HUT74073A - New compounds of the secomacrolide and secoazalide class and a process for the preparation thereof - Google Patents

Abstract

The present invention relates to novel compounds of the formula (Ia), such as R1 and R2, which are identical to H or CH3; R3 and R4 are different from H or CH3; Y is -O-or-NHg and Z is CH3 or CH (CH3) CH (OH) COH (CH3) CH (OH) C2H5 -, a pharmaceutically acceptable acid addition salt thereof, a process for their preparation, and a novel intermediate used in their preparation. Compounds of formula II wherein X is O or NOR7, wherein R7 is H, acyl or arylsulfonyl; R3 and R4 are different from H or Cf3; R5 and R6 are the same or different for H or acyl; Y is O or NH 4 Z is CH 3, - CH (C 2 H 5) COH (CH 3) CH (OR 8) CH (CH 3) NHR 9 or CH (CH 3) CH (OR 10) COH (CH 3) CH (OR 1 j) C 2 H 5,

Description

PLIVA, Pharmaceutical, Chemistry, Prehrambena i kozmeticka industry, dionicko drustvo, Zagreb, HR

EXTRACT

The invention relates to novel compounds of the type of the sesquacrolide or the secoazalide of formula (I): wherein:

Rj and _R2 are identical and are H or-CH _3;

R ₃ and R ₄ are independently H or -CH ₃ ;

Y is -O or -NH; and

Z is CH ₃ or

CH (CH ₃ ) CH (OH) COH (CH ₃ ) CH (OH) C ₂ H _5, their pharmaceutically acceptable acid addition salts, the process for their preparation, and the novel compounds of formula II used as intermediates in their preparation:

X is O or NOR ₇ , wherein

R ₇ is H, acyl or arylsulfonyl;

R ₃ and R ₄ are independently H or C _{11 3} ;

R ₅ and R _{6, the} same or different, are H or acyl;

Y is O or NH

Z is CH ₃ ,

- CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ or CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR [

R ₈ is H or acyl;

R ₉ is H, acyl or arylsulfonyl, and

Rio and 1 \. * _ _to apply.

R _n is identical to H or acyl 3. _K \ _{| X} fi - <-L <-yy fit, £ W cE _ c'T 3 ΛΆ · '^<V' j

4 / eaJUJL o-ui'LXx

r

82883-5076 Sl

• · · · · · · · · · · · · · · · · ···

Representative:

Danubia Patent and Trademark Office Ltd.

NEW SECOMACROLID AND SECOAZALID COMPOUNDS

PROCEDURE FOR THE PRODUCTION OF THEM

PLIVA, Pharmaceutical, Chemistry, Prehrambena i kozmeticka industry, dionicko drustvo, Zagreb, HR

inventors:

LAZAREVSKI Gorjana, Zagreb, HR

KOBREHEL Gabrijela, Zagreb, HR

Date of filing: 23.11.1995.

Priority: 03/23/1995 (P950145A) HR

The present invention relates to novel compounds of the type secomacrolide and secoazalide, to potential intermediates for the preparation of new macrolide and azalide antibiotics, and to a process for their preparation.

Erythromycin A is a valuable macrolide antibiotic whose structure is characterized by a 14-membered lactone ring containing a keto group at the C-9 position [McGuire, Antibiot. Chemother., 2, 281 (1952)]. For over 40 years, erythromycin A has been considered a safe and active antimicrobial agent for the treatment of Gram-positive infections. The main disadvantages of the use of erythromycin A in human medicine are as follows: It has only a limited effect against gram-negative bacterial strains, is not tolerated in the stomach of many patients and loses its activity in an acidic medium, forming anhydroerythromine. Spirocyclization of the aglycone ring of erythromycin A has been successfully inhibited by the chemical conversion of the ketone at C-9 or the hydroxyl at C-6 and / or C-12. For example, oxime formation of the C-9 ketone group with hydroxylamine hydrochloride followed by Beckmann rearrangement of the resulting 9 (E) -erythromycin A-oxime and reduction of the resulting bicyclic 6,9-iminoether with 9-deoxo-9a. aza-9a-homoerythromycin A results in the first macrolide having a 15-membered azalactone ring (Kobrehel, G. et al., U.S. Patent No. 4,328,334, 5/1982). Reductive methylation of the 9a-amino group by the Eschweiler-Clark method 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (azithromycin) (G. G. Kobrehel et al., BE 892 357, 7/1982). , a new antibiotic of the azalide type. Wide Antimicrobial Effect • · · · · · · · · · · · · · · · · · · · · · · · · · · ···

In addition to its 3 spectra, including Gram-negative bacteria and intracellular microorganisms, azithromycin is characterized by a specific transport mechanism to the site of action, a long biological half-life and a short therapeutic period.

Hydrolysis and alcoholysis of the C-1 lactone of erythromycin A and B have been described to give the corresponding linear seco acids or esters (Martin, S. F., J. Am. Chem. Soc., 113, 5478-5480 (1991)). In addition, base-catalyzed transformations which lead to the opening of the macrocyclic ring during the formation of the C-1 carboxylate have been described (Waddel, S.T. and Blizzard, T.A., WO 94/15617, 7/1994). In addition, the formation of new macrolide and azalide rings for 9-deoxo-8a-aza-8a-homoerythromycin A and 9-deoxo-9a-aza-9a-homoerythromycin A for "eastern" 9a-aza (Cl / C-8) have also been reported. ) and 9a-aza- (Cl / C-9) fragments and various fragments forming the "western" half of the molecule. It is emphasized that the C-1 / C-9 linear fragment thus obtained differs from the corresponding azithromycin fragment with respect to the additional ethylene group at the C-9 carbon atom.

Linear 9a-azalide fragments of the azalide type macrolide antibiotics of formula (I) have not yet been reported in the literature.

R 1 and R ₂ are independently H or CH ₃ ; R ₃ and R ₄ are independently H or CH ₃ ; Y is O or NH; and is CH ₃ or • · · ·

- 4 CH (CH ₃ ) CH (OH) COH (CH ₃ ) CH (OH) C ₂ H ₅ - and their addition salts with pharmaceutically acceptable inorganic or organic acids. The substituents R ₃ and R ₄ define two epimeric forms of the compounds of formula I which differ in structure only in the configuration of the chiral C-8 carbon atom. Even without determining the stereochemistry of the C-8 carbon atom, the compounds in which R _{3 is} considered to be in the (R) -configuration of the CH ₃ group are the above compounds and the starting C-8 (R) -constituted 6,9-iminoethers based on the similarity of its chemical shifts.

The present invention also relates to a process for the preparation of the compounds of the formula I as well as to intermediates which have not been described so far. The above intermediates in the general formula (II)

X is O or NOR ₇ , wherein

R ₇ is H, acyl or arylsulfonyl;

R ₃ and R ₄ are independently H or CH ₃ ;

R ₅ and R _{6, the} same or different, are H or acyl;

Y is O or NH, and

Z is CH ₃ ,

CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ or CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR ₁₁ ) C ₂ H ₅ , wherein _R8 is H or acyl;

R ₉ is H, acyl or arylsulfonyl, and

_R10 and _u are the same H or acyl.

The present invention also relates to pharmaceutically acceptable addition salts of the above compounds with inorganic or organic acids.

In general, in the novel compounds of formulas I and II, the "eastern" part of the molecule, which includes both sugars, is structurally identical to erythromycin A.

6,9-iminoether or the Cl / C-9 moiety corresponding to the macrolactone ring of 9-deoxo-9a-aza-homoerythromycin A, whereas the "western" portion is the Cl at position containing the terminal, unsubstituted or substituted primary group of the imino ether represents a methyl ester group, either an unsubstituted or substituted C-10 / C-15 fragment, or the same moiety, inverted to the Cl atom, thus yielding new Cl amides instead of the Cl lacion.

The novel 9a-azalide fragments of formula (I) are represented by formula (I)

R 1 and R ₂ are the same as H or CH ₃ ; R ₃ and R ₄ are independently H or CH ₃ ;

Y is O or NH and

Z is CH ₃ or

CH (CH ₃ ) CH (OH) COH (CH ₃ ) CH (OH) C ₂ H ₅ and their pharmaceutically acceptable addition salts with inorganic or organic acids are prepared according to the present invention by reacting the starting erythromycin A- 6,9-imino ether

A) treated with acid resulting in hydrolysis of the imino group

- under 6 conditions and then optionally N- and / or O-acylation with acid anhydrides or acid chlorides followed by solvolysis if desired, or

B) reacting with hydroxylamine hydrochloride in the presence of appropriate inorganic or organic bases in one or two reaction steps and then optionally

B1) is treated with a suitable inorganic or organic acid under conditions which result in the hydrolysis of the hydroxylimino group and then optionally N- and / or O-acylated and then solvolized according to Step A) or optionally

B2) N- and / or O-acylated with acid anhydrides or acid chlorides, followed by solvolysis if desired or optional

B3) is treated with suitable organic or inorganic bases under conditions which result in the acylation of the internal amine, optionally N- and / or O-acylated with acid anhydrides or acid chlorides and optionally solvolized to give the compound of formula II wherein X is O or NOR ₇ where

R ₇ is H, acyl or arylsulfonyl;

R ₃ and R ₄ are independently H or CH ₃ ;

R ₅ and R _{6, the} same or different, are H or acyl;

Y is O or NH and

Z is CH ₃ ,

CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ or CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR ₁₁ ) C ₂ H ₅ , • ·

- 7 where

R ₈ is H or acyl;

R ₉ is H, acyl or arylsulfonyl, and

R ₁₀ and R _n are the same as H or an acyl group or a pharmaceutically acceptable addition salt thereof with a pharmaceutically acceptable inorganic or organic acid and optionally N-alkylated with appropriate alkylating agents in the presence of a suitable reducing agent to give compounds of formula I wherein R 1, R ₂ , R ₃ , R ₄ , Y and Z are as defined above.

The preparation of the novel compounds of formula (I) and (II) is accomplished by the use of

Schemes 1 and 2 illustrate.

A compound of formula (II) wherein

X and Y O is O; r ₃ is CH ₃ , and r ₄ is H, R ₅ and R ₆ has the same meaning as H, Z is CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where R ₈ and R ₉ are identical as H

(Scheme 1, Compound 2a) is prepared by Method A by treating erythromycin A-6,9-iminoether of formula (III) with an acid, preferably glacial acetic acid, under conditions resulting in hydrolysis of the imine at room temperature for 3 days. through which the C-9 / 9a-N bond is cleaved; or a compound of formula II obtained by process B), wherein

X is NOR ₇ where

R ₇ is H; r ₃ is CH ₃ and r ₄ is H; R ₅ and R ₆ identically H; Y is O, and Z is CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where R ₈ and R ₉ are identical as H -

with an inorganic or organic acid under conditions which result in the hydrolysis of the hydroxylimino group. Hydrolysis of the hydroxylimino group is preferably carried out by standing in methanol / HCl at room temperature for 10 days. The product obtained, containing the new 5-membered lactone ring, was isolated by a known gradient extraction procedure (pH 5.5, 6.5 and 8.3) and then concentrated by evaporation of the combined organic extracts (pH 8.3). followed, if desired, by N- and / or O-acylation with an acid anhydride or acid chloride.

Acylation of the resulting lacion with acid anhydride is known in the art (Jones et al., J. Med. Chem., 1971, 5, 631) and Banaszek et al., Rocy. Chem., 43, 763 (1969)] to give the corresponding tetraalkanoyl derivatives. For example, by acylation with acetic anhydride in a reaction inert solvent, preferably pyridine, at room temperature for up to 7 days, 2 ', 4', 11-O, 10-N-tetraacetate of formula II is obtained, wherein

X and Y are each O;

R ₃ is CH

R ₄ is H;

• ·· ·

- 9 _R5 and _R6 are the same _COCH3;

Z represents

CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ , wherein R ₈ and R ₉ are the same as COCH ₃ (Compound 2b).

Leaving the 2 ', 4 ", 10,10-N-tetraacetate in methanol at room temperature for up to 3 days, and solubilizing the 2'-ester group with 4", 11-0, 10-N-triacetate of formula II we get where

R ₅ is H; and

X, Y, Z, R ₃ , R 4, R ₆ , R ₈ and R ₉ are as defined above for tetraacetate (compound 2c).

The acylation is carried out with an acid chloride, preferably 4-bromobenzoyl chloride, in a reaction inert solvent, preferably diethyl ether, at a temperature of 0 to 5 ° C for up to 3 hours, as a reaction product of 10-N-bromine (II). benzoyl derivative, where

X and Y are each O;

R ₃ is CH

R ₄ is H;

_R5 and _R6 azonosanH;

Z represents

CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where R ₈ is H, and

R ₉ is 4-bromobenzoyl (Compound 2d).

The reaction of erythromycin A-6,9-imino ether of formula (III) with hydroxylamine hydrochloride according to Method B is carried out in a reaction inert solvent in the presence of an inorganic or organic base in one or two reaction steps, at a temperature between 25 and 70 ° C. temperature. If the reaction is carried out in a single step, the C-9 / 9a-N bond is cleaved at the C-9 atom to form a hydroxylimino group and the C-10 atom has a primary amino group, and as the only product of the reaction (II). to give a compound of the formula wherein

X is NOR ₇ , wherein R ₇ is H; Y is O; r ₃ is CH ₃ ; r ₄ is H; R ₅ and R ₆ is identical to H, and Z meaning CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where _R8 and _R9 are the same H

(Scheme 3, Compound 3a).

The reaction is carried out with an excess of 1.1 to 30 moles of hydroxylamine hydrochloride, preferably 5.2 moles. Suitable solvents for the reaction include, for example, C 1 -C 4 alcohols, preferably methanol. As acid scavengers, inorganic bases such as alkali metal carbonates or bicarbonates, preferably sodium carbonate or potassium carbonate; or organic bases such as pyridine, which at the same time act as a reaction-inert solvent. Isolation using standard extraction procedures ··············································

- 11 with organic solvents, preferably chlorinated hydrocarbons, preferably methylene chloride, at pH 10. If the reaction is carried out in two steps, that is, in the first step, the erythromycin A-6,9-imino ether of formula (III) is treated with at least 1.3 mol of the above inorganic or organic base in a reaction inert solvent, preferably 1 In a C 4 -C 4 alcohol, preferably methanol, while refluxing the reaction mixture until the imino ether (TLC) is consumed, the resulting product mixture is isolated by extraction, preferably with chlorinated hydrocarbon, preferably methylene chloride, at pH 8, and The crude product is treated with hydroxylamine hydrochloride in the presence of the aforementioned inorganic or organic base, the reaction is not clear. The resulting product mixture is isolated by gradient extraction with organic solvents, preferably methylene chloride, at pH 8 and 10. Concentration of the combined organic extracts (pH 10) gives a mixture of two products, one of which is the same as 3a and the other is the C-8 (S) enantiomer of formula II, wherein

X is NOR ₇ , wherein R ₇ is H; Y is 0; r ₃ is H; r ₄ is CH ₃ ; R ₅ and R ₆ is identical to H, and Z meaning CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where _R8 and _R9 are the same H

···· ········································· ·

- 12 (Scheme 2, Compound 3b).

The combined organic extracts obtained at pH 8 are evaporated to give, in addition to Compounds 3a and 3b, two isomers of C-8-oxime of formula (II):

X is NOR ₇ where

R ₇ is H;

Y is O;

R ₃ and R ₄ are independently H or CH ₃ ;

_R5 and _R6 are identical and are H, and

Z is CH (Scheme 2, Compounds 7a and 7b) as a result of the simultaneous cleavage of the C-9 / 9a-N bond and the macrocyclic Cl lacion during formation of Cl methoxylate. The resulting compounds 7a and 7b were chromatographed on a silica gel column eluting with chloroform / methanol / conc. NH ₄ OH (6/1/1) and then catalytically reduced if desired.

The terminal amino group oximes 3a and 3b are optionally N- and / or O-acylated with an acid anhydride or acid chloride as described in process A) and then optionally solvolized. For example, acyl anhydride acylation of 3a gives 2 ', 4', 11-O, 10-N-tetraacetyl-9 (E) -acetoxime of formula II, wherein

X means NOR ₇ where R ₇ is COCH ₃ ; r ₃ is CH ₃ ; R ₄ is H;

· · · · · · · · · · · · · · · · · · · · · · · · ···

- 13 R-5 and R ₆ are each COCH ₃ ;

Y is O; and

Z represents

CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ , wherein R ₈ and R ₉ are the same as COCH ₃ (compound 3c), which is optionally solvolized, preferably methanolized. The compound of formula (II) is obtained in which

X is NOR ₇ , wherein R ₇ is H; r ₃ is CH ₃ ; R ₄ and R ₅ identically H; r ₆ is COCH ₃ ; y is 0; and z denotes CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ , wherein R ₈ and R ₉ have the same meaning as CO ₂ CH ₃

(Compound 3d). Reaction of 3a and 3b with acid chloride in the reaction inert solvent in the presence of an inorganic or organic base at 0 to 25 ° C afforded mono and disubstituted acyl derivatives which were optionally separated by column chromatography on silica gel with CH ₂ Cl ₂ 85/15. _{3 using an} OH solvent system. Preferably, compound 3a is reacted with tosyl chloride in the presence of NaHCO ₃ in acetone for up to 3 hours to give compounds of formula II wherein

X is NOR ₇ where

R ₇ is tosyl;

· ··· · · ··· · · · · · · · · · · · · ·

- 14 R ₃ is CH ₃ ;

R ₄ , R ₅ and R ₆ are each H;

Y is O; and

Z represents

CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where R ₈ is H, and

R ₉ is tosyl, (3e), or wherein

X is NOR ₇ where

R ₇ is H;

R ₃ is CH ₃ ;

R ₄ , R ₅ and R ₆ are each H;

Y is O; and

Z represents

CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where R ₈ is H, and

R ₉ is tosyl (compound 3f).

If desired, Compounds 3a and 3b are treated with a base under the conditions of acylation of the internal amine and optionally reduced catalytically. The internal acylation reaction of the above primary amines is carried out at room temperature in the presence of an inorganic or organic base, preferably ammonium hydroxide, potassium or sodium hydroxide or triethylamine, whereby the Cl acyloxy is converted from the oxygen atom to the terminal amino group. inversion of the C10 / C-15 western molecule fragment results in Cl amides of formula II, where

- 15 X

R ₃ and R ₄

R ₅ and R ₆

Y

Z is NOR ₇ where

R7 is H;

each independently represents H or CH ₃ ; identically H;

is NH; and meaning

CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR ₁ wherein

_R10 and _u are the same H (Scheme 2 Compounds 4a and 4b) which is optionally N-, / or O-acylation with an acid anhydride to catalytic reduction or acid chloride or, if desired.

N- and / or O-acylation of 4a and 4b with acid anhydride according to Method A yields 2 ', 4 "-O-diacyl-1 N- (2,4-O-diacyl) -9 (E) -acyloxime . For example, 4a is acylated with acetic anhydride in pyridine at room temperature for up to 4 days to give a compound of formula II wherein

X is NOR ₇ , wherein R ₇ is COCH ₃ ; r ₃ is CH ₃ ; r ₄ is H; R ₅ and R ₆ identical to COCH ₃ ; Y is NH; and Z meaning CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR ₁ wherein

R ₁₀ and R _n are the same as COCH ₃ (Compound 4c). If desired, the compound 4c is solvolized, preferably methanolized, whereby the 2'-position or the 2'- and 9-

deacylation of the oxime ester group results in a compound of formula II in which

X

R ₃ r ₄ r ₅ r ₆ yz

means NOR ₇ where

R ₇ is COCH ₃ ;

is CH ₃ ;

is H;

is H;

is COCH ₃ ;

is NH; and meaning

CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR ₁ wherein

R ₁₀ and R _n are the same as COCH ₃ (Compound 4d) or in which

X is NOR ₇ , wherein R ₇ is H; r ₃ is CH ₃ ; r ₄ is H; r ₅ is H; r ₆ is COCH ₃ ; y is NH; and z CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR _h ) C ₂ H R ₁₀ and R _n have the same meaning as COCH ₃

(Compound 4e). Similarly to the tosyl derivatives 3e and 3f, monosubstituted acyl derivatives are also obtained by reaction with acid chlorides. Preferably, compound 4a is tosylated

chloride in acetone in the presence of NaHCO ₃ at room temperature for up to 12 hours to give the tosyl derivative II

X is NOR ₇ where

R ₇ is tosyl;

R ₃ is CH ₃ ;

R4, R5 and _R6 is H;

Y is NH; and

Z represents

CH _(CH3) CH _(OR10) COH _(CH3) CH (OR) C ₂ H _5, wherein R ₁₀ and R _n are the same H (Compound 4f).

The catalytic reduction of the above-mentioned oximes (4a, 4b, 7a and 7b) is carried out in a reaction-inert solvent in the presence of a noble metal catalyst or its oxide at room temperature under a hydrogen pressure of ⁵ x ^{10 5 to 7} x ^{10 6} . Preferably, the reduction is carried out in glacial acetic acid using platinum (IV) oxide catalyst over 10 hours at a hydrogen pressure of ⁷ x 10 ⁶ Pa and then isolated by standard gradient extraction (pH 5.5, 9.0 and 10.5) with chlorinated hydrocarbons, preferably chloroform, and the combined organic extracts (pH 10.5) were evaporated. The resulting amines of formula (I) in which

Rj and _R2 are identical and are H;

R ₃ is CH ₃ and

R ₄ is H or

R ₃ is H and

R ₄ is CH ₃ ;

Y is O or NH; and • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · services

- 18 Z is CH ₃ or

CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR ₁₁ ) C ₂ H ₅ (Scheme 2, Compounds 5a, 5b, 8a and 8b) is optionally subjected to reductive N-alkylation. Preferably, reductive N-methylation is carried out with 1-4 equivalents of formaldehyde (37%) in the presence of an equal or double amount of formic acid (98-100%) in a reaction inert solvent such as halogenated hydrocarbon, preferably at the reflux temperature of the reaction mixture. , 2 to 20 hours, depending on the amount of aldehyde or acid used. The product obtained is isolated by a standard gradient extraction procedure (pH 5.0 and 9.5) and the combined organic extracts obtained at pH 9.5 are evaporated and, if desired, purified by silica gel column chromatography (6/1/1 0.1). ₃ / CH ₃ OH / concentrated NH ₄ 0H system. (I) is dimethylamino derivative is obtained, wherein R and R ₂ are identical and are CH _3;

R ₃ is CH ₃ and

R ₄ is H or

R ₃ is H and

R ₄ is CH ₃ ;

Y is O or NH; and

Z is CH ₃ or

CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR _n ) C ₂ H ₅ (Scheme 2, Compounds 6a, 6b, 9a and 9b).

The present invention also provides pharmaceutically acceptable addition salts which are prepared so that the seco derivatives of formula (I) or (II) are at least equimolar. ·· ·· · ··· ···

- with 19 appropriate inorganic or organic acids, such as hydrochloric acid, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, citric acid, stearic acid, succinic acid, benzoic acid sulfuric acid, methanesulfonic acid, sulfonic acid, etc. reacting it in a reaction inert solvent. The addition salts are isolated by filtration if they are insoluble in the reaction inert solvent, or precipitated with a non-solvent, or the solvent is evaporated, most often by lyophilization.

By performing the reactions of the above steps, the 15-membered azalactone ring of erythromycin A-6,9-iminoether is opened, resulting in various derivatives of highly reactive terminal functional groups, allowing novel macrolides or azalides having modified macrocyclic aglucone production of his entire series. For compounds in which the "western" portion of the molecule is inverted (4, 5 and 6), the 2,3,4-trihydroxy-1,3-dimethylhexyl group is represented by erythromycin A-6,9-iminoether. The C-10 / C-15 fragment was retained for the sake of simplicity in the description of the spectroscopic data, as it was prior to the inversion of the fragment. These symbols are illustrated in Schemes 1 and 2.

The invention is further illustrated by the following non-limiting examples.

Example 1

9-Deoxo-6-deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A-9 (E) -oxime (Compound 3a)

Procedure A)

To a solution of 36.0 g (0.049 mol) of erythromycin A-6,9-iminoether (compound 1) in 750 ml of anhydrous methanol was added 18 g (0.259 mol) of hydroxylamine hydrochloride and 6.8 g (0.0642 mol). sodium carbonate was added and the reaction mixture was refluxed for 3 hours. The suspension was evaporated in vacuo and 240 ml of water and 240 ml of dichloromethane (pH 6.8) were added to the resulting solid residue. The pH is adjusted to 10 with 20% w / v sodium hydroxide solution and the aqueous phase is repeatedly extracted with dichloromethane. The combined organic extracts were dried over anhydrous potassium carbonate, evaporated to dryness and dried under high vacuum at 40 ° C for 6 hours. TLC gave 34.3 g (91%) homogeneous material (3a).

IR (CHC1 ₃₎ ^cm-1: 3425, 2970, 1720, 1690, 1580, 1455, 1380, 1300, 1260, 1165, 1050;

1 H NMR (300 MHz, CDCl ₃ ) δ: 4.98 (H 1 '), 4.78 (H-13), 4.45 (H-1'), 4.60 (H-3) , 3.90 (H-5), 3.49 (H-11), 3.28 (3 '-OCH ₃ ), 3.05 (H-10), 2.92 (H-8), 2, 84 (H-2), 2.28 ([3'-N (CH ₃ ) ₂ ], 2.08 (H-7a), 1.88 (H-7b), 1.87 (H-14a), 1.82 (H-4), 1.51 (H-14b), 0.87 (H15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 175.5 (Cl), 161.1 (C-9), 103.1 (C-1 '), 95.0 (Cl'), 88 , 5 (C-6), 81.9 (C-5), 78.1 (C-13), 76.7 (C-3), 73.5 (C-12), 72.5 (Cl ), 48.7 (3 ”• · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

- 21 -OCH ₃ ), 46.7 (C-10), 43.4 (C-2), 39.8 [3'-N (CH ₃ ) ₂ ], 39.7 (C-4), , 9 (C-8), 21.3 (C-14), 10.6 (Cl 5);

FAB (MH ⁺ ): 764.4.

B) live trench

To a solution of erythromycin A-6,9-iminoether (36.0 g, 0.049 mol) in pyridine (100 ml) was added hydroxylamine hydrochloride (18 g, 0.259 mol) and the mixture was stirred at room temperature for 3 hours. Water (400 mL) and dichloromethane (140 mL) were added to the reaction mixture and the product was isolated by gradient extraction at pH 7.0 and 10.0. The combined organic extracts obtained at pH 10.0 were evaporated to give 25.0 g (66.4%) of Compound 3a having the same physico-chemical constants as the product of Method A.

Example 2 2 ', 4 ", 11-O, 10-N-Tetraacetyl-9-deoxy-6-deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A -9 (E) -acetoxime (Compound 3c)

To a solution of 3a (1.0 g, 0.0013 mol) in pyridine (40 mL) was added acetic anhydride (4 mL) and the reaction mixture was allowed to stand at room temperature for 7 days. After completion of the acetylation (TLC), the mixture was poured into 200 mL of ice water and extracted with chloroform at pH 9.0. The combined organic extracts were evaporated in vacuo to give crude product (1.3 g) which, after repeated precipitation from diethyl ether / petroleum ether, afforded product (3c) homogeneous by TLC (1.13 g). 1 H NMR (300 MHz, CDCl ₃ ) δ 6.15 (CONH), 4.97 (H-13), 4.81 (H-2 '), 4.78 (H 1'), δ , 69 (H-4 "), 4.67 (Hl 1),

4.48 (H-10), 4.59 (H-1 '), 4.11 (H-3), 3.79 (H-5), 3.30 (H · · ·

- 22 -3 "-OCH ₃ ), 3.14 (H-8), 2.75 (H-2), 2.27 [3'-N (CH ₃ ) ₂ ], 2.16,

2.13, 2.12, 2.05 and 1.96 (COC // _3), 1.90 (H-4), 1.52 (H-14), 0.90 (H-15).

Example 3

4 ", 11,10,10-N-Triacetyl-9-deoxy-6-deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A-9 (E) - oxime (compound 3d)

A solution of 0.5 g (0.0005 mol) of pentaacetate (Compound 3c) in 20 ml of methanol was allowed to stand at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (90: 9 / 1.5 chloroform / methanol / concentrated ammonium hydroxide). 0.250 g of 4 ", 11 l-O, 10-N-triacetate (3d) having the following physico-chemical constants are obtained:

1 H NMR (300 MHz, CDCl ₃ ) δ: 6.31 (CONH), 4.95 (H-13), 4.85 (H 1 '), 4.67 (H-4'), 4, 65 (H-II), 4.49 (H-10),

4.49 (Η-Γ), 4.21 (H-3), 3.79 (H-5), 3.29 (H-3 ′ -OCH ₃ ), 3.28 (H-2 ′), 3, O 2 (H-8), 2.78 (H-2), 2.30 [3'-N (CH ₃ ) ₂ ], 2.17, 2.13 and 1.96 (COC / ₃ ), 2 , 07 (H-7a), 2.02 (H-4a), 1.85 (H-14a),

1.49 (H-14b), 0.88 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 175.0 (Cl), 172.0,

170.7 and 169.3 _(COCH3), 162.1 (C-9), 103.5 (C-Γ), 95.5 (C-1 '), 89.6 (C-6), 81 , 2 (C-5), 78.3 (C-11), 78.1 (C-3), 76.8 (C-13), 74.9 (C-12), 49.3 (3 " -OCH ₃ ), 45.0 (C-10), 42.5 (C-2), 40.1 [3'-N (CH ₃ ) ₂ ], 39.5 (C-7), 38.4 (C-4), 32.7 (C-8),

23.1, 20.6 and 20.6 (COC // _3), 21.9 (C-14), 10.7 (C-15).

Example 4

9-O, 10N-Ditosyl-9-deoxy-6-deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A-9 (E) -oxime (Compound 3e) and

10-N-tosyl-9-deoxo-6-deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A-9 (E) -oxime (Compound 3f)

Compound 3a from Example 1 (2.0 g, 0.0026 mol) was suspended in acetone (70 mL) and cooled to 0-5 ° C. A solution of tosyl chloride (1.34 g, 0.007 mole) in acetone (30 ml) and sodium bicarbonate (0.6 g, 0.007 mole) in water (95 ml) was added dropwise over 30 minutes with stirring. After stirring the reaction slurry at room temperature for 3 hours, the acetone was evaporated in vacuo and the aqueous residue was extracted with chloroform at pH 5.0. After drying over anhydrous potassium carbonate and evaporation of the chloroform, 2.58 g (3e and 3f) are obtained. The crude product (1.8 g) was purified by column chromatography over silica eluting with 85/15 dichloromethane / methanol. TLC (0.250 g, 7: 3 chloroform: methanol) gave 3e (Rf 0.63) and 1.1 g of 3f (Rf 0.43).

Compound 3e:

IR (CHCl ₃ ) cm ^-1 : 3460, 2975, 2940, 1730, 1660, 1600, 1455, 1370, 1190, 1180, 1160, 1090, 1050, 1000, 975, 855, 815, 665;

1 H-NMR (300 MHz, CDCl ₃ ) δ: 7.80 (p-Ph), 7.30 (p-Ph), 4.81 (H-13), 4.78 (H 1 '), δ , 48 (H-1 '), 4.26 (H-3), 3.96 (H-5'), 3.76 (H-5), 3.68 (H-5 '), 3.60 (Hl 1), 3.50 (H-10),

- 24 ·· * · · · · · · · · · · · · · · · · ··· ·

3.41 (Η-2 '), 3.23 (3 ′ -OCH ₃ ), 3.09 (Η-8), 3.03 (H-4 ′), 2.94 (Η-2), 2 , 54 [3'-N (CH ₃ ) ₂ ], 2.43 (p-Ph-CT / ₃ ), 2.41 (p-Ph-CW ₃ ),

2.24 (H-7a), 2.09 (H-7b), 1.91 (H-4a), 1.83 (H-4'a), 1.68 (H-14a), 1.52 (H-2 'b), 1.41 (H 4b), 1.49 (6-CH ₃ ), 0.89 (H-15).

Compound 3f:

1 H-NMR (300 MHz, CDCl ₃ ) δ: 7.43 (p-Ph), 7.14 (SO ₂ NH), 4.91 (H-13), 4.78 (H _{1 '} ), δ , 60 (Η-Γ), 4.36 (H-3), 4.00 (H-5 ”), 3.82 (H-5), 3.73 (H-10), 3.68 (H -5 '), 3.64 (H-11), 3.41 (H-2'), 3.28 (3 '-OCH ₃ ), 3.08 (H-8), 3.00 (H- 4 "),

2.79 (H-2), 2.39 (p-Ph-C 2 Z ₃ ), 2.24 (H-2 'a), 1.73 (H-14a), 1.52 (6-CH ₃ ) , 0.85 (H-15).

Example 5

6-Deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A (Compound 2a)

Procedure A)

A solution of 10.0 g (0.014 mol) of erythromycin A-6,9-iminoether (1) in 60 ml of glacial acetic acid was allowed to stand at room temperature for 3 days. The solvent was evaporated in vacuo and water (100 mL) was added to the oily residue and the reaction mixture was extracted with chloroform at pH 5.5, 6.5 and 8.3. The combined organic extracts obtained at pH 8.3 were dried over anhydrous potassium carbonate, evaporated to dryness and the product dried under high vacuum at 40 ° C for 6 hours.

8.2 g (80.0%) of TLC gave homogeneous product (2a). IR (CHCl ₃ ) cm ^-1 : 1740 (Cl, lactone) and 1710 (C-9, lacion);

- 25 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 300 MHz, CDC1 ₃₎ δ: 4.77 (III '), 5.00 (H-13), 4.39 (III'), 4.18 (H-3), 3.74 (H 5), 3.35 (Hl 1), 3.29 (H-3 '-OCH ₃ ), 3.16 (H-10), 2.76 (H-8), 2.72 (H-2) , 2.29 [3'-N (CH ₃ ) ₂ ], 2.22 (H-7a), 2.10 (H-7b), 2.00 (H-4), 1.85 (H 14a), 1.55 (H-14b), 0.88 (H-15);

¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 179.6 (Cl), 176.1 (C-9), 103.9 (C-1 '), 95.7 (Cl'), 86 , 1 (C-6), 81.2 (C-5), 78.8 (C-13), 77.9 (C-3), 75.7 (Cl-1), 74.5 (C-12) ), 49.5 (3 '-OCH ₃ ), 47.9 (C-10), 43.2 (C-2), 40.4 [3'-N (CH ₃ ) ₂ ], 39.7 ( C-4), 38.0 (C-7), 34.1 (C-8), 22.2 (C-14), 11.6 (C-15);

EI-MS (M ⁺ ) 748.

Procedure B

A solution of 3a (2.0 g, 0.0026 mol) in methanol (30 mL) was acidified to pH 3.0 with 1 N hydrochloric acid and allowed to stand at room temperature for 10 days. The reaction mixture was adjusted to pH 7 with 10% sodium hydroxide solution, the methanol was evaporated in vacuo, and chloroform was added to the aqueous residue, followed by extraction at pH 5.5, 6.5 and 8.3. The combined organic extracts obtained at pH 8.3 were dried over anhydrous potassium carbonate and evaporated to dryness. Compound 2a is obtained having the same physico-chemical constants as the product obtained in Process A).

Example 6

2 ', 4' -1,10,10-N-Tetraacetyl-6-deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A (Compound 2b)

To a solution of compound 2a (3.4 g, 0.0045 mol) in pyridine (45 ml) was added acetic anhydride (12 ml) and the reaction mixture was allowed to stand at room temperature for 7 days. The acetylation

After completion of the reaction (TLC), the reaction mixture was poured onto 200 ml of ice and extracted with chloroform at pH 9.0. The combined organic extracts were washed with saturated sodium bicarbonate solution and water, dried over anhydrous potassium carbonate and evaporated in vacuo. The crude product obtained is dried under high vacuum at 40 ° C for 6 hours. 4.10 g (98.0%) of product are obtained by chromatography (2b).

IR (CHCl ₃ ) cm ^-1 : 1740 (Cl, lactone) and 1720 (C-6, lacion), 1720 and 1240 (C = O, ester), 1655 (C = O, amide);

1 H NMR Spectrum (300 MHz, CDCl ₃ ) δ: 6.35 (COA / f), 4.99 (H-13), 4.79 (HI), 4.79 (H-2 ') , 4.68 (Hl 1), 4.62 (H-1 '),

4.44 (H-10), 4.14 (H-3), 3.76 (H-5), 3.32 (H-3 '-OCH ₃ ),

2.74 (H-8), 2.65 (H-2), 2.28 [3'-N (CH ₃ ) ₂ ], 2.10, 2.06, 2.03 and 1.92 (COCH ₃ ), 2.08 (H-7a), 1.96 (H-7b), 1.90 (H-4a), 1.81 (H-14a), 1.60 (H-14b), 0, 86 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 179.3 (Cl), 174.7 (C-9), 171.9, 170.5, 169.9 and 169.2 (COCH ₃ ) ;

EI-MS (M ⁺ ) 916.

Example 7

4 ", 11,10-N-Triacetyl-6-deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A (Compound 2c)

A solution of compound 2b (1.5 g, 0.0016 mol) in methanol (40 mL) was allowed to stand at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the resulting oily residue was dissolved in dichloromethane (50 mL), water (pH 6.6) (100 mL) was added and the reaction mixture was adjusted to pH 9.0 with 10% sodium hydroxide solution. set. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous potassium carbonate and the solvent was evaporated in vacuo. 1.35 g of crude product are obtained, which is purified by column chromatography on silica gel, elution being carried out with chloroform / methanol / concentrated ammonium hydroxide (6/1/1). TLC shows homogeneous triacetate (2c) having the following physico-chemical constants:

1 H NMR Spectrum (300 MHz, CDCl ₃ ) δ: 6.39 (CONH), 4.99 (H-13), 4.79 (HI), 4.68 (H-4 '), δ , 66 (H-11), 4.48 (H-1 '), 4.46 (H-10), 4.21 (H-3), 3.76 (H-5), 3.30 (3 "-OCH ₃ ), 3.23 (H-2 '), 2.75 (H-8), 2.70 (H-2), 2.29 [3'-N (CH ₃ ) ₂ ], 2 , 26 (H-7a), 2.16, 2.12 and 1.96 (COCtf ₃ ), 2.02 (H-7b), 1.94 (H-4),

1.83 (H-14a), 1.56 (H-14b), 0.86 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 179.2 (Cl), 174.7 (C-9), 171.7, 170.3 and 169.0 (COCH ₃ ), 102.9 (C-1 '), 94.9 (C-1'), 85.6 (C-6), 80.5 (C-5), 78.3 (C-3), 78.2 (C ), 76.7 (C-13), 74.7 (C-12), 49.2 (3 '-OCH ₃ ), 45.1 (C-10), 42.4 (C-2), 40 , 0 [3'-N (CH ₃ ) ₂ ], 39.3 (C-4), 37.3 (C-7), 33.9 (C-8),

21.9 (C-14), 21.1, 20.9 and 20.6 (COC77 ₃ ), 10.7 (C-15).

Example 8

10-N- (4-Bromobenzoyl) -6-deoxy-6,9-epoxy-8 (R) -methyl-10-amino-9,10-secoerythromycin A (Compound 2d) g (0.013 mol) Compound 2a To a solution of 60 ml of diethyl ether and 8.0 g (0.095 mol) of sodium bicarbonate was added dropwise 4.0 g (0.018 mol) of 4-bromo dropwise over 1 hour at 0-5 ° C with stirring. Benzoyl chloride dissolved in 20 ml of diethyl ether was added. After stirring for 2 hours at the above temperature, the solvent was evaporated in vacuo, then chloroform (70 ml) and water (50 ml) were added to the resulting solid residue and extracted at pH 8.5. The reaction mixture was concentrated in vacuo and the resulting 5.0 g solid was purified by column chromatography on silica gel eluting with dichloromethane / methanol / concentrated ammonium hydroxide (90/9 / 1.5). TLC provides homogeneous 4-bromobenzoate (2d), the physicochemical constants of which are described below.

IR (CHCl ₃ ) cm ^-1 : 1740 (Cl, lacion) 1710 (C-9, lacion), 1640 and 1500 (C-10, amide), 1580 (Ph);

1 H-NMR (300 MHz, CDCl ₃ ) δ: 7.60 (Ph), 7.05 (CO NH), 4.91 (H-13), 4.70 (HI), 4.35 ( H-1 '), 4.37 (H-10), 4.21 (H-3), 3.70 (H-5), 3.67 (H-11), 3.27 (3' -OCH) ₃ ), 3.15 (H-2 '), 2.91 (H-4'), 2.73 (H-8), 2.71 (H-2), 2.26 [3'-N ( CH ₃ ) ₂ ], 2.21 (H-7a), 2.10 (H-7b), 1.94 (H-4a), 1.86 (H-14a), 1.57 (H-14b) , 0.89 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 179.6 (Cl), 176.7 (C-9), 165.4 (CONH), 133.8, 131.6, 128.9 and 125.8 (Ph), 104.0 (C-1 '), 95.0 (Cl'), 86.4 (C-6), 81.7 (C-5), 79.9 (C-3) ), 75.6 (C-13), 73.4 (Cl-1), 74.6 (C-12), 49.4 (3-OCH ₃ ), 47.3 (C-10), 43, 2 (C-2), 40.0 [3'-N (CH ₃ ) ₂ ], 40.0 (C-4), 37.8 (C-7),

34.2 (C-8), 22.5 (C-14), 11.2 (C-15);

EI-MS (M ⁺ ) 931.

• ·

Example 9 1- [N- (2,3,4-Trihydroxy-1,3-dimethylhexyl) amido] -

-10.1 l, 12,13,14,15-hexanor-9-deoxy-6-deoxy-6,9-epoxy-8 (R) -methyl-9,10-secoerythromycin A-9 (E) -oxime (Compound 4a) g (0.041 mol) of Compound 3a prepared in Example 1 was dissolved in 80 ml of 1/1 dichloromethane / methanol, 350 ml of concentrated ammonium hydroxide solution was added and the reaction mixture was stirred at room temperature for 6 hours. The solution was allowed to stand overnight, concentrated in vacuo and the resulting solid residue was suspended in dichloromethane, filtered and the filtrate was evaporated to dryness. 29.5 g (95%) of TLC (chloroform / methanol / concentrated ammonium hydroxide = 6/1 / 0.1) gave homogeneous product (4a).

IR (CHCl ₃ ) cm ^-1 : 3420, 2980, 1690, 1650, 1530, 1455, 1380, 1260, 1175, 1050;

¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.53 (CONH), 4.93 (H-1 ”), 4.45 (,4-Γ), 4.20 (H-3), 4.11 (H-10), 3.79 (H-11), 3.66 (H-5), 3.39 (3 '-OCH ₃ ), 3.22 (H-13), 3.04 (H-8), 2.53 (H-2),

2.29 [3'-N (CH ₃ ) ₂ ], 2.10 (H-7a), 1.97 (H-4), 1.79 (H-7b),

1.59 (H-14a), 1.33 (H-14b), 1.04 (H-15);

¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 174.4 (Cl), 162.0 (C-9), 105.6 (C-1 '), 96.2 (Cl'), 90 , 3 (C-6), 86.3 (C-5), 83.0 (C-13), 79.8 (C-3), 75.1 (Cl-1), 74.9 (C-12) ), 49.3 (3 '-OCH ₃ ), 48.6 (C-10), 42.8 (C-2), 41.0 (C-7), 39.8 [3'-N (CH) ₃ ) ₂ ], 38.6 (C-4), 32.9 (C-8), 24.8 (C-14), 11.5 (C-15); FAB (MH ⁺ ) 764.4.

• · ·

- Example 10 1- [N- (2,3,4-Trihydroxy-1,3-dimethylhexyl) amido] -10,11,12,13,14,15-hexanor-9-deoxo-6 deoxy-6,9-epoxy-8 (R) -methyl-9,10-secoerythromycin A-9 (E) -oxime (Compound 4a) and 1- [N- (2,3,4-Trihydroxy-1), 3-dimethyl-hexyl) amino] -10, ll, 12,13,14,15-hexanor-9-deoxo-6-deoxy-6,9-epoxy-8 (S) -methyl-9,10-secoerythromycin A-9 (E) -oxime (Compound 4b) g Erythromycin A-6,9-iminoether (1) (0.041 mol) was dissolved in methanol (600 ml), sodium carbonate (5.6 g, 0.053 mol) was added and the reaction mixture stirred. while refluxing until starting imino ether is consumed (8 hours). The reaction suspension was concentrated in vacuo, dichloromethane (130 mL) and water (pH 11.1) (130 mL) were added and the mixture was extracted at pH 8. The combined organic extracts were dried over anhydrous potassium carbonate and evaporated to give 28 g of a solid residue. The precipitate is dissolved in 600 ml of methanol, 14 g of hydroxylamine hydrochloride and 5.1 g of sodium carbonate are added and the mixture is refluxed for 3 hours with stirring. The reaction mixture is evaporated to dryness, 150 ml of dichloromethane and 300 ml of water (pH 6.6) are added and the mixture is extracted by gradient extraction at pH 8 and 10. The combined organic extracts obtained at pH 10 were dried over anhydrous potassium carbonate and evaporated to give 15.6 g of a precipitate. The precipitate was dissolved in a mixture of 40 ml of 1/1 methanol / dichloromethane and 170 ml of concentrated ammonium hydroxide solution and stirred at room temperature for 12 hours. The reaction is ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···

The solvent was evaporated to dryness and the product mixture was separated by column chromatography on silica gel. From 2.2 g of crude product using 6: 1 / 0.1 chloroform / methanol / concentrated ammonium hydroxide solution, 1.08 g of chromatographically homogeneous product 4a (Rf = 0.38) is obtained having the same physico-chemical constants as in Example 9. and 0.8 g of compound 4b (Rf = 0.26) having the physico-chemical constants below.

Compound 4b:

IR (CHCl ₃ ) cm ^-1 : 3340, 2975, 1685, 1650, 1530, 1450, 1380, 1280, 1240, 1160, 1040;

1 H NMR (300 MHz, CDCl ₃ ) δ: 7.30 (CONH), 4.88 (H-1 '), 4.35 (,3-Γ), 4.23 (H-3), δ , 15 (H-10), 3.82 (H-11), 3.60 (H-5), 3.29 (3 '-OCH ₃ ), 3.26 (H-13), 3.14 ( H-8), 2.78 (H-7a), 2.52 (H-2), 2.29 [3'-N (CH ₃ ) ₂ ], 2.06 (H-4), 1.61 (H-14a), 1.51 (H-7b), 1.37 (H-14b), 1.04 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 173.9 (Cl), 162.7 (C-9), 104.6 (C-Γ), 95.4 (Cl '), 90, 7 (C-6), 84.3 (C-5), 81.6 (C-13), 78.5 (C-3), 74.5 (Cl-1), 74.4 (C-12) , 48.8 (3 "-OCH ₃ ), 47.4 (C-10), 42.7 (C-2), 42.0 (C-7), 39.4 [3'-N (CH _{3) 2} ], 38.7 (C-4), 33.8 (C-8), 24.1 (C-14), 11.0 (C-15);

FAB (MH ⁺ ) 764.5.

• · · ·

Example 11

2 ', 4 "-0-diacetyl-l- [N- (2.4-0-diacetyl-3-hydroxy-l, 3-dimethyl-hexyl) amino] -10, ll, 12,13,14, 15-Lexaloyl-9-deoxo-6-deoxy-6,9-epoxy-8 (R) -methyl-9,10-secoerythromycin A-9 (E) -acetoxime (Compound 4c)

To a solution of compound 4a (1.0 g, 0.0013 mol) in pyridine (40 mL) was added acetic anhydride (4 mL) and the reaction was allowed to stand at room temperature for 10 days. The reaction mixture was poured into 200 ml of ice water (pH 4.8), basified with 20% sodium hydroxide solution and extracted with chloroform at pH 9. The combined organic extracts were dried over anhydrous potassium carbonate and concentrated in vacuo. 1.25 g (98%) of pentaacetate (4c) having the following physico-chemical constants are obtained.

1 H-Nuclear Magnetic Resonance Spectrum (300 MHz, CDCl ₃ ) δ: 6.61 (CONHj, 4.94 (H-13), 4.82 (HI), 4.80 (H-2 ′), δ 69 (H-4 ”), 4.58 (Η-Γ), 4.58 (H-10), 4.55 (H-11), 4.04 (H-3), 3.79 (H- 5), 3.32 (3 '-OCH ₃ ), 3.13 (H-8), 2.59 (H-2), 2.27 [3'-N (CH ₃ ) ₂ ], 2.15 , 2.12, 2.12, 2.06 and 2.01 (COC / f ₃ ), 2.07 (H-7a), 2.03 (H-4), 2.03 (H-7b), 1.82 (H-14a), 1.55 (H-14b), 0.90 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 173.4 (Cl), 171.8,

170.6, 170.2, 169.8 and 168.8 _(COCH3), 167.2 (C-9), 100.6 (C-l '), 95.5 (C-1 "), 91.7 (C-6), 79.6 (C-3), 79.8 (C-5), 78.6 (C11), 75.7 (C-13), 74.7 (C- 12), 49.3 (3 '-OCH ₃ ), 45.1 (C-10), 42.6 (C-2), 40.2 [3'-N (CH ₃ ) ₂ ], 38, 8 (C-7), 36.7 (C-4), 33.5 (C-8), 21.6 (C-14), 20.9, 20.5, 20.5, 20.4 and

19.4 (COC7f _3), 10.5 (C-15).

· · · · · · · · · · · · · · · · · · ···

Example 12

4 "-0-acetyl-l- [N- (2.4-0-diacetyl-3-hydroxy-l, 3-dimethyl-hexyl) amino] -10, ll, 12,13,14,15-hexanor -9-deoxo-6-deoxy-6,9-epoxy-8 (R) -methyl-9,10-secoerythromycin A-9 (E) -acetoxime (Compound 4d) and 4 "-O-Acetyl-1- [ N- (2.4-0-diacetyl-3-hydroxy-l, 3-dimethyl-hexyl) amino] -10, ll, 12,13,14,15-hexanor-9-deoxo-6-deoxy-6 , 9-epoxy-8 (R) -methyl-9,10-secoerythromycin A-9 (E) -oxime (Compound 4e)

A solution of 0.5 g (0.0005 mol) of Example 11c (4c) in methanol (20 mL) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the resulting mixture was purified by column chromatography on silica gel eluting with 6: 1 / 0.1 chloroform / methanol / concentrated ammonium hydroxide solution system. Evaporation of the chromatographically homogeneous fractions Rf 0.47 and Rf 0.34 gives 0.213 g of tetraacetate (4d) and 0.151 g of triacetate (4e) having the following physico-chemical constants.

Compound 4d:

1 H-NMR (300 MHz, CDCl ₃ ) δ: 7.38 (CO 7 W 7), 4.94 (H-13), 4.83 (H 1 "), 4.66 (H-4"), 4, 62 (H-II), 4.55 (H-10),

4.44 (Η-Γ), 4.10 (H-3), 3.80 (H-5), 3.32 (3 ”-OCH ₃ ), 3.35 (H-2 ′), 3, 18 (H-8), 2.76 (H-2), 2.30 [3'-N (CH ₃ ) ₂ ], 2.07 (H-7a), 2.13, 2.10, 2, 09 and 2.03 (COC77 ₃ ), 1.90 (H-7b), 1.96 (H-4), 1.84 (H-14a), 1.53 (H-14b), 0.90 ( H-l5);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 174.4 (Cl), 171.1,

170.7, 170.4 and 168.4 _(COCH3), 167.2 (C-9), 105.2 (C-l '),

96.9 (C-1 '), 92.9 (C-6), 84.5 (C-5), 81.3 (C-3), 78.5 (C-11), · · ·

75.9 (C-13), 75.0 (C-12), 49.4 (3 "-OCH ₃ ), 44.6 (C-10), 41.1 (C-2), 40.1 [3'-N (CH ₃ ) ₂ ], 40.8 (C-7), 38.0 (C-4), 33.8 (C-8),

21.7 (C-14), 20.7, 20.5, 20.4 and 19.2 (COC / ₃ ), 10.5 (C-15). Compound 4e:

1 H NMR Spectrum (300 MHz, CDCl ₃ ) δ: 7.24 (COV / f), 4.88 (H-13), 4.81 (HI), 4.68 (H-4 ") , 4.62 (H-11), 4.50 (H-10),

4.45 (H-1 '), 4.07 (H-3), 3.75 (H-5), 3.34 (3' -OCH ₃ ), 3.26 (H-2 '), 2 , 98 (H-8), 2.56 (H-2), 2.30 [3'-N (CH ₃ ) ₂ ], 2.09 (H-7a), 2.14, 2.09 and 2 , 03 (COCT / ₃ ), 1.92 (H-7b), 1.89 (H-4),

1.83 (H-14a), 1.51 (H-14b), 0.89 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 174.6 (Cl), 171.1,

170.8, 170.8 _(COCH3), 162.5 (C-9), 104.2 (C-l '), 96.4 (C-1'), 90.4 (C-6); 83.9 (C-5), 79.6 (C-3), 78.7 (C-11), 76.1 (C-13), 75.1 (C-12), 49.5 (3 -OCH ₃ ), 44.7 (C-10), 43.7 (C-2), 40.1 [3'-N (CH ₃ ) ₂ ], 40.4 (C-7), 39, 3 (C-4), 32.5 (C-8),

21.8 (C-14), 20.7, 20.7 and 20.6 (COC / 7 ₃ ), 10.7 (C-15).

Example 13 1- [N- (2,3,4-Trihydroxy-1,3-dimethylhexyl) amido] -

-10,11,12,13,14,15-hexanor-9-deoxy-6-deoxy-6,9-epoxy-8 (R) -methyl-9,10-secoerythromycin A-9 (E) -thyloxime ( Compound 4f)

Example 9 Compound 4a (0.5 g, 0.0007 mol) was suspended in acetone (10 mL) and cooled to 0-5 ° C. A solution of tosyl chloride (0.486 g, 0.0026 mol) in acetone (10 ml) and sodium bicarbonate (0.425 g, 0.0051 mol) in water (25 ml) were added dropwise over 30 minutes with stirring. The reaction mixture was stirred at room temperature for 12 hours and then stirred at room temperature.

- The acetone (35) was evaporated in vacuo and chloroform (30 mL) was added to the aqueous residue, followed by gradient extraction at pH 5.0 and 8.0. Concentration of the combined organic extracts at pH 5.0 gives 0.320 g of crude product (compound 4f). The product was purified by column chromatography on silica gel eluting with chloroform / methanol / concentrated ammonium hydroxide 6/1 (0.1). 0.260 g of TLC gives a homogeneous product (4f).

1 H NMR (300 MHz, CDCl ₃ ) δ: 7.80 (COW), 7.62 (Ph), 3.21 (H-13), 4.96 (HI), 4.41 (H -1 '), 4.17 (H-3), 4.11 (H-10), 3.79 (H-1), 3.58 (H-5), 3.39 (H-2'), 3.25 (3 "-OCH ₃ ), 3.10 (H-8), 2.94 (H-4"), 2.55 (H-2), 2.29 [3'-N (CH ₃₎ ) ₂ ], 2.08 (H-7a), 1.86 (H-4a), 1.64 (H-7b), 1.56 (H-14a), 1.43 (H-14b), 1 , 05 (H-15).

Example 14 1- [N- (2,3,4-Trihydroxy-1,3-dimethylhexyl) amido] -10,11,12,13,14,15-hexanor-9-deoxo-9-dihydro -9a-amino-8 (R) -methyl-9a-homoerythromycin A (compound 5a)

6.0 g (0.008 mol) of the crude product of Example 9 (4a) are dissolved in glacial acetic acid (60 ml), treated with platinum dioxide (2.0 g, 83% platinum) and hydrogenated at ⁷ x ^{10 6} H _{2 for} 10 hours with stirring. . The reaction suspension was filtered, the filtrate was concentrated in vacuo, water (100 mL) and chloroform (60 mL) were added to the residue, followed by gradient extraction at pH 5.5, 9.0 and 10.5. The combined chloroform extracts obtained at pH 10.5 were concentrated in vacuo. 4.3 g (73%) homogeneous by TLC

36 products (5a) having the following physico-chemical constants are obtained.

IR (CHCl ₃ ) cm ^-1 : 3400, 2975, 1650, 1535, 1450, 1375, 1165, 1040;

1 H NMR (300 MHz, CDCl ₃ ) δ: 7.52 (CONH), 4.94 (H-1 '), 4.37 (,3-4), 4.26 (H-3), 4.17 (H-10), 3.76 (H-11), 3.41 (H-5), 3.28 (3 '-OCH ₃ ), 3.17 (H-13), 2.62 (H-9a), 2.52 (H-2), 2.27 [3'-N (CH ₃ ) ₂ ], 2.20 (H-7a), 2.01 (H-4), 1, 85 (H-8),

1.55 (H-14a), 1.34 (H-7b), 1.34 (H-14b), 1.05 (H-15);

¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 174.1 (Cl), 106.7 (C-1 '), 96.0 (Cl'), 92.3 (C-5), 83 , 8 (C-13), 79.7 (C-3), 75.1 (C-12), 74.8 (Cl-1), 74.6 (C-6), 49.3 (3 "- OCH ₃ ), 49.2 (C-10), 49.1 (C-9), 42.8 (C-7), 41.6 (C-2), 39.6 [3'-N (CH ₃ ) ₂ ],

37.5 (C-4), 31.0 (C-8), 25.0 (C-14), 11.5 (C-15);

FAB (NH ⁺ ) 752.3.

Example 15 1- [N- (2,3,4-Trihydroxy-1,3-dimethylhexyl) amido] -10,11,12,13,14,15-hexanor-9-deoxo-9-dihydro -9a-amino-8 (S) -methyl-9a-homoerythromycin A (compound 5b)

Compound 4b (0.71 g, 0.009 mole) was dissolved in glacial acetic acid (30 mL), treated with platinum dioxide (0.350 g, 83% platinum) and hydrogenated at ⁷ x ^{10 6} H ₂ for 10 hours with stirring. The reaction mixture was filtered, the filtrate was evaporated and the resulting thick oily residue was obtained by gradient extraction, pH

Extracted at 5.5, 9.0 and 10.5 as described in Example 14. The combined organic extracts obtained at pH 10.5 were evaporated to give the title compound (5b) as homogeneous by TLC (0.260 g, 38.0%).

- 37 • · · · · · · · · · · · · · · · • • · · · · · ¹H-NMR (300 MHz, CDC1 ₃₎ δ: 7.63 (CONH), 4.93 (H-1 ”), 4.40 (Η-Γ), 4.23 (H-3), 4.19 (H-10), 3.75 (H-11), 3.53 (H-5) ), 3.29 (3 '-OCH ₃ ), 3.18 (H-13), 2.72 (H-9a), 2.57 (H-9b), 2.52 (H-2), 2 , 27 [3'-N (CH ₃ ) ₂ ], 1.93 (H-4), 1.78 (H-8), 1.57 (H-14a), 1.47 (H-7a), 1.36 (H-14b), 1.23 (H-7b), 1.04 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 174.3 (Cl), 107.2 (C-Γ), 97.0 (Cl '), 92.3 (C-5), 83, Δ (Cl 3), 80.7 (C-3), 75.7 (C-12), 75.2 (Cl 1), 75.2 (C-6), 49.6 (3 ′ -OCH _3). ), 49.2 (C-9), 49.2 (C-10), 43.7 (C-7), 42.1 (C-2), 39.8 [3'-N (CH ₃ ) ₂ ],

37.8 (C-4), 31.3 (C-8), 25.0 (C-14), 11.7 (C-15).

Example 16 1- [N- (2,3,4-Trihydroxy-1,3-dimethyl-hexyl) -amido] -10,11,12,13,14,15-hexanor-9-deoxo-9-dihydro -9a- (Dimethylamino) -8 (R) -methyl-9a-homoerythromycin To a solution of compound 5a from Example 14 in g (0.0013 mol) g (0.0013 mol) in chloroform (80 ml) was 0.25 mol (0.005 mol). 98-100% formic acid and 0.232 mL (0.003 mol) of 36% formaldehyde were added. The reaction mixture was adjusted to pH 5.0 with 2% w / v sodium hydroxide solution and heated under reflux for 9 hours. Water (100 mL) was added and the product was isolated by gradient extraction with chloroform at pH 5.0 and 9.5. The organic extracts obtained at pH 9.5 were combined and concentrated in vacuo. The product obtained was subjected to silica gel column chromatography, eluting with chloroform / methanol / concentrated ammonium hydroxide 6/1 / 0.1.

solution. 0.63 g of product (6a) is homogeneous by TLC.

IR (CHC1 ₃₎ cm ^-1: 3400, 2970, 1650, 1530, 1450, 1375, 1165, 1040;

1 H NMR (300 MHz, CDCl ₃ ) δ: 7.26 (CONH), 4.91 (H-1 '), 4.37 (H-1'), 4.27 (H-3) , 4.18 (H-10), 3.77 (H-11), 3.41 (H-5), 3.29 (3 '-OCH ₃ ), 3.18 (H-13), 2, 57 (H-2), 2.52 (H-9a), 2.30 [3'-N (CH ₃ ) ₂ ], 2.27 [9a-N (CH ₃ ) ₂ ], 2.20 (H -9b)

2.16 (H-4), 2.01 (H-8), 1.56 (H-14a), 1.50 (H-7a), 1.37 (H-14b), 1.15 (H -7b), 1.04 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 174.7 (Cl), 106.1 (C-1 '), 95.4 (Cl'), 90.5 (C-5), 83 , 3 (C-13), 79.8 (C-3), 74.8 (C-12), 74.6 (Cl-1), 73.7 (C-6), 68.2 (C-9) ), 49.2 (3 '-OCH ₃ ), 48.6 (C-10), 45.3 [9a-N (CH ₃ ) ₂ ], 44.2 (C-7), 41.7 (C -2), 39.6 [3'-N (CH ₃ ) ₂ ], 37.3 (C-4), 26.4 (C-8), 24.9 (C-14), 11.5 ( C-15);

FAB (MH ⁺ ) 780.6.

Example 17 1- [N- (2,3,4-Trihydroxy-1,3-dimethylhexyl) amido] -10,11,12,13,14,15-hexanor-9-deoxo-9-dihydro -9a- (dimethylamino) -8 (S) -methyl-9a-homoerythromycin A (compound 6b)

To a solution of 0.3 g (0.0004 mol) of Example 15b in 50 ml of chloroform in 0.12 ml (0.0032 mol) of 98-100% formic acid and 0.13 ml (0.0016 mol) % formaldehyde is added. The reaction mixture was adjusted to pH 5.0 with 2% w / v sodium hydroxide solution and heated under reflux with stirring for 4 hours. The product was isolated as in Example 16 followed by silica gel.

- Purify by 39 column chromatography using a 6: 1 / 0.1 chloroform / methanol / concentrated ammonium hydroxide solution system. 0.150 g of product (6b) is homogeneous by TLC.

1 H-NMR (300 MHz, CDCl ₃ ) δ: 7.58 (CONH), 4.95 (H-1 '), 4.41 (H-1'), 4.25 (H-3), 4.18 (H-10), 3.76 (H-1), 3.43 (H-5), 3.28 (3 '-OCH ₃ ), 3.17 (H-13), 2.51 ( H-2), 2.27 [3'-N (CH ₃ ) ₂ ], 2.23 [9a-N (CH ₃ ) ₂ ], 2.06 (H-9b), 2.19 (H-4). ), 1.97 (H-8), 1.57 (H-14a), 1.47 (H-7a), 1.37 (H-14b), 1.16 (H-7b), 1.05 (H-15);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 173.5 (Cl), 106.0 (C-1 '), 95.3 (Cl'), 91.9 (C-5), 83 , 2 (C-13), 79.0 (C-3), 74.4 (C-12), 74.1 (Cl-1), 74.2 (C-6), 67.5 (C-9) ), 48.6 (3 '-OCH ₃ ), 48.4 (C-10), 44.9 [9a-N (CH ₃ ) ₂ ], 43.1 (C-7), 40.8 (C -2), 38.9 [3'-N (CH ₃ ) ₂ ], 36.7 (C-4), 25.8 (C-8), 23.9 (C-14), 10.4 ( C-15).

Example 18

9-Deoxo-6-deoxy-6,9-epoxy-8 (R) -methyl-10,11,12,13,14,15-hexanorerythromycin A-9 (E) -oxime (Compound 7a); -Deoxo-6-deoxy-6,9-epoxy-8 (S) -methyl-10,11,12,13,14,15-hexanorerythromycin A-9 (E) -oxime (Compound 7b)

The combined chloroform extracts obtained in Example 10 at pH 8 were dried over anhydrous potassium carbonate and evaporated in vacuo. 8.0 g of a mixture of 7a and 7b are obtained. Chromatography on silica gel column, using 6: 1 / 0.1 chloroform / methanol / concentrated ammonium hydroxide system, from 2.0 g of crude product 0.530 g 7a

- 40 ·· ·· · · · · · · • ··· • ···· · · · · ··· ··· ·· compound (Rf 0.44) and 0.880 g of compound 7b (Rf 0.39 ) which were identified as C-8 stereoisomers by spectroscopic methods.

Compound 7a:

IR (CHC1 ₃₎ ^cm-1: 3360, 2980, 2940, 1730, 1690, 1650, 1455, 1380, 1245, 1165, 1040;

¹ H NMR (300 MHz, CDCl ₃ ) δ: 4.72 (H 1 '), 4.44 (H-1'), 4.11 (H-3), 3.84 (H-5) , 3.67 (1-OCH ₃ ), 3.29 (3 "-OCH ₃ ), 3.26 (H-2 '), 3.03 (H-8), 3.01 (H-4") , 2.84 (H-2), 2.09 (H-7a), 2.33 [3'-N (CH ₃ ) ₂ ], 1.97 (H-4), 2.01 (H-7b). );

¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 176.1 (Cl), 161.8 (C-9), 103.8 (C-1 '), 95.8 (Cl'), 89 , 7 (C-6), 81.0 (C-5), 79.8 (C-3), 51.8 (1-OCH ₃ ), 49.4 (3 '-OCH ₃ ), 39.9 (C-7), 41.7 (C-2), 40.4 [3'-N (CH ₃ ) ₂ ], 37.8 (C-4), 33.0 (C-8);

FAB (MH ⁺ ) 619.4.

Compound 7b:

IR (CHC1 ₃₎ ^cm-1: 3360, 2980, 2940, 1730, 1690, 1650, 1455, 1380, 1245, 1165, 1040;

1 H NMR (300 MHz, CDCl ₃ ) δ: 4.61 (H 1 '), 4.43 (H-1'), 4.09 (H-3), 3.71 (H-5) 3.68 _(1-OCH3), 3.28 (3 "-OCH _3), 3.17 (H-8), 2.89 (H-7a), 2.74 (H-2), 2 , 33 [3'-N (CH ₃ ) ₂ ], 2.16 (H-4), 1.47 (H-7b);

¹³ C NMR (75 MHz, CDCl ₃ ) δ: 176.0 (Cl), 162.9 (C-9), 102.7 (C-1 '), 95.1 (Cl'), 90 , 4 (C-6), 80.1 (C-5), 79.0 (C-3), 51.6 (1-OCH ₃ ), 49.2 (3 '-OCH ₃ ), 42.5 (C-7), 41.0 (C-2), 40.3 [3'-N (CH ₃ ) ₂ ], 38.1 (C-4), 34.5 (C-8).

···· ·

• · · «· · ··· * ··· ·

Example 19

9-Deoxo-9-dihydro-9a-amino-8 (R) -methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycin A (Compound 8a)

Compound 7a (0.90 g, 0.0015 mole) was dissolved in glacial acetic acid (30 ml), treated with platinum dioxide (0.30 g, 83% platinum) and hydrogenated at ⁶ x ^{10 6} H ₂ with stirring for 15 hours. The reaction mixture was filtered and the filtrate was evaporated, and the resulting thick oily residue was isolated by gradient extraction at pH 5.5, 9.0 and 10.5 as described in Example 14. Concentration of the combined organic extracts at pH 10.5 gave 0.530 g (60%) of TLC homogeneous title compound (8a).

¹ H NMR (300 MHz, CDCl 3) δ: 4.64 (H 1 '), 4.40 (H-Γ), 4.14 (H-3), 3.67 (1-OCH 3), δ , 54 (H-5), 3.29 (H-3 '-OCH 3), 2.85 (H-2), 2.74 (H-9a), 2.50 (H-9b), 2.30 [3'-N (CH 3) 2], 2.10 (H-4), 1.84 (H-8), 1.44 (H-7a), 1.22 (H-7b); ¹³ C NMR (75 MHz, CDCl 3) δ: 176.4 (Cl), 104.4 (C-Γ), 96.0 (Cl '), 85.9 (C-5), 80.3 (C-3), 73.8 (C-6), 51.5 (1-OCH ₃ ), 49.2 (3-OCH ₃ ), 49.1 (C-9), 42.9 (C -7), 41.2 (C-2), 40.2 [3'-N (CH ₃ ) ₂ ], 37.3 (C-4), 31.1 (C-8).

Example 20

9-Deoxo-9-dihydro-9a-amino-8 (S) -methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycin A (Compound 8b)

Compound 7b (0.70 g, 0.0011 mole) was dissolved in glacial acetic acid (25 mL), platinum dioxide (83%, platinum dioxide, 0.23 g) was added followed by stirring at ⁶ x ^{10 6} H _{2 for} 15 hours. ·· t · ··· • · · · · · · · · · · · · · · · · · · · · · · · · ·

- Hydrogenate 42. The reaction mixture was filtered and the filtrate was evaporated, and the resulting thick oily residue was isolated by gradient extraction at pH 5.5, 9.0 and 10.5 as described in Example 14. Concentration of the combined organic extracts at pH 10.5 gave 0.350 g (52.4%) of the title compound (8b) homogeneous by TLC.

IR (CHC1 ₃₎ cm ^-1: 3400, 2975, 2940, 1735, 1580, 1455,

1375, 1260, 1170, 1050, 1000;

1 H NMR (300 MHz, CDCl ₃ ) δ: 4.64 (H 1 "), 4.37 (H-H), 4.15 (H-3), 4.04 (H-5") , 3.67 (1-OCH ₃ ), 3.60 (H-5 '),

3.51 (H-5), 3.37 (H-2 '), 3.28 (H-3' -OCH ₃ ), 2.98 (H-4 '),

2.75 (H-2), 2.68 (H-9a), 2.56 (H-9b), 2.54 (H-3 '), 2.31 [3'-N (CH ₃ ) ₂ ], 1.93 (H-4), 1.79 (H-8), 1.70 (H-4'a), 1.47 (H-2 'b).

Example 21

9-Deoxo-9-dihydro-9a- (dimethylamino) -8 (R) -methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycin A (Compound 9a)

To a solution of Example 8a (0.3 g, 0.0005 mol) in chloroform (50 mL), 98-100% formic acid (0.05 mL, 0.0013 mol) and 36% (0.052 mL, 0.0007 mol) os formaldehyde is added. The reaction mixture was adjusted to pH 5.2 with 2% sodium hydroxide solution and heated under reflux for 2.5 hours. The product was isolated as described in Example 16 to give 0.280 g (89.0%) of TLC homogeneous title compound (9a).

IR (CHC1 ₃₎ cm ^-1: 3450, 2975, 2940, 1735, 1465, 1375,

1260, 1200, 1165, 1000;

- 43 • · · · · · · · · · · · · · · · · · · · · · · · · · ··· 1 H NMR Spectrum (300 MHz, CDCl ₃ ) δ: 4.641 (H 1 '), 4.43 (H-Γ), 4.13 (H-3), 4.06 (H-5'), 3, 65 (1-OCH ₃ ), 3.64 (H-5),

3.53 (H-5 '), 3.30 (H-3' -OCH ₃ ), 3.27 (H-2 '), 2.97 (H-2),

2.53 (H-3 '), 2.29 [3'-N (CH ₃ ) ₂ ], 2.28 (H-2'a), 2.24 [9a-N (CH ₃ ) ₂ ], 2, 10 (H-4), 1.96 (H-8), 1.67 (H-7a).

Example 22

9-Deoxo-9-dihydro-9a- (dimethylamino) -8 (S) -methyl-10,11,12,13,14,15-hexanor-9a-homoerythromycin A (Compound 9b)

To a solution of Example 8b (0.6 g, 0.001 mol) in chloroform (50 mL), 98-100% formic acid (0.1 mL, 0.0026 mol) and 36% formaldehyde (0.104 mL, 0.0014 mol). We are added. The reaction mixture was adjusted to pH 5.2 with 2% w / v sodium hydroxide solution and heated under reflux for 2.5 hours with stirring. The product was isolated as described in Example 16 to give 0.550 g (87.7%) of the title compound (9b) homogeneous by TLC.

Claims (4)

Patent claims • «• · · · Compounds of formula (I): wherein R.! are the same and R_2 H or CH _3; R ₃ and R ₄ are independently H or CH ₃ ; Y is O or NH; and Z is CH ₃ or CH (CH ₃ ) CH (OH) COH (CH ₃ ) CH (OH) C ₂ H ₅ or pharmaceutically acceptable addition salts thereof with inorganic or organic acids. Compounds according to claim 1, wherein R _1? R ₂ and R ₄ are identical and are H, R ₃ is CH ₃ , Y is NH and Z represents CH (CH ₃ ) CH (OH) COH (CH ₃ ) CH (OH) C ₂ H ₅ . The compound of claim 1, wherein R 1, R ₂ and R ₃ have the same meaning as H, R ₄ is CH ₃ , Y is NH and Z represents CH (CH ₃ ) CH (OH) COH (CH ₃ ) CH (OH) C ₂ H ₅ . The compound of claim 1, wherein R 1, R ₂ and R ₃ have the same meaning as CH ₃ , R ₄ is H, Y is NH and Z represents CH (CH ₃ ) CH (OH) COH (CH ₃ ) CH (OH) C ₂ H ₅ . The compound of claim 1, wherein R ,, R ₂ and R ₄ are identical and are -CH _3, r ₃ is H, y is NH and z is CH (CH ₃ ) CH (OH) COH (CH ₃ ) CH (OH) C ₂ H ₅ . The compound of claim 1, wherein R _H R ₂ and R ₄ have the same meaning as H, r ₃ is CH ₃ , y is O and z is CH ₃ . The compound of claim 1, wherein R _H R ₂ and R ₃ have the same meaning as H, r ₄ is CH ₃ , Y is 0 and z is CH ₃ . The compound of claim 1, wherein Ri, R ₂ and R ₃ are identical and are -CH _3, r ₄ is H, Y is 0 and z is CH ₃ . The compound of claim 1, wherein R _1s R ₂ and R ₄ are the same as CH ₃ , r ₃ is H, y is 0 and z is CH ₃ . 10. Compounds of formula (II): wherein X is 0 or NOR ₇ where · · · · · ··· ················································· ··· - 46 _R7 is H, acyl or arylsulfonyl group; R ₃ and R ₄ are independently H or CH ₃ ; R ₅ and R _{6, the} same or different, are H or acyl; Y is O or NH and Z is CH ₃ , CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ or CH (CH ₃ ) CH (OR ₁₀ ) COH (CH ₃ ) CH (OR ₁₁ ) C ₂ H ₅ , where r ₈ is H or acyl; r ₉ H, acyl or arylsulfonyl; and Rio and Rj j identical H or acyl group - or pharmaceutically acceptable addition salts thereof with inorganic or organic acids. The compound of claim 10, wherein X and Y are O, R ₃ is CH ₃ , _{R4, R5} and _R6 are identical and are H and Z represents CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where R ₈ and R ₉ are identical as H. The compound of claim 10, wherein X and Y has the same meaning as O, r ₃ is CH ₃ , r ₄ is H, R ₅ and R ₆ is identical to acetyl and · · · · · · · · · · · · · · · · · · · · · · · · ··· - 47 Meaning of Z CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where R ₈ and R ₉ are each acetyl. The compound of claim 10, wherein X and Y are O, R ₃ is CH ₃ , R ₄ and R ₅ are the same as H, R ₆ is acetyl and Z represents CH (C ₂ H ₅ ) COH (CH ₃ ) CH (OR ₈ ) CH (CH ₃ ) NHR ₉ where R ₈ and R ₉ are each acetyl. The compound of claim 10, wherein X and Y are O,