JPS5951298A - 19-deformyl-23-demycinosyl-23-o-substituted carbamoyldesmycosin derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is (substituted) phenyl; R2 and R3 are H or lower alkyl] and its salt. EXAMPLE:19-Deformyl -23- demycinosyl -23-O-( N-methylbenzylcarbamoyl)-desmycosin. USE:An antibacterial agent, a remedy for infectious diseases of animal, and a feed additive. It has strong antibacterial activity especially against Gram-positive bacteria. PROCESS:The objective compound can be prepared by reacting the compound of formula II (R4 is OH-protecting group) with 1,1'-carbonyldiimidazole in an inert organic solvent (e.g. dichloromethane) at room temperature to convert the 23-OH group to imidazolide, reacting the imidazolide derivative with the amine of formula III (e.g. benzylamine) in an inert organic solvent (e.g. dichloroethane) at about 70-90 deg.C, and heating the reaction product in a lower alcohol (e.g. methanol) to eliminate the OH-protecting group.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 19-deformyl-23-demai/no/ru-23-0-1t-substituted carbamoyl desmyconone derivative and a method for producing the same. More specifically, the present invention is based on the formula (wherein RI is a phenyl group which may have a substituent,
R2 is an f atom or a lower alkyl group, R3 is a hydrogen atom or a lower argyl group, or a salt thereof. 1. In the present invention, a compound represented by the formula (wherein R4 represents a hydroxyl group protecting group) is reacted with 1,1'-carbonyldiimidazole in an inert organic solvent to convert the 23-position hydroxyl group into an imidazolide. , the obtained imidazolide compound was reacted with an amine represented by the formula % (in the formula, R1, R2 and R3 mean the same groups as above) under heating, and then 2'
This is a method for producing compound [1] or a salt thereof, which is characterized by removing the protective groups for the hydroxyl groups at the positions and the 4' positions.

The above salts are 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 novel compound [1] shows strong antibacterial activity against Durum-positive bacteria and Durum-negative bacteria, and in particular shows much stronger antibacterial activity against Durum-positive bacteria than diyosamicin and tylosin, and is stable in vivo. Therefore, it is an antibacterial agent that is expected to have excellent clinical efficacy in treating infections. It is also useful as a therapeutic agent for animal infections, and as a feed additive for preventing infection or promoting growth.

Compound [3] used in the present invention is 19-depormylo-23-demycinofludesmaicone, that is, the compound represented by the formula, with the hydroxyl groups at the 2' and 4' positions protected with an appropriate protecting group. be.

The above starting material [5] is 23-demycinosyl desmy: + syn [Tetra-hedron Letter
s, 4737 (1970)) with [(C6H5)3P]3Rh CI under heating in an inert organic solvent (JP-A-56-55399).
.

Suitable protecting groups mentioned above include lower alkanoyl groups such as ace, thyl, propionyl, and butyryl, and halogenated acetyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl, with acetyl groups being particularly preferred. .

The protection of the hydroxyl groups at the 2' and 4' positions of the compound [5] with acetyl groups is carried out by reacting the compound [5] with acetic anhydride in an inert organic solvent.

As the inert organic solvent, dichloromethane, chloroform, dichloroethane, and acetonate are preferred. The reaction proceeds satisfactorily at room temperature. The progress of the reaction can be tracked by thin layer chromatography (TLC) using silica gel, high performance liquid chromatography (HPLC), etc.
The reaction may be appropriately terminated after the disappearance of the compound [5]. To collect the reaction product [3] from the reaction solution,
This is carried out by adding water to the reaction solution and extracting with a non-hydrophilic organic solvent such as fLjt hachloroform, dichloromethane, methyl in butyl ketone, ethyl acetate, butyl acetate, etc. under an alkaline pH of 8 to 9.5. If further purification is required, separation and purification is performed by column chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin and eluting with an appropriate solvent such as a benzene-acetone solvent or a chloroform-methanol solvent. be able to.

In order to convert the hydroxyl group at position 23 of compound [3] into a 〇-substituted carbamomomation, the hydroxyl group is first converted into an imidazolide. All you have to do is react. Examples of the inert organic solvent include lysinated hydrocarbon solvents such as dichloroethane, chloroform, and dichloroethanat. The reaction is usually carried out at room temperature. Since the progress of the reaction can be monitored by thin layer chromatography (TLC) using silica gel or the like, high performance liquid chromatography (HPLC), etc., the reaction may be appropriately terminated after the disappearance of compound [3].

The imidazolide obtained by the above reaction may be used directly in the first reaction, that is, the reaction with amine [4], without being isolated from the reaction solution, or it may be used after isolation. When isolating the imidazolide compound, the reaction solution is poured into water, the p)l of the aqueous layer is adjusted to 8 to 9.5, and then an extraction operation is performed to distill off the solvent from the organic solvent layer. can get. When the imidazolide compound is directly used for the reaction with the shredded amide/[4] without isolating, the compound [3] and 1
, 1-carbonyldiimidazole, preferably uses a high boiling point organic solvent such as dichloroethane.

The amine [4] includes benzylamine, α-lower alkyl-pendylamino, such as α-methylbenzylamino, α-ethylbenzylamine, N-lower alkyl-benzylamine, such as N-methyl-benzylamine, N- Ethyl-benzylamine, Al1- N-lower alkyl-α-lower alkyl-benzylamine, e.g.
-Methyl-α-methylhensylamine, N-methyl-α
-ethylbenzylamine, N-ethyl-α-methylhensylamine, and the like. The above phenyl group may have a substituent, for example, may be substituted with 1 to 3 substituents such as a lower alkyl group, a lower alkokene group, or a halogen atom.

The reaction between the imidazolide and the amine [4] is carried out in an inert organic solvent under heating. Examples of inert organic solvents include dichloroethane, benzene, toluene, dioxane, and the like. Heating is carried out at a temperature equal to or lower than the boiling point of the organic solvent, usually about 70 to 90°C.

The 23-o-substituted rubamoyl compound thus obtained, that is, the compound represented by the formula (wherein R1, R2, IL3, and I (4 means the same group as above)) is collected from the reaction solution. To do this, add water to the reaction solution and extract with a non-hydrophilic organic solvent such as 'chloroform, dichloromethane, dichloroethane, methyl imbutyl ketone, ethyl acetate, butyl acetate, etc. under alkaline conditions at pH 8 to 9.5. If further purification is required, purification is performed by column chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin and eluting with a suitable solvent such as benzene-acetone solvent or chloroform-methanol solvent. can do.

Next, the protective groups for the hydroxyl groups at the '2' and 2-positions of the reaction product [2], especially the acetyl groups, are eliminated, and this elimination is done by heating in a lower alcohol that may contain water. This is done by processing. Examples of lower alcohols include methanol-I+, ethanol, and methanol is particularly preferred. Since the above elimination reaction can be monitored by TLC, I]PLC, etc., the reaction may be appropriately terminated after the reaction product [2] has disappeared.

In order to collect the target compound [1] obtained in this way from the reaction solution, the lower alcohol is distilled off, and the pH is adjusted to 8 to 9.
5 by extraction with a non-hydrophilic organic solvent such as chloroform, dichloromethane, dichloroethane, methylinobutyl ketone, ethyl acetate, butyl acetate, etc.

If further purification is required, it can be purified by chromatography using an adsorbent such as silica gel, activated alumina, or adsorption resin.

In the present invention, when R3 is a hydrogen atom, the reaction product [2] in that case can also be produced by another method. That is, compound [3] is reacted with bis(tri-lower alkyltin) oxide under heating in an inert organic solvent to form 2.
By converting the hydroxyl group at the 8-position into tri-lower alkylstanylation and reacting the resulting reaction product with an isocyanate represented by the formula % (wherein "I and R2 mean the same groups as above)" can get.

As the above-mentioned inert organic solvent, benzene-based solvents such as benzene and toluene are preferable. As the bis(tri-lower alkyltin) oxide, bis(tributyltin) oxide is particularly preferred.

Heating is carried out at a temperature equal to or lower than the boiling point of the solvent, and is usually carried out within the range of 80 to 110°C. In the above reaction, since water is produced, it is convenient to carry out the reaction by adding an insoluble dehydrating agent, such as a molecular sieve, to the reaction solvent.

The obtained tri-lower alkyl stannyl compound is subjected to 0-substituted carbamoylation to obtain compound [5]. In this carbamoylation, if the dehydrating agent used is separated from the reaction solution, the tri-lower alkyl stannyl compound can be converted into a tri-lower alkyl stannyl compound. The reaction is carried out by directly adding the inocyanate represented by the formula [6] to the reaction solution without isolation or purification.

Examples of the isocyanate [6] include benzyl isocyanate, α-lower alkylbenzylino/anate, such as α-methylbenzyl iso/anate, α-ethylbe/zylisonane, and the like. These phenyl groups may be substituted with a substituent in the same manner as above.

The above tri-lower alkyl stannyl compound and inocyanate (
6] usually proceeds satisfactorily at room temperature.

Since the reaction can be monitored by TLC, HPLC, etc., the reaction can be appropriately terminated after waiting for the disappearance of the tri-lower alkyl stannyl compound.

The reaction product [5] thus obtained can be separated and purified from the reaction solution in the same manner as described above.

Next, the minimum inhibitory concentration (MIC) of the target compound [1] of the present invention was measured, and the results are shown in the following table.

Table 1 MIC (ttf/ml) A; 19-deformyl-23-demycinosyl-23-0-(N-methyl-benzylcarbamoyl)-desmycosin TS; tylosin, JM; josamycin/Next, Reference Examples and Examples Production examples of the present invention will be specifically explained by giving examples.

Note that R and f values in Reference Examples and Examples were measured by TLC using the following carrier and developing solvent unless otherwise specified.

Carrier: D C-Fcrtigplatten manufactured by Merck & Co.
Kiescl gel 60 F254 Art
5715 developing solvent a; chloroform-methanol (20:1) b; chloroform-methanol-ammonium, aqueous solution (150:10:
1) C: Hexane-benzene-acetonoacetate-ethyl methanol (90: 80: 25: 60:30) Reference example 1 2', 4'-di-acetyl-19-deformy #-
23-temainosyldesmycosin 19-deformyl-23-demysinosyldesmycosin 1.11 F
(1,95mM) was dissolved in 5.5ml of dichlorothane,
To this was added 0.92 ml (9.7 mM) of acetic anhydride, and the mixture was stirred at room temperature for 1.5 hours. Pour the reaction solution into ice water, adjust the pH to 9 with 7% ammonia water, and add 20 ml of chloroform.
1 was extracted three times.

The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 2',4'-di-0-acetyl-19-deformyl-23-demycinosyl desmycocin powder. Yield: 1.161 (91% yield). Dissolve this in as little chloroform as possible and add silica gel 4
07 column and purified by Chromadog 2F using chloroform-methanol (150:1) as an eluent to obtain 475 m9 of purified product.

T L C; Rf,, -0,39 Example 1 19-deformyl-28-f Minenonru 23-0-
(N-Jf sil-endylcarbamoyl)-desmycosin 2/, 4/-diO-acetyl-19-deformyl-2'a-f mycinosyl desmycosin 176.1
+++9 (0.27mM') and 52.4cm (0.32mM) of 1.1'-carbonyldiimidazole were dissolved in 2.6ml of dichloroethane and stirred at 50°C for 1.5 hours.

The reaction solution was poured into ice water, and the p l-1 of the aqueous layer was diluted with IN hydrochloric acid.
After adjusting to ~3, 20 ml of chloroform was added for extraction. Water was added to the chloroform layer, the pH of the aqueous layer was adjusted to 7 to 9 with diammonium water, and the mixture was washed. The chloroform layer was dried over anhydrous magnesium sulfate/ram and concentrated under reduced pressure to obtain crude 2,4-di-O-acetyl-1!11-deformyl-
23-demycinosyl-23-O-(imidazole-
1-yl) carbonyl desmicron powder 192.
TLC to obtain 3 mg; Rf = 0.61 23-0-(imidazol-1-yl) carbonyl compound obtained above and 0.066 ml of N-methylbenzylamine (
1.5 equivalents) was dissolved in 2.3 ml of dichloroethane, and 7
Stir overnight at 0°C. Pour the reaction solution into ice water and remove the aqueous layer.
Adjust pH to 2-3 with hydrochloric acid, add 20 rnl of chloroform
was added and extracted. Water was added to the chloroform layer, and the aqueous layer was adjusted to pH 9 with 7% ammonia and washed. The chloroform layer was dried over anhydrous magnesium sulfate/rum and concentrated under reduced pressure. The residue was mixed with the developing solvent hexane-benzene-acetone-ethyl acetate-methanol (90:80:25:60:30).
) using preparative silica gel (Merck Art5717)
, 20 x 20 cm, 1 sheet) was purified by thin layer chromatography. After scraping off a spot around Rfo-0.8 and eluting with chloroform-methanol (1:1), the eluate was dried under reduced pressure to give 2',4'-di-0-acetyl-19-deformyl-23- Demai 7no/Lou 23-O
120.7 mp of powder of -(N-methyl-benzylcarbamoyl)-desmyconone was obtained.

TLC; Rfc=Q, 83 Dissolve 110.7 m2 of the 23-O-(N-methyl-benzylcarbamoyl compound obtained above in 5 ml of methanol,
The mixture was stirred overnight at 5°C. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 ml of chloroform, water was added, and the pH was adjusted to 9 with 7% aqueous ammonia and washed. After drying the chloroform layer with anhydrous magnesium sulfate/ram, Dry under reduced pressure 1
9-depormilou 23-demycinosyl 23-O-(
A powder of N-methyl-benzylcarbamoyl)-Tesmaicone was obtained. Yield: 95.9 mg.

H, CH3-12), 2.50 (s, , 6H, (
CH3)2N), 2.82.2.93 (each S,, total 30.N-Cl-13), 4.22 (d, .

2HX CH2-23), 4.29 (d
, , 11-1. H-1'), 4
．． 45(br, s,, 3H, -CH, C61-15
), 4.7-5.2 (br.

1 [1, H-15), 5.65.5.77 (each br
, d,, total I H, l-1-13), 6.26 (d,
r, d,, IHXH-10), 7.3-7.4 (6H
, -C6H5,H-11) MS (CI); 7
18 (MII''), 174 As a result of NMR, this compound was confirmed to be a mixture of 77 and anti isomers in the carbamoyl moiety.

Patent Applicant Toyo Jozo Co., Ltd. Representative Ito Registered Shima Proceedings Amendment/Small Case Indication 1982 Patent Application No. 7! ;792.2. No. λ\Name of the invention/9-deformyl-λ3-temainnonoru: 113-
0-K Rubamoyltes mycozone derivative and its manufacturing method 3 - Relationship with famous cases requiring amendments Patent applicant residence PJT 632 Sanpuku, Ohito-machi, Tagata-gun, Shizuoka Prefecture / Daily spontaneous SS amendment of the amendment order Target B - Details of amendment No. C/Negative line g "B, -2A <d-r-d,, / 8% H/"
[B, -2A (br, d, 7 / H-H/θ)”
I am corrected.

Claims (5)

[Claims] (1) Formula (wherein RI is a phenyl group which may have a substituent,
R2 is a hydrogen atom or a lower alkyl group; R3 is a hydrogen atom or a lower alkyl group; or a salt thereof. (2) 19-deformy V-28-demycinosyl 23
2. The compound according to claim 1, which is ru-0-(N-methylbenzylcarbamoyl)-tesmycosin or a salt thereof. (3) The hydroxyl group at position 23 is converted into an imidazolide by reacting with vinyldiimidazole, and the resulting imidazolide is given the formula (in the formula, R1 is a substituent). a phenyl group which may have
R2 is a hydrogen atom or a lower alkyl group, R3 is a hydrogen atom or a lower alkyl group) is reacted under heating, and then the protective groups for the hydroxyl groups at the 2' and 4' positions are removed. A method for producing a compound represented by a characteristic formula (wherein R1, R2 and R3 mean the same groups as above) or a salt thereof. (4) The manufacturing method according to claim 3, wherein the protecting group for the hydroxyl group is a lower alkamyl group. (5) The production method according to claim 4, wherein the lower alkanoyl group is an acetyl group.