JPS58208297A - 23-o-acyl-23-demycinosyl-4'-deoxydesmycosin and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is phenyl which may be substituted, thienyl which may substituted, thiazolyl which may be substituted; A is lower alkyl, lower alkylene which may be substituted with aminos or lower alkoxyiminos; X is O, S; n is 0, 1) or its salt. EXAMPLE:23-O-Phenylacetyl-23-demycinoxyl-4'-deoxydesmycosin. USE:Antibacterial, remedy for infections in animals, feed additives for infection prevention and growth acceleration: it shows much stronger antibiotic activity against gram-positive bacteria than known erythromycin and tylosin and the same level to gram-positive as erythromycin. PREPARATION:The compound of formula II (R1 is hydroxyl-protecting group) is acylated with a carboxylic acid of formula III or its reactive derivative on the hydroxyl in the 23-position, then deprotected in the 2'-position.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 23-0-acyl-23-demycinosyl-11'-f oxidesmycovy-containing compound and a method for producing the same. More specifically, the formula (wherein R is an optionally substituted phenyl, an optionally substituted chenyl group, or an optionally substituted thiazolyl group, and A is a lower alkyl, amino, or lower alkoxyimino group) The compound is a compound represented by an optionally substituted lower alkylene group or lower alkenylene group, X is an oxygen atom or a sulfur atom, n is 01fc is /, or a salt thereof. In the present invention, a compound represented by the formula R-(X)n-A-C-QH (3 ml (in the formula, R,X , A and n have the same meaning as above), the hydroxyl group at the 23rd position is acylated with its reactive derivative, and the hydroxyl group at the 23rd position is acylated.
Also included is a process for producing a compound of the formula [/] or a salt thereof, which is characterized by removing the protective group for the hydroxyl group of 'x'.

The above salts include pharmaceutically acceptable salts.

Such suitable salts include salts with inorganic acids such as hydrochloric, sulfuric, and phosphoric acids, and salts with organic acids such as acetic, propionic, tartaric, citric, succinic, malic, aspartic, and glutamic acids. is included. Other non-toxic salts are also included.

The above-mentioned new compound [/] exhibits much stronger antibacterial activity against Gram-positive bacteria than the known erythromycin and tylosin, and has antibacterial activity comparable to erythromycin against Gram-negative bacteria. It is an antibacterial agent that is expected to have excellent infection treatment effects. In addition, animal infection treatment agents,
It is also useful as a feed additive for preventing infection or promoting growth.

The starting material [2] used in the present invention is 23-dayqisinosyl-11'=focindesmycosin CJ.

Antibiotics,, 1-Ku (10), /3
7'l~/37 Otsu (79g/), JP-A-1973-. 2g
No. 100], the hydroxyl group at the 2' position is protected with an appropriate protecting group.

Such protecting groups include acetyl, propionyl,
Lower alkanoyl groups such as butyryl, chloroacetyl,
Norogenated acetyl groups such as dichloroacetyl, trichloroacetyl, and trifluoroacetyl are preferred, but
Particularly advantageous is the acetyl group.

The introduction of the acetyl group is 23-demysinosyl t′
-Deocin desmycosin V is carried out by reacting acetic anhydride in an inert organic solvent.

As the inert organic solvent, dichloromethane, chloroform, dichloroethane, acetate, etc. are preferred. The reaction proceeds satisfactorily at room temperature. The progress of the reaction can be tracked using thin layer chromatography (TLC) using silica gel, high performance liquid chromatography (HPLC), etc.
The reaction may be appropriately terminated after the disappearance of 3-demycinosyl-l-deoxydesmycocin. Other protecting groups can also be introduced by filtration as above.Q To collect the reaction product C,2,) from the reaction solution, water is added to the reaction solution, and the pH,! Under alkalinity of i'-93,
Non-hydrophilic organic solvents such as chloroform, dichloroethane, methyl isobutyl ketone, ethyl acetate.

− Ta − 〇Further e performed by extraction with butyl acetate etc.
If this purification is required, use an adsorbent such as silica gel, activated alumina, or adsorption resin, and use a four-part column eluted with an appropriate solvent, such as a benzene-acetone solvent or a chloroform-methanol solvent. It can be decomposed and purified by chromatography.

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

The above carboxylic acid [3] has a cyclic group and a carbo + l:/
A ring side chain carboxylic acid having a 7-carbon chain, and this carbon chain is bonded to the cyclic group via an oxygen atom or a sulfur atom. A lower alkylene group or a lower alkenylene group which may have a substituent of a lower alkyl, amine or lower alkoxyimino group, and the cyclic group is a phenyl, chenyl or thiazolyl group, which has a substituent. It may have.

Examples of the above-mentioned carbonic acid [3] include huevir vinegar-/
O- acid, α-phenylpropionic acid, β-phenylbu-2-phenyl-methoxyiminoacetic acid, D(-)-phenylglycine, D(-)-1)-hydroxyphenylglycine, nochenylacetic acid, 2-aminothiazole -guacetic acid, 2-(2-aminothiazole-guyl)-2-
Examples include methoxyimino-acetic acid. When these carboxylic acids have one functional group in the molecule, such as an amine group or a hydroxyl group, it is preferable to protect this in advance with a suitable protecting group by a known method.

The above-mentioned reactive derivatives include acid halides, acid anhydrides, mixed acid anhydrides, active esters such as p-nitrophenyl ester, p-nitrophenylthioester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester. Examples include. Other acylating agents known in the art may also be used in addition to those listed above. When carboxylic acid [3] is used as is -//-, N,N'-dicyclohexylcarbodiimide (DCC), N,N'-bis (p-
Carbodiimides such as dimethylaminophenyl) carbodiimide, N-hair diclohexyl N'-,2J (morpholyl-1 ethyl-carbodiimide, N-ethyl-N'-dimethyl 7minoprobyl-carbodiimide, /,
N such as /'-carbonyldiimidazole, /,/-thiocarbonyldiimidazole.

N'-carbonyldiimidazole, azodicarboxylic acid diethyl ester/I・! Acylation may be carried out using a condensing agent commonly used in esterification such as phenylphosphine.

Non The acylation reaction is usually carried out in a specific protic solvent.

Examples of aprotic solvents include dichloromethane, chloroform, dichloroethane, tetrahydrofuran, dioxane, and benzene. The above reaction usually proceeds sufficiently at room temperature, so there is no need to cool or heat it unless the reaction rate is too fast or too slow. The progress of the reaction can be monitored using TLC, IPLC, etc. Since - /2 - can be achieved, the reaction can be appropriately terminated after waiting for the disappearance of the starting material [2]. In the above acylation reaction, when producing an acid, a tertiary organic base such as triethylamine, pyridine, picoline, collidine, quinoline, isoquinoline, N-methylmorpholine, tribenzylamine, dimethylaniline, etc. It is preferable that they coexist.

The formula obtained from the above acylation reaction (where R1,
Collect the reaction product represented by R,
Extract with non-hydrophilic organic solvents such as hachloroform, dichloroethane, methyl isobutyl ketone, ethyl acetate, butyl acetate, etc. under Z5 alkalinity? This is done from here. If further purification is required, use the starting material [
2) Column chromatography as described for the production? It can be separated and purified from this.

Next, a protecting group for the hydroxyl group at the 2' position of the reaction product IJ),
In particular, the acetyl group is eliminated, and this elimination is carried out by heat treatment in a lower alcohol which may contain water. Preferred lower alcohols include methanol and ethanol. The above reaction was performed by TLC,
HPLC etc? Since it can be traced from this, the reaction product 14
) may disappear and terminate the reaction as appropriate.

If the reaction product has a protected functional group in its molecule, it can be prepared using a known method. From this, the protecting group can be removed.

In this way, the obtained target compound [/] is reacted with -
/II- Collected from the liquid, the lower alkanol is distilled off and P
Hza~9S alkaline non-hydrophilic organic solvent, flj'
lf Extract with chloroform, dichloroethane, methyl isobutyl ketone, ethyl acetate, butyl acetate, etc.
This will be done. If further purification is required, it can be separated and purified by means of chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin. The results of measuring the minimum inhibitory concentration (P/mg) of microbial growth of compound [/] are shown in the following table. The symbols in the table have the following meanings.

A-E; R-(X) n-A- group is the following? Indicates that the target compound [/] is a group in this description.

EMi Erythromine TS; Tylosin*; Macrolide-resistant Bacteria Group A Next, production examples of the present invention will be specifically explained with reference to Reference Examples and Examples. The Rf values in the examples were measured by thin layer chromatography (TLC) using the following carrier and developing solvent, unless otherwise specified.

Carrier: D C-Fertigplatten manufactured by Merck & Co.
Kiese1gelOtsu0F254, Art! ;
7/3 Developing bath medium; a; benzene-acetone (3:/) b; chloroform-methanol (5:/) C; chloroform-methanol-concentrated aqueous ammonia CI! ;0 :I
O:/) didichlororum-methanol-concentrated ammonia water Cl0
O'', IO', /') Reference example / !-〇-acetyl-23-f maydinosyl-≠-deoxydesmaicone = 3-demysinosyl≠'-deoxydesmyconn = 3.33 f\dichlorothane 2Qmlt To this, 36 ml (λS times the mole) of acetic anhydride was added under water cooling, and the mixture was stirred at room temperature for 2 hours.The reaction solution was poured with diluted aqueous ammonia, and the pH of the aqueous layer was adjusted to 100 g. was checked and extracted.The chloroform layer was washed with water and extracted using Whatma
n,,IPS filter paper? After passing through this, it was concentrated under reduced pressure to obtain a white foamy Ω'-〇-acetyl-23-demycinosyl-c'-deoxydesmycocin (yield: 9).
/%) was obtained.

TLC; Rfd=OIIg NMR (/00MHz, CDC13) δppm;
/,,! r2 (s,) 1.2.0g (s,,3
H,0COCH3), 2.23 (s, ), 3.711
(d,), 1A21/l(d,),'l-,7!
;(d, d,, /H, 2'-H'I, 4Ari Otsu (d
,t,)1.5:g,! i'(d,), Otsu32 (d,
) , 7.31d, ) , Ri Otsu Day / 1
- Mass (CI); Otsu2Il (VilH+),
Otsu Otsu (P111H+-7g>, sg, 2 (MH
+-G2) 1.2/g, 20 Examples / 23-, -0-(2-chenylacetyl)-23-temaicinosyl-It-deoxydesmycosin 2'-〇-acetyl-23-demycinosyl-1'- Theoxides Maicon 200m? , 2〒thinyl acetic acid 1
1 ssmg (equimolar) and gauge methylaminopyridine 3. yrqt (o, 7 times the mole) in dichloromethane, 1
After the reaction, the insoluble matter was dissolved in E. Then, strain the filtrate with dilute aqueous ammonia to pH 7, then extract 3 times with chloroform%QmlV.

Whatman/PS fM chloroform layer
After passing through the solution, it was concentrated under reduced pressure. 93. Pour the liquid into silica gel
20x. 20α.

2 sheets, Merck Art37/7) preparative TLCC exhibition-
20 - Opening solvent chloroform-methanol-concentrated aqueous ammonia (1
00'. 10", /):]. Rf) = 0
Seven pots each weighing 6 g were scraped out and eluted with chloroform-methanol (3:/). Concentrate the eluate under reduced pressure and
'-〇-acetyl-23-0-<2-chenylacetyl)-23-f maydinosyl-re was dissolved in 3 ml of methanol, heated at 33°C for S hours, and then concentrated under reduced pressure. 1 ml of dilute ammonia water was added to the remaining solution to adjust the pH to ~g, and the mixture was extracted with chloroform. Whatman/chloroform layer
After passing through P S Fi paper, it was concentrated under reduced pressure to obtain 23-0-
C2-chenylacetyl) -23-f maydinosyl-
l'-deoxydesmycosine white foam gλOm
g (yield 3.2%) was obtained.

TLC; Rfc=0. ! ; 2 HMR (Fx / O O, CDCIs) δpp
m? /． 73 (s 111 3 H, C12-
'CH3), 2. , 2 Otsu (S., Otsu H.

-N (CH3'12), 3. g'I (s.,
2H. -COCH2), lA20 (d, 3H.
/'-H and 2 3 - CH2, - +2/- ty, q3 (a, t,, /H, 13-H)
2. fjs (a,.

/H, /3-H), Otsu30 (d,, /H,'
/ 0-H), Otori 1 (m,,, 2H, 3.1I-H of thiophene ring), 7.2/ (m,, /H, 3-H of thiophene i), 729 (d,, /H', /
/ -H), 9.7.2 (s,, /H, CHO) Mass (CI); 70 Otsu (MH + 1.6gg
(MH+-1g), /7 Otsu, /,! ;g, /I13
Example 2 23-0-Phenylacetyl-23-demycinosyl-t'-deoxydesmycosin real M Example/t Where, -1-thenyl acetic acid <z 3s Using 36 m2 of phenylacetic acid instead of mg, Rfc 2 with -077
'-〇-acetyl-23-7enyl acetyl-23-demycinosylug'-deoxytesmycosin/ /
Obtained Omfl. This was deacetylated according to Example/Described Method 1 to give 23-〇-phenylacetyl-23-
-f Mysinosiluk'wa-deoxydesmycosin white color Enoki Akimono 73 mg (
A yield of 33 g% was obtained.

2-- TLC; Rfc=0.33 NMR (FX-/00.CDCll3) δppm;
/, 72 (s,), 2.26 (s,), 3 Otsu 2 (s,), 44/7 (m,, 3 H)
,'AriO(d,t,),j72(d,),Example 3 23-O-Phenylthioacetyl-23-demycinosyl-11'-f Oxidesmycocin Practical Example/1 where, - Monothenyl acetic acid'xts
Using 33.9 mW of phenylthioacetic acid instead of m'i, 2'-〇-acetyl-23-phenylthioacetyl-23-f mightinosyl- with Rfc = 0.73
t,t/-deoxydesmycosin/337nt was obtained. This was deacetylated according to Example/Described Method e to give 23-0-phenylthioacetyl-23-demycinosyl-11'-f oxidesmycocin as white foam g/m9 (yield 34Z, 5%). ) was obtained.

TLCi Rfc=O,! ;3 NMR (FX-/00.CDCll3A-23-7G Is,), 2.2 Otsu (s,), 3 Otsu 5 (s,),
≠/ta (m,,3H), '1. g7
(d, t,), 3 Otsu Otsu (d,
) Ωta (d,) ,7.23; (d,) ,7.
3/ (m,,5H.

phenyl proton), 9.72 (s,)Mass
(CI); 73.2 fMH force, 7/4 (
MH”-1g), /7 Otsu, /Otsuri, 73g Example G23-0-cinnamoyl-23-f maydinosyl-+-
f Oxydesmycocin Example/l Here, -1-thenyl acetic acid l Ltssmy
Instead of trans-cinnamic acid 4/7.4' mW e, 2'-〇-acetyl 23 with Rfc=07
200 mW of -0-cinnamoyl-,23-f maydinosyl-gudeoxydesmycocin was obtained. Dissolve this in 3 me y of methanol, 3! After heating at i°C for 3 hours, the mixture was concentrated under reduced pressure. Add dilute ammonia water to the residue and p
After passing the 0 chloroform layer extracted with Hg-7 and chloroform through Whatman/PS F' paper,
Concentrate under reduced pressure to obtain 2 liters of white 23-O-cinnamoyl-23-demycinosilug'-deoxydesmycocin.
39 mf (yield Og%) was obtained.

TLC; Rfc=0.5 II NMR (FX-100, CDCll5>δppm i
/.

g 2 (s,) , 2.26 (s,) , Il,
/ 7~'A 32 (m,.

770 (d, /H,CH-Ph),? ';'2
(s,)Mass (CI) Near/2 (MHj
, A9'l (MH"-1g>, /7 Otsu, 75g,
/Gude Example 5 23-0-(α-phenylbutyryl)-23-demycinosyl-j'-deoxydesmycosin Example/In 2-chenylacetic acid'x Yos my
Instead of? Using this α-phenylbutyric acid S2, Rfc
2′-〇-aceti/re23-(α
-Phenylbutyryl)-23-demycinosyrugadeoxydesmycosin 200 ■ was obtained.

This was deacetylated according to the method described in Example G to obtain a white foamy product of 23-0-(α-phenylbutyryl)-2325--temaicinosyl≠-deoxydesmycocin, yield of 739 mg, /%. ) was obtained.

TLCi Rfc=0. 'Iri N M R (FX - / OO, CD C (13) δ
ppm; /Otsu3,7.70<each s,) 1.2.2
7 (s,), lA10-≠-za (m,, JH)
, 'Ag1l (d, t,), left, proton)
,9.73 (s,)Mass (CI)
; 72g (MH), 710 (MH"-/g)
, / 7 Otsu, isg Patent Applicant Toyo Jozo Co., Ltd. Representative Ito Fujima Kazufuru Procedural Amendment July 3, 1980 Patent Application No. 7gg95 2, Title of Invention 23-〇-Ashiru 23-Demycinosiluk'-deoxydesmycocin and its manufacturing method 3 Relationship with the case of the person making the amendment Patent applicant ≠ Date of amendment order r 5treptococcus pyoquenes
N, Y, 3 J [5treptococcus py
oquanes / 022 J [5treptoc
occus pyogenes / 022*].

In the third line of the first page of the same page, "It was checked and extracted." was corrected to "It was checked and extracted with chloroform."

Same page 2/page 2nd line "(100:10:/)" Correct it to "(150:10:/)".

Claims (1)

[Scope of Claims] Formula (1) (wherein R is an optionally substituted phenyl, an optionally substituted chenyl, or an optionally substituted tipzolyl group, A is a lower alkyl, an amino acid X is a lower alkylene group optionally substituted with a lower alkoxyimino group or a lower alkenylene group,
is an oxygen atom or a sulfur atom, and n is 0 or /). (2), 23-0-phenylacetyl-23-demycinosyl-pl-thioxidesmycocin, 23-0-phenylthioacetyl-23-fmycin Sik-II
'-f, txidesmycosif, 23-0-(α-phenylphthyryl)-23-demycinosyl-11'-f
oxidesmycocin, 23-O-CD(-)-α-amino-phenylacetyl]-23-f maydinosyl-1
1'-thioxidesmycosin, '23-0-cinnamoyl-23-demysinosyl-+'-deoxydesmycosin, 23-0- (2-phenyl-nomethoxyiminoacetyl)-! J-demycinosyl-l'-deoxydesmycosine, 23-O-(2-thenylacetyl)-23-fmysinosyluge'-deoxydesmycosine, 23-0-(,2-aminothiazol-q-yl)acetyl -23-demycinosyl+'-deoxydesmycosin, 23-O-C2-(,2-chloroacetamido-thiazole-guyl)-2-methoxyiminoacetyl)-23-f"r-i □Shinosylug'-
Deoxydesmycosin or 23-O-C2-(2-
The compound or a salt thereof according to claim 1 which is aminothiazol-l-yl)-2-methoxyiminoacetyl)-23-desmycinosyl-l-deoxyde\mycosine (3), the formula (in the formula , R, represents a protecting group for a hydroxyl group). A carboxylic acid or a reactive derivative thereof represented by a lower alkylene group or a lower alkenylene group which may be substituted with a lower alkoxyimino group, where X is an oxygen atom or a sulfur atom, and where Oti is /, Acylation of the hydroxyl group at the 2'-position, followed by elimination of the retaining group of the 2'-position hydroxyl group (wherein R, A, X and n have the same meanings as above) Salt manufacturing method. 4. The production method according to claim 3, wherein (ll-)R1 is a lower alkanoyl or a halogenated acetyl group. (5) The production method according to claim 1, wherein the lower alkanoyl group is an acetyl group. (B) The production method according to claim 3, in which the reactive derivative is an acid oride, an acid anhydride, or an active ester. (7) Elimination of the acetyl group in a lower alkanol that may contain water. And heat treatment? Claim No. S made hereunder
Manufacturing method described in section. (g) The production method according to claim 7, wherein the lower alkanol is methanol or ethanol.