Process for producing thylosine derivatives

专利摘要:
Derivatives of tylosin and 10,11,12,13-tetrahydro tylosin of the general formula whereinR stands for CHO, CH₂OH CH=NOH or CH(OCH₃)₂,R¹ stands for H,R² stands for OH orR¹ + R² stand for =O or =NOH,R³ stands for a mycarosyl group or a hydrogen atom, and stands for a single or a double bond;methods for the manufacture thereof; their use as anti­microbial agents and processes for the preparation of the latter.
公开号:SU1731063A3
申请号:SU894613684
申请日:1989-03-27
公开日:1992-04-30
发明作者:Нарандя Амалия；Шушкович Божидар；Дьекич Слободан；Лопотар Новенка
申请人:Соур Плива Фармацойтска, Кемийска, Прерамбена И Козметична Индустрия, Н.Сол.О.(Инопредприятие)；
IPC主号:

专利说明:

The invention relates to the preparation of new biologically active compounds of the tylosin series used in pharmaceutical preparations, in particular in microbicides.
Tylosin is a 1b-membered macrolide antibiotic used in veterinary practice. However this
The compound does not have high antibacterial activity.
The purpose of the invention is to obtain new tylosin derivatives with higher antimicrobial activity.
This objective is achieved by a process for the preparation of tylosin derivatives of the formula I
s
4) l
nssooosn, vdu vp-4 HLF
Ho- Vo - H, r, y о rVHDr0111
Vo n R0LL7 MCHj
where R1 is mycarosyl or a hydrogen atom; R2 is CHO group.
R - CHO group, according to which the compound of formula II
P
I 9CH3 Hs (J o- (r7-o-HjC-rh
 NES-CHS-b
R
i but
o- (Gl-ok1 och
CE}
| de R has the indicated meanings;
The Ri2 – CH (OCH3) 2 group is subjected to oxidation by the action of a 1–10 molar excess of hydroxylamine hydrochloride in the presence of an excess of pyridine, or No. 2 (CO 2), if necessary, in an environment of a solvent such as alcohol, in a stream of nitrogen temperature between ambient temperature and the boiling point of the reaction medium over a period of 15 minutes to 10 hours, and the resulting compound, form I, where RI is CH (OCH3) is a group, is hydrolyzed in an aqueous solution of acetonigril in the presence of a catalytic amount of trifluoroacetic acid or hydrochloric acid with room temperature.
Isolation of the product is carried out, for example, by precipitation or extraction of halogenated solvents from aqueous solutions of alkalis and evaporation to dryness.
Before spectral analysis, the products were purified on a column of silica gel.
In the 13C-NMR spectrum of tylosin-oximes, the characteristic signal of the carbonyl group in the region of 200 ppm disappears, and a new chemical shift in the region of 150-165 h / mpn characteristic for the group appears.
In the H-NMR spectrum of the aldoximes obtained, the characteristic shift of aldehydes in the region of 9.6 ppm disappears, and new shifts in the region of 10.0-10.7 hOmyl appear, corresponding to the -NOH group, which disappear after mixing with D20.
The invention provides tylosin oximes, some of which exhibit significant biological activity.
The antimicrobial activity of some compounds of formula I was tested on a laboratory strain of Sarclna lutia and on 50 different strains isolated from fresh patient samples. The minimum inhibitory concentration (MIC) was determined by the dilution method on agar.
The test results presented in table 1 and 2.
The compounds of formula I have low toxicity. PRI me R 1. Tylosin aldoxime (la).
Tylosin (Na) A, 58 g (5.0 mmol) was dissolved in ethanol (100 ml) and after stirring pyridine (2.5 ml) and hydroxylamine hydrochloride (0.348 g, 5 mmol) were added, the mixture was heated with reflux for 15 minutes under a nitrogen atmosphere. After cooling, 50 ml of water was added and the pH of the system was adjusted to 7.0 with 1N NaOH solution. The mixture was then concentrated under reduced pressure to 1/3 of the original volume and extracted with chloroform.
(2 x 150 ml). The chloroform extracts were combined and dried over K2CO3. Filtered and evaporated to dryness to obtain 3.95 g (84.9%) of the product as an isomer mixture, which can be separated on a column of silica gel (System A:
methylene chloride: methanol: ammonium hydroxide ammonium 90-9: 1.5). PC () 1585, 1670, 1705, disappearance of the band at 2720 cm 1. UV (Et OH) Dmax 283 nm, loge 4.3.
H-NMR (DMSO-de / b ppm: 10.07)
N OH, C-20, disappears after mixing with DaO, 7.19 (H, doublet, H-11), 6.47 (H, doublet, H 10). 5.87 (H, doublet, H-13).
GZS-NMR (DMSO-de / ppm: 202.72 (C9), 172.46 (C-1), 149.83 (C-20), 147.12 (C-11), 142.14 ( C-13), 134.86 (C-12), 118.90 (C-10), 103.89 (C-11), 100.73 (Cf), 96.05 (Cf). M + 930.
PRI mme R 2. Dimethyl acetal tylosin oxime (IG).
Dimethyl acetal thylosin (Hc) 4.40 g (4.6 mmol) was dissolved in 20 ml of pyridine, hydroxylamine hydrochloride (2.76 was added).
g, 39.7 mmol) and the mixture was stirred under nitrogen at room temperature for 9 hours. 200 ml of water was added to the reaction mixture and 1 l of it was made alkaline with 1N NaOH solution until pH 9,
after which the mixture was concentrated under reduced pressure and extracted with chloroform (1 x 200 ml), the chloroform layer was dried over K2CO3 and filtered, the filtrate was evaporated to dryness to form 3.9 g
(86.9%) raw product. 2.0 g of this product was purified by chromatography on 200 g of silica gel (system A).
The result was 1.50 g of pure desired product having the following physic: chemical constants:
Rf (A) 0.443: Rf (B - chloroform-methanol-ammonium hydroxide 6: 1: 0.1) 0.786;
IR (UHF) 1710. 1610 cm 1;
UV / E10H / A "max; 272 pm, log e 4.18;
1 H-NMR (DMSO-s1b), 5 ppm, 10.51 (-N-OH), disappears after mixing with D20. 7.07 (1H, doublet, H-11); 6.17 (1H, doublet, H - 10), 5.56 (1H, doublet, H-13), 3.46 (ZN, singlet, 3 OCHs): 3.37 (ZN, singlet, 2 OCHs): 3.20 (6H. Singlet, 2 x 20) OCHNs, 2.41 (6H, singlet, NfCHsfc).
M 976.
Example Tylosin-oxime (1C).
Tylosin-oxime (Ib) dimethyl acetal (Ib), 1.91 g (1.95 mmol), was dissolved in 50 ml of acetonitrile, after which 50 ml of water and 0.2 ml of trifluoroacetic acid were added. After stirring for 3 hours at room temperature, the reaction solution was basified to a pH of 8-8.5 by the addition of a saturated solution of sodium bicarbonate and the mixture was extracted with chloroform. The combined extracts were washed with a saturated solution of sodium chloride and dried over " 2Coz, 1.15 g of crude product was isolated, which was subjected to chromatographic purification on a column of silica gel.
Output: 0.65 (35.8%) of the product with the following characteristics;
Rf (A) 0.314;
H-NMR (DMSO-de) b ppm 10.65 (HM-OH), disappears after mixing with DaO, 9.65 (1H. Singlet, -CHO).
EXAMPLE 4 4-Demicarosyl-tylosinoxime dimethyl acetal (Id) 2.0 g (2.45 mmol) dimethyl acetal 4-demicrosyltylosin (lid) 20 ml pyridine and 1.38 g (19.86 mmol) hydroxylamine hydrochloride was stirred in a stream of nitrogen at room temperature for 4 hours, after which the product was isolated according to the procedure of Example 2,
Output: 1.7 g (83.4%) of the product with the following characteristics:
Rf (A) 0.253; Rf (D) 0.599.
YO (Et OH) Dmax. 272 nm, log E 4.26.
IR (KBV) 1705, 1615 cm 1.
1 H-NMR (AMCO-de) ppm: 10.65 (N-CH), disappears after stirring with LaO, 3.20 (6H, singlet, 20-) OCH3 (2).
PRI me R 5. 4 -Demicosyl-tylosin-oxime (e).
The target product (Id) of Example 4 1.34 g (1.72 mmol) was dissolved in 40 ml of a mixture of 0.1 NHCI and CHs CN (2.5: 1) and stirred in
for 2 hours at room temperature, after which the product was isolated according to the method of example 3.
The crude product (1.25 g) was purified on a silica gel column.
Output: 0.95 g (70.3%) of the product with the following characteristics:
Rf (A) 0.146; Rf (B) 0.468.
UV (E1 OH) Yamax. 272 nm, log e 4.26.
1 H-NMR (DMSO-yb) (5 ppm: 10.65 (N-OH), disappears after mixing with D20, 9.65 (H, singlet-CHO).
Example Tylosin dioxime (If).
The crude target product (la) of Example 1 2.93 g (3.15 mmol) was dissolved in 20 ml of methanol, after which 1.6 ml of pyridine and 0.22 g (3.16 mmol) of hydroxylamine hydrochloride were added and the resulting mixture heated under reflux in a stream of nitrogen for 10 hours. After cooling, 40 ml of water was added to the reaction mixture and the mixture was basified with 1N NaOH solution to a pH of 9.0 and then concentrated to 1/3 of the original volume. The suspension was stirred for 1 h and filtered. The precipitate was resuspended in 10 ml of water, stirred for 10 minutes, filtered and washed with water to obtain 1.4 g of product.
The original filtrate and the filtered washings were combined and extracted with chloroform. The combined extracts were washed with water and dried over K.2CO3 to form 0.7 g of product.
Total yield: 2.1 g (70.6%) of the product with the following characteristics:
And K (KB g) 1705, 1630 cm 1.
UV (Et OH) .. 272 nm. log Ј 4.2.
1 H-NMR SDMSO-de) ppm, 10.66 and 10.11 (2x N-OH) disappears after mixing with D20.
Example. Relomycin oxime (Ig).
Relomycin (He) 15 g, (16.6 mmol) was dissolved in 75 ml of pyridine, after which hydroxylamine hydrochloride 5.64 g (81.2 mmol) was added, and the mixture was stirred under nitrogen for 7 hours at room temperature. temperature The crude product (13.8 g) was isolated according to the procedure described in Example 6.
The crude product (2.9 g) was purified on a silica gel column. 1.2 g of pure product was obtained with the following characteristics;
Rf (A) 0.302, Rf (C) (CH2Cl2: CH3OH -85: 15) 0.462,
UV (Et OH) Jamss. 272 nm, log Ј 4.21.
And K (KB r) 1700, 1630cm.
1 H-NMR (flMCO-de) 5 ppm; 10.66 (-N-OH), disappears after mixing with DaO.
13C-NMR () dppm: 173.99 (C-1). 160.45 (C-9.), 137.03 (0-11), 135.58 (0-13), 134.78 (C-12), 117.07 (C-10), 105.21 (C- 1), 100.83 (0-1), 95.99 (CT).
788 (M-mycrosis).
Example 10,11,12,13-Tetrahydro-thilosin-aldoxime (Ih) and 10,11,12,13-tetrahydro-tylosin-dioxime (I),
10,11,12,13-Tetrahydrotylosin (llf) 3.68 g (4.0 mmol) was dissolved in 20 ml of methanol, after which hydroxylamine hydrochloride 1.39 g, (20.0 mmol) and Na2COa were added 1.06 g (10.0 mmol) and the resulting mixture was heated under reflux for 3 hours. 40 ml of water was added to the cooled reaction mixture, the pH was set to 7.0 with 1N NaOH and the mixture was extracted with chloroform. The crude product (3.2 g) was a mixture of two compounds that can be separated on a column of silica gel (system A).
Yield: 0.95 g (25.4%) of a more polar product (Ih) with the following characteristics:
KG (B) 0.429.
1 H-NMR (DMSO-C b) (5 ppm: 10.17 (1 M-OH, C-20), disappears after mixing with DaO.
13C-NMR (DMSO-C b) (5 ppm, 223.40 (C-9), 171.22 (C-1) 150.9 (0-20), 104.91 (C-1). 100.57 (C- f), 96.17 (C-U
M + 934.
Output. 0.90 g (23–7%) less polar product with the following characteristics:
Rf (B) 0.366.
1 H-NMR (DMSO-de) 5 ppm: 10.62 and 10.17 (2x N-OH), disappears after mixing with DaO.
13C-NMR (DMSO-de) 5 ppm: 171.17 (C- 1), 150.79 (C-20), 150.18 (C-9), 104.74 (C-1), 100 51 (C-1), 96.11 (C-1).
Mf949.
PRI me R 9. Dimethyl acetal 10,11,12,13-tetrahydro-tylosin oxime (I J).
From 4.25 g (4.4 mmol), 10,11,12,13-tetrahydrotylosin dimethyl acetal (llg) dissolved in 20 ml of pyridine and 2.76 g (39.7 mmol) of hydroxylamine hydrochloride were obtained 3.5 g of crude product in accordance with the method described in example 2.
1.5 g of the crude product was purified on a column of p silica gel (system A) to obtain 1.0 g of pure product with the following characteristics:
IR (KBg) 1700, 1620.
1 H-NMR (DMSO-de) b ppm: 10.65 (M-OH, C-9), disappears after mixing with DaO. 3.23 (6H, singlet, 20-) OCHZ (2).
13C-NMR (DMSO-s1b) dh / ppm: 171.17 (C-1), 150.23 (0-9).
GGy and mep 10. 10,11,12,13-Tetrahydrotylosin-oxime (Ik).
From the crude product (Ij) of example 9 (2.0 g, 2.1 mmol) of 50 ml of acetonitrile, 50 ml of water and 0.2 ml of trifluoroacetic acid, according to the procedure described in Example 3, 1.6 g of the crude desired product were isolated. After purification on a column of silica gel, 1.2 g (61.2%) of the product were obtained with the following characteristics:
1 H-NMR (DMSO-de) b ppm: 10.65 (M-OH, C-9), disappears after movement with DaO. 9.65 (H, singlet, -CHO).
13C-NMR (DMSO-de) b ppm: 202.72 (C-20). 171.17 (C-1), 150.18 (C-9).
PRI me R 11. 10,11.12,13-Tetrahydrorreomycin-oxime (II).
From 3.68 g (4 mol) of 10.11.12.13-tetrahydro-relomycin (llh), 20 ml of pyridine and 1.38 g (19.86 mmol) of hydroxylamine hydrochloride according to the procedure of example 2, received 2.86 g (76.4%) of the crude product.
The crude product (1.5 g) was purified on a silica gel column (CHCl3: C2HbON: LH4 OAO, 15%, 85: 15: 1) (system D), to give 1.06 g of pure product with the following characteristics:
IR (KBV) 1700, 1640cm.
1 H-NMR (DMSO-de) ppm; 9.95 (M-OH), disappears after mixing with DaO.
13C-NMR (CDCI3) b ppm: 172.30 (C-1), 165.06 (C-9. C-N).
M + 936.

权利要求:
Claims (1)
[1]
The invention of the method for the preparation of tylosin derivatives of the general formula I
NZSO OCH3 Ґ
(S3
about n3s-n2s
Of f
4 np "
: sns- ° -Chg
CHj
"Ft gi
J 0 where R1 is a group (mikarozil) or
Sis hydrogen,
R2 is a CHO group, characterized in that the compound of formula II
NON YvPg-SNZ
ihco OSN V Wi H5J№i --ffi
G0 NzS-H1S-vpLg -ON U GHj CHju
where R1 has the indicated meaning;
Ri2 - CH (OCH3) 2-group is subjected to the reaction of oxidation with the action of 1-10 M hydroxylamine hydrochloride in the presence of an excess of pyridine or sodium carbonate and, if necessary, in an environment of a solvent, such as alcohol, in a stream of nitrogen for 15 minutes to 10 hours at room temperatureAntibacterial activity in vitro and compounds of formula I
to the boiling point of the reaction mixture, and the resulting compound of the general formula I, where R2 is CHfOCHafe-rpynna. deacetalized in an aqueous solution of acetonitrile in the presence of a catalytic amount of trifluoroacetic acid or hydrochloric acid at room temperature.
Table 1 Tylosin (On)
Strain
IIIC
On la Jlc Jle If jjt
, $ b 6.25 0.78 3.125 6.25 50 0.4 6.25 0.4 0.4 0.78 50
100 100
-315 1.560, 0.786.25 12.5
0.78 3.1251.56 1.56 3.125
1.56 SO 1.56 1.56 50 6.25 50 1.56

0.70 1.56 3.125 3.125 50 0.78 0.7D 0.4 0.78 3.125 6.25 0.4 0.73 0.4 3.125 6.25 25
50
50
П p and м с ч and н and e. lla - tylosin; lie - relomycin; la - aldoxime-ty / yuzina} 1C - ° «™
Tylosin: If - Tylosin dioxime; le - oxime 4 -demikroei -thyloein; Ig - oxime relomycin; IL - aldoxime 10,11,12, P-tetraggi-Drotylosin I - „ioxime 10,11,12,13-tetragyl-tylozine; lЈ - oxime "..
II - LI ° KSIM IU, I I, It, 1Л-ГС1М01 «Н - g. ,
tetrahydro-tylosin; R is stable and the MIC values obtained refer to 90% of the tested strains.
100 100

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3910892A|1971-03-23|1975-10-07|Hoffmann La Roche|Benzodioxane derivatives|

---

CH630391A5|1975-02-28|1982-06-15|Scherico Ltd|Process for preparing derivatives of rosaramicin|

---

US4205163A|1977-11-08|1980-05-27|Sanraku-Ocean Co., Ltd.|Tylosin derivatives|

---

DE2826760A1|1978-06-19|1980-01-03|Hoechst Ag|DERIVATIVES OF 1,2,4-TRIAZOLE|

---

NL8004922A|1979-09-19|1981-03-23|Toyo Jozo Kk|DEFORMYLTYLOSINE DERIVATIVES.|

---

US4357325A|1981-04-20|1982-11-02|Eli Lilly And Company|Methods of controlling Pasteurella infections|

---

AU551142B2|1981-07-09|1986-04-17|Zaidan Hojin Biseibutsu Kagaku Kenkyukai|Tylosin derivatives|

---

AU555304B2|1982-04-05|1986-09-18|Merck Sharp & Dohme Limited|Stabilization of drugs in alginic acid and magnesium hydroxide granules|

---

US4443436A|1982-09-13|1984-04-17|Eli Lilly And Company|C-20-Modified macrolide derivatives of the macrolide antibiotics tylosin, desmycosin, macrocin, and lactenocin|

---

GB8405087D0|1984-02-27|1984-04-04|Omura S|Antibiotic|

---

JPH053476B2|1984-10-26|1993-01-14|Taisho Pharma Co Ltd|

---

JPH0568478B2|1985-02-20|1993-09-29|Asahi Chemical Ind|

---

JPS62221695A|1986-03-24|1987-09-29|Microbial Chem Res Found|Tylosin oxide derivative and production thereof|

---

OA08732A|1987-05-06|1989-03-31|Adir|New macrolide derivatives, their preparation process and pharmaceutical compositions containing them.|

---

JPH02221695A|1989-02-22|1990-09-04|Hitachi Ltd|Rotary compressor|

---

JP3141148B2|1995-08-08|2001-03-05|大鵬薬品工業株式会社|Condensed indane derivatives and salts thereof|FR2638458A1|1988-10-27|1990-05-04|Adir|NOVEL TYLOSIN DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|

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SI8911498B|1989-07-26|1998-10-31|Pliva|Process for the preparation of tylosin derivatives|

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US5140014A|1989-11-13|1992-08-18|Abbott Laboratories|Rosaramicin derivatives and method of treating bacterial infections|

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---

US7247617B2|2004-07-13|2007-07-24|Kosan Biosciences Incorporated|Sixteen-member macrolide antiinfective agents|

---

KR101538599B1|2006-07-28|2015-07-21|인터벳 인터내셔널 비.브이.|Macrolide synthesis process|

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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YU674/87A|YU45033B|1987-04-14|1987-04-14|Process for preparing 10,11,12,13-tetrahydro derivative|

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