JPH02191295A - 3,4-didehydro-3-deoxy mycaminosyl tylonolide derivative - Google Patents

Abstract

NEW MATERIAL:A compound (salt) shown by formula I (R<1> is H or OH). EXAMPLE:3,4-Didehydro-3,4'-dideoxy mycaminosyl tylonolide. USE:An antibacterial agent against a wide range of Gram-positive and Gram-negative bacteria. PREPARATION:For example, mycaminosyl tylonolide 9,20-bis(ethylene acetal) shown by formula II [A is (protected) carbonyl; B is (protected) aldehyde] is reacted with a halogenated alkylsilyl compound to give a compound shown by formula IV, which is reacted with binzylsulfonic acid and hydroxyl group at 4'-position is eliminated to give a compound containing a double bond at 3- and 4-positions and optionally hydroxyl group at 4'-position is iodated, substituted with hydrogen and protecting groups of carbonyl group and aldehyde group are removed to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a macrolactone compound having excellent antibacterial activity.

That is, the compound of the present invention is a 3,4-didehydro-3-deoxy mycaminosyltylonolide derivative represented by the following general formula (I) or a salt thereof.

In formula C, R1 means a hydrogen atom or a hydroxyl group. ) A 3,4-didehydro-3-deoxymycaminosyltylonolide derivative or a salt thereof.

(In the formula, 11 means a hydrogen atom or a hydroxyl group. The same applies hereinafter.) (Prior art) The target compound of the present invention is mycaminosyl silonolide or a 4'- This is a novel compound whose chemical structure is characterized by having double bonds at the 3 and 4 positions of deoxymycaminosyltylonolide. Conventional.

No such compound is known.

(Compound) That is, 9 the present invention is a compound of 3 or 4 represented by the general formula (I) above.
-didehydro-3-deoxy mycaminosyltylonolide derivative or a salt thereof.

The compound represented by the above general formula (I) can also form a salt. Examples of such salts include salts with inorganic acids such as hydrochlorides and sulfates, and formic acid.

Examples include salts with organic acids such as acetic acid and toluenesulfonic acid.

(Production method) The compound (I) of the present invention can be produced by the following method.

First manufacturing method (In the formula, A is a carbonyl group that may be protected.

B is an optionally protected aldehyde group, R2 is an alkylsilyl group, X is a)-rogen atom, and Y is 1 to 3
means a phenyl group optionally substituted with lower alkyl groups. The same applies hereinafter) Among the compounds of the present invention, 3,4-didehydro-3,4'-dideoxymycaminosyltylonolide represented by formula (Ia) is produced by the following steps.

(First step) The compound represented by the general formula (III) is a compound represented by the general formula (II)
It is produced by reacting the compound represented by the formula (■) with the alkylsilyl compound represented by the formula (■).

The carbonyl group or aldehyde protecting group of the compound represented by formula (II) includes those protected with acetal (or thioacetal), ketal (or thioketal), etc. Specifically, dimethyl acetal (dimethyl ketal), diethyl acetal (diethyl ketal),
These include diethylthioacetal (diethylthioketal), ethylene acetal (ethylene thioketal), and propylene acetal (propylene ketal).

Examples of the halogenated alkylsilyl compound represented by formula 2 (VII) include trimethylsilane chloride, triethylbromide, tri(tart-butyl)silane chloride, tert-butyldimethylsilane chloride, sexyldimethylsilane chloride, etc. .

The reaction is carried out in a solvent such as acetone, acetonitrile, tetrahydrofuran, benzene, chloroform, or dimethylformamide, preferably in the presence of an inorganic or organic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, pyridine, lutidine, picoline, or imidazole. The reaction temperature is from room temperature to elevated temperature.

(Second Step) In this step, compound GII) is reacted with benzylsulfonic acid or a reactive derivative thereof (Vllll). The benzylsulfonic acid used here can have 1 to 3 substituents such as methyl groups and ethyl groups on the benzene ring. Further, as reactive derivatives of benzylsulfonic acid, halides such as chloride and bromide, and acid anhydrides are used.

This reaction is usually carried out in a solvent under cooling or at room temperature. As the solvent, solvents such as acetonitrile, acetone, dimethyl sulfoxide, and dioxane can be used. Also,
Pyridine, triethylamine, etc. can also be used as a basic catalyst or as a solvent.

(Third step) A compound having double bonds at the 3 and 4 positions represented by the general formula (Vl) is added to the compound represented by the formula (IV) with an alkali such as sodium iodide, potassium iodide, lithium bromide, etc. It can be obtained by reacting metal halides. Acetone is used as the reaction solvent.

Methyl ethyl ketone, tetrahydrofuran, diosane, etc.

Further, the reaction temperature is from room temperature to heating. Heating may be performed near the boiling point of the solvent or at a temperature higher than that in a sealed tube.

In addition, in case of 2 non-reaction, if the reaction is to be completed in a short time,
Or when the reaction is carried out at low temperature.

It is also possible to isolate a compound (V) in which only the benzylsulfonyl group at the 4' position of compound ('Iv) is substituted with a norogen atom.

(Fourth Step) This step is a step in which a halogen atom at the 4' position of compound (Vl) is substituted with a hydrogen atom, and then a protective group is removed if desired.

First, examples of substitution of halogen atoms include trialkyltin hydrides such as triethyltin hydride and tri-n-butyltin hydride, and triaryltin hydrides such as triphenyltin hydride.

Suitable reaction solvents include toluene, benzene, dioxane, tetrahydrofuran, and the like. This reaction proceeds at room temperature or under heating, but it is preferable to add a radical initiator 1, such as .alpha..alpha.'-azobisisobutyronitrile (AIBN), to accelerate the reaction.

If the compound obtained in the above steps has a protecting group,
Protecting groups are removed if desired. Removal of the protecting group of the aldehyde group is usually carried out using hydrochloric acid in the presence of water.

Treat with a mineral acid such as acetic acid or an organic acid such as trifluoroacetic acid or trichloroacetic acid. In addition, in addition to the acid used to remove the aldehyde group, the ketal protecting group can be removed using
It is also possible to treat with an alkyl sulfonic acid such as arylsulfonic acid, methanesulfonic acid, etc. with % p-)luenesulfonic acid. This reaction is carried out in a solvent such as dioxane, dimethylformamide, dimethyl sulfoxide, or acetonitrile.

It is carried out at room temperature or under heating.

(Second Production Method) Among the compounds of the present invention, 3,4-didehydro-3-deoxymycaminosyltainoralide represented by formula (Ib) can be obtained by the method shown by the following reaction formula.

(In the formula, R3 means an acyl group. The same applies hereinafter) (1st
Step 2) The compound represented by formula (IX) is produced by acylating the compound represented by (m).

The acylation reaction can be performed using acid halides such as acetyl chloride, acetyl bromide, propionyl chloride, pivaloyl chloride, benzoyl chloride, acid anhydrides such as acetic anhydride, benzoic anhydride, or G! acid,! -p-
Active esters such as nitrophenyl ester, 2,4-dinitrophenyl ester, etc. can be appropriately employed in consideration of the reaction conditions. Furthermore, the acid can be used in the form of a free acid or a salt thereof, and in this case, the dehydration is carried out in the presence of a dehydrating agent such as hydrochloric acid or sulfuric acid.

Reaction solvents include water, acetone, and dioxane.

Acetonitrile, chloroform, benzene, dichloromethane, tetrahydrofuran, ethyl acetate.

It is a commonly used solvent that does not adversely affect the reaction, such as N,N-dimethylformamide and pyridine, or a mixed solvent thereof. The reaction temperature is not particularly limited, but is usually under cooling or heating.

Hereinafter, the second two steps, the third two steps, and the fourth step are performed according to the deprotection methods of the second step, third step, and fourth step of the first production method, respectively.

The target compound (I) thus produced is isolated and purified by extraction with an organic solvent, recrystallization, column chromatography, etc.

(Effects of the Invention) The compound (I) of the present invention exhibits antibacterial activity against a wide range of microorganisms belonging to Durham-positive and -negative bacteria.

In particular, the compound (1) of the present invention is suitable for S. taphylococcus, for which conventional macrolide compounds do not show antibacterial activity.
cusaureus (Staphylococcus aureus) MS8710, 5taphylocoeua a
ureus (Staff 40 Kotsukas aureus) M
It also has excellent antibacterial activity against macrolide group A-resistant bacteria such as S9610.

To use the compounds of the invention as medicines.

Tablets, powders, and granules can be used as usual pharmaceutical carriers.

It is prepared into capsules, injections, etc., and administered orally or parenterally. Administration: 50 to 2,000 doses per day for adults
Divide (①) into 1 to 4 times.

(Example) Examples are shown below to explain the nine compounds of the present invention in further detail. The manufacturing method of the raw material compounds in Examples is shown as a reference example.

In the examples, Mass means a mass spectrum, and 'H-nmr means a hydrogen nuclear magnetic resonance spectrum.

Example (1) 3.00 g of tyronlide 9.20-bis(ethylenemycaminosylsilonolide 9.20-bis(ethylene acetal)) was added to 23-0-t-butyldimethylsilylphicami/'/ in anhydrous form. Dissolved in 24mZ of dimethylformamide, 1g of imidazole 536ff and t-butyldimethylsilane chloride. After concentrating the reaction solution, the residue was diluted with saturated hydrogen carbonate). Added to 300mA of IJium aqueous solution, extracted with chloroform, washed the organic layer with water, and dried. Concentration gave a syrup. Silica gel column chromatography (
Purified with Fuco-gel C-200; 120: 0.1) to give 23-o-t-butyldimethylsilyl minocylsilonolide 9.20-
Bis(ethylene acetal) (3,01g (yield 86%)
) was obtained as a colorless solid.

Physical and chemical properties (1) [α] u 10° (c 1. CHCl5) (
11) Elemental analysis (C41HtsNOu Si・1/2
As H10) C (%) H (%) N (%) Experimental value 60.84 9.04 1.83 Calculated value 60.86 9.22 1.73 (fti)
Mass m/z=800 (M”) (2)
3.4'-di-0-benzylsulfonyl-23-〇-1
-Butyldimethylsilyl Myrikiminosyltylonolide 9.20-Bis(ethyleneace23-0-t-Butyldimethylsilyl Myrikiminosyltylonolide 9,2
1.00 g of 0-bis(ethylene acetal) was dissolved in 20 ml of anhydrous pyridine, cooled to -40°C, 0.67 g of benzylsulfonyl chloride was added, and the mixture was heated to -20°C and reacted for 90 minutes. After adding 0.67 ml of water, the mixture was returned to room temperature, stirred for 1 hour, concentrated, and 100 ml of a saturated aqueous solution of hydrogen carbonate (IJ) was added, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain unstable, unpurified 34'-di-0-benzylsulfonyl 23-〇-t-butyldimethylsilyl mycaminosyltai 9 nolide.9. 20-bis(ethylene acetal) (1.38 g) was obtained as a pale yellow solid.

(3) 23-0-t-butyldimethylsilyl-3
, 4-didehydro-3,4'-dideoxy-4'-iodomycaminosylsilonolide 9.20-bis(ethylene acetal) Obtained in Reference Example 2. 3.4'-di-0-benzylsulfonyl-23-0-t-7'' tildimethylsilyl
9. Dissolve 1.32 g of the crude product of 20-bis(ethylene acetal) in 25 mA of anhydrous 2-butanone, and add 0.94 mA of sodium iodide.
g was added thereto, and the mixture was heated and stirred at 80° C. for 6 hours under an argon atmosphere. The reaction solution was cooled to room temperature, filtered and washed with acetone, the P washings were combined and concentrated, and the residue was extracted with ethyl acetate.

The organic layer was washed successively with a saturated aqueous sodium carbonate solution, a 0.1M aqueous sodium thiosulfate solution, and a saturated saline solution, dried over magnesium sulfate, and concentrated to obtain a yellow syrup. This was subjected to silica gel column chromatography (Wakogel C-
200.60g, benzene:ethyl acetate=55:10)
Manufactured by C1, 23-0-t-butyldimethylsilyl 3,4-didehydro-3,4'-dideoxy-4'-iodo mycaminosyltai 9nolide 9,20-bis(
0.33 g of colorless solid (ethylene acetal) was obtained.

Physical and chemical properties (1) [α37. -72°(c1.CHCl3)
(11) Elemental analysis (C41H?.NIO,.Si) C (%) H■) N (%) I (%) Experimental value 55
．． 09 7.80 1.47 13.97 Calculated value 55
．． 21? , 91 1.57 14.23 (flD
Mams m/z = 892 (M”) (4
) 23-0- t-butyldimethylsilyl-3,4
-didehydro-3,4'-dideoxy minosyltylonolide 9.20-bis(ethylenea 23-0-
t-butyldimethylsilyl-3,4-didehydro-3,
4'-dideoxy-4'-iodomycaminosyltylonolide 9.20-bis(ethylene acetal) 0.
23 g' anhydrous Hensen? , 0.22 ml of tributyltin hydride dissolved in 5 ml of 1. Add 10 cm of azodiisobutyronitrile.

After purging with argon, the reaction was carried out at 80°C for 2 hours. 2 hours later 2
The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (30 g of Wakogel C-200, hexane:acetone (3:1) 80 mA → chloroform (120 ml).
) → Chloroform: Methanol: @Aqueous ammonia = 10
:1:0.1) to separate and purify 23-0-t-butyldimethylsilyl-3,4-didehydro-3,4'-dideoxymycaminosylsilonolide 9.20-bis(ethylene acetal). 185 rQg of colorless solid (yield 94
%) was obtained.

Physical and chemical properties (1) [α]l'+ 53° (c 1. CHO5)
(II) Elemental analysis (C++ Hlt Not. 5t-
H, o) C (%) H (%) N (%)
Experimental value 63.02 9.12 1.76 Calculated value 62.80 9.13 1.79 (i!OMI
LBII m/z = 766 (M”) (5
) 3.4-didehydro-3,4'-dideoxycaminosyl tylonolide my23-0-t-butyldimethylsilyl-3,4-didehydro-3,4'-dideoxy mycaminosyl tylonolide 9.20 -Bis(ethylene acetal) 155
Dissolve 1 g of ff in 2.3 rnl of acetonitrile,
．． 4.6 ml of 5M hydrochloric acid was added and the mixture was left at 40°C for 2 hours. To the reaction solution, 20 m/ml of saturated deuterated water was added and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain a yellow syrup. This was purified using silica gel column chromatography to prepare 1 # Wako Gel C-200, 7.5 g, chloroform:methanol:concentrated ammonia water = 10:1:0.1) 3.4-didehydro-3,4'-dideoxy. Minosyltylonolide (86.6 mg, yield 76%) was obtained as a colorless solid.

Physical and chemical properties (1) [α B -28° (c 1. C
HCl5 ) (11) Elemental analysis (Cs+ H*e
(as NOa) C (%) H (%1 N (%) Experimental value 65.55 8.57 2.13 Calculated value 66.05 8.76 2.48 (iiOMa
sa m/z = 564 (M”+1)
(iV) 'H-nmr (CDCl, TMS internal standard) δ0.96 (3H,t, CHs-17) 1.
76 (3H, s, CHs 18) 1.83 (3H,
d, CHs 22) 2.27 (6H, s, 3'-N
Met) 2.35 (IH, m, H-2a) 2.4
5 (IH, m, H-3') 2.75 (IH, m, H
-2b) ~3.7 (2H, m, H-23a, b)
4.00 (IH, d, H-1'.

J+' zI= 7.3 Hz) 4.36 (IH,b:, )(-s)5.55 (
IH, t, H-3) = 10Hz) 6.23 (IH.

7.14 (IH, d, H-11) 4.94 (IH, m, H-15) 5.75 (I H, d, H13, Jrs 14d,
H-10,J. , ,, =16Hz)9.76
(IH, s, 2O-CHO) Patent applicant Seiya Fujino, agent of the Microbial Chemistry Research Foundation, patent attorney

Claims (1)

[Claims] 1. 3,4-didehydro-3-deoxymycin represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 means a hydrogen atom or a hydroxyl group.) A caminosyltylonolide derivative or a salt thereof.