU, g0.1
Example 4. According to the method described-0.1 n. sol on
Nomu in example 1, but starting from 5.27 acid, cm1,46
pristinamycin II and 1.7 g of 2- (1-pyr-15 Distilled rolidinyl) ethanethiol, after purification of the water, cmDo 5
flash chromatography (eluent: 1 -, (2 Mercaptoethyl) -4-methyl-piperachloroformmethanol, 95-5 by volume) isin can be obtained by the known
concentration to dryness of fractions 19-60 method.
under reduced pressure (2.7 kPa) and 20. Example 6. According to the method described. The temperature of the obtained 3.9 g 26- "th in example 1, but starting from 3.15 g
2- (1-pyrrolidinyl) methyl thiopristine-pristinamycin 11, and 1.8 g of 1-diethylmycin IIb as a yellow powder, amine-2-propanethiol, after purification
melting at temperature around the flash chromatography (eluent:
.x-CHO methylene chloride methanol, 90-10 by volume NMR spectrum: 1.90 (mt, 4 j) w) and concentrating to dryness
u 3-5 under reduced pressure (2.7 kPa)
 2and temperature get 1.4 g
a26- (1-diethylamino-2-propyl) thiopris V 30thinamycin II g in the form of a yellow powder. melt at a temperature of about
3.40 (d, 1H: H 26), 4.75 (d, 1H: 160 C., „
H 27), 8.10 (S, 1H: H 20). Spectrum HtIP: 1 (m, 9H; H 32 +
Get 5% aqueous solution of 26 - N (j)); 2.50 (m, 6H-,
(1-pyrrapidinyl) ethyl thiopristin-35Lo .b 8 g H-
Mycin II g (product BD) in the form of chlorine and O / hydrate of the following composition:
Product BD, G01 Get a 5% aqueous solution
0.1 n. salt on -26- (1-diethylamino-2-propyl) thiopriscle acid 540thinamycin IIg (product BF) as
Distilled hydrochloride of the following composition:
water, CMiTo 2Product BF, mg20
2- (1-Pyrrolidinyl) ethanethiol may °
be obtained by a known method. acid, cm0,3
Example 5. According to the method described - 45 Distilled
Nomu in example 1, but starting from 3.15 gvod, cmDo 0.4 pristinamycin IL and 1.1 g of 1- (2-mer-1-diethylamino-2-propanethiol can captoethyl) -4-methylpiperazine, after obtained by the well-known method, purification method flash chromatography and measure 7. According to the method, opi (eluent: chloroform-methanol, 95-5 according to 50 in the example 1, but proceeding from the volume) and concentrating to dryness, 15 g of acid and 1.7 g of fractions 14-20 at a reduced pressure of 1-methyl-4-piperidintiol with the addition of (2.7 kPa) and a temperature of 0.6 triethyl 1.4 g of 26-G2- (4-methyl-1-piperazi-amine obtained to the reaction mixture, after purification using the flash method, nyl) ethyl thiopristinamicin Ilg in chromatography (eluent: methylene chloride of yellow poropps, melting with methanol, 92–8 by volume) and concentrating to a temperature of about 4 to 20 NMR spectrum: 2.30 (S, ZI: -JN-CH,), puff pressure (2.7 kPa) and temperature- 2.40-2.80 (t, 12H: 0.9 g of 26- (1- methyl "14-piperidinyl) thioprinstimine II as a yellow powder, melting at a temperature of about 180 ° C, NMR spectrum: 2.10 (t, 4H:
R
-g-v);
-ru- /
2.25 (S, NN:
 JСНз)
,with%
15
/ N
2.80 (gp, 4H: - S- (N-);
SNG
3.55 (t, 1H: H 26), 4.62 (t, 1H:
H 27), 7.70 (t, 1H: H8); 8.10 (s,
1H: H 20), 20
A 5% aqueous solution of 26- (1-methyl-4-piperidinyl) thiopristinamine cyc IIb (product BG) is obtained as the hydrochloride of the following composition:
Product BG mg 1025
Sol on acid, cm 0.14
Distilled water
 0.2
1-Methyl-4-piperidintiol can be obtained by a known method.30
Example 8. According to the method described in example 1, but based on 5.25 g of pristinamycin 11d and 10 cm 5 n. a solution of gaseous dimethylamine in ethanol, after cleaning method 35
flash chromatography (eluent: chloroform-methanol, 90-10 by volume) and concentration to dryness: fractions 14-24 under reduced pressure (2.7 kPa), and a temperature of 30 ° C, 0.8 g40 are obtained
26-dimethylaminopristinamycin 11 in the form of a yellow powder, melting at a temperature of about 230 ° C. Nuclear Magnetic Resonance Spectrum (CDClI - 10%): 2.35 S, 6H: -N (CHj) i); 3.25 (d, W: H 26) 545, 05 (d, 1H: H 27); 8.20 (s, tH: H 20),
Get 2% aqueous solution of 6-dimethylaminopristinamycin IIg (product VN) in the form of the hydrochloride of the following composition:, 50
Product VN, rO, 1
0.1 N hydrochloric acid, cm Distilled water, cm
1.75
Up to 5
Example 9. According to the method described in example 1, but proceeding from 5.25 g of pristinamycin 11 and 5 g of 4-methylpiperizin, after purification by the flash method
chromatography (eluent: chloroform-; methanol, 90-10 by volume) and concentration to dryness of fractions 20-44 under reduced pressure (2.7 kPa) and a temperature of 30 ° C give 0.7 g of 26- (4-methyl-1 - piperazinyl) pristinamycin Ilg R as a yellow powder, melting at a temperature of about 140 C. NMR spectrum: 2.30 (S, 3H: N-CHp-,
.CH2 CH2X
2.40 - 2.65 (m, 8H: -TVTI.
SNg-CHg3, 40 - 3.70 (m, containing H. 26); 5.75 (d, 1H: H 27), 6.10 (S, 1H: H 20).
A 3.3% aqueous solution of 26- (4-methyl-1-piperazinyl) pristinamycin Ilg (product BI) is obtained in the form of a chlorine hydrate of the following composition:
Product BI, g Oh, 1
Oh, 1 n. sol on
acid, cm - Distilled water, cm
1.6
Until 3
Example 10 “A solution of 5.2 g of pristinamycin 11 in 20 cm of 1-methyl-piperazine is stirred for
1.5 hours at a temperature of about, then poured into 600 cm of distilled water. The resulting emulsion is extracted three times with methylene chloride (total amount 600 cm); the organic phases of the compounds are dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. The residue obtained is purified by flash chromatography (eluent: chloroform — ethanol 90–10 by volume); after concentrating to dryness the fractions 13-30 under reduced pressure
(2.7 kPa) and temperature is obtained
2.6g 26- (4-methyl-1-piperazinyl) acronamycin IIj in the form of a beige powder melting at a temperature of about.
The NMR spectrum of this product is identical to the spectrum of the product described in example 9.
Example 11. According to the method described in example 1, but starting from 12.6 g of pristinamycin IId and 5.2 g of 2,3-bis-dimethylaminopropanethiol, after purification by flash chromatography (eluent: methylene chloride methanol, 90-10 by volume) and concentration of the 29-42 fractions to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C to obtain 0.3 g of 26- (2,3-bis-dimethylaminopropyl) thiopristinamine Ilg as a yellow powder, melting at about 10 ºC.
NMR spectrum: 2.30 (t, 12H;
CH,
i-n.
SP
) l
2.50 (m, 2H: -CHj-NOi 2.90 (m, 1H: -CH-NC); 3.56 (m, 1H: H 26); 4.64 (d, 1H: H 27); 4.66 (d, 1H, H 27); 7.81 (S, 1H: H 20).
A 2% aqueous solution of 26- (2,3-bis-dimethylaminopropyl) thioistinamine Ilg (product BI) is obtained in the form of hydrochloride of the following composition: Product BI, mg 0.1 N, hydrochloric acid, cm Distilled
water, cm10. 0.14 to 0.5
2,3-Bis-dimethylaminopropanethiol can be obtained by a known method.
Example 12. An operation similar to that described in example 1, but starting from 11.8 g of pristinamycin IL and 3.58 g of 2-piperidinoethanethiol and after purification by flash chromatography eluent: chloroform-methanol (85-12 by volume), collecting fractions 60 cm and a dry concentrate of fraction 21-33 under reduced pressure (2.7 kPa) with 2.5 g of 2- (piperidino) ethylthio-26-pristinamycin II6 (mixture A 60%, B 40%) are obtained in form a light yellow powder with a tempering temperature of about 134 C.
NMR spectrum:
Isomer A
1.08 (d, 32) 1.14 (d, -CH in 3 1.40-1.60 (mt, CH, 1.40-1.60 (rat, in a)
1.60-1.80 (mt, CH-1 in v)
1.73 (S, -CH3 in 33) 1.56 (S,
in 33)
Isomer B
SN in a) 1.60-1.80 (mt, CH in in)
-CHi

2.90 (mt, 5-CHi N. Sn
2.45-2.90 (mt,
5-CHi-CH -N CHj
(mt, nts) (S, CH7 17)
(S, NgO
3.53 (rat,) 55
3.74-3.91 (2o,
CHi17)
4.61 (d,)
(d, H, j) (mt, Ilj and Hj) (S,
)
6.64 (mt, HS) 7.72 (mt, Hj) 7.81 (d, H ,,).
0
Reference Example 1, To a solution of 0.41 cm 3-dimethylaminopropylamino in 15 cm of methanol containing 2.4 cm 2 n. a methanolic solution of gaseous hydrogen chloride is added at 55 C, 0.5 g of pristinamycin 1d and
15
20
25
thirty . . 40
20 mg sodium cyanoborohydride. The resulting solution is allowed to cool to about 20 ° C for about 2 hours, then it is concentrated to dryness under reduced pressure (2.7 kPa) and temperature. The resulting residue is triturated with a mixture of 50 cm of methylene chloride and 50 cm of a saturated aqueous solution of sodium bicarbonate, the organic phase is decanted and the aqueous phase is extracted twice with methylene chloride (total amount 20 cm). The organic phases are combined, dried over magnesium sulfate, filtered, then concentrated under reduced pressure pressure (2.7 kPa), and temperature. The residue obtained is purified by flash chromatography (eluent: chloroform-methanol, 80-20 by volume). Fractions 15-30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) temperature 30 ° C, the resulting residue was triturated with 5 cm of ethyl ether, filtered and dried 35 under reduced pressure (0.027 kPa) and temperature.
Thus, 60 mg of deoxy-5t- (3-dimethylaminopropyl) aminopristinamine 1d is obtained in the form of a cream-colored powder melting at a temperature of about 160 ° C.
The full NMR spectrum gives the following characteristics (Table 2). A 10% aqueous solution of 5-deoxy (5-y (3-dimethylaminopropyl) (R) aminopristinamine 1d (product A) is obtained in the form of the hydrochloride of the following composition: Product A, g
 2 n. salt on acid 3
lot, cm Distilled water, cm
0.1 0.52
Up to 1
According to the method similar to that described in Reference Example 1, the following synergistins are obtained (Table 3), which can be added to the products offered.
t1
Reference Example 8. To a solution of 2 g of Pristamina 1 in 25 cm of methanol was added 2.8 cm of 5N. ethanol solution of dimethylamine, then 2 cm 5 n. methanol solution of gaseous hydrogen chloride. To the solution thus obtained, 76 mg of cyanoborohydride is added, and 1.2 g of 5-deoxy-5-N- (2-di-methyl-amino-ethyl) -N-methyl-amino acid is added. Namycin 1 as a white powder.
melted at a temperature of about
120 C,
A 10% aqueous solution of 5 deoxy-5 (2-dimethylaminoethyl) -N-methylamino pristinamycin 1 is obtained (stir, then stirred for 48 hours JQ duct D) as hydrochloride. at a temperature of about 2 ° C. After the Ciphering Example 11. This reaction mixture is added with a concentrated 5 g molecular sieve of 3 A to the solution
dry under reduced pressure (2.7 kPa) and temperature. Remainder
139696812
1.2 g of 5-deoxy-5-N- (2-di-methyl-amino-ethyl) -N-methyl-amino is obtained. Namycin 1 as a white powder.
melted at a temperature of about
120 C,
3 g of pristinamycin I., 3.3 g of 4-diethylamino-1-methylbutylamine, 0.11 g
triturated with a mixture of 25 cm of methylene-iscyanborohydride Na and 9 cm 5 n. metachloride and 25 cm of a saturated aqueous solution of sodium bicarbonate chlorine gas; hydrogen chloride in 75 cm of methanol, decanted phase and the aqueous phase. The resulting suspension is stirred in
. extracted twice 50 cm (generally over 4 days at a temperature of about
amount) of methylene chloride. Organized by 2020 C, then filtered {filtrate con. The phases are combined, dried over magnesium sulphate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and temperature. The residue is purified by flash of a saturated sodium bicarbonate aqueous solution; chromatography (eluent: chloroform-organic phase is decanted and dry-methanol, 92-8, according to volume), Fractions. The second phase is extracted twice with 50 cm. 5-12 are combined and concentrated with do- (total) methylene chloride, under a reduced pressure (2.7 kPa). The organic phases are combined, dried and the temperature. Thus, 30% over magnesium sulfate, filtered, get 0.7 g of 5-deoxy-5 with 11-dimethyl is concentrated to dryness with low-amino-peristinamide 1 in the form of a powdered pressure (2.7 kPa) and a temperature of beige color melting at this temperature. The residue is purified by the method
center to dryness under reduced pressure (2.7 kPa) and temperature. The residue is triturated with a mixture of 50 cm of methylene chloride and 50 cm of grains.
peratura about 170 C.
NMR spectrum: 0.70 (dt, 1H: 5/5) -; 2.10-2.60 (t, 2H: 5 5 fi, + + 5j.) J 2.15 ((G, 3N X 0.8, -N (CHj) i first isomer), 2.20 (f , HN x 0.2: - —N (CH j) j second isomer).
Get 2% aqueous solution
5-deoxy-5jf-dimethylaminopristinam-spectrum R11R: 1.10 (rat, 9H:
cina 1d (product B) in the form of chlorohydra- - () + -CH-CHj); about 1.7
the following composition: Product B, 0.1 n g, hydrochloric acid, cm Distilled water, cm
0.05 0.56 to 2.5
Session example 9. According to the method.
(t, 4H: -CHi-CH-CHi)); 2.90 (m, 6H: -CHj N (,),) J 45 7.70 (mt, 1H xO, 45: Gn first isomer) 7.77 (mt, 1H to 0.55: 1 n second isomer) ,
A 10% aqueous solution of 5 deoxy-5- (4-diethylamino-1-methyl- described in Reference Example 8, podd butyl) aminopristinamycin 1 is obtained (the product is obtained 0.35 g of 5-deoxy-5 v-methyl- F) in the form of the following hydrochloride hydrate of co-aminopristinamine 1 in the form of a yellow powder, melting at a temperature of about.
Get 1% aqueous solution gc
5-deoxy-5g, -methylaminopristinami0, 1
on 1y (as hydrochloride,
Bulk Example 10, According to the method described in Bulk Example 8,
Product F, g
0.1 n salt on
acid, 1
Ciphering example 12, To a solution of 12.5 g of 5-deoxy-5-oxyimino-cristiminacin 1d in 300 cm of methanol containing 10 cm 2 of n, methanol
an aqueous solution of sodium bicarbonate; the organic phase is decanted and the aqueous phase is extracted twice with 50 cm (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 temperature. The residue is purified by the method
center to dryness under reduced pressure (2.7 kPa) and temperature. The residue is triturated with a mixture of 50 cm of methylene chloride and 50 cm of grains.
flash chromatography (eluent: chloroform-methanol, 90-10 by volume). Thus, 0.7 g of zoxy-5- (4-diethylamino-1-methylbutyl) aminopristinamine 1 is obtained in the form of a white powder, melting at a temperature of about
0.1
tava:
Product F, g
0.1 n salt on
acid, 1
Ciphering example 12, To a solution of 12.5 g of 5-deoxy-5-oxyimino-cristiminacin 1d in 300 cm of methanol containing 10 cm 2 of n, methanol
13
solution of gaseous hydrogen chloride, 0.7 g of daanborohydride sodium is added. The resulting solution is stirred for 2 days at a temperature of about, then concentrated to dryness under reduced pressure (2.7 kPa) and temperature. The residue is triturated in a mixture of 200 cm-meth.
high isomer), 7.90 (dd, 1H x 0.60: l H4 second isomer).
Kit Example 13. According to a method P similar to that described in Reference Example 11, 0.8 g of (carboxymethyl) methylamino-5-deoxychrysistristinamycin 1 is obtained in the form of a cream colored powder V melted at temperature.
Get 2% aqueous solution of N- (carboxymethyl) methylamino} -5 deoxypristinamycin I of the following composition:
Product K, g
Distilled
Ly, (product to 0.2
water, cmto 10
Reference Example 14. To a solution of 3.2 g of 5-deoxy-5- (2-dimethylamino-chloride and 100 cm of saturated aqueous sodium bicarbonate solution; the organic phase is decanted and the aqueous phase is extracted with 100 cm of methylene chloride. The organic phases are combined. are dried, dried over magnesium sulphate, filtered ig and concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. After purification by flash chromatography (eluant g chloroform-methanol, 95-5 by volume), 6.8 g 20 etsh1) aminopristinamycin 1 in 50 cm 52-deoxy-5 hydroxyamino-peptides on chloroform, containing its 0.6 cm tri- 1e as a white powder, melting at a temperature of about 70 ° C.
Spectrum 0.4 (t, 1H,); 2.45 (d, 1Ы: 5, 3.1 (comp, lex array); 7.80 (mt, 1H to X 0.75: 1 and the first isomer); 7.95 (mt, 1H X 0, 25: 1 n the second isomer).
5) -Deoxy-52-oxia1 shnopristinam-, qing 1d can be obtained by remixing for 5 hours at a temperature of about 20 ° C to 15 g of pristinamia25
ethylamine, 0.3 cm of acetyl chloride is added. The reaction mixture is stirred for 30 minutes at a temperature of about 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa). and a temperature of 30 ° C. The residue is purified by flash chromatography (eluent: chloroform-methanol, 90-10 by volume); after concentrating dry to fraction 10-21 under reduced pressure (2.7 kPa) and temperature, 1.8 g of 5-deoxyn-5U-U- are obtained (2 in 1 and 7.5 g of hydroxyethylamine hydrochloride, 0.3 cm acetyl- chloride. The reaction mixture is stirred for 30 minutes at a temperature of about 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) and 30 ° C. The residue is purified by flash chromatography (eluent: chloroform-methanol, 90- 10 by volume); after concentrating to dryness, fraction 10-21 under reduced pressure (2.7 kPa) and temperature, 1.8 g of 5-deoxyn-5 are obtained y-Y- (2 amines dissolved in 150 cm of metha-. dimethylaminoethyl) acetamido stastainol containing 8 cm 2 and meta-tmvfiHa I / in the form of a white powder, a solution of gaseous hydrogen chloride, then the reaction mixture is concentrated under reduced pressure pressure (2.7 kPa) and temperaplav melt at a temperature of about MO ° C.
NMR spectrum: 0.9 (n, 4H: 2 | + 5 / ij) j 2.05-2.15 (m, 3N: 5, + 5 (1+ 5 y);
40
2.15 (S, ZP: -ССНз); 2.45 (S, 6H; -N (SND); 2.35-2.60 (t, 5H: N-CHi-ClIi-NC +,) j 7.8 (mt, 1Hx X 0.75i IH first isomer); 8.25 (mt, 1H / 0.25: 1 H; second isomer).
round. The residue is triturated with a mixture of 100 cm of chloroform and 100 cm of a saturated aqueous solution of sodium bicarbonate; the organic phase is decanted and the aqueous phase is extracted with two
times 200 cm (total) chlorine 45 Get a 10% aqueous solution of roforma. The organic phases are combined, 5 g of deoxy-5- M- (2-dimethylaminoethyl) is dissolved over magnesium sulphate, the filter
are concentrated and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature of 30 ° C. 14 g of 5-U1-deoxy-5-oxyimino riser are thus obtained.
Namycin T in the form of a beige powder, melted at a temperature of about .210 ° O.
NMR spectrum: 0.35 (dd, 1H:); 3.25 (s, 2H: 5p,); 5.05 (d, 1H: 5c (); 5.5 (t, 2H, of which 58,); 7.80 (dd, 1H x 0.40: l Hg per55
acetamido pristinamycin 1 (product L) in the form of the hydrochloride of the following composition:
Product L, 0.1 g
0.2 n. sol on
acid, cm 0,51
Distilled
water, Up to 1
5-Deoxy-5 | - (2-dimethylaminoethyl) aminopristinamycin 1d can be obtained as described in Example 5.
Reference Example 15. By a method similar to that described in Reference.
69681
high isomer), 7.90 (dd, 1H x 0.60: l H4 second isomer).
Kit Example 13. According to a method P similar to that described in Reference Example 11, 0.8 g of (carboxymethyl) methylamino-5-deoxychrysistristinamycin 1 is obtained in the form of a cream-colored powder melting at temperature.
Get 2% aqueous solution of N- (carboxymethyl) methylamino} -5 deoxypristinamycin I of the following composition:
Product K, g
Distilled
Ly, (product to 0.2
ig. 0 etsh1) aminopristinamycin 1 in 50 cm of chloroform, containing 0.6 cm tri-
water, cmto 10
1) aminopristinamycin 1 in roforme containing 0.6 s
Reference Example 14. To a solution of 3.2 g of 5-deoxy-5- (2-dimethylamino-eth1) aminopristinamine 1 in 50 cm of chloroform containing 0.6 cm of tri-
ethsh1) aminopristinamycin 1 in 50 cm of chloroform containing 0.6 cm tri-

ethylamine, 0.3 cm of acetyl chloride is added. The reaction mixture is stirred for 30 minutes at a temperature of about 20 ° C, then concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. The residue is purified by flash chromatography (eluent: chloroform-methanol, 90-10 by volume); after concentrating to dryness, fraction 10-21 under reduced pressure (2.7 kPa) and temperature, 1.8 g of 5-deoxyn-5y-V- (2-dimethylaminoethyl) acetamido pristin-tmvfiHa I / are obtained as a white powder,
dimethylaminoethyl) acetamido pristine- tmvfiHa I / as a white powder,
melted at a temperature of about MO ° C.
NMR spectrum: 0.9 (n, 4H: 2 | + 5 / ij) j 2.05-2.15 (m, 3N: 5, + 5 (1+ 5 y);
2.15 (S, ZP: -ССНз); 2.45 (S, 6H; -N (SND); 2.35-2.60 (t, 5H: N-CHi-ClIi-NC +,) j 7.8 (mt, 1Hx X 0.75i IH first isomer); 8.25 (mt, 1H / 0.25: 1 H; second isomer).
Get 10% aqueous solution of 5 g-deoxy-5- M- (2-dimethylaminoethyl)
Get 10% aqueous solution of 5 g-deoxy-5- M- (2-dimethylaminoethyl)
acetamido pristinamycin 1 (product L) in the form of the hydrochloride of the following composition:
Product L, 0.1 g
0.2 n. sol on
acid, cm 0,51
Distilled
water, Up to 1
5-Deoxy-5 | - (2-dimethylaminoethyl) aminopristinamycin 1d can be obtained as described in Example 5.
Reference Example 15. By a method similar to that described in Reference.
Example 14, 1.6 g of 5 -leroxy-5-M- (3-dimethylaminopropyl) acetamido-pristinamycin in the form of an ocher color, melting at 210 ° C is obtained.
Get 10% aqueous solution of 5-deoxy-52 - N- (3-dimethylaminopropylcetamido pristinamycin 1 (product M) in the form of hydrochloride.
Reference Example 16, To a solution of 3.6 g 5 ((-methylene pristinamine 1d) in a mixture of 25 cm of methanol and 5 cm of chloroform was added 1.95 g of 3-dimethyl-aminopropanethiol, then stirred the resulting solution for 20 hours at a temperature of about 20 ° C, After that, the reaction mixture is drunk in 250 cm of distilled water, the resulting emulsion is extracted three times with 250 cm (total amount) of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2 , 7 kPa) and temperature. The resulting residue is very good flash chromatography (element: chloroform-methanol, 95-5 by volume) J fractions 10-38 are concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. The resulting residue is dissolved in 30 cm of ethyl ether; the resulting the crystals are separated by filtration, then dried under reduced pressure (2.7 kPa and temperature). Thus, 2.4 g (3-dimesh1aminopropyl) thiomethylprystinamycin 1 are obtained in the form of white crystals, melting at a temperature of 234 ° C.
The NMR spectrum is shown in table 4. A 10% aqueous solution of 5 (/ - (3-dimethylaminopropyl) thiomeshch1-pristinamycin T (product AA) of the following composition is obtained:
Product AA mg 30 0.1 n. hydrochloric acid, 0.3 to 5 G-Methylenpristinamycin 1, can be obtained as follows.
To a solution of 12 g of 5cA-dimethylaminophenylene methacrylate Ij in 230 cm of tetrahydrofuran containing 1.2 cm of trifluoroacetic acid was added 0.43 g of sodium cyanoborohydride. The resulting solution is transferred for about 4 hours at a temperature of about, then concentrated to dryness under reduced pressure (2.7 kPa) and temperature. The residue obtained is purified by flash chromatography (eluent: chloroform-methanol, 95-5 by volume); fractions 4–15 are concentrated to dryness under reduced pressure (2.7 kPa and temperature. 5.5 g of 5-methylene priistinamine 1d are obtained in this way in the form of white crystals, melt — psihs at a temperature of 245 C.
NMR spectrum: 0.55 (dd, 1H: 5 / Jj), 2.40 (d, 1H: 5l,); 3.55 (dd, 1HJ 5 e) 5.25 (t, 2H: 5et + 5E,) -, 5.30 and 6.10
(2sl 211: MF,); 7.85 (dd, 1H: 1 nr.
5 -Dimethylaminomethylenprinstinamine 1 can be obtained by following this procedure.
To a solution of 46 g of pristinamycin 1d in 460 cm of 1,2-dichloroethane, 230 cm of tert-butoxy-bis- (dimethyl-amino) methane are added and the resulting solution is stirred for 18 hours at a temperature of about 20 seconds. The reaction mixture is diluted with 1 L of methylene chloride. and then washed three times with 3 liters (total amount) of 0.4 Z-Horo aqueous solution of ammonium chloride. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2, / kPa) and temperature. The resulting residue is triturated with 600 cm of distilled water, the mixture is filtered and the solid is dried under reduced pressure (2.7 kPa) and temperature. 41 g of crude 5 cG-dimethylaminomethylene-pristinamycin Id are obtained in the form of a beige powder. The quality of this product is sufficient to apply it in this form in the subsequent steps. However, it can be cleaned as follows.
23.5 g of crude 5 (dimethylaminomethylene prystinamycin 1 is purified by flash chromatography (eluent: chloroform-methanol, 98-2 by volume). Fractions 16-25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and temperature 30 C. In this way, 12 g of 5 (-dimethylaminomethyl tetristinamicin 1d) are obtained in the form of a beige powder that melts at a temperature of about.
NMR spectrum: 0.9 (t, 3N: 2j.), 1.0 - (dd, 1H: 5 (ij) -, 2.50 (d, 1H: S / i,) -, 3.10 (S , 6H: -N (CII, y) j) i 3.70 (d, 1H: SEi); 5.50 (d, 1H: 56,), 7.40 (S, 1H: CHN. (CH}) j); 7.75 (dd, 1H: I HJ),
Reference Example 17. In a similar manner as described in Example 16, but starting from 0.9 g of 5J -methylenvirginiamycin S and 52 g of 3-dimethyl-aminopropanethiol, after purification by flash chromatography (eluent: chloroform-methanol, 90-10 by volume) and concentration to dryness of fractions 13-25 under reduced pressure (2.7 kPa) and a temperature of 30 ° C to obtain 0.3 g of 5 {/ - (3-dimethylaminopropyl) thiomethylvirzhiniamycin S in the form of a white powder melting at a temperature of about.
NMR spectrum: 0.45 (dd, 1H: 5 p, 1.90 (t, 2H: -S CH7CH,), 2.40
I -nu
(S, 6H: -CH, -Nr.,.); 2.60 (m, 4H:
 - j
-S); 3.45 (d, 1H: 5) i 4.85 (tn, 3H of which 5,), 5.25, (dd, 1H: 5o), - 7.78 (dd. III: I HJ).
A 10% aqueous solution of 5 (f- (3-dimethylaminopropyl) thiomethylvirginiamycin S (product AB) is obtained in the form of the hydrochloride of the following composition:
Product AB, g .0,1
Sol na acid,
 one
5cG-Methylenevirginiamycin S can be obtained by a method similar to that described in Reference Example 16 for 5 (G-methyleneprintinamycin 1, but starting from 2 g 5 ($ dimethylaminomethylenevirginiamycin S and 74 g 1D1 sodium boron hydride). After purification by flash chromatography (eluent: chloroform-methanol, 98-2 by volume) and concentration to dryness of fractions 2-5 under reduced pressure (2.7 kPa) and a temperature of 30 ° C give 1 g of 5 / -methylenvirginia 1 S in the form of a beige powder, melt at a temperature of about.
NMR spectrum: 0.35 (dd, 1H: 5fbi) i 2.45 (dd, 1H: 5 / i,); 3.55 (dd, 1H: 5Ea) -, 5.25 (dd, 1H: 5E,) -, 5.25 (m, 1P: 5o (); 5.30 and 6.15 (2 S, 2H: .N
. ); 7.75 (dd, W: 1 n).
5cG-Dimethylaminomethylenevirinyamicin S can be obtained by a method similar to that described in Reference Example 16 for 5 rf-dimethylaminomethylene prystyne 1, but starting from 2 g of virginiamycin S and 10 cm of bis-dimethylamino-tert-butoxymethane, and after cleaning by the flash method ChromeX
Sc
five
0
five
0
by chromatography (eluent: chloroform-methanol, by volume) and concentration to dryness of fractions 9-12 under reduced pressure (2.7 kPa) and temperature, 0.8 g of 5 cf-dimethylamino-ethylene virimine amycin S in the form of a yellow powder, melting at about 175 C.
NMR spectrum: 0.9 (t, 4H: 2 y + 5 p.,) -, 3.05 (S, 6H: CH-H (CHe),) 1 3.65 (d, 1H: 5Ei) -, 4.85 (d, 1H: 5,); 5.15 (dd, 1H: 5o (); 7.10-7.40 (t, aromatic + CH - NC); 7.70 (dd, 1H: t H,).
Reference Example 18. According to a method similar to that described in Reference Example 16, but starting from 6 g 5 (G-methylenpristinamycin 1 and 4 cm 2- (4-methyl-1-piperazinyl) ethanethiol, after purification by flash chromatography (eluent : chloroform-methanol, 97-3 by volume) and concentration to dryness of fractiongday 8-20 under reduced pressure (2.7 kPa) and a temperature of 30 ° C; 2.6 g (4-methyl-1-piperazinyl) ethyl thiomethylpristinamycin 1 / in the form of white crystals melting at 21b C.
NMR spectrum: 0.60 (dd, 1H: 5 fi,),. 2.27 (S, ЗН :: М-СНз) 2.40-2.80 (ha,
/ CH oClIov
11H: -CH2- -N- 5/5,) -,
0
five
0
five
5.05 (dd, 1H: 5e,), 5.27 (t, 2H: 5o (+ 4s /), 7.85 (lut, 1H xO, 8: H is the first isomer); 7.95 (mt, 1H x 0,2: IH second isomer).
Get 5% aqueous solution of 5 "i - 2- (4-methyl-1-piperazinil) -ethyl thiomethylpristinamycin Id (product AC) in the form of the hydrochloride of the following composition:
Product AS, g
Oh, 1 n. sol on
3
0.1 0.96 Up to 2
acid, CM
Distilled
water see
Reference Example 19. According to a method similar to that described in Reference Example 16, but starting from 2 g of tylenpristinamicin 1 and 3 cm 3- (4-methyl-1-piperazinyl) propanethiol, after purification by flash chromatography (eluent: croform-methanol, 90- 10 by volume) and concentration to dryness of fractions 10-25 with reduced
191396968
; 2. 2.9 g (4-methyl-1-piperazinyl) propyl thiomethyl prythinamination
on 1 in the form of white powder, melting at a temperature of about 156 C.
Nuclear Magnetic Resonance Spectrum: 0.65 (dd, 1H: 5 / b); 2.30 (S, ZN: -M-CH3);
/ CH2 CHg, 2.50 (t, 13H: -CHg-11 N
/
SNG-SNG
b-SCHj- + 5 /.,); 5.27 (m, 2H:); 7.85 (dd, 1H X 0.8: 1 H first isomer)} 7.95 (dd, 1H X 0.2: 1 H second isomer).
A 10% aqueous solution of 3- (A-methyl-1-piperazinyl) propyl thiomethylpristinamycin 1 (product AD) is obtained in the form of the hydrochloride of the following composition:
Product AD, 0.1 g
0.5 n. sol on
acid, 38
Distilled
water, cm Up to 1
Reference Example 20. According to a method similar to that described in Reference Example 16, but starting from 4 g of 5f-Methylenpristinamine 1 and 4 cm bis- 1, 3-dimethylamino-2-propanethiol, after purification by flash chromatography (eluent: chloroform methanol, 95–5 by volume) and concentration of the 20–60 fractions to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C to obtain 0.59 g 5 (1,3-dimethylamino 2-thromo thiomethylpritistinamycin 1 in the form white powder, melted at about.
NMR spectrum: 0.63 (dd, 1H: 5,), 2.40 (S, 6H: -N (CH,;) j) i 2.50 (m, YN
-SN
/
I
SNG:
+ - (CHj)); 4.97 (S, IH
5,) v 5.30 (m, 2H: 5o + 40) 7.85 (mt, 1H X 0.85: I H first isomer);
The reference example 22, According to the method described in Reference Example 16, but starting from 2 g 5 (D-methylenedium namycin 1 and 0.66 g 2-diethylamino-ethanethiol, is obtained after purification by flash-xpromatography (eluent: chloroform-methanol, 95-5 by volume) and dryness of fractions 9-18 under reduced pressure (2.7 kPa) and temperature 30 ° С 0.8 g 5 if- (2-cc-ethylaminoethyl) thiomethylpristinamycin
7.95 (mt, 1H X 0.15: I H the second is-j powder of a beige color, plummer), 50
Get a 7.5% aqueous solution of 5 (G-bis (1,3-dimethylamino-2-propyl) thiomethylpristinamine If (product AE) in the form of the hydrochloride of the following composition:
Product AE, g 0.03 55 0.1 n, hydrochloric acid,, 3 Distilled
at work at a temperature of 230 C,
NMR spectrum: 0.65 (dd, 1H: 5 / ii), 2.38 (d, 1H: 50,), 2.3-2.8 (m, 8H:
-S-CH-jCH NC JJ I) i 3.15 (dd, W:
); 3.35 (dd, 1H: -)} 5.01 (dd, 1H: 5,), 7.81 (dd, 1HX X 0.9: I HJ, first isomer); 7.90 (dd, 1H X 0.1: 1 Hb second isomer).
water, cm to 0.4
20
Reference Example 21, According to the method described in Reference Example 16, but starting from 3 g of 5-methylene prime
-MO
15
th
Mitsina 1d and 0.97 g of 1-methyl-4-mercap-toperiperidine, after purification by flash chromatography (solvent: chloroform-methanol, 95-5 by volume) and by 1 centrifugation of the fractions 10-16 under reduced pressure (2.7 kPa) and temperature, 1.1 g (1-methyl-4-piperidyl) thiomethylpristinamicin 1 are obtained in the form of a white powder melting at a temperature. NMR spectrum: 0.6 (dd, 1H: 5 /},) i
2 (p), 4H:
/ SNg
); 2.20 (s,
SNG20
ZN: -S

, 35 (t, 1H; 5,);
2.90 (ha, 4H: - S

sn
, 30 (t, СН /
five
0
2H: 5o + 4flf); 7.85 (dd, 1H: I H). A 5% aqueous solution of 5 / - (1-methyl-4-piperidyl) thiomethylpristinamycin 1d (product AF) is obtained in the form of the hydrochloride of the following composition:
Product AF, g 0.03 0.1 n. hydrochloric acid, cm
Distilled
3
water, cm0, 3 To 0.6

Reference Example 22, According to the method described in Reference Example 16, but starting from 2 g 5 (D-methylenepristi namycin 1 and 0.66 g 2-diethylamino-ethanethiol, is obtained after purification by flash-xpromatography (eluent: chloroform-methanol, 95-5 by volume) and dryness of fractions 9-18 under reduced pressure (2.7 kPa) and temperature 30 ° С 0.8 g 5 if- (2-cc-ethylaminoethyl) thiomethylpristinamycin
j powder beige, flat
j powder beige, p
at work at a temperature of 230 C,
NMR spectrum: 0.65 (dd, 1H: 5 / ii), 2.38 (d, 1H: 50,), 2.3-2.8 (m, 8H:
-S-CH-jCH NC JJ I) i 3.15 (dd, W:
); 3.35 (dd, 1H: -)} 5.01 (dd, 1H: 5,), 7.81 (dd, 1HX X 0.9: I HJ, first isomer); 7.90 (dd, 1H X 0.1: 1 Hb second isomer).
21
A 5% aqueous solution of 5cf- (2-AH3THnaMHHO3THn) THOMeTHnnpHCTH- titanium is obtained by 1d (product AF () in 1% chlorine hydrate of the following composition:
Product AF, mg 0.1 n. hydrochloric acid, see Distilled water,
thirty
cm
0.29 .To 0.6
Reference Example 23. To a solution of 5.5 g of 5 C-dimethylaminomethylene pristinamycin 1d in 60 cm of acetic acid
5.3 g of 2-dimethyl-aminoethylamine is added dropwise so that the temperature does not exceed 25 ° C. The resulting solution is stirred for 20 hours at a temperature of about 20 ° C, then it is slowly drunk into a saturated sodium bicarbonate aqueous solution; The resulting mixture was extracted twice with 750 cm (total) of methylene chloride. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) and temperature. The residue is purified by flash chromatography (eluant: chloroform-methanol, 90-10 by volume); fractions 10-12 are concentrated to dryness under reduced zo pressure (2.7 kPa) and temperature
139696822
Neither fractions 15–20 dry with a reduced pressure (2.7 kPa) and a temperature of 30 ° C give 4.0 g of 5cH- (1-methyl-4-piperidyl) amino compounds Ienpritistinamina 1 as a yellow powder, melting at temperature
NMR spectrum: 0.40 (ha, 4H: 2);
.SNg
2.0 (ha, 4H :-( N4: 2.35 (S, NN:
SNG- /
N-CH5); 2.45 (d, 1H: 5p); 2.90
Nych
7J-1,3,20 (under massive, tH:
2
ten
sn /
—CH N 3.50 (d, 1H: 5,), 4.85
(under massive, 1H: 58,); 6.65 (d, 1H: CHNH-); 9.70 (dd, 1Hx 0.25: iCH - NH - first isomer); 10.03 (dd, 1H X 0.85: CH-NH - second isomer).
Get 10% aqueous solution of 25 5 (/ f (1-methyl-4-piperidyl) amino (R,)
Methylenepristinamycin Id (product AT) “in the form of the hydrochloride of the following composition:
Product AT, g
0.1 n. salt on kitty, -
0.03 0.03
30 s. Thus, 3 g of 5 (G- (2-dimethylaminostil)) amino (R,) methylenpristinamine 1u is obtained in the form of a beige-colored powder melting at a temperature of about.
NMR spectrum: 0.90 (mt, 4H: ,,), 2.25 (mt, 6H: -N (CHj) j); 2.50 (mt, ЗН: -С1ЦЫС4- 5,) -, 3.25 (mt, 2Н: -N-Cn -), 3.50 (mt, 2H; 5 i + 3c /,) 4.90 ( mt, 1H:) i between 7.15 and
7.4 (m, ni:); 9.90 (mt, 1H / / replaced by -Sh-).
A 1% aqueous solution of 5c / - (2-dimethylaminoethn1) aminomethylene-pristinamycin 1 / (product AG) of the following composition is obtained:
Product AG, r0 1
Distilled
water, 10
Reference Example 24, According to a method similar to that described in Reference Example 23, but starting from 13.8 g 5 (f-dimethylaminomethylene-pristinamycin 1d and 3.4 g 4-amino-1-methylpiperidine, after purification by flash chromatography (zluent: chloroform methanol, 92.5-7.5 by volume) and concentrated35
40
lot, cmDistilled
water, 0.3
4-amino-1-megylpiperidine can be obtained by a known method.
According to the method described in Referential Example 23, the following are obtained: synergistic and histile of the general formula (I), which can be added to the offered products (Table 5).
Reference Example 40. To a solution of 1.84 g of 5e / -dimethylamino (V) methylenepristinamine Ift in 40 cm of acetic acid was added 2.1 g of 2-dimethylaminoethanethiol. The resulting solution is stirred for 20 hours at a temperature of about 20 ° C, then slowly poured into a saturated aqueous solution of sodium bicarbonate, the mixture is extracted three times with 400 cm (total) of methylene chloride. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure of 55 (2.7 kPa) and a temperature of 30 ° C. The residue obtained is purified by flash chromatography (eluent: chloroform-methanol, 96-4 by volume); fractions 5 and 6 are combined and concentrated to dryness
45
50
2
sn /

CH N 3.50 (d, 1H: 5,), 4.85
(under massive, 1H: 58,); 6.65 (d, 1H: CHNH-); 9.70 (dd, 1Hx 0.25: iCH - NH - first isomer); 10.03 (dd, 1H X 0.85: CH-NH - second isomer).
Get 10% aqueous solution of 5 (/ f (1-methyl-4-piperidyl) amino (R,)
Methylenepristinamycin Id (product AT) in the form of the hydrochloride of the following composition:

Product AT, g
0.1 n. salt on kitty, -
0.03 0.03
lot, cmDistilled
water, 0.3
4-amino-1-megylpiperidine can be obtained by a known method.
According to the method described in Referential Example 23, the following are obtained: synergistic and histile of the general formula (I), which can be added to the offered products (Table 5).
Reference Example 40. To a solution of 1.84 g of 5e / -dimethylamino (V) methylenepristinamine Ift in 40 cm of acetic acid was added 2.1 g of 2-dimethylaminoethanethiol. The resulting solution is stirred for 20 hours at a temperature of about 20 ° C, then slowly poured into a saturated aqueous solution of sodium bicarbonate, the mixture is extracted three times with 400 cm (total) of methylene chloride. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. The residue obtained is purified by flash chromatography (eluent: chloroform-methanol, 96-4 by volume); fractions 5 and 6 are combined and concentrated to dryness
Ciphering example 56, at a temperature of 0.87 g of 1- (2-mercaptopropyl) -4-methnl, about 0.42 cm of tristi-amine, piperazine in 50 cm of ethanol, to which 0.5.5 g 0.34 g of sodium ethylate, sulfonic acid was added to the p-toluene acid chloride. Then a solution of 5.2 g of 5 s / - (4-methyl-35 is added to the reaction mixture and the mixture is stirred for 2 hours (nprf)) sulphonyloxymethylenprythinam-. the temperature is about .C, then it is 1 to 50 cm of methylene chloride. The mixture is reduced to dryness under reduced pressure. The mixture is stirred at a pressure (2.7 kPa) and at a temperature of 16 hours at a temperature of about 20 ° C, - 30 ° C, the residue is purified and then diluted with 500 cm of methylene chloride flash chromatography. (eluent: read and 100 cm "distilled water, methylene chloride methanol, 96-4 by volume. After stirring, the aqueous phase is extra-. After concentration to dryness, twice twice 50 cm (total fractions 4-6 under reduced pressure) of methylene chloride. The organic temperatures of the obtained phase are combined, dried over sulfate. Volume 45 2.2 g (4-methylphenyl) sulphonium magnesium, filtered, then concentrated by halogen oxymethylene prystinamine 1 as dry under reduced pressure. The white powder melts at 2.7 kPa and temperature. about 265 C., purified by flash chromatography. NMR spectrum: 0.50 (dd, W:). (customer: chloroform - methanol, 97.5-, i. 2.5 by volume). Fractions 33-80 of compound ЗНг-180г- СН5); 3.30 (dd, ny and concentrated to dryness under reduced pressure (2.7 kPa) and a temperature of 30 ° C. Thus obtained 1.25 g (4-methyl-1-piperazinyl) 2- Propyl Thiomethylene Prystinamycin as oroshka beige, melting at about 195 C.
1H: 5yy); 5.25 (d, IH: 5o); 5.30 (5d, IH: 5,); 7.35 - 7.90 (AB + system
n n
V
+ t, 8H: 4 + 7, 85 (dd, 1H: Gn).
chloride is added at a temperature of about 0.42 cm trisy of amine, then 0.57 g of p-toluene sulfonic acid chloride. Then the reaction mixture is stirred for 2 hours. The nprf temperature is about .C, then it is concentrated to dryness under reduced pressure (2.7 kPa) and 30 ° C, the resulting residue is purified by flash chromatography (eluent: methylene chloride methanol, 96- 4 by volume. After concentration to dryness of Fractions 4-6 under reduced pressure, 2.2 g of (4-methylphenyl) sulfonyloxymethylene prystinamine 1 is obtained in the form of a white powder, melting at a temperature of about 265 C. NMR spectrum: 0 , 50 (dd, W:)., I g ЗНг-180г- СН5); 3,30 (dd
1H: 5yy); 5.25 (d, IH: 5o); 5.30 (5d IH: 5,); 7.35 - 7.90 (AB + system
n n
V
+ t, 8H: 4 + chloride is added at about 0.42 cm then 0.57 g of sulphonic acid chlorine. The mixture is then stirred at a temperature of approximately centered to dryness under pressure (2.7 kPa) and 30 ° C. The chromate-methylene chloride methane obtained by flash is left. After concentrating Fractions 4-6, 2.2 g (4-methyl-oxymethylenepropylenamyl powder, floatation at about 265 C. NMR spectrum: 0.50 (., g ЗНг-180г-
7.85 (dd, 1H: H).
5-Oxymethylenediamine I can be prepared as follows.
K 420 cm 0.1 n. 10.6 g of 5c-dimethylaminomethylenprystinamycin 1 are added with stirring to the aqueous solution while stirring. Then the resulting solution is stirred for 3 hours at a temperature of about 20 ° C. Then 30 cm of a saturated aqueous solution of sodium bicarbonate is added dropwise. to obtain a pH of about 4. The precipitated product is separated by filtration, then washed 3 times with 30 cm (total) of bottled water. After drying under reduced pressure (2.7 kPa) and a temperature of about, 9.5 g of 5o-oxymethylenepenistinamycin 1 are obtained, in the form of a beige powder. The quality of this product is sufficient to apply it in this form in the subsequent stages. However, it can be cleaned as follows,
9.5 g of crude 5 (oxymethylene prystinamine 1 is dissolved in 50 cm of ethyl acetate; the resulting solution is drunk on 100 g of silica gel in a 2.8 cm column. Elute first with 400 cm of ethyl acetate and remove the corresponding eluate, then elute at 1600 ml of ethyl acetate and the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) and temperature. 6.8 g of 5 / -oxymethylene prystinamine are obtained in this way for 1d as white crystals, melting at 220 ° C.
NMR spectrum: 0.69 (dd, 1H: 5 / ü), 2.43 (d, 1H:) 3.40 (d, 1H: 5fj) -, 4.04 - 4.2 (m, 3N: 4 o + 5, +, + 5fl () i 8.15 (S, 1H: CH - OH) -; 11.63 (S wide, 1H: CH-OH).
Reference Example 57. According to a method similar to that described in Reference Example 56, 1 g (3-dimethylamino-2-propyl) thiomethylene pristinamycin 1d is obtained in the form of a yellow powder, melting at.
A 5% aqueous solution of 5 (G- (3-dimethylamino-2-propyl) thiomtientiphenistinamycin I. (product AAO) is obtained as chlorine hydrate.
Reference Example 58. According to a method similar to that described in Reference Example 56, 1.32 g of 5 G- (5-diethylamino-2-pentyl) thiome tylenene rrhtinamycin IA in the form of a beige powder is obtained.
colors melting at about 185 ° C.
A 10% aqueous solution of 5c / - (5-diethylamino-2-pentil) thiomethylene is given by pristines IU to I / (product AAP) in the form of hydrochloride.
Reference Example 59. A solution of 7.6 5cf (4-methylphenyl) sulfonyloxymethylene pristinamycin 1 in 60 cm, tetra hydrofuran is bhlamed to a temperature of about -10 ° C. A solution of 0.65 g of 2-dimethylaminoethanol in 60 cm of tetrahydrofuran, to which 0.35 g of 50% sodium hydride dispersion in mineral oil is added, is slowly added while maintaining this temperature. After the addition is complete, the temperature is allowed to rise slowly to approximately 20 ° C. The reaction mixture is stirred for 24 hours at this temperature, then diluted with 500 cm of methylene chloride and washed twice with 50 cm of saturated ammonium chloride solution, the organic phase is dried over magnesium sulfate, filtered, the concentrate is then concentrated under reduced pressure (2.7 kPa) and temperature 40 ° C. The residue obtained is purified by flash chromatography (eluent: chloroform-methanol, 95-5 by volume. Fractions 12-17 are combined and concentrated to dryness under reduced m pressure (2.7 kPa) and a temperature of 25 ° C. In this way, 1.5 g (2-dimethylaminoethoxymethylene) pristinamycin 1d are obtained in the form of a beige powder melting at a temperature of about (.
NMR spectrum: 0.65 (dd, 1H: 5 A) -, 2.3 (SJ 6H: - M (CH3),) -, 2.65 (t, 2H:), 3.42 (dd, 1H: 5 f); 4.15 (t, 2H: -OSP, -); 5.15 (d, 1H: 5f,); 7.45 (aromatic, 1H:) C CHO-); 7.80 (dd, 1H: 1 n.).
Get 1% aqueous solution 5sG- (2-dimethylaminoethoxymethylene) pristinamycin I l (product AAO) in the form of the hydrochloride of the following composition.a:
Product AAO g 0.03
0.1 n. sol on
acid, cm
Distiller about vna
water Until 3
The invention also relates to medicaments consisting of the product of the general formula (1) in free form or, preferably, in the form of an acid addition salt with a pharmaceutical
0.3
with an acceptable acid in combination with known synergistins or, preferably, with synergistins of the general formula, and any other pharmaceutically compatible product, inert or physiologically active, can also be included in the combination. The medicinal substances according to the invention can be used parenterally, orally, rectally or topically.
The sterile compositions for parenteral administration may be aqueous or non-aqueous solutions, suspensions, or emulsions. As solvents or carriers, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, organic injection esters, for example ethyl oleate, or other suitable organic solvents, can be used. These compositions may also contain additives, in particular wetting agents, isotonizing agents, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in various ways, for example by disinfecting filtration, by incorporating sterilizing agents into the composition, by irradiation or heating. They can also be prepared in the form of sterile solid compositions that can be dissolved at the time of use in a sterile injectable medium.
Tablets, pills, powders, or granules can be used as solid compositions for oral administration. In these compositions, the active present product (optionally in combination with another pharmaceutically compatible product) is mixed with one or more inert diluents or additives, for example sucrose, lactose or starch. These compositions may also include, in addition to dilution, other substances, for example, a lubricant, for example magnesium stearate.
Pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents can be used as liquid compositions for oral administration.
0
five
0
five
-
0
five
0
five
five
for example water or paraffin oil. These compositions may also include, in addition to diluents, other substances, for example wetting agents, sweeteners or flavoring agents.
Compositions for rectal administration are suppositories or rectal capsules that, in addition to the active substance, contain carriers, for example, cocoa butter, semi-synthetic glycerides or polyethylene glycols.
Compositions for topical application can be, for example, creams, lipsticks, lotions, eye drops, rinses, nasal drops or aerosols.
In the treatment of humans, the products offered in combination with known synergistins or, preferably, with synergistins of the general formula are especially useful for the treatment of infections of microbial origin. The dose depends on the desired effect and the duration of the treatment; for an adult, it is usually in the range of 500-2000 mg per day for parenteral administration, in particular for intravenous administration with slow perfusion, and the dosage of synergistine of the general formula is 500-2000 mg per day. .
Usually, the doctor sets the dose that he considers most suitable depending on the age, weight, and many other factors characteristic of the Subject to be treated.
The following non-limiting options illustrate the application of the proposed compositions.
Example A. In accordance with the usual procedure, an injection solution for perfusion is prepared containing 5 g / l of the active mixture of the following composition:
26 - (2-Diethylaminoethyl)
thiopristinamycin IIj g 3
5 (L- (3-Dimethylaminopropyl)
Thiomethylpristinamycin I.j g
0.1 n. water solution
hydrochloric acid, cm
Distilled water, cm Up to 1000
Example B: Prepare an injection solution for perfusion containing -. Containing 1 g / l of the active mixture of the following composition:
26- (4-methyl-2-piperazinyl)
pristinamycin 11b, g0,6
g
65
29
5f- 2- (A-Methyl-1-piperaznnl) ethyl thiomethyl-pristynamycin I /, g 0.1 n, aqueous hydrochloric acid, cm - Distilled water, cm
Bacteriostatic activity in vitro.
To a group of plates containing a known volume (20 cm) of the corresponding culture medium (Mueller-Hinton agar), 1/10 of this volume of a group of geometrically increasing (factor 2) solutions of the test product was added. The plates were seeded with a multipoint inoculum, which gave a spot of 104 colonies of the microorganism in tryptic soy broth incubated for 18 hours with and diluted 1/100 with the same medium.
After seeding, the plates are incubated for 24 hours at 37 C.
The minimal inhibition of concentration is the lowest concentration at which the growth (development) of microorganisms is inhibited.
Action against abdominal infection in younger.
0.5 cm of the corresponding 18-hour culture of the test microorganism in Brain Heart Infusion (Difco) medium, appropriately diluted with 5% pork mucine, was injected into the peritoneum. Such seeding caused the death of control animals within 24 to 28 hours. The test compound was administered subcutaneously twice with an interval of 5 hours per day, with the first dose being administered after seeding by microorganisms. A dose per unit weight of 50 was used.
The 50% therapeutic dose (CDj) is the dose of the test compound that, when administered in each case, ensures that half of the treated animals survive for a test period (8 days).
The results are shown in tabLo7,
The toxicity of the compounds obtained is presented below: Example Toxicity (m) U mg / kg
1900
900
1396968
thirty
five
0
0
five
four
five
6
7
9 and
12
ten
650 900 700 400 900 700
five
0
five
five
The compounds obtained in Examples 8 and 11 are not sufficient to simultaneously determine biological activity and toxicity. However, it is unlikely that both of these compounds have a DL ,, (toxicity value) significantly different from that of the other compounds, since the structures of the substituted chains are very similar. Indeed, the difference in the toxicity values of the DL compounds obtained in Examples 1 and 3, and the substances obtained in Example 8, is barely perceptible, since it was noted that no differences were found in the values of the compounds obtained in Examples 5 and 9. Substitution of the second radical of dimethylamine with the chain of the compound obtained in Example 11 does not entail an increase in the toxicity of the compound compared with the value established for the compound obtained in Example 3.
The proposed substances themselves do not possess or have a small degree of biological activity. They synergistically increase the biological activity of pristinamycin 1d, virginiamycin S or soluble derivatives of the basic formula.
The advantage of the proposed pristinamycin derivatives is not in the superiority of the biological activity of the mixtures in comparison with the previously known ones, but in the possibility of assigning these compounds by parenteral route, which is still not feasible.
Below are the solubilities of the compound of formula I compared with the solubility of pristinamycin Id. Example compound Solubility, mg / cm
120
2 20
333
450
20
7.05
7
6.90
6.70
6.40
6.50
5.75
5.45
5.25
five
4.75
4.60
4.45
4.40
3.4
3.20
3
3
2.80
2.65
2.35
2.25
2.20
1.60
1.25
0.90
0.50
------- ,, L „-
-N (CHj) -NH (CH) N (CH3) 2 Yellow powder
m.p. approx. 180 s
m (sns) -.
/
Roky)
Roky)
worldly)
6-6f
1 H,
1 H,
4tr + 4
2 NH
18
6o
4o /
five
S
2o (
5E,
3o (
3,
(wide) 3 (Y
g
4 SP
3
 , S 1 et 4 N (CHj) j (chain) 5/3, (uenb) -N (CHj) (chain)
-CH, - (chain)
hf.iy
J2r
Table 3
10% aqueous solution in the form of hydrochloride
White powder m.p. 195 С
35
g:
-K (CH3), -CN- / - CH3
-NCCHj), -NHOH
-NCCHj) -N H (CH2) j OH
- N - Sh (CH2) z NCCH), Beige powder
M.p. approx.140 10% water
139696836
 Continued. 3
f
10% aqueous solution in the form of hydrochloride
Beige powder m.p. approx.
3.7% aqueous solution in the form of hydrochloride
White powder, m.p. approx. 70 ° C
10% aqueous solution in the form of hydrochloride
Cream powder, mp, approx.
2% aqueous solution in the form of hydrochloride
Beige powder
M.p. ca.140 With 10% water
-NH- (CHi) -I NCCjHj) Yellow powder,
M.p. approx ZO S
5% aqueous solution in the form of hydrochloride
—NH (CH) jNH, CHj Yellow powder,
M.p.
1% aqueous solution in the form of hydrochloride .27 - -NH (CH,). S (SNE) 2
L yellow powder,
M.p. approx C
6.6% aqueous solution in the form of hydrochloride
28 - - t-su - su, xsn,) ,, ,,,, „„ p „„
CH So pl. approx. 160 ° C
ABOUT
1% aqueous solution in the form of hydrochloride
29-. -ShNS.SY-ZhSN orange powder,
 M.p. approx.
SNS
| 10% aqueous solution in the form of hydrochloride
30- -Tffl-CH- (SNGHSANa) R
I of 5/2 Beige powder,
(p. approx.,
ABOUT. ,
1% aqueous solution
-ng (sn,) -iTl I yellow powder,
M.p. ,
1% aqueous solution in the form of hydrochloride
.32 - -Ш1 (СН2) Yellow powder m.p. 170 ° O
1% aqueous solution in the form of hydrochloride
33- - NH (CH2) / Yellow powder,
- m.p. Approx. ,
1% aqueous solution in the form of hydrochloride
34- -NH (CH., -And O Beige powder,
  X- / t pl. approx. ,
1% aqueous solution of Hg RT1 in the form of hydrochloride
i
35 NH Cll5r-p Beige powder,
 - m.p. about 160 ° C
1% aqueous solution
 hkh.v in the form of hydrochloride - NH-G
36 L J Beige powder,
M.p.
CHA1% AQUEOUS solution
in the form of hydrochloride
37H - lilH- (11- CHxBegeo powder,
- / .Т.пл. approx. 195 ° C
-N (CH, V -Sh {CH,), - 74 - CH3 ,,,
5% rogue
m.p.
39 -N (CH,)
3 2
. ™ (with „4
41
-N-CCHj)
42 - "- (SNZ
43
44
45
46
-N
-NCCHj), -N (CHj) -N (CUj) i
-S- (CH) j N () 2 Beige powder, m.p. approx.
1% aqueous solution in the form of chlorine hydrate
-8- (SI) s N (CH j) Beige powder, T. pl. approx. 170 ° C
1% aqueous solution in the form of chlorine hydrate
-8 (СН) з NCCHj) Beige powder, m.p. approx. 140 ° C
10% aqueous solution in the form of chlorine hydrate
-S-CH -CH-CH NCCHj) Beige powder, m.p. 234 ° C
CHj1% aqueous solution in the form of hydrochloride
g (-1JJ - C} Beige powder, mp. approx., / S / 2
CH CH1% aqueous solution in the form of chlorine hydrate
- S (CH2) I Beige powder, m.p. approx. 180 ° C
1% water solution in the form of chlorine hydrate
SNE
.Ks
1% water solution in the form of chlorine hydrate
47
48
-N (CHj) j) I Beige powder, m.p. ca.215 C-8- / T1-CH3
0.6% aqueous solution, in the form of chlorine hydrate
-N (CH3) j
Yellow powder, m.p. 170 C,
,,,
5% aqueous solution in the form of chlorohydrate
,,,
powder, mp,
10% aqueous solution in the form of hydrochloride
Yellow powder, m.p.
10% aqueous solution in the form of hydrochloride
Table 6
1% water solution in the form of chlorine hydrate
Beige powder, m.p. approx.215 With
0.6% aqueous solution, in the form of chlorine hydrate
Beige powder, m.p. approx.215 With
Yellow powder, m.p. 170 C,
1% water solution in the form of hydrochloride
3
-7-1
49
-N (CH5) j T C
Beige powder, m.p. G1ribl.175 C 1% aqueous solution in the form of chlorhydric gchttrat
SP2SPz
50-С (СНз), -5-СН (СНг) НЫ- (СН,) ,Ы {СН) Yellow powder, m.p. approx.
SPz1% aqueous solution in the form of hydrochloride
51-N (CHj) j S (CH5) 1 Beige powder, m.p. approx. .
1% water solution in the form of chlorine hydrate
52-N (CHj) j-g (CHj-N N-CH3 Beige powder, mp. Approx.,
1% aqueous solution in the form of chlorine hydrate
53-N (CHj) g (CH2) - N N-CHT Beige powder, m.p. approx.
10% aqueous solution in the form of chlorine hydrate
54-N (CHj), - S-CH., - CH-CH, -N (SNL. Powder of ocher color,
- (if
CH,
©
1% aqueous solution as chlorohydrate
55-NCCHj) -S (CH,) 2
mz
44 Continuation of table 6
1% aqueous solution as chlorohydrate
Yellow powder, m.p. 5% aqueous solution
Product Comparison Ok. 15 pristinamycin
..- Taking into account the insolubility of the natural mixture, the purpose of this product requires application techniques that cause changes in the results.

权利要求:
Claims (1)
[1]
Claim
The method of obtaining derivatives
32
C _g - C ₃ -alkylthio, substituted
one or two radicals
K *, or 1-methyl-4-piperi _/ diltio,
K - C / -C - ^ - dimethyl amino, 1-pyrrolidinyl, ι-piperidyl, 4-methyl-1-piperazinyl groups,
characterized in that the interaction is subjected to pristinamycin and _l formulas
ABOUT
with the compound of the formula I-H, where I has the indicated values, with the subsequent, if necessary, separation of the isomers of the ¹ ··: product obtained and its conversion into the hydrochloride.
Table!
"· ***" MM · * in "MV
Attribution ^ ppm The form one. g 3 6.10 δ And 20 6.60 Wide ΝΗ8 6.55 aa H 5 6.15 but I11 5.80 aa I am 6 · 5.65 ahh ήΊο 5.50 but H 13 4.95 ahh And 14 4.77 aa H 3 4.75 but H 27 4.27 ahh H 24 / 4.05 ahh H 9
Continued table. one
I * one 3 3.87 ahh H 9 3.80 eight ’.Y 17 3.55 ahh H 24 3.40 ahhh H 26 3.10 aa | system H 15 2.9 aa avh H 15 2.75 eight “Z-SNGSVg 2.74 at I'm 4 2.60 9 -Ν- (CH ^ CHRd 2.15 and 1.85 a n 25, 29 1.70 '. eight . H 33 1.05 at 0.95 aa Th 30 + H 31
table 2
<See D.• one Waveformone Attribution3 - 8.40 but 6 ΝΗ 8.25 but 1 ΝΗ 7.55 aa ’H
33 1396968Etc 34a favor table 2 one I ⁷ ' 3 7.05 t 6y + 6 <^ + 6 £ 7 on 1'n ₄ 6.90 88 1'n ₅ 6.70 eight one 6.40 - eight ] 4sG + 4 £ 6.50 eight 2 ΝΗ 5.75 888 18 5.45 eight 6o < 5.25 88 4s / . five 8 (wide) 5o ( 4.75 88 S 4.60. tp 2οί 4.45 8 (wide) £ 5 4.40 88 3οί 3.4 88 (wide) 3 < 3.20 88 (wide) 3 <r ₂ 3 eight 4 CH ₃ 3 TP 5 | +4 / 3 1 еС ₂ 2.80 ^eight 4 Ν (ΟΗ ₃ ) ₂ 2.65 e - HSN ₂ ~ (chain) 2.35 sh 5 £ _r + 5/3 ' 2.25 WITH -CH ₂ - (chain) 2.20 five -M (CH ₅ ) _g (chain) 1.60 sh -С1Ь - (chain) 1.25 <1 0.90 ί² 0.50 8888 5 / 3ι Table 3
Referenceexample Ζ K ₁. Solubility m.p. one g 3 4 ~ 2 -Ν (ΟΗ ₃ —syn (sn _g ) _g AND (sn ₃ ) ₂Yellow powder m.p. approx. 180 ° C / - - "Ν Ν-0Η, aqueous solution 10 ^ in the form of hydrochloride 3 -s (n ₃ ) _g . White powder m.p. 195 ° C
35
1396968
four
36
Continuation of table 3
4-Ν (ΕΗ ₃ ), 'ΝΗ- ^ Ν- CH ₃
-Ν (0Η ₃ ), -ΝΗΟΗ
-Y (CH ₃ ) ₁ -Ν H (CH ₂ ) ₃ OH
10% aqueous solution in the form of hydrochloride
Beige powder, m.p. approx.
195 ° C
3.7% aqueous solution in the form of hydrochloride
White powder, m.p. approx.
170 ° C
10% aqueous solution in the form of hydrochloride
Cream powder, m.p. approx.
16 ° C
-ZH (CH ₂ ) ₃ Ν (ΟΗ ₃
2% aqueous solution in the form of hydrochloride
Beige powder, m.p. approx.140 s
10% aqueous solution in the form of hydrochloride
Table.4
^ ppm The form Attribution ---------------— ----------—- one one ·  3 11.65 8 (wide) he 8.70 but 6ΝΗ 8.40 but 1ΝΗ 7.80 aa 1'N, 7.45 t 1'n ₊ -1 7.27 t 6 y +6 "F +6 £ 7.17 sh 7.05 6.60 AV system 4 </ M · 4 £ 6.47 but 2ΝΗ 5.87 ahh GR 5.83 but 5.24 t • 5 ((+4 "
37 1396968. 38
__________. __ Continuation of table 4
.....! ^! ..................., ..... ί
5.03 88 £ 8 £ 5 4.85 88 and 4.80 ha 14 4.53 88 34 3.53 ha H 3.35 88] 3.15 88 AVH-CH ₂ -8-CH system - 3.25 eight 4MSN ₃ 3.25 t H 2.90 eight 4S (CH ₅ ) ₁ 2.90 t 4/1sn. 2.55 6 -0Η, Ν ^Χ mon. 2.50 88 5E, 2.40 WITH -sn ₂ ssn 2.40 a2.20 ta 58 ¹ + 50, '2.25 8 —CH _g L (CH3) ₄ • 2 t · thirty·, 1.75 ta -CSN _g CH _g CH _g “ 1.8 to 1.45 ta² / ". ^{+ 2} 0 _g ⁺ zu, 1,30,8 1st 1.25 k, 1.05 t³ P ^{+ 3} 0.9 1² y 0.60 88 five
Table 5
Referenceexample Have y _hM.p. Solubility one . one Have four 25 -ΝΗ-ίΟΗ-χ) _g ν (ο ₂ η ₅ Yellow powderM.p. approx. 150 ° C5% aqueous solution in the form of hydrochloride 26 - -ΝΗ (CH _g ) ₂ HH _; CH _}Yellow powderM.p. 174 ° C
³⁹ 1396968 40 ί ¹ .. ³Continuation of table.5four - -ΝΗ (ΟΗ,) Ν (0Η ₃ ) 2 1% aqueous solution in the form of 'hydrochlorideYellow powderM.p. approx. 155 ° C --ΝΗ- CH - CH ₂ H (CH ₃ ) 'CH ₃6.6% aqueous solution in the form of hydrochlorideYellow powderM.p. approx. 160 ° C - - ·: Η ₂ 0Η-Ν (αΗ ₃ ) ₂1% aqueous solution in the form of hydrochlorideOrange powder ch ₃M.p. approx. 175 ° Cί10% aqueous solution
in the form of hydrochloride
- -TSH-CH- (CH _z) n (C ₂ H _5, Y _to
I < 2 5/2 Beige powder,
ld So. approx.160 ° C
1% aqueous solution .. -m (si _g ) _g - £]. in the form of hydrochlorideYellow powderM.p. 183 ° C1% aqueous solution - -TO1 (CH ₂ ) -T0. in the form of hydrochlorideYellow powder mp. 170 ° 01% aqueous solution in the form of hydrochloride —That (sn ₂ ) _g - N ^ 2 Yellow powderM.p. Approx. 162 ° C1% water plant ~ - · (ΟΗ ₂ ) ₂ -1θ> thief in the form of hydrochloride Beige powder,M.p. approx. 172 C,1% aqueous solution ch _d ch ₃in the form of hydrochloride Beige powderM.p. about 160 ° C1% aqueous solution Chk| in the form of hydrochlorideBeige powderM.p. 177 ° C ch ₃1% aqueous solution n -zh- ^removed and in the form of hydrochlorideBeige powder. M.p. approx. 195 ° C
41
1396968
42
Continuation of table.5
38
/ -
-and (snA - · νη (οη ₂ ) ₂ - · ν_ ^
5% aqueous solution in the form of hydrochloride
SN _Oh „
⁰ Yellow powder, mp. 150 ^to C,
10% aqueous solution in the form of hydrochloride
39 -Msn ₃ ) ₂ "· --ΝΗ (ΟΗ ₂ ) ₂ - / ^Ν '-ΝΗ Yellow powderM.p. 138 ° С10% aqueous solution in the form of hydrochloride | Table b Referenceexample Have M.p. Solubility • V. one four 41 s- (ch ₃ ) _g-5- (CH _g ) _g Ν (Ο ₁ Η ₅ -) ₁Beige powder, m.p. approx. 192 ° C1% aqueous solution in the form of hydrochloride 42 Ν- (ΟΗ ₃ -5- (CH _l ) ₃ N (CH ^ Beige powder, T. pl. approx. 170 ° C1% aqueous solution in the form of hydrochloride 43 H - _{c (} dd _g ) ₃ TKSND Beige powder, m.p. approx. 140 ° C
44
N (CH D
10% hydrate
-3-CH2-CH-CH _g H (CH _e ) Beige powder, T CH ₃
45
46
47
48
H (SND - 8 - CH ₂ - C - K (CH ₃ ) ₂ CH ₃ CH ₅
• N (0113), -CsnD - / ^]
ch ₅
I
ν (οη ₃ “3 ( ^mn 2) g ~" (2_2)
"(CH,>, -δ-θΙ-CH3
aqueous solution in the form of chlor. pl. 234 ° C
1% aqueous solution in the form of hydrochloride
Beige powder, m.p. approx. 200 ° C
1% aqueous solution in the form of hydrochloride
Beige powder, mp, approx. 180 ° C
1% aqueous solution in the form of hydrochloride
Beige powder, m.p. approx.215 ° C
0.6% aqueous solution, in the form of hydrochloride.
X (yellow powder, mp. 170 ° C,
1% aqueous solution in the form of chlorine · rata
63
1396968
χτζ ...... □
49 -Ν (ΟΗ,) ₂
44
Continuation of table 6
ch _d ch ₃
Beige powder, m.p. approx. 175 ° C
1% aqueous solution in the form of hydrochloride
50
51
52
53
54
-Ν (ΟΗ ₃ ) ₇ -5-СН (СН _g ) ₂ М- (СН ₂ ) ₂ Ы (СНр _г Yellow powder, mp approx. 160 ° С;
SI 5 1% aqueous solution in the form of hydrochloride
-Ν (0Η ₃ ) | ~~ 8 - CH ^ CH ^ CH ^ ^ Beige Powder, m.p. approx. 190 ° C.
² 1% aqueous solution as hydrochloride
-M (CH ₃ ) ^ - 2) ^ - ^ Ν ~ CH ₃ Beige powder, m.p. approx. 170 ^e C,
1% aqueous solution in the form of hydrochloride
-H (CH,) ^ ~ 8 (CH ₂ ) - Χ ~ Ν — CH ₃ Beige powder, m.p. approx. 190 ° C
10% aqueous solution in the form of hydrochloride
-N (CH _{1) 1} -8-CH ₂ -CH-CH ₂ -N (CH,) _ ocher powder,
- I ©
CH ₃ 1% aqueous solution in the form of hydrochloride
55 -ΝίΟΗ ^ -B (CH ₂ ) ₅ 50, N
Yellow powder, m.p. 280 ° C 5% aqueous solution
T a b l and yes 7
The activity of the products of General formula (T ·) mixed with pristinamycin Ι _Λ
Example Activity in the laboratory 8 barUsossis aegeis BttSJ CM1, mg / cm ’ The activity on the body 8barblossaurus aegeis Cctc DS ₅₀₎ mg / kg one¹ 1 3 one four 20 2 B 20 3 eight 22 four eight 27 five eight 50 6 four 7 7 four 22 eight eight 70
45 1396968 46
Continuation of table 7
one 2 3 9 and 10 four 15 eleven eight 26 12 four 12 Product comparisons OK. 15* pristinamycinΙ, ΖΙΙ, 0.12
F
Given the insolubility of the natural mixture, the appointment of this product requires application techniques that cause changes in the results.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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FR2549063B1|1983-07-13|1985-10-25|Rhone Poulenc Sante|NOVEL SYNERGISTIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|FR2576022B1|1985-01-11|1987-09-11|Rhone Poulenc Sante|NOVEL DERIVATIVES OF PRISTINAMYCIN II B, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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FR2599036B1|1986-05-22|1988-09-09|Rhone Poulenc Sante|NOVEL SYNERGISTIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|

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DE3778359D1|1987-07-07|1992-05-21|Rhone Poulenc Sante|METHOD FOR PRODUCING DERIVATIVES OF PRISTINAMYCIN IIB.|

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FR2655343B1|1989-12-05|1992-05-07|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF SYNERGISTINE.|

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FR2664599B1|1990-07-16|1993-06-18|Rhone Poulenc Sante|VINYLSULFONYL PRISTINAMYCIN AND ITS PREPARATION.|

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US5242938A|1992-08-27|1993-09-07|Merck & Co., Inc.|Derivatives of virginiamycin M1|

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FR2701709B1|1993-02-17|1995-04-07|Rhone Poulenc Rorer Sa|Purified form of streptogramins, its preparation and the pharmaceutical compositions containing it.|

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FR2755857B1|1996-11-19|1998-12-24|Rhone Poulenc Rorer Sa|STABILIZED PHARMACEUTICAL COMPOSITIONS BASED ON QUINUPRISTINE AND DALFOPRISTINE AND THEIR PREPARATION|

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FR2766489B1|1997-07-28|1999-08-27|Rhone Poulenc Rorer Sa|STREPTOGRAMIN DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM|

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FR2795733B1|1999-06-30|2001-09-07|Aventis Pharma Sa|STREPTOGRAMIN DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM|

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FR2818644B1|2000-12-21|2004-10-22|Aventis Pharma Sa|STREPTOGRAMIN DERIVATIVES, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM|

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CN103360463B|2012-04-08|2016-06-08|浙江海正药业股份有限公司|A kind of isolation and purification method of dalfopristin and intermediate thereof|

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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FR8311707A|FR2549065B1|1983-07-13|1983-07-13|NOVEL SYNERGISTIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME|

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