Method of obtaining analogues of lincomycine and clindamycine

专利摘要:
Novel useful analogs of the well known antibiotics lincomycin and clindamycin. These analogs are prepared by condensing a cyclic acid with a sugar amine.
公开号:SU1169543A3
申请号:SU813444858
申请日:1981-08-19
公开日:1985-07-23
发明作者:Дейвид Биркенмайер Роберт
申请人:Дзе Апджон Компани (Фирма)；
IPC主号:

专利说明:

11169 The invention of otHocHTCH to a method for producing new compounds of lincomycin and clindamycin analogues of the structural formula K 6 HC-C1 nI C-fH-CH where R Et, Bu. 5 10 3 The purpose of the invention is to obtain, based on the well-known method, new antibiotics, possessing stronger bacteriostatic properties as compared with the widespread analogues lincomycin and clindamycin. Example 1. Amide-4-cis-ethyl-1-pipecolinic acid 7-SvMTL NS (compound V), where MTL is methyl-1-thio-about-lincosaminadeh. Part 1 .
,
ftl xO -NSI-T-SG-MTYA
 he
CH: i

H-C-C1 ItH-CH
to a saturated ly to a solution of 67 g (0.357 mol) of the amino acid HC (C.A. 51.1643a, 1957) and 71.5 g (0.714 mol) of triethylamine in 2.5 l of adetonitrile, 47.6 g (0.354 mol) isobutyl chlorine; formate. This mixture (solution) is stirred for 1 hour. Solution B is prepared by dissolving 97.7 g (0.357 mol) of 7 Cg-MTL in a warm mixture of 1500 ml of acetone and 1500 ml of water, cooled to one solution and added to solution A. The reaction mixture was stirred at 25 ° C for 18 h, acetone and
2H5
HCl
C-bT-Cl-MTA
A mixture of 4.05 g (0.01 mol) of starting material, 40 ml of water, 60 MP of methanol, 1.0 ml of 37% hydrogen chloride and 8.0 g of a catalyst based on platinum dioxide is reduced in a Parr hydrogenator under pressure 3 , 4 kg / cm for 3h. The TLC data of the reaction mixture on a snake gel plate was removed by acetonitrile in vacuo. The soft residue is filtered off and the crystal is collected and dried to obtain 95 g of pure product. By processing the filtrate by chromatography, another 10 g of product is obtained. The overall yield is 73%.
Calculated: C 50.42; H 6.22; N 6.92, S 7.92, CI 8.76.
C.HjjCINjOfS.
Found: C 50.67-, H 6.40-, N 6.64; S 7.90 i CI 8.70.
otJ CHCci: (С-1,0) + 293С
Part II ..
CjHsCHj
,
HE
In the system, the SNCES methanol (6: 1) shows that all the starting material is converted into two more polar substances in a ratio of 1: 1. In order to separate the catalyst, the reaction mixture is filtered and the filtrate is concentrated in vacuo to give a white, soft crystalline substance, which is filtered off while preserving the resulting filtrate.
The white solid, which turned out to be the more polar of the two obtained products according to TLC of the reduced mixture, is recrystallized from water. To obtain the desired product V 57.930 from 222-224 0 and in a yield of 25-35%.
Calculated: C A5.63, H 7.21; N 6.26; S 7.17; From 15.85.
Found: C 45.77; H 7.44;
N 6.39; S 7.21; CI 16.17.
(o) p HjjO: (C-1.0), +176.
The absolute configuration and stereo chemistry of the target product was determined by X-ray structural analysis. According to Example 1, compound VA is prepared. The preserved according to part II of example 1, the filtrate is concentrated to dryness in a vacuum and the residue
V Epimeriza, and
UA Epimerization of Compound U and UA can also be hydro-. to obtain amino acids. У and УЕ, respectively, which can then be epimerized by known
.2 “5
SHH hydrolysis
N N VD
1695434,
converted to the free base, chromatographed on silica gel using CHCf: methanol (6: 1) as a solvent. 5 A less polar of the two products mentioned in Part II is obtained.
It is converted to the hydrochloride salt and recrystallized from acetone and water. This isome10, ru can be attributed to the structure of VA
CH:
| 2H5
H-CC1 P
k-wxHtiCin-s
-HoJ o
H
0fi
VA
--r $ -CH:
he
Obtained by epimerization, m (v1 / isomers, HC and CM are enriched by the usual methods of crystallization or chromatography
65
..ABOUT
 , /
H
V S-7-C1-MTL
VC
gaHs
Epinerizacil J
r (f
N N
vF
H techniques in the compounds of VF and VG, respectively. The latter can be associated with any linkosaminidine described.
2H5
Hydrolysis
W
VE H
SzNd

, 0 Zimerazats, al OHV G Example 2. Amide A-tsm-p-buS4N9 o - C-7-C1-MTL (Ci7H
A mixture of 4.0 g (0.0093 mol) of starting material, 40 ml of water, 40 ml of methanol, 2 ml of 37% hydrogen chloride and 8.0 g of a catalyst based on platinum dioxide is reduced using Parr hydrogenator at a pressure of 3.4 kg / cm for 18 hours. In order to remove the catalyst, the reaction mixture is filtered and the filtrate is concentrated in vacuo to give an amber oil. The latter is dissolved in 20 ml of a solution of CHCl j and methanol (2: f) and a sufficient amount of triethylamine is added to neutralize the hydrogen chloride present. This solution is chromatographed on silica gel using a solvent system: methanol (2: 1). A fraction of the two main products is obtained. Fractions containing faster advancements. the material is collected and evaporated in vacuo to give a white solid fraction A.
4H9
C4H
6 T | C-7-C1-MTL
(С17Н32С1 1Г205 $ -ХН2о)
Fraction A from the previous experiment is converted into its hydrochloric acid salt in the same way as fraction B. A product is obtained with a yield of 25-35%, which is based on NMR spectrum data,
 Fractions containing slower moving material are collected and evaporated in vacuo to give white solid fraction B, which dissolve in a small amount of water and add a sufficient amount of 37% hydrogen chloride to bring the pH to 2. Then crystallization is carried out. The solid material is collected and recrystallized from water to obtain white crystals of the desired product Art. square 224-22 S and a yield of 25-35%.
It is calculated: C 47.99 N 7.63-, N 5.89 S 6.75 C t 4.92.
.
Found: C, 47.97) H, 7.42; N 6.23i S 6.90, C 14.87.
oijjMeOH: + 178 (C-1.0). 5- The structure is confirmed by NMR spectrum analysis data.
EXAMPLE 3. Am1ad-4-cis-p-bu. thyl-C-pipecolinic acid - Sv-MTL.
SNS
VIA C-Cl
I
-sn,
It is identical with the product from fraction B.
The minimum bacteriostatic concentration (MBC) of compound V and clindamycin relative to aerobic bacteria is shown in Table 1, thil-b-pipecolic acid / -SGMTL; --3 (0 Н-С-С1 -НС Tjf (-КН-С-Н (Х) Н20 n нЛЛ-0 | фи Ч - Г5-СНз 32CJl2K205 WH20)
Staphyjococcus aureus
Staphytococcus epidermidis
Streptococcus faecatis Streptococcus pyogenes Streptococcus viridans Diplococcus pneumoniae I Diplococcus jpneumoniae II Escherichia coli
25
25
20
. 0.5 0.25
20
25 0.5
25
78
0.25
20 -10
20 25 25
05
78 25 25 -10 -39
10 0.5
39
39 0.5
10 0.5
0.5
20
78
20
39
ten
20
ten
20
25
6.25
0.12 0.12 rO, 12 0.5 rO, 12 0.12 -: 0.12: 0.12 50
50
Continuation of table
11 These tests are carried out as follows. A dilution series of the corresponding antibiotic is prepared in a ratio of 1: 2 in Shedper broth (1.0 ml each), and then 9.0 ml is added.
11695AZ
.12 . Continued table. 2 r. Molten under the agar medium Vuilkensa Chalgrena. After mixing with the antibiotic, the agar medium is poured onto the chaopsi petri (100 ml 0 mm) and before sowing, the latter are boiled overnight. Cultures are seeded with Vuilkens-Chalgren and agar plates. grow them for 48 hours at. Collect the lawn of microbes and prepare the cell suspension in Schedler broth to a turbidity of 0.5 Mafarland Standard (10 cells / ml). The resulting suspension is pipetted into the reservoirs of the Steers replicator and from there about 1-2 µl is applied to the surface of the agar plates. After the seeded suspension has dried for several minutes, the plates are placed in a vessel (85% N, 10% H, 5% CO) and incubated at 37 s for 72 hours. MBC means the minimum concentration of active principle that inhibits the growth of bacteria, and very thin bacteria film, i.e. less than 3 colonies are considered negative.
Vuilkens-Chalgren agar medium.
The solvent is the following components, g, in 1000 ml of distilled water (pH 7.0, 7.2):
Trypticase 10
Gelisat10
Yeast Extract 5
glucose1
NaCI5 12.3 (8.8 + 17.3) The above tests were carried out in a melting manner. Groups of 10 conventional laboratory labyrms of strain CF-1 weighing 18-20 g are injected intraperitoneally by free from arginine
Sodium salt of pyruvic acid Agar
Heme and vitamin K solutions are added to obtain a final concentration of 5 µg / ml of hemin and vitamin K. Hold the autoclave at 121c for 15 min in aerobic
conditions The main solution of heme: 0.5 g hemin + 10 ml 1 n. NaOH + 990 ml Hj. Hold the autoclave for 12 minutes. Add 10 ml of the basic solution per liter of medium. The main solution of vitamin 0.05 ml of solution of vitamin K + .20 ml of 95% ethanol. Sterilized filters. Add 0.2 ml of the stock solution per liter of medium. The mean LD value (intraperitoneal in a smaller) compound. Of the two identical determinations, it is 592 mg / kg, which is approximately twice as large as LD clindamycin, i.e. os1: Pa the intraperitoneal toxicity of compound V is approximately two times less than that of clindamycin, HCP.
Tests for the protection of us. The technique is given in table. 3..
Table 3
5.7 (4.2 + 7.8)
L / S 2,3 (1,6 + 3,3)
3.3 (2.6 + 4.2) 12.3 (10.2 + 14.8)
4.2
320 55 approximately 100 doses of LD normalized suspensions of bacteria cells, which were preliminarily frozen at, and then quickly thawed and properly diluted. Immediately, treatment is started and continued for 4 days (the preparation is administered once a day, the first daily period is equal to 1. The groups of untreated infected mice serve as a virulent control culture.
After 7 days after the start of treatment, the surviving animals are killed and the average ED of the antibiotic and its 95% confidence interval are calculated in terms of the mortality of the environment of the treated animals according to Sparman and Carber using CVM 360. from tab. 1 brain and heart broth. It has an antibacterial effect. The test results are presented in Table. four.
Table 4
The values of MBC, µg / ml, VI in various bacteria are presented in Table. five.
Table

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING ANALOGUES 'LINCOMYCIN AND CLINDAMYCIN of the general formula
Λθ
Ί
Η
—CH ₃ where R ₁ is ethyl or butyl, characterized in that in the presence of a catalyst a compound of the general formula is hydrogenated, wherein R ₁ has the indicated meanings;
X - 7 (S | - chloromethyl-1-thio-d-linkosaminide.
Priority: n about signs:
11/23/79 at R _z - ethyl. 05/19/80 at R., - butyl.
SLL 1169543>

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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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US9665279A| true| 1979-11-23|1979-11-23|

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US06/148,056|US4278789A|1979-11-23|1980-05-19|Lincomycin compounds|

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