JPS58188897A - 23-o-acyl-23-demycinosyldesmycosin and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula [R is formula II (R1, R2 are lower alkyl; R3 is halogen; n is 1,2), formula III (R4, R5 are phenyl which may have substituents; X is single bond, S, SO2)] or its salt. EXAMPLE:23-O-[alpha-(4-chlorophenoxy)isobutyril]-23-demycinosyldesmyco sin. USE:Antibacterial effective against gram-positive and -negative bacteria: an additive for feed. PREPARATION:For example, a compound of formula IV (R6, R7 are hydroxy- protecting groups) such as 2',4'-di-O-acetyl-23-demycinosyldesmycosin is acylated on the hydroxyl in the 23-position with a carboxylic acid of the formula: RCOOH or its reactive derivative, then deprotected on the hydroxyls in the 2' and 4'-positions to give the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel 23-〇-acyl, 23-demainononrudenumaicocune derivative and its preparation different, represents a lower alkyl group, R3 is a halogen atom f5n is/or 2 yJ<L, R4 and R5 are the same or different and represent a phenyl group which may have a substituent, X is a single bond, -8- or -802-) or a salt thereof. The present invention also includes:
A compound represented by the formula (wherein R and R2 represent a hydroxyl protecting group) is reacted with a carboxylic acid or -fry represented by the formula (wherein R has the same meaning as in niJ) Also included is a process for producing the compound of formula [1] or a salt thereof, which is characterized by acylating the 23rd position with a chemical derivative and then removing the protecting groups of the 2' and 77th positions.

The salt mentioned in item 1 above is a pharmaceutically acceptable salt.

Such suitable salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and vinegar, +'n acid, propionic acid, alcoholic acid, citric acid, succinic acid, malic acid, aspartic acid, and glutamic acid. Includes salts with organic acids such as. Other non-toxic salts are also included.

The above-mentioned new compound [1] exhibits a much stronger antibacterial activity against Durham-positive bacteria than the known erythromycin and tylosin, and has the same antibacterial activity as erythromycin against Durham-negative bacteria. "Clinical" - An antibacterial agent that is expected to have excellent infection treatment effects. It is also useful as an animal infection treatment agent, infection prevention, or feed additive for promoting bioIT.

The starting material [2] used in the present invention is 23-demainosyldenumycosin ('p6jrabc(+nL
e-Lter8. 'l 737 (/ri70)] no 2
The hydroxyl groups at the ' and 77th positions are protected with appropriate protecting groups. Such protecting groups include lower alkanoyl groups such as acetyl, propionyl, butyryl, chloroacetyl, dichloroacetyl, trichloroacetyl/L/
, ) halogenated acetyl groups such as trifluoroacetyl are preferred, but especially the acetyl group is advantageous.

The introduction of the acetyl group is carried out by reacting 23-demycinone with acetic anhydride in an inert organic solvent. Preferred inert organic solvents include dichloromethane, chloroform, dichloroethane, acetone, and the like. The reaction proceeds satisfactorily at room temperature. Since the progress of the reaction can be monitored by thin layer chromatography (TLC) such as silica gel, high performance liquid chromatography (HPLC), etc., the reaction can be appropriately terminated after waiting for the disappearance of 23-temainnondesmycocin. Other protecting groups can also be introduced in the same manner as described above.

Collect the reaction product [2] from the reaction solution. Add water to the reaction solution, add water to the reaction solution, and add a non-hydrophilic organic solvent such as chloroform, dichloroethane, methyl isobutyl ketone, ethyl acetate under alkaline pH of ~5. , butyl acetate, etc. If further IM is required, use an adsorbent such as silica gel, activated alumina, or absorbent resin, and use a suitable solvent such as he/cene-acetone solvent or chloroform-methanol solvent. It can be separated and purified by column chromatography.

The unarylation of the 23-position hydroxyl group of the starting material [2] is carried out by reacting the starting material [2] with the carboxylic acid [3] or its reactive derivative.

Examples include α-halofenimoso-branched lower fatty acids represented by (R1, R2, R3 and 1 have the same meanings as above). This halophenyl group is a phenyl group substituted with one or two halogen atoms, and examples of the substitution positions include the 2-position, the 3-position, the G-position, the 2.3-position, and! ,l/
, 2nd, 5th place,! , 6th place, 3. Examples include 1st place and 3.5th place. The above R□ and R2 are the same or different,
It is a straight chain or branched alkyl group having 7 to 7 carbon atoms.

For example, methyl, ethyl, propy/L/, isopropyl,
Examples include butyl and isobutyl.

Other than the above carboxylic acids [diphenylacetic acid, α-phenylthio-phenylacetic acid, α-phenylsulfo = /L/
-phenylacetic acid. The above phenyl group may have a substituent, examples of which include those substituted with 7 to 3 lower alkyl groups, lower alkokene groups, and halogen atoms.

The above-mentioned reactive derivatives include acid hafides, acid anhydrides, mixed acid anhydrides, active esters, such as p-dil-lophenyl ester, p-nitrophenyl thioester, cyanomethylnis 7-/, N-hydroquine. Examples include succinimide ester and N-hydroquine phthalimide ester. Other unwrapping agents known in the industry may also be used in addition to those listed above. When carboxylic acid [3] is used as it is, N,l'J/-synchrohexylcarbodiimide (DCC), N,N'-his(P-7methylaminophenyl-cyclohexyl-N '-,i!-(Morholi Luke)
Levodiimide, i. i'-carbonyldiimidazole, i. i'
-Thiocarbonyldiimidazole, N,N'-carbonyldiimidazole, azodicarboxylic acid diethyl ester/triphenylphosphine, etc. General Q-esterification 1) Acylation may be carried out using the condensing agent used.

The acylation reaction is usually carried out in an aprotic solvent.

Examples of aprotic solvents include dichloromethane, chloroform, cycloethane, tetrahydrofuran, dioxane, and benzene. '', the reaction normally proceeds sufficiently at room temperature, so there is no need for cooling or heating unless the reaction rate is too fast or too slow.

Since the progress of the reaction can be monitored by TLC, HPLC, etc., the reaction can be appropriately terminated after the starting material [2] has disappeared. In the above acylation reaction, when an acid is to be produced, it is preferable that all tertiary organic bases such as triethylamine, pyridine, picoline, collidine, quinoline, isoquinoline, and N-nonalone are allowed to coexist.

To collect the reaction product represented by the formula (in the formula, R, R2 and R have the same meanings as above) obtained from the above acylation reaction from the reaction solution, add water to the reaction solution. In addition, extraction is carried out in a non-hydrophilic bath under alkalinity with I) H2-7j, for example, with chloroform, dichloroethane, methyl isobutyl ketone, ethyl acetate, butyl acetate, etc. Sarat
If this purification is required (this is the same as described above for the production of starting material [2]), it can be separated and purified by column chromatography.

Next, hydroxyl J at the 27th and 77th positions of the reaction product [4]
The protecting group of 1 (5), especially the acetyl group, is eliminated. This elimination is carried out by heat treatment in a lower alcohol which may contain water. Examples of the lower alcohol include methanol, Ethanol is preferred. Since the above reaction can be monitored by ζ-chromatography such as TLC, HPLC, etc., the reaction can be appropriately terminated after waiting for the disappearance of the reaction product [4].

In order to collect the target compound [upper] obtained in this way from the reaction solution, lower alkano-/L/f is distilled off, and p
This is carried out by pouring an alkali of Hg-15 and extracting with a non-hydrophilic organic solvent such as chloroform, dichloroethane, methyl isobutyl ketone, ethyl acetate, and acid-resistant butyl. If you also require IAffV,
It can be separated and purified by means of chromagraphy using an adsorbent such as glue gel, activated alumina, or adsorption resin.

Next, the minimum inhibitory concentration for microbial growth (Cllf/ml) of the object compound (1) of the present invention was measured.The results are shown in the following table. In addition, the symbols in the table have the following meanings A to D,
R or the following t indicates the target compound [1] which is a group as described above.

EM, Erynuromycin TS, Tylosin; Macrophyto IIJ Group A bacteria (elinulomycin, oleandomycin, / macrolide antibiotic resistant patient isolates) Next, reference examples and examples will be given to explain the production of the present invention. Can you give a concrete example? I will explain this. The Rf values in the examples were measured by thin layer chromatography (TI, C) using the following carrier and developing solvent, unless otherwise specified.

Carrier: D C-Fertigplaten manufactured by Merck & Co., Ltd.
Kieso1gelOtsu0F254T ArL j 7/
! ;Developing solvent; a; Benzene-acetone (J:/) b; Chloroform-methanol (J-:/) C: Chloroform-methanol-concentrated aqueous ammonia (150:1O:
1) didichlororum-methanol-my ammonia water (10
θ:lO:/) Reference example / U', 9'-C〇-acetyl-23-demycinone lutesmycocin 23- temainnonlutesmycocin 2 /, 2
/'/ (3 left J m M) was dissolved in dichloro C'') Tough / OJ m'k, and to this was added 73 ml (6 times the mole) of acetic anhydride and stirred at room temperature for 1.5 hours. Reaction liquid Pour the rare ammonia oomeh, black 1
Extracted twice with 300 ml of 1 form. After drying the chloroform layer over anhydrous magnesium sulfate, it was concentrated under reduced pressure.
/,/-C0-acetyl-λ3-demainnosyldenumycocin, 2IAO/r (yield: 9.3%) was obtained.

TLC; Rfa=0.3.2 C23-temacinone Rf' c20/3)23-0-C
C-(q-chlorophenoquine)inbutyryl]-, z3
-Temainosyltenumaiconno/, 41/-G-O-acenal-23-temainosyldesmyconone 200~(0,,29'3'l
mM) and α-(chlorophenoxy) iso-6 acid 30my and gauge methylaminobilicin 3m7
Dissolved in 1 ml of dichloromethane, cooled at 0°C, and diluted with N,N'-cyclohexylcarbocimite (D
CC) 60 g ~ dichloromemene (/ml) R
After adding Solution i, the mixture was stirred at room temperature for 1 hour. After the reaction, insoluble materials were removed, and the fP solution was added to dilute aqueous ammonia j-m7' and extracted three times with 29 ml of chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with silica gel (20 x 20 cm, 2 sheets, manufactured by Luk Co., Ltd., Art J 7/7) preparative Tr, C1c open m
1jX=-methano-Jvc3:/). The eluate was dried under reduced pressure to give 2', d'-0-acetyl-23-
〇-[α-(II-chlorophenoquine)inbutyryl)
-23-temaicinosyldenumycosin/99~ was obtained. TLC;'Rf a=o, s2 The above product is methanol! ;'ml p1 water at 55℃ 1. The mixture was stirred for S' time. After the reaction, methanol was distilled off under reduced pressure and the remaining aIf
It was dissolved in Qml of chloroform and washed with dilute ammonia water. The water belly was extracted with chloroform, 1Qml, combined with the previous chloroform layer, and dried over anhydrous magnesium sulfate.
The mixture was dried under reduced pressure to obtain 23-0-(α-(&-1'-(2-phenoxy)inbutyryl)-:13-7'mycinosyltesmycocin/Otsu11t~ (yield 703%).

TLC, IJ1～～% Rf c = 0.2
3NMR (100MHz, CDCI3) δ11
p nl, 3H, C,, -CD5), -2, jO(s,
+ Otsu H1N (Cn 3) 2), 1A12
(do, SuH9λ3-CH2-), ≠23; Cd,,
/H, /'-H)% lAdoJ-(d, to, /H
, /j-H), yo 6 g (d,), Otsu.

, Hyos), 5' near 0 (s,, / H,'CHO)
Example 2 23-0-diphenylacetyl-,23-temaicinone Vtesmycocin j',lI'-cy0-acetyl-23-tebuicinone 200 m8 (0,,293&n1M,
), diphenylacetic acid 62.2 ~ and goo-dimethylaminohy”lysine 36 ■ (0/fold mole) basin dichloromethane 1
Melt the m1k and cool it to 0°C with DCC.
After adding a dichloronotane (/ml) solution (isomol I), the mixture was stirred at room temperature for 0.45 hours. After the reaction, insoluble matter was removed, P solution was added with diluted ammonia solution, and chloroform 2
Extracted three times at zero temperature. The chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Approximately 200 m9 of the residue was soaked in silica gel (20 x 20 cm, 2 sheets, manufactured by Merck, Art
37/7) Preparative TLC (developing solvent benzene-acetone =
3:l) Purified from tco. Rfa=0. ,G
E: , Rfc = 0. The section around ey 2 was scraped off and eluted with chloroform-methanol (3:/). The eluate was dried under reduced pressure to obtain 2',q'-di-O-acety/v-,23-0-diphenylacetyl-23-temaicinosyldenumycosin i'yom9.

TLC; Rf a =0. ．． 6S, Rfa-Qri 2
Dissolve the above product in 5 ml of methanol at 55°C.
The mixture was stirred for 3 hours. After the reaction, methanol was distilled off under reduced pressure,
The residue was dissolved in 20 ml of chloroform and washed with dilute ammonia water. Extract the aqueous layer with 20ml of chloroform and
After drying with anhydrous magnesium sulfate and the OA form layer of 1j1 paste, drying under reduced pressure yields "C23-0-diphenylacetyl-23-temysinosyltenumycosin"ymL.
i (yield 2-,/%) was obtained.

TLC; Rf a=0.31 NMR (100MHz, CDCI 3) δp p m
;/, B and (s,, jH, C yo 2 'H3) 1.2
．． 3; / (s.

, Otsu H1-N(CH3)2), 441. ! i'~IA3
! ;C8, 3H, 23〒CH2,/'-H), tdoS
(d.

t+l jH, / j-H), friend 0s (so, jH, C
H・Ph2), Yootori (d,, jH, /3-H), Otsu2'lCd,, /H,1O-H), 71ri ((1,, j
H, //-H), 7. ．． 2g (s,, / OII,
CPh 2),! 77/ (s,, jH, CHO) MS, 77.2 (MW”), 77ri (MW”-/, 5'
), 2/3, /92, /71I Example 3 23-0-C2-phenylthiosephenyl)v 7
ceti/l/)-23-temycinonerutenumycocin Example 2tHere, DifeniJvlIi'lOt,z,
Q instead of x 2-phenylthio-2-phenyJv11
11 acids 7/, 6~' with Rf a =0.65. 2',4''-di-0-acetyl-23-0-C2
-Phenylthiolmy-phenylacetyl) -23-temaicinosyldesmycosin was obtained.

2 product was dediacetylated according to the method described in Example 2 to give 23-O-C2-phenylthio-nophenylacetyl)-,23~demycinocy/L/7' sumycocin 1/-2~ (yield 5 7%).

TLC; Rf c=0.3/NMR (10f near 1VIHz, CDCl3)
δ$1 pini /, 67(B,, 3H,C-,
2~C" 3), 2.!; / (δ0.OtsuH, -N
(CH3)2),! /,2(Tn,,2m,23-CH
2-), ≠1 (d,, jH, /'-H)%dog≠X% (d, L,,7H,H,),≠9/(8,,
jH.

71 (respectively (I, , /H, / /-H), 7.
．． 29 ((1,.

/ Q H, phenyl proton),? ,7/(s,,
jH, CHO) MSiza2hiro (M,H), gOtsu (MH-1g), 2daj, /riλ, /7'1 Example q, 23-O-C2-phenylnulfonyl-phenyl acetyl)-,23-temysinosyldesmycosin λ', t'-di0-acetyw-23-demysinosyldenumycosin, 200Ing<0.293'lrnM
), 2-phenylsulfonyl-λ-phenylacetic acid and 70
~ and dacimethylaminopyridine 3.6 ~ (0,/
IV) Add m to 2 ml of dichloromethane.

This was cooled to 0°C.
<Equimolar) dichloromethane (l) solution was added and the mixture was heated to 0.0% at room temperature. The mixture was stirred for S hours. The reaction solution was mixed with 2/v-2-phenylacetyl 7L/)-23-demycinosyldesmycosine/9o mg*mt as described in Example λQ.
, :.

The above product was dediacetylated according to the method described herein to give 23-O-C2-phe = jv 7. /
l/Honilu! -phenylacetyl) L/) -23-temainnonrudenumycosin/jriq (yield A 3.3
%) was obtained.

TLC; Rf c =0.29 NM, R(/(7(7MHz, CD C
I 3 ) δppm, /, 72. /, 73 (each s, , /
H,Cyu2"H3)1.2.,fOCs,,OtsuH,-N
(CH3)2), ≠2~≠3 (ml, JH, 23-
CH2+, 7/-I()%! ,! i'41 (d, L,
, jH, /3r-H), Kei 01. ．． 5o7 (8 each
．． ．． jH, CH-Ph), 5 Otsu 3 (d,, jH
.

/ 3 = H), Otsu 21. (d,,' jH,/ 0
-H), 7j/(d,,jH,//-H), 730C
m,, 6H, phenyl proton), 7g to 77 (m,,
jH.

5o2--p), ? ,70 (s,, jH,C
HO) MS, Ml (..., 233./1.2.
/ Patent applicant Representative Toyo Jozo Co., Ltd. Ito Fuji 7 yen July 9, 1932 Patent application No. 7/g03 of 1982! 3. Title of the invention, 23-0-acyl-,23-demysinosyldenumycosin and its manufacturing method 3. Relationship with the case of the person making the amendment. Patent applicant: Date of the amendment order. Invention specification, page 7, No. 1. Correct "aquatic group" in lines 2 and 2 to "hydroxyl group."

page 13, line 73 "It will be done." "It will be done." Correct.

Same page 20, line 7 "2H" [Corrected as 2H, J.

Same page 20 line 70 "d, t,, J "Correct it as d, t, , J.

Page 20, line 1/ rI(+34 [Corrected to H+14.

Delete r Rfc =0.92 J in the disciple line on page 27.

Same page 23, line 1g "Each d..." Correct it to ``Each m...''.

Same page 25 line 75 1'-Ml (delete J.

Claims (1)

[Claims] 2 -R5 -CH-Ra group, Ryu and R2 are the same or different and represent a lower alkyl group, R3 is a halogen radical r-1n
ii/or 2, R4 and R5 are the same or different and represent a phenyl group which may have a substituent,
X is a single bond, -8- or -5o2-1) or a salt thereof. 2), , 23-0-(α-(guchlorophenoxy)isobutyryl)-23-f mycinonludesmicon7.
23-0-diphenylacetyl-23-temaicinone, 23-O-(2-phenylthio-,2
-phenylacetyl)-23-f mycinosyldesmaicone or 23-〇-C2-phenylnulfonylunophenylacetyl)-23-fmydinoV)vfnumaicone, or (In the formula, R6 and R7 represent a hydroxyl group protecting group)
A compound represented by the formula R-C-OH 12 -R5 -C)l-R, a group, R and R2 are the same or different 9, lower alkyl)V group, R3 is a halogen atom -f,
+i represents 1 or 2, R6 and R6 are the same or different and represent a phenyl group which may have a substituent, X is a single bond, -8- or -5o2-2) A person characterized in that the hydroxyl group at position 23 is unnulated with a carboxylic acid or a reactive derivative thereof, and the protecting groups of the hydroxyl group at the no' and 7' positions are debuccalized (in the formula, R is nIJ A method for producing a compound or a salt thereof. 3), wherein the protecting group is a lower alkanoyl or a halogenated acetyl group. 5) The production method according to claim 9, wherein the lower alkanoyl group is an acetyl group. 6) The manufacturing method according to claim 3, wherein the reactive derivative is an acid halide, an acid anhydride or an active ester.
1.7) The production method according to claim 5, wherein the elimination of the acetyl group is carried out by heat treatment in a lower alkanol which may contain water. g) The production method according to claim 7, wherein the lower alkanol is methanol.