JPS59225198A - Antibacterial 9-deoxo-9a-aza-9a-homoerythromycin a and intermediate - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel derivatives of 9-deoxo-9a-aza-9α-homoerythromycin A and its 4"-epimer useful as antibacterial agents, their intermediates and the above-mentioned d5 conductors, their Related to the method for producing intermediates.Details;'III is 9
-deoxo-9a-aza-9α-homoerythromycin 71&tJ' 1 for the cyclic ether derivative of its epimer
．． g4, further acid addition salts thereof, use of the above-mentioned compounds as antibacterial agents, intermediates of the above-mentioned compounds, suitable for use as pharmaceuticals;
and related to their manufacturing methods.

Erythromycin A is a macrolide antibiotic produced by fermentation and is described in US Pat. No. 2,653,899 (4J). A number of derivatives of erythromycin A have been produced to modify its biological and/or pharmacokinetic properties. The ester amount of erythromycin A with mono- and dicarboxylic acids is An
ti6iotics Ann, ual.

1953-1954, Pro
c, S'/rn, posiqtmAntibiotic
s (Washington, D.C.) 500-5
Reported on page 13 and waves 514-521. US Patent No. 3,417,077 describes cyclic carbonate esters of erythromycin A, reaction products of erythromycin A, and ethylene carbonate as active antimicrobial agents.

U.S. Patent No. 4.328,3, issued May 4, 1982.
No. 34, 9-deoxo-9α-aza-9a-homoerythromycin A was converted into 11-aza-10-thioquino-
It is described as 10-dihydroerythromycin A. The above-mentioned compound fd is a ring-expanded (homo) derivative of erythromycin, and is also a compound in which a nitrogen (aza) atom is introduced into the ring system, so the ALjQ of the compound of the present invention includes:
The nomenclature of 9-thioquine-9cL-other 9a-homoerythromycin A is favorable.

Belgian patent number 892, issued June 1, 1982.
357 and its UK application 2,094°293A
(published September 15, 1982) contains 9-deoxo-
9cL-aza-9a, -N- of homoerythromycin A
Does it describe the methyl J4 body? This is 198
U.S. Chamberlain Application No. 399,401 filed July 19, 2013
U.S. Patent Application No. 4 seeking priority recognition from No.
No. 41,981 (filed on November 15, 1982) is in dispute.

U.S. Patent No. 4,382,08 issued May 3, 1983
No. 5 contains 4-ebierythromycin A, that is, 4〃-O
Compounds in which the H group has an axial bond are described.

The 4-011 group of erythromycin A is an equatorial bond.

It has been found that 9-thioquine-9a-other 9α-po←erythromycin A and its 4"-specific cyclic ether of epimer 2 are effective antibacterial agents against Durham-positive and Durham-negative bacteria. The object has formula (1).

CIi3 where n is 1.2 or 3; the wavy line at the 4"-position is generic and includes both epimers. If n is 1, then 4"
“-Hydroxy group is an equatorial bond.
In the case of JI'i3, the epimer form of the above compound is ¥i
"", only the bond at the chiral center at the 4"-position is different.

That is, the 4"-OH group is an axial and equatorial bond. An axial bond is represented by a solid line or a wedge shape, and an equatorial bond is represented by a broken line.

"Axial" and "F-atorial" F used here
Two possible chiral epimers are represented for the 4"-hydroxyl and hydrogen in iC-4".

The present invention also covers acid addition salts of the above-mentioned compounds which are suitable as pharmaceuticals and which are used for the same purpose as the compounds of formula (1). These salts include, but are not limited to, the salts listed below, such as, but not limited to, hydrochlorides, hydrochlorides, sulfates, phosphates, formates, acetates, propionates, butyrates, citrates, glycols. Acid salt, lactate, tartrate, malate, maleate, fumarate, gluconate, stearate, mandelate, pamoate, benzoate, succinate, p-F luenesulfonic acid salt, aspartate.

The scope of the present invention also includes a process for producing formula (1) and intermediates useful for its production. The intermediates are represented by formulas (1) and (III) below.

In the formula, R1 is -(C1l,)pCM or (ma-(Cl12
) m, NHt "p is 1 or 2; m is 2 or 3.

The wavy lines at the 4''-position in 2 and 2 represent both epimers, ie, axial and equatorial bonds at this position.

The present invention further encompasses compounds of formula (IV') which are formed as by-products (where n is 3) in the preparation of compounds of formula (1).

The wavy line at the 4"-011 group in the formula represents, at this position,
Represents axial and equatorial bonds.

Formulas (1), (It) and (■), acid addition salts thereof which are suitable as pharmaceuticals, are suitable for Durham-positive bacteria, e.g. m
tt, Ltocida) 1, r-4 Tuceria 27
±Z for h (Neisseria 5icca)
In addition, the compound of formula (1) IrJ-winterΔtwootjwo↓τ Neisseria gonorrhea and Haemophilus <l1aernophi Lqbs) It shows excellent activity against many Durham-positive and Durham-negative bacteria in vitro and is active against many Durham-positive and Durham-negative bacteria in vivo. For oral anti-infective activity, compounds of formula (1) have 9-deoxo-9
It is completely different from the corresponding 9-deoxo-9α-aza-9α-homoerythromycin A, which has no Nissin properties.

The compound of formula (1) where the number is 3 is a suitable 9-deoxo-
It can be produced by cyanoethylation of 9a-aza-9α-homoerythromycin A epimer. Acrylonitrile is used in excess and is used as both reactant and solvent. The reaction is generally carried out at the reflux temperature of acrylonitrile, about 77°C.
Continue until the reaction is complete. For example, it is possible to carry out the reaction at a low temperature such as 50°C, but since the reaction time becomes longer, it is better not to react at a lower temperature. Using a reaction inert solvent other than excess acrylonitrile, that is, a solvent that does not enter the reaction system together with the reactants and/or products and does not adversely affect the yield of the desired cyanoethyl visiting conductor, and further Can react at high temperatures. Of course, the reaction-inert solvent can be used at any temperature at which the reaction will proceed. Suitable solvents are CI-, alkanols; cyclic or acyclic ethers, such as dioxane, tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether; aromatic hydrocarbons, such as benzene, toluene, xylene. However, it is a good practice to use excess acrylonitrile as solvent.

The reaction progresses using a silica gel plate, cIltc'v'
CHs OII/(mNIh011 (6/i10.i
), spray with vanillin/ethanol/H3PO4, heat, and check. The solvent is evaporated and the product is obtained as a colorless foam. For convenience, we can make 4 steps to use in the next step. ? 'LC indicates that it is essentially a monocyanoethylated product. slight opening 1
The presence of diluent products was also detected by TLC.

The thus obtained 9α-cyanethyl derivative was hydrogenated with Raney nickel according to the method described below to obtain the corresponding 9α-cyanethyl derivative.
Convert to a-(gamma-aminopropyl) derivative (II). This is reacted with at least a stoichiometric amount of isoamyl nitrite and glacial acetic acid according to the method described below to convert it into the corresponding seven-membered ring, cyclic needle. At this time, the corresponding 9a-(gamma-acetoxypropyl) derivative, a compound of formula (IV), is obtained as a by-product.

For compounds of formula (1) where n is 2, the appropriate 4"-01i epimer of 9-thioquine-9-aza-9a-hydroxy-9a-homoerythromycin A3'-N-oxide is added in a reaction-inert solvent. It is prepared by alkylation with excess bromoacetonitrile at 20° C. to 100° C. (room temperature is preferred). Suitable solvents include dihalokenated hydrocarbons such as methylene chloride and chloroformamy; aromatic solvents such as benzene, toluene, and xylene. Group hydrocarbons; ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, and diethyl ether.

The reaction is carried out in the presence of an acid acceptor, such as a C,-, ) argylamine, an organic base such as pyridine, or an inorganic base such as an alkali metal carbonate or bicarbonate. The acid acceptor is used in an equivalent amount to the excess bromoacetonitrile used to achieve optimal conversion of the macrochloride reactant to product.

In the presence of 1) d/C in an inert solvent such as ethanol, (
2) Hydrogenation and removal of 9α- and 3'-oxides to obtain a cyanomethyl compound of formula (II) where p is 1.

The 9α-cyanomethyl derivative thus obtained (formula (■
)) with sodium borohydride in the presence of cobalt chloride in a solvent with or without hydroxy groups at room temperature to give the corresponding 9α-(beta-aminoethyl) derivatives. In this reaction, the molar ratio of CoCl to NaBH is preferably 1:5. In practice, NaBH, is used in excess, e.g. 10 moles of Na to 1 mole of substrate.
BH, is used.

The corresponding 6-membered mfE-like ether is obtained by reaction of the 9α-(beta-aminoethyl) derivative with at least a chemical amount of amyl subate/glacial acetic acid.

The 5-membered ring of formula (1), the cyclic needle (equatorial coordination to rL-1,4'-○H), is 9-thioxo-9α-aza-9α-homoerythromycin Af: 1-4 equivalents of formaldehyde (37 % aqueous solution) and formic acid in a reaction inert solvent at room temperature. Typical solvents are logenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride.

This reaction is limited to relatively low reaction temperatures.

The reaction proceeds easily at about 15°C to 30°C (20°C to 25°C is better). For example, when the reaction is carried out at a high temperature such as reflux temperature, 9α-methyl derivative 6 is produced KSj.

That is, reductive methylation occurs. Methylation occurs exclusively at high temperatures of about 50°C. However, under our reaction conditions, cyclic ether formation is
Occurs between 11 and 9a-aza groups.

Compounds of formula (1), (IID and (IV); R1 is -<
Cll2) Combination of 2' and/or 4''-hydroxy groups in aCM! proboscis 1;t,, 1;'+1 For example, Jones et al., J, Mecl, Chem, ! 5, 631 (1
972): Bana, 5zelc, etc.
cy, Chent, 43.

The corresponding 02-3 alkynoyl derivatives can be prepared by n-method acylation, such as in the method in 763 (1,969). The 2'- and 4"-hydroxy groups are acylated by reaction with a suitable acid anhydride (eg (R2CO) to) in pyridine. By solvolysis of the 2',4"-ester with methanol! l14"-ester is obtained.

Mixed esters, e.g., 2'-acetyl-4"-propionyl-, can be prepared by reacting 4"-ester (11, = 7" robionyl) with potassium carbonate in an inert solvent according to the mixed ester preparation method of John et al. (described above). It is first produced by reacting with acetic anhydride in the presence of if.

The acid+J salts of this invention are prepared by reacting a compound of formula 1-4V with at least an equivalent amount of the appropriate acid in an inert reaction solvent. In the case of hydrochloride, it is reacted with pyridine hydrochloride. Since more than one basic group is present in the compound of formula I or H, enough acid is added to give rl:2 for each basic group.
It is possible to produce a wide variety of addition salts. 2'-0
When preparing 1W acid addition salts of compounds of formulas I-IV in which 11 is acylated, Impropatool is used as a solvent to prevent solvolysis of the alkanoyl group. Acid addition salts can be prepared by filtration if insoluble in the reaction inert solvent, precipitation by addition of a non-solvent to the C1,:2 addition salt, or evaporation of the solvent. Bacteria, such as spherical or oval (coccus) bacteria, have the formula (1), (1
Sensitive to compounds 1) and (IV). 3Z
In vitro activity was determined using the 2-fold dilution method in brain-heart infusion medium at 1! Various types of bacteria can be easily tested using in vitro assays. Above them y M) above (to activate the sword),
Topical application in cream form; sterilization of equipment in hospital rooms; water treatment, sludge treatment! It is useful for use as an antimicrobial agent in industrial applications such as paints and wood preservatives.

The selected compounds may be conveniently formulated into lotions, ointments, creams, or gels by methods known to those skilled in the art for use in general administration, such as for topical application. . For this purpose d) the active ingredient is added to about 0.0 of the total ingredients.
It is common to use concentrations of 1 percent to 10 percent (by weight).

The method of administration is to apply any amount to the site of infection, generally at least once a day.

Furthermore, the compounds of formula 1 of the present invention are active against Gram-positive bacteria and certain Gram-negative bacteria in animals, including humans, in vivo by oral and/or parenteral administration. These in vitro activities are well-restricted with respect to the affected microorganisms, and are demonstrated by infecting mice of substantially uniform body weight with the bacteria being tested and then administering the test compound orally or by subcutaneous injection. , examine its activity. In practice, for example, 10 mice are injected with LDlon (1
The minimum concentration of bacteria necessary for 00% death) is approximately 1 to 1
A 1:00 diluted bacterial culture is inoculated intraperitoneally.

To check for changes in the virulence of the test bacteria, a baseline test is performed simultaneously using mice inoculated with low dilution bacteria.

Test compounds were administered 30 minutes after inoculation, and administration was repeated 4,24, and 48 hours later. Four days after administration, surviving mice are retained and the number of survivors is recorded.

For in vivo use, these new compounds can be administered orally or parenterally, such as by subcutaneous or intramuscular injection, in doses of about 1 mg to 20 g per body weight per day.
Administer 0m9. A good dosage range is about 5 lng
/try/day to 100 mg/kg 7' day, preferably about 5 mti/kg/day to 50 mg/9/day. Good vehicle systems for parenteral administration include aqueous vehicles such as water, isotonic saline, isotonic dextrin aqueous Ringer's solution; vegetable oils (cottonseed oil, peanut oil, corn oil, sesame oil); Non-aqueous vehicles such as dimethyl sulfoxide; other non-aqueous vehicles (glycerin, polyethylene glycol, sorbitol) that do not prevent the therapeutic effect of the formulation and are non-toxic in the volume or ratio used. Furthermore,
It is advantageous to prepare a composition suitable for an instant solution prepared prior to administration.

Such compositions include liquid diluents such as propylene glycol, diethyl carbonate, glycerin, sorbitol; buffers; hyaluronidase; local anesthetics;
Contains inorganic salts and is good! Gives physical activity to I.

These compounds are mixed with a pharmaceutically suitable inert carrier such as a solid diluent, an aqueous vehicle, a non-toxic organic solvent,
Capsules, tablets, lozenges, troches, dry mixtures, ) ``static agents, bath solutions, elixirs, parenteral solutions or! l
i, '4 It can be made into the form of candle liquid. Generally, compounds are
Various dosage forms are used at concentrations of about 0.5 to 90 percent of the total composition.

The examples set forth below are not intended to obtain the highest yield of product produced or to achieve the highest yield of product. The examples are merely illustrative of the steps and products obtained therefrom.

In all examples, [vanillin/ethanol/1i
3Po, spray” and “Vanillin // to PO, spray” contain 1.0 g vanillin, lOOml ethanol and 100ml/! represents a solution of H3PO4.

Example 1 4″-epi-9-deoxo-9α-(betacyanoethyl)-9a-aza-9a7-homoerythromycin A 4″-epi-9-deoxo-9α-aza-9α-homoerythromycin A (11,6L 15 .8 mmol) Dissolve in 10 (1 m(!) of acrylonitrile.

The solution was refluxed for 19 hours and then concentrated under vacuum to give an ivory colored foam. TLC check (silica gel plate; C
H2Cl2/CII, OH/NJI, 0II=6
/ 1 / Expanded in 0.1: Vanillin / Ii, P
Spray with O, V; Heat; I? , f 0951) contains trace amounts of impurities (high IX properties). Shows a single product (less polar). This is used in the next step without being purified.

"CnrnrCCDCL3 H(C1f3)4Ss internal standard') pprrL177.92 (Lactone"; c=
o), 118.86 (-C3N), 102.49 CC
-1'), 96.04<C-1''), 4 0.
2 5 C(C1is)2N 3゜Example 2 4"-epi-9-degiso9cL-(comma-aminopropyl)-9α-aza-9a, -homoerythromy25
12.8. dissolved in 0 ml of absolute ethanol. '7 (
16,2 mmol) of 4"-epi-9-thioxo=9a
-(beta-cyanoethyl)-9cL-aza-9a-homoerythromycin A +? ) K't 'c 12.
8/? Raney nickel catalyst (50% water-humidity) and bar /L/ (7) +7 in 50 ps.
i (3,521c97cm2) for 19 hours. TLC check (silica gel plate: C11C1
, /C1130H/concentrated NIi+OH= 6/1/ 0,
Developed with 1; vanillin/ll3P Q4 spray: heating; reaction is complete according to RfO, 13). When the catalyst is filtered and the p liquid is concentrated, a foamy substance is obtained.

Dissolve the phase-forming acid in approximately 100 m/ml of methylene chloride. Shake the solution with an equal volume of saturated sodium carbonate water,
Separate the organic layer. Dry with II sulfate and concentrate in vacuo to give an ivory foam (io, sg). Crystallize with hot ether to obtain 4.0 fl. 771. , p
, 135°C (decomposition) 13Cnrnr L CI) C1B
+ IC'13)4 Internal group! ','S〕
Irprn177.07 (Lactone C=O) 10
2.22 ((,”/ 1′), 95.77 (C-1″), 40.30 C
(0/3)2N-).

Example 3 4″-epi-9,11-thioquine-11beta, 9α=
(Epoxypropano)-9cL-aza-9a-homoerythromycin A [formula (Iin1.L=3,4rr-axialhydroxy] and 4"-shrimp-9-thioquino-9
α-(comma-acetoxypropyl)-90L20ml
4"-shrimp-9-deoxo- dissolved in chloroform of
9cL-(gamma-aminopropyl)-9α-aza-9
574 #1 g (0.66 ml;
4.9 mmol) amyl nitrate and 51,1111
g (8.52 mmol) of glacial acetic acid.

The mixture is refluxed vigorously for 1 hour. According to TLC Elag (silica gel plate: briefly immersed in formamide/acetone solution for 1 moment and air-dried; developed with Cl1C1,/acetone-1/1; vanillin/1isPO4 spray: heated), the reaction was completely completed, It shows the presence of two main products.

The reaction mixture '150d was shaken with 10% potassium carbonate water and the organic layer was separated. Wash with 50H saturated saline,
Dry with sodium sulfate.

Precipitate under vacuum to obtain a colorless foam. (3,17j7) Formamide-treated silica gel was prepared in a well-stirred solution of 30 (l of silica gel (230-240 mesh)/600 ml).
Add 120ml of formamide to the acetone slurry,
A powder is obtained by removing the solvent on a rotary evaporator. The crude product is purified by chromatography using 300I formamide-treated silica gel, eluting with CIJct3/hexane = 98/2, and checking the fractions with tic (the above-mentioned development system). Two components purified by reaction: the listed compound (low polarity, 344m'?, 10% yield)
and 4"-shrimp-9-thioquino-9α-(gamma-acetoxypropyl)-9α-aza-9α-homoerythromycin A (400 mF, 11% yield), isolated as a colorless amorphous solid.

The title product purified by chromatography is then crystallized from acetone/water (yield 94~, m, p, 139-
141°C) 4″-shrimp-9,11-deoxo-11beta.

9α-(epoxypropano)-9α-aza-9α-homoerythromycin A: “Hnrnr (CDC4s)
Delta 2.28 CG 11, 8, <C11s)J
J), 3.28 (3H28, Fraginose CII
BO-] ;, “C-nrnrC, CDCl2, (
Cll3)4 S i internal standard) pprn 176.
28 (Lactone ゛'''C=O), 102-36 CC-
1'), 96.18 (C-1"), 40.26 CC
CH3)2A': ]: Mass spectrum (ηL, /e
)774 (molecular ion), G16.4.599.4.4
58.3.442.3.158.2.127.1゜4"-shrimp-9-deoxo-9α-(gamma-acetoxypropyl)-9rz-a+1'-9α-homoerythromycin A: 'H-nrnr (CDCl2) delta 2.02 (3H,s, C11sC), 2
．． 27 (611, s.

1CCH3)tN), 3.28 [11,s, fradinose Cll30-).

Example 9 - Thioquino-9α-(beta-cyanoethyl)-9α
-aza-9α-9-deoxo-90,-aza-9α in acrylonitrile of homoerythromycin A10ml
- Dissolve homoerythromycin A (1.0 g). The mixture is refluxed for 6 hours.

Then stir overnight at room temperature. Concentrate the mixture in vacuo to
A brown foam is obtained. Silica gel (40,9,70-
230 mesh), ctt2ct2/Cl-40
The crude product was purified by chromatography flowing out with a mixed solvent of B'/#ammonia = 10/110.1, and the fraction was tic (silica gel plate: C1bC1t/Cl1s0
Developed with 11/concentrated ammonia=6/I10.1 and checked with vanillin/H3PO4 spray and heating; R10,57) to obtain the title compound as a colorless foam.

605 evenings (56% yield).

'II-nny (CDC4) delta 2.34 (6/
:/, s.

(C#3) 2A':), 3.33 (311-s
, fradinose C1l, O-) ; '3C-nrnr
CCDC13+ ((,”#,), Sj internal standard) p
pmx 77.62 (Lactone C=O), 118.
85 (-C-N), 103.01 (C-1'), 9
5-91(C-1"), 40.33'[(C1is)
2N: ].

Example 5 9-deoxo-9α-(gamma-aminopropyl) 52
A solution of 47 g (59.6 mmol) of 9-deokine-9α-(beta-cyanoethyl)-9α-aza-9α-homoerythromycin A in 0 mA' ethanol is mixed with 47 g of Raney nickel catalyst (50% water-wet). and hydrogenated in a Parr apparatus at 50 psi for 2.75 hours. In TLC check (silica gel plate:
CIICLs/Cl1sOII/INIi+ OII
= Expanded at 6/1/0.1; Vanillin/1f
3PO, spray; heat), indicating that the reaction is not complete at this point. To the mixture was added another 25 g of catalyst and heated to 50 psi (1.2
Hydrogenate for 5 hours. The catalyst was filtered and Part F was concentrated in vacuo to yield a colorless foam (10%). The crude product is dissolved in 600 ml of ethyl acetate. Stir the solution with 800-6N water.
- Adjust pH to 9.5 with sodium hydroxide. The organic phase is dried over sulfuric acid and concentrated in vacuo to give a foam. Silica gel chromatography (800g, 70-
230 mesh), ClIC1, /CII, O
H/concentrated NH4011=6/110. o 5CRf
0.15), 14. '# pure title compound is obtained as a colorless foam (31% yield).

Crystallize 1.1g of sample with diethyl ether to give 545■
colorless crystals are obtained. m, p, 180-183°C.

'If-nrnr (CDCAs) delta 2.30
(6#, 8.

CCH3) 2, IV), 3.32 (3H, 8,
Fradinose C11sO): “Cnmj”CGDC4
1° (C113), sz internal standard] ppm177.0
1 (lactone C=0), 102.69 (C-1
'), 95°27 (C-1"), 40.33 [CCl
l5)2N).

Example 6 9.11-thioquine-11beta,9α-(epoxypropano)-9a-aza-9a-homoerythromycin A
[Formula (1), n = 3, 4//- equatorial hydroxyl] and 9-deoxo-9α-(gamma-acetoxypropyl)-9a-aza-9α-homoerythromycin A 128 mJ? 9-deoxo- dissolved in chloroform of
9α-(gamma-aminopropyl)-9a-aza-9a
- 1.01 g (1.16 ml.

8.63 mmol) of nitrous to amyl and 0.97
g(0,92+n), 16.2 mmol) of ice (Il
Ej:i'&lr, and rinse the mixture thoroughly for 1 hour. The mixture was stirred with 150 ml of water, rubbed with J0 Japanese charcoal fβ hydrogen, and brought to pH 8.0 with IJum. Separate the shoulder layer and wash with an equal amount of water.

Dry with a ram and tighten under vacuum to remove a yellow foam. 7" LC check shows the presence of crude product Ll: + 2 main products. (Silica gel plate, 15:85, flash immersed in formamide/acetone solution. Then air-dried, Cf1C1J acetone = 1: 1
Developed with vanillin/If3P O, sprayed, heated)
.

900 g of formamide-treated silica gel was mixed well.
Silica gel (230-400 mesh)/1800m/
Add 360ml of formamide to the acetone slurry,
The solvent is distilled off using an evaporator to obtain a powder. The crude product (5,8,&)(il - Purify.

The fractions collected in 5 ml aliquots are checked using it l"lc (the system described above). In this way, the two components produced by the reaction - the listed compound (low polarity) (0.79 g, 13% yield) ) and 9-deoxo-9α-(gamma-acetoxypropyl)-9a.

-Aza-9α-homoerythromycin A (0,761
112% yield) as colorless, amorphous solids.

9.11-deoxo-11beta,9a-(epoxypropano)-9a-aza-9a-homoerythromycin A
:'II-nnw (CDCAs)te)L#2.
30(611,,s,(C1is)tN-1,3,
33 (311,s, fradinose CHsO-):
"C-nm, r CCDCLB) pprn176.
3 (lactone C=0), 103.2 ((,? -1
'), 103.2 (C-1'), 96.2 (C-1")
), 40.4 ((CIi8)2N-); f :2
．． Spectrum (m/e) 616.599.458
．． 442.158.127゜9-deoxo-9a, -
(gamma acetoxib o pill)-9α-aza-9α-
Homoerythromycin A: '1i-nTnr (C
DC1B) Delta 2.01 (31-1°s, CHs
C), 2.29 (3H,s, (CH3)2/
11'), 1 3.31 (311,s, fraginose closed, 0->
; Mass spectrum (+>t/e) 834.6° Example 7 9-deoxo-9α-(cyanomethyl)-9α-aza-
9a-homoerythromycin A3', 9α-bis-N-
1)-deoxo-9 dissolved in chloroform of oxide 138H
α-Hydroxy-9cL-aza-9α-homoerythromycin A3”N-oxide (11,0,9,14,4
79 g (0.57 mol) of anhydrous potassium carbonate and 69 g (0.58 mol) of bromoacetonitrile are added to the solution. The mixture is stirred at room temperature for 5.25 hours. tic check (silica gel plate, CHCAs/C
l1s OH/ill! ! N & Off = 6 /
Developed at 110.1; vanillin/HsPO+spray, heating), the starting material is consumed and the product (low polarity, lcofO
028) is shown. This indicates the presence of trace amounts of impurities. The mixture was filtered and F# was evaporated to give a viscous oil. The oil is stirred in 600 rue diethyl ether to give a granular solid, which is filtered. 1
Wash with 00ml needle and dry once. The title compound thus obtained (10.4 g, 9.9% yield, colorless granular solid) was used in Step 11 and the next two steps.

Example 8 9-thioquine-9a-other 9a-one anomethyl-9α
-Homoerythromycin A Example 70 Product (1,0,!i'), 1.0 m
g of ethanol, 0.25. Pour JV's 5% Pd-C into a Parle container and replace with nitrogen gas. Hydrogen gas is then introduced at 10 psi (0.70 kg/am) and hydrogenated for 4.5 hours at room temperature. The reaction mixture is removed from the vessel, filtered and concentrated in vacuo to yield a foam. Dissolve this in 100 ml (D; ethylene chloride and add 100 rnl of water. 6 N Na0I
Add i to make 1) li 9.5. The methylene chloride layer is separated and dried (NfS(h). Evaporation under vacuum gives 700 mg of foam. Silica gel (2
1,! 7,70-230 mesh), C112C
t, /Me011/dark NII+011-. 18 /
Perform chromatography eluting at 1/0.05. Distillation of the fractions yields the title product. (135mq) RJ [Nrikageru board: Exhibition 1411 series Cl1C1s/C1
130H/dense N114.014 = 671/0
, 1: Vanillin/11. ．． P (input spray; heating)
, 0.61'H-nrnr (CDCt3) delta 2.26 [6
1)', 8°(C1is)2N ), 3.28 (3
11,s, fradinose CHsO): “CIIJ7
Lr[CDCl3. (C#3)4 SZ internal group Ns
] ppm17 s, o (lactone C=(1)
), 116.76<-C3N), 1 (12,78CC
-1, 95.16 (C-1"), 4 0.3
0 [<C11s)tN].

Example 9 1)-Deoxo-9(L-(beta-aminoethyl)-
9σ-Aza-9α-Homoerythromycin A-9-Dene-Anomethyl-9a-Aza-9α-Homoerythromycin A (2.4 g, 3.1 II mol),
72 mg methanol and anhydrous cobalt chloride (0,79
Sodium borohydride (1.17 g, 0.0309 mol) is added to a mixture of 2fj, 6.1 mmol) at room temperature. An exothermic reaction occurs and foaming occurs. Chamber the mixture? ii
When it is boiled for 211q and then concentrated under reduced pressure (aspirator), a black curved substance is formed. Add the residue to 50ml of a 1:1 water:methylene chloride mixture (gravity)
1/V/ICL to pH 2.5. Separate the water and add 25 ml of methylene chloride. l
Add JV Na0II'z - C1plj to 9.5.

Separate the organic layer and add Kasanui water. I N-111C
Add I to make phl 2.0. Separate the aqueous layer again
Add methylene chloride of t L, , 25d t I A
Add l' Na011 to pl-19.5. Separate the organic layer and dry <NO,2SO41. Reduced pressure L″
Shrink the foamy crude product (1.15 g
).

1, (15,!i' sum product, 30g of 70-23
Using 0 mesh silica gel, CJiC: Cl 011: Nll, Oli (6: 1°o, 1)-c
The effluent was fractionated into 5 mg portions and subjected to 7/ζ chromatography using a 4d filter. Fractions 80-150 contain the target substance (high polarity). These are combined and made into a receiver under reduced pressure. The concentrate is washed with saturated sodium bicarbonate water and dried. -ru.

Concentrated in vacuo as a foamy substance of 75 liters: ? - Obtain the following product.

9,11-deoxo-11be, 9α-(epoxymethano)-9cm aza-9α-homoerythro [Formula (1)
, a-2+, 4rt-Efuatrial Hydroxy] 9-deoxo-9a-(beta-aminoethyl)-9a
, ~Acer 9 a-homoerythromycin A (0,3
8g, 0.488mmol), chloroform (4ml)
, lll1 nitrate f'i'2 (:/ 7 mi/l/ (0,
072ml! .

0.536 mmol), wood vinegar e (0,056 ml).

A mixture of 0.976 mmol) was refluxed for 1 hour.
．． do.

Additional isoamyl nitrite and glacial acetic acid are added and the mixture is refluxed for 2 hours. Cool, add lOmJ of chloroform and 15
m/! 2. Add rim water. I
Add N NaOHk and 7) I-19,5K. The organic layer is separated and dried (Nα2S(1)4). Concentrate under reduced pressure to obtain 0.37 g of brown foam. 55 g of formamide-treated silica gel (as in Example 3)
Using chloroform:hexane (90:10) as the eluate, fractions were fractionated into 5 ml portions and subjected to column chromatography to obtain the products in fractions 81-130. Combined, 111 cars were washed with water and dried (N(F, 2 SO
< ). Concentrate under reduced pressure to obtain a white solid.

Dissolve the solid in methylene chloride and filter.

Evaporation under vacuum gives 2c+, 5 mg of product as a white solid.

13C-nrrLr (CDC1, chloroform internal standard) ppm 177.71 (lactone carbonyl),
103.36 (C-1'), 9 5.9 7 (
C-1”), 40.40[(C1ls)vN
;Mass spectrum (m, 7g) 602.444.
428゜Example 11 9.11-deoxo-11beta,9α-(epoxymethano)-9cmaza-9CL-homoerythromycin A [Formula (n-1,4''-equatorial hydroxy with I)] Dissolved in 150 ml of chloroform , 10.Og(
13,64 mmol) of 9-thioquine. 9α-other 9a-homoerythromycin A, 1.19 g (],,
10 ml, 14.0 mmol) of 37% formaldehyde in water, 0.488 El (0.40 ml,
0.01 mol) of formic acid at room temperature (approximately 25°C)7
Stir for 0 hours. In TLC (silica gel plate, C1i,
(4/C113011/dense N1mu0Ii=6/110A
development; vanillin/H8po, spray, heat) indicating the presence of at least five components. The mixture was stirred with saturated hydrogen carbonate (400 ml) and the aqueous layer was brought to a pli of 9.5 with 6N sodium hydroxide. Separate the organic layer and dry with +1 um of sulfuric acid. Concentrate to obtain a colorless foam. The crude product was purified by silica gel chromatography to obtain 405 g of 70-230 m7
Schnorr 1 force'y'JIi; Cl12C1JCI
I3011/Concentrated Nl14011 = 12 / 1 /
563 mg (5.5% yield) of pure title product are obtained as a colorless foam.

Rf (silica gel plate; Cl12C1JCII3011
/Concentrated NII+ 0II=6/110.1), 0.5°"Cnmr [CDCl3+ CCll3)4 St internal standard] ppm173.37 (Lactone C=O),
103.48 (C-1'), 9 7.0 7 (
C-1', 8 3.3 1 CC-5), 81.0
1 (OC112N), 78.01.76.11
．． 75.56.40.24 ((C1is)tN −1
: Mass spectrum (yn/e) 588, 571, 430
, 414.158, 127° Example 12 The following compound is prepared following the method of Example 7.8.9 and using the appropriate starting materials.

0C1i.

C112CN axial and its 3', 9α-
Bis-N-oxide CH2CH2Nl12 Axial Example 13 Using the method of Example 3, 9α of Example 12 as the reactant
- Reaction using beta-aminoethyl conductor, 4
“A six-membered ring ether derivative in which the —OH group has an axial coordination is obtained.

Production Example A 9-thioquine-9a-other 9α-hydroxy-9α-
Homoerythromycin A 3'-#-Oxide 9-deoxo-9α dissolved in 40 rnl methanol
-aza-9α-homoerythromycin A (10,, Og
) to a solution of 30-hydrogen peroxide (50 mA) dropwise under stirring over 5-10 minutes. After stirring overnight at room temperature, the mixture was mixed with stirred ice (20(1), ethyl acetate (200 d
) into a slurry of water (100 ml). Excess hydrogen peroxide is decomposed by carefully adding dropwise saturated sodium sulfite solution until the iododenzone reaction is no longer present.

Separate the layers and wash the aqueous layer twice with 200 rLLl of ethyl acetate. Combine the organic extracts, dry with sodium sulfate, and distill off the Roxy 9α-homoerythromycin A3'-
N~oxide is obtained as a colorless foam (8,6jj).

The crude product is sufficient for use in the sea bream process below.
J11 product uses silica gel chromatography (methylene chloride: methanol: #ammonia aqueous system (12:1)
: 0.1). The progress of separation and purification is checked by thin layer chromatography using a silica gel plate (developed with methylene chloride:methanol:concentrated aqueous ammonia (9:1:0.1)). Silica 'y'le & ij Vanillin Spray [Meta/-Jl/ (50ml: 85%l1sPO4)
(50ml): Vanillin (1,oy)]
Heat.

'H-nmr (CDCAs) delta 3.21 (6#
, s.

CCH,), N→0], 3.39 (311,s, fraginose CIimb-). MS: King Peak m7'e
576 (ion from desource amine fragment), 418 (aglycone ion - both sugars). Both peaks are characteristic of the -N-01-1 residue in the aglycone.

Production Example B 4"~Eierthromycin A (50g, 0.064
Dissolve 6 mol) in 2651 nl of pyridine. Hydroxylamine hydrochloride (112.2g, 1.615mol)
and stir the slurry for 16 hours. The reaction mixture is distilled off to a viscous slurry. Dilute with 300d Improper Tool and stir well. Filter this and use 3X100
Clean with 1ff of isopropanol. The filtrate and washings are combined and distilled off to give a water bath foam. This is triturated with ether to give the crude product as the hydrochloride salt (100 g).

Crude product f: cIi2ct2 and dilute Na0If"'Cp
Purify A'a Ii'C (Js) at H' 9.5 by distributing it in water. Separate the aqueous layer and wash with vinegar, ethyl, and then ether. Combine all organic layers and dry. (Na2S
O<). This is evaporated to give the title product as a white foam (59.5 g).

59.5g; tLcRl 0.5 (60: 10
: IClI2C12: CH, 01)°#NH+Q
II) :'II nmr(CI)C1s) delta 2.31 [6H, s, (CIJs)2N-], 3
．． 32 (311', 8. Fradinose C I 0- to Preparation Example C 4"-epi-9a-aza-9a-pomoerythromyproduct (59,2L O, 0787 mol) NomHK225
Add a slurry of DNAHCOs (60 g) in ml (DIItO) dissolved in 50 ml of acetone / /
+, meta-7sulnyl/11'7(t-'(36,3g,
24.5'ml) (Add solution D dropwise over 10 minutes.

During this time, the temperature is kept below 30°C in a cold bath. Mixture 4.5
Stir for an hour and distill off the acetone. C12Ct2 (40
In addition to leaving (J fil) aqueous, 6NIIC
1 to pH 5 or 6. Separate the aqueous layer, C112C1,
T Wash twice. Next K 6 # pH 9 with Na0II
, make it 5. The aqueous base solution is combined with 2 x C112Ct, n1fe and dried (Ha, 2sQ4). This is distilled off to give the title product as an ivory foam. 4
Engineering 41! i'; tjc RfO, 4 (60:10
:1(,'l12 C4: CH8CII : Concentrated NlI
4011);'II-nmr (C1)C1,)
Delta 2.27 (611, 8, (CHshN),
3.29 (3H,s, fraginose on '7/30
): l5C-nntr [CDCt3r (C11B
) 4 SL internal standards: ) ppm, 177.24 (lactone', C=O), 163.53 (amide'/C=
O), 102.29 and 95.24 CC-3, C-
5'), 40.22 t: (CH3)ty-).

Preparation Example D 4"-epi-9-deoxo-90-aza-9a-homoerythromycin A
Dissolve in NaBI 011 and keep below 38℃.
i.

(45 g) over 45 minutes. The reaction mixture was 64:1
After evaporation, a viscous slurry containing sodium borohydride and the boron ester complex of the product is obtained. The latter complex is partitioned between 500rnl CH2Cl and 500d water. Repeat the next step three times.

Under stirring, maintain pH 2,5 with dilute 11 ct;
Stir vigorously for minutes; If, separate the 0 layer, 500 m
l's (: merge with 1i2CAt; rare Na0Il "'
CpI) to 9.5. Separate C1,12Cf21m. Merging CH2C4 layer in TH9,5, 500++
/ Add H and O. After repeating 3 times, ctj, Cf
The two layers are dried (Nα2SO4) and evaporated to give the phase product as a foam. Crystallize with 34 g0.150 m/l of hot isopropyl ether, cool and dilute with 300 m/l of garlic. The pure title product is obtained.

25.8g. White crystal.

tic R10,5 (9: I CHCl5'diethylamine); R1O,1 (90: 10: I
CH2Ck 'CHs011: concentrated NH, OB), η
rp170180°: 111-n-rnr(C?DC
t3) Delta 2.26 (6H,s, (C1i3)2
N), 3.29 (3H,s, fraginose Cl1
80-);”C-nmr[CDCl2, (Cfl3
)4Si internal standard]・pprrL179.44 (lactone C=0), 103.57 and 96.70 (C3,
C5): 41.50 [(Cfl3)2-N-].

Production Example E 4"-epi-9-deoxo-9σ-hydroxy-9α-
Aza-9α-Homoerythromycin A3'-N-Ogizide Stirring, N, under gas, labeled product (3, OI) as in the preparation example
7"IIF of 15d: Cl1SOIi, 1:
Dissolve in 1.

Add 30% Ib0t (5 ml). After 0.5 hours, add 30% Ib0t (2.5 ml), and after 0.5 hours, add C11 containing excess Na and SO3.
, Cf2: J-1,01: i Carefully pour the reaction mixture into the mixture (exothermic).

pII is 9. The aqueous layer is washed with Cfl, C12, then ethyl acetate. Combine the organic layers and dry (Na
, 2SO4). Evaporation gives the title product. 2.7g,
tlcRfO, 15 (60:10:1, C1l, C12
:CHs OH: (21NII4011) :'
Ji NA4R (CDCt31 Delta, 3.21
[6II, s, (CIIS)2N→0], 3
．． 38 (3II, s, fraginose Cl130
); MS: Main peak m/e 576 (C
-5 position), 41
8 (#-hydroxyaglycone ion-both sugars), both peaks are characteristic of the -N-OR group in the aglycone.

Claims (1)

[Claims] Compounds and pharmaceutically suitable acid addition salts thereof (wherein the wavy line of the 1.2 or 3:4"-OR group indicates an axial and equatorial bond at this position; , when n is 1, the 4"-011 group is an equatorial bond). 2. The compound of claim 1, wherein n is 2. 3 - The compound of claim 161, wherein n is 3. 4. The compound according to claim 3, wherein the 4"-011 group is an axial bond. 5. The compound according to claim 3, wherein the 4"-0ff group is an equatorial bond. 6. The compound according to claim 1, wherein n is 1. 7. Compounds of the formula: and pharmaceutically suitable acid addition salts thereof (wherein R1 is -(CH,) pCN or -(C112)
m ”” ”p is 1 or 2: m is 2 or 3; 4”-0f
The wavy line of the f group represents the axial and equatorial bonds at this position). 8. R, is ((HI3) 7) C? #; p is 2; 4" -Off group is an axial bond, the compound of claim 71iα, item 7; 9, R, is -(Cf1t) p CN" is 2;
The compound according to claim 7, wherein the 4''-011 group is an Equa) IJ Al bond. YO, R1 are -(Cl12) m Nlk; Milk is 3
; 4"-011 group is EQUA) IJ al. 11, 1+!1 car(CH2) -NH,; rn is 3; 4"-on group 17+ is axial The compound of claim 7 which is a bond. Formula n: (In the formula, the wavy line at the 4"-OH group represents an axial and equatorial bond at the car position. , axial, and equat-real connections). 14. An antibacterial compound consisting of a compound of the following formula or its medicinal acid (; The wavy line of the OH group indicates the axial and equatorial bonds in the imperial 1a: where n is 1, the 1. easy is 4"-Off group is an equatorial bond). 15. A compound of the formula: A process for the preparation of a compound of the formula: characterized in that the compound is reacted with at least stoichiometric amounts of isoamyl nitrite and acetic acid in an inert solvent, provided that in the above formula, ??L Company 2 or 3; The wavy line in the 2 or 3;4″-OH group represents the axial and equatorial bonds in the imperial position. 16.9-Deoxo-9-aza=9-homoerythromycin A7.r in formaldehyde in an inert solvent as well as@
characterized by reacting with an acid at 15°C to 30°C,
A method for producing a compound of formula: 17. Claim 1, wherein the solvent is chloroform
Method of Section 6.