BG60758B2 - C-20-dihydro-desoxy-(cyclic amino)-derivatives of macrolide antibiotics - Google Patents

Abstract

The invention relates to c-20-dihydro-deoxy- (cyclenic amino) derivatives of the macrolide antibiotics tylosin, desmycosin, macrocine, lactenocin, 2 "-O-demethylmucrocin and 2" -O-demethyllactenocin which suppress pathogenic bacteria, in particular gram-positive bacteria of the species rasteriae and myrislla, and to their respective pharmaceutical compositions.

Description

SUMMARY OF THE INVENTION

The present invention relates to C20-modified macrolide derivatives of formulas 1 and 2:

wherein R is a saturated or unsaturated secondary amino group of formula 20

-N) wherein the nitrogen nitrogen atom is part of a carbocyclic ring system selected from a monocyclic ring containing 5 to 16 25 atoms or from a bi- or tricyclic ring system containing from 8 to 20 atoms, where one or more carbon atoms may are substituted by C ₁ -C ₄ alkyl, C ₁ -C, alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C _A alkoxy, C 1 -C alkoxycarbonyl, hydroxyl, C-C ₄ alkanoyloxy, halogen, halogen-C _] - C ₄ alkyl, -N (C ₁ -C 6 alkyl), -N (CH 3),

22 m οο

IIII-C-N (C 1 -C-alkyl) -C-N (CH 3

4 22 m cyano, ethylenedioxy, benzyl, phenyl or phenyl substituted with 1 to 3 substituents such as nitro, halogen, C ₁ -C ₄ -alkyl, C ₍ -C ₄ alkoxy, hydroxy, amino or mono- or di- ( C [-C ₄ ) 30 amino; n is an integer from 4 to 7; R ₁ is

dream ₃ dream ₃

R ₂ is hydrogen, optionally substituted C 1 -C ₅ alkanoyl or benzoyl, phenylacetyl or phenylpropionyl; R ₃ is hydroxy; optionally substituted C 1 -C 6 alkanoyloxy, benzoyloxy phenylacetoxy or phenoxyacetoxy; or

where

Q ¹ is

CH ₃ SN ₃

Q ² is hydrogen or a hydroxy protecting group; Q ³ is hydrogen or iodine; and R and R ² are as defined in formula 1; and to the acid addition salts of these compounds.

The compounds of the invention are useful as antibiotics and / or as intermediates for the production of antibiotics. The present invention also relates to pharmaceutical compositions containing these compounds and to methods of treatment in which the compounds or compositions are administered to produce an antibiotic effect or to enhance the growth of treated animals.

Detailed description of the invention

The present invention relates to novel antibiotics, in particular to a group of C-20-modified macrolide antibiotic derivatives tylosin, desmycosin, macrocine, lactenocin, 2'-O-demethylmacrocin (DOMM) and 2 "-O-demethyllactenocin (DOML) and acid addition salts of these derivatives. The invention also relates to methods of treating certain infections, methods of enhancing the weight of animals and pharmaceutical compositions containing said derivatives and their pharmaceutically acceptable acid addition salts.

The practice constantly requires new, 30 advanced antibiotics in both human and veterinary medicine. Some of the goals of advanced antibiotics are to increase potency, expand the spectrum of suppressed bacteria35, increase efficacy in vivo, and improve pharmaceutical properties (such as greater oral absorption, higher concentrations in blood or tissues; longer half-lives; of the pharmaceutical form and a favorable rate or pathway of excretion and the rate or nature of metabolism).

Unfortunately, the conversion of tylosin-like macrolides into derivatives with more than 45 good properties is not very successful. A large number of derivatives have been created, but their efficacy is similar to or lower than that of the parent compound.

Unexpectedly, it has been found according to the invention that modification of the C-20 aldehyde group by reductive amination to the C-20-dihydro-deoxy- (cyclic tertiary amino group) results in derivatives with significantly increased activity.

One group of novel macrolides of the invention are compounds of formula 1:

wherein R is a saturated or unsaturated secondary amino group of the formula wherein the nitrogen atom is part of a carbocyclic ring system as a monocyclic ring containing from 5 to 16 atoms or by a bicyclic or tricyclic ring system containing from 8 to 20 atoms in which one or more carbon atoms may be substituted by C ₁ -C ₆ alkyl, C ₂ -C ₄ alkenyl, C-C. alkynyl, C-C. alkoxy, C-C. alkoxycarbonyl, hydroxyl, C 1 -C ₄ alkyloxy, halogen, halogen-C 1 -C ₄ alkyl, -N (CC ₄ alkyl), -N (CH),

IL W

ΟΟ

IIII-C-N <C, -C-alkyl) -C-N (CH3) m cyano, ethylenedioxy, benzyl, phenyl or 25 phenyl substituted with from 1 to 3 substituents selected from nitro, halogen, C, -C ₄ -alkyl, C 1 -C ₄ alkoxy, hydroxy, amino or mono- or di- (C 1 -C ₄ alkyl) amino; m is an integer from 4 to 7; R ¹ is

dream ₃ dream ₃ dream ₃

R ² is hydrogen, optionally substituted C 1 -C ₅ alkanoyl or benzoyl, phenylacetyl or phenylpropionyl; R ³ is hydroxy; optionally substituted C ₍ -C ₅ alkanoyloxy, benzoyloxy, phenylacetoxy or phenoxyacetoxy; or

HE

and the acid addition salts of these compounds.

Another group of novel macrolides of the present invention are compounds of formula 2:

in which Q ¹ is

dream ₃ dream ₃

Q ² is hydrogen or a hydroxy protecting group; Q ³ is hydrogen or iodine; and R and R ² are as defined in formula 1; and the acid addition salts of these compounds.

Although stereochemical definitions are not made in the structures herein, their stereochemistry is identical to that of the antibiotics from which the compounds, for example tylosin, are derived.

When R is a unsaturated substituent, it may mean 1,2,3,6-tetrahydropyridine-

1-yl; 1,2,3,4-tetrahydroquinolin-1-yl; 1,2,3,4 tetrahydroisoquinolin-2-yl; indol-1-yl; isoindol-2-yl; indolin-1-yl; isoindoline-

2-yl; 2,3,4,5-tetrahydro-1 N-1-benzazepin-1 yl; 2,3,4,5-tetrahydro-1H-2-benzazepin-2-yl; 2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl; pyrrol-1-yl; 1H-azepin-1-yl; carbazol-9-yl; acridin-10-yl; and acridin-9-one-10-yl.

Representatives for R, when a monocyclic ring is saturated, may be mentioned pyrrolidin-1-yl, piperidin-1-yl, hexahydroazepin-1-yl, octahydroazocin-1-yl, octahydro-1H-azonin-1-yl, azacyclotridecan-1-yl and the like.

When R is a saturated bicyclic or tricyclic ring, it may be decahydroquinolin-1-yl; decahydroisoquinolin-2-yl;

decahydrocyclohepta [b-] pyrrol-1-yl; decahydrocyclohepta [c-] pyrrol-2-yl; decahydrocyclopent [c-] azepin-2-yl; decahydrocyclopent [d-] azepin-3-yl; an azabicycloheptanyl group such as 3-azabicyclo [3.2.0] heptan25 3-yl; an azabicyclooctanyl group such as 6azabicyclo [3.2.1] octan-6-yl; an azabicyclononanyl group, for example 3-azabicyclo [3.2.2] nonan-3-yl; an azabicyclodecanyl group such as 4-azabicyclo [5.3.0] decan-4-yl;

an azatricyclo group, for example 2-azatricyclo [6.2.2 ^3b ] tetradecan-2-yl or dodecahydrocarbazol-9-yl; a spiro-concentrated system such as 1-azaspiro [4.5] decan-1-yl.

When the substituent R has one or 35 more substituents on the carbon atom of the ring system, it may mean 1,3,3-trimethyl-6-azabicyclo [3.2.1] octan-6yl; 4-piperidinopiperidin-1-yl; 3,3,5-trimethylhexahydroazepin-1-yl; 4-phenylpiperidin-1-yl, 3,5-dimethylpiperidin-1-yl; 3 (N, N) -diethylcarbamoyl) piperidin-1-yl; and similar.

The term C-C means a hydrocarbon group of from 1 to 4 carbon atoms, which 45 may form a straight, branched or cyclic chain. Alkenyl or akinyl means a hydrocarbon group containing, respectively, a double or triple bond. As used herein, the term C1-C6-alkanoyl refers to an acyl moiety separated from a carboxylic acid containing from 1 to 5 carbon atoms. When the alkyl group is substituted, it may have one to three halogen substituents, for example Cl, Br and F. Examples of such groups are acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, n-butyryl, isobutyryl, n-valeryl and isovaleryl. The term (C1-C6-alkanoyloxy refers to the corresponding acyloxy moieties.

The terms "optionally substituted benzoyl, phenylacetyl or phenylpropionyl" and "optionally substituted benzoyloxy, phenylacetoxy or phenoxyacetoxy" mean that the phenyl group of the moiety is optionally substituted by one to five halogen or methyl groups or by one to two methoxy groups hydroxyl groups

The term "hydroxy protecting group" means a substituent that is not identified during the reaction but which can be easily separated after completion to release the starting hydroxyl group. Hydroxyl protecting groups are known. (T. W. Greene, "Protective groups in organic synthesis," Wiley-Interscience, 1981, 10-86). A suitable hydroxy protecting group is a tetrahydropyranyl group.

The C-20-modified macrolide derivatives of the present invention 5 are obtained from the macrolide antibiotic group, which includes tylosin, relomycin, desmycosin, 20-dihydrodesmicosin, macrocine, 20-dihydromecrocine, 2'-O-demethylmacrocin (DOMM), 20-dihydro-dichromide (20) -Dihydro (DOMM), lactenocin, 20-dihydro-lactenocin, 2-O-demethyllactenocin (DOML) and 20-dihydro-DOML.

Tylosin and desmicocin have been described by R. L. Hamill et al. Macrocin and lactenocin are described by Hamill et al. in US 3 326 759, DOMM, dihydpo-DOMM, DOML and dihydro-DOML are antibiotics described by Richard N. Baltz, Gene M. Wild and Eugene T. Seno in US 4 385 116. 20 The structures of these antibiotics are shown by formulas 3-14:

QR ^a R ^b R ³

3 (tylosin) -SNO -Sn ₃ -Sn ₃ -O-micarosil 4 (Relomycin) -from _{2 about} -Sn ₃ - ^{CH of} -O-mycazoril 5 (desmycosin) -SNO -Sn ₃ -Sn ₃ -He 6 (dihydrodesmycosin) -Sn _{2 he} -Sn ₃ -Sn ₃ -He 7 (Macrocin) -SNO n -Sn ₃ -O-micarosil 8 (dihydromacrocin) -Sn _{2 he} n -Sn ₃ -O-macrosil 9 (lactenocin) -SNO n -Sn ₃ -He (0 (dihydrolactenocin) -Sn _{2 he} n -Sn ₃ -He 11 (DOMM) -SNO n -N -O-macrosil 12 (dihydro-DOMM) dream _{2 he} n n -O-macrosil 13 (DOML) -SNO n -N -He 14 (dihydro-DOML) -Sn _{2 he} n -N -He Preparation of C-20 modified va induced amination on the C-20-alde-

derivatives of the invention include the tylosin moiety desmicosis6

I of, macrocin, lactenocin, DOMM or DO ML. This can be done by the following two methods.

Method 1

The aldehyde group of compound 3,5,7,9,11 or 13 is first reduced to give the corresponding 20-dihydro compounds, i.e. the compounds of formulas 4,6,8,10,12 and 14. Then C-20 the hydroxyl group of these compounds is converted into a leaving group suitable for substitution reactions by one of the following two methods. In one method, the C-20 hydroxyl group is converted to the trifluoromethanesulfonyloxy (triflate) group, which can be further converted to another leaving group, such as iodine if necessary. In the other method, which can be used only with desmycosin, lactenocin and DOML, the iodine derivative is prepared directly by adding iodine (which can be dissolved in a suitable solvent, such as dimethylformamide) to a solution of the 20-dihydro derivative and triphenylphosphine in nitrogen atmosphere.

The C-20 cleavage group (iodine, triflate, etc.) is then reacted with a suitable amine in a suitable solvent such as acetonitrile to give the desired 20-modified derivative.

Method 2

The aldehyde group of compound 3,5,7,9,11 or 13 is reacted directly with the corresponding amine in the presence of a suitable reducing agent and solvent until the desired product is obtained. Examples of suitable reducing agents are sodium cyanoborohydride and sodium borohydride, and anhydrous methanol is a suitable solvent. The reaction may be carried out in a nitrogen atmosphere, but this is usually not required.

The C-20-modified derivatives of desmycosin, lactenocin and DOML can also be obtained by acid hydrolysis of mycarose from the corresponding C-20modified derivatives, respectively, of tylosin, macrocin and D0MM. Hydrolysis methods are well known. DOMM is hydrolyzed in a similar manner to obtain DOML.

The 4'-deoxy derivatives of the invention, i.e., the compounds of formula 2 in which Q ¹ = H, are readily prepared by methods analogous to those described above, using 4'-deoxydesmicosin as a starting product. The starting product 5 can be obtained by the procedures described in J.

Antibiotics 34, 1381–1384 (1981). In many cases, the C-20-modified desmycosin derivative can be converted to the C-20-modified 4'-deoxy analogue by 10 similar methods.

The ester derivatives of the C-20-modified compounds of this invention are prepared by esterifying the appropriate C-20-modified derivative of the 2'15 or 2 'and 4'-hydroxyl groups by treatment with acylating agents using standard methods specified in the prior art. The 2'-O-ester derivatives of C-20-modified derivatives were prepared by methods similar to those described by Baltz et al. in US 4 321 361 and US 4 321 362. The 2 ', 4'-O1-O-ester derivatives of the C-20 modified derivatives can be prepared by methods analogous to the 25 described by Herbert A. Kirst in US 4 401 660.

The C-20-modified derivatives of the present invention form salts, especially acid addition salts, which are also useful as antibiotics and are part of the invention. In another aspect, these salts are used as intermediates, for example in separation and purification, and have improved water solubility.

Suitable salts are those salts obtained by standard reactions with both organic and inorganic acids, for example sulfuric, hydrochloric, phosphoric, acetic, succinic. citric, lactic, maleic, fumaric, 40 palmitic, choline, pamoinic, ligaceous, D-glutamine, d-camphoric, glutaric, glycolic, phthalic, tartaric, antic, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic ,45 benzoic, cinnamon and others.

Pharmaceutically acceptable acid addition salts are a particularly preferred group of salts of the present invention.

The compounds shown in Tables IVIII are C-20 modified derivatives illustrating the invention.

Table I

C-20-modified tylosin derivatives

Compound No. R

T1 pyrrolidin-1-yl T2 piperidin-1-yl TK 4-hydroxypiperidin-1-yl T4 4-Phenylpiperidin-1-yl T5 hexahydroazepin-1-yl T6 octahydroazocin-1-yl T7 octahydro-1H-azonin-1-yl T8 decahydroazecin-1-yl T9 azacycloundecan-1-yl TJ azacyclotridecan-1-yl T11 1,2,3,4-tetrahydroquinolin-1-yl T12 1,2,3,4-tetrahydroisoquinolin-2-yl T13 3-Azabicyclo (3.2.2] nonan-3-yl T14 3,5-dimethylpiperidin-1-yl T15 cis-3,5-dimethylpiperidin-1-yl T16 trans-3,5-dimethylpiperidin-1-yl

R ² = H; and P ³ = mycarosyloxy dream ₃ dream ₃ Table I

Compound #

C-20-modified desmycosin derivatives

R

R ³ or Q ³

D1 pyrrolidin-1-yl HE Dla pyrrolidin-1-yl n D2 piperidin-1-yl HE D2a piperidin-1-yl n D3 4-hydroxypiperidin-1-yl HE D3a 4-hydroxypiperidin-1-yl n D4 4-Phenylpiperidin-1-yl HE D4a 4-Phenylpiperidin-1-yl n D5 hexahydroazepin-1-yl HE D5a hexahydroazepin-1-yl n D6 octahydroazocin-1-yl HE D6a octahydroazocin-1-yl N.

C-20-modified desmicosin derivatives "

Compound #

D7 octahydro-1H-azonin-1-yl HE D7a octahydro-1H-azonin-1-yl N. D8 decahydroazecin-1-yl HE D8a decahydroazecin-1-yl N. D9 azacycloundecan-1-yl HE D9a azacycloundecan-1-yl N. PART azacyclotridecan-1-yl HE DlOa azacyclotridecan-1-yl N. DI 1 1,2,3,4-tetrahydroquinolin-1-yl HE DI la 1,2,3,4-tetrahydroquinolin-1-yl n D12 1,2,3,4-tetrahydroisoquinolin-2-yl HE DI 2a 1,2,3,4-tetrahydroisoquinolin-2-yl n D13 4-Piperidinopiperidin-1-yl HE D13a 4-Piperidinopiperidin-1-yl n D14 3-Azabicyclo [3.2.2] nonan-3-yl HE DI 4a 3-Azabicyclo [3.2.2] nonan-3-yl n D15 3- (N, N-Diethylcarbamoyl) piperidin-1-yl HE D15a 3- (N, N-Diethylcarbamoyl) piperidin-1-yl n D16 4- (N, N-dimethylamino) hexahydroazepin-1-yl HE D16a 4- (N, N-dimethylamino) hexahydroazepin-1-yl n D17 2-Azabicyclo [2.2.2] octan-2-yl HE DI 7a 2-Azabicyclo [2.2.2] octan-2-yl n D18 decahydrocyclopent [d] azepin-3-yl HE D18a decahydrocyclopent [d] azepin-3-yl n D19 1-Azaspiro [4.5] decan-1-yl HE D19a 1-Azaspiro [4.5] decan-1-yl n D20 decahydroquinolin-1-yl HE D20a decahydroquinolin-1-yl n D21 1,3,3-trimethyl-6-azabicyclo-p3.2.1] octan-6-yl HE D21a 1,3,3-trimethyl-6-azabicyclo- [3.2.1] octan-6-yl n D22 1,2,3,6-tetrahydropyridin-1-yl HE D22a 1,2,3,6-tetrahydropyridin-1-yl n D23 3,3,5-trimethylhexahydroazepin-1-yl (isomer 1) HE D23a 3,3,5-trimethylhexahydroazepin-1-yl (isomer 1) n D24 3,3,5-trimethylhexahydroazepin-1-yl (isomer 2) HE D24a 3,3,5-trimethylhexahydroazepin-1-yl (isomer 2) n D25 dodecahydrocarbazol-9-yl HE D25a dodecahydrocarbazol-9-yl n D26 4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl HE D26a 4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl n D27 4-Benzylpiperidin-1-yl HE D27a 4-Benzylpiperidin-1-yl n D28 4- (Ethylenedioxy) -piperidin-1-yl HE D28a 4- (Ethylenedioxy) -piperidin-1-yl n D29 decahydroisoquinolin-2-yl HE

C-20-modified desmicosin derivatives · ¹

Compound #

D29a decahydroisoquinolin-2-yl N. D30 7-Azabicyclo [2.2.1.] Heptan-7-yl HE D30a 7-Azabicyclo [2.2.1] heptan-7-yl N. D31 pyrrol-1-yl HE D31a pyrrol-1-yl N. D32 carbazol-9-yl HE D32a carbazol-9-yl N. D33 3,5-dimethylpiperidin-1-yl HE D33a 3,5-dimethylpiperidin-1-yl n D34 cis-3,5-dimethylpiperidin-1-yl he D34a cis-3,5-dimethylpiperidin-1-yl n D35 trans-3,5-dimethylpiperidin-1-yl he D35a trans-3,5-dimethylpiperidin-1-yl n D36 3-methylpiperidin-1-yl he D37 3,4-dimethoxypiperidin-1-yl he D38 2-ethylpiperidin-1-yl he D39 4,4-dimethylpiperidin-1-yl he D40 3,3-dimethylpiperidin-1-yl he D41 2,6-dimethylpiperidin-1-yl he D42 2,3-dihydroindol-1-yl he D43 3-azaspiro [5.5] undecan-3-yl he D44 octahydroindol-1-yl he D45 octahydro-isoindol-2-yl he D46 3-Azabicyclo [3.2.1] octan-3-yl he D47 1,8,8-trimethyl-3-azabicyclo [3.2.1] octan-3-yl he

Table III

Compound # C-20-modified macrocine derivatives R Ml pyrrolidin-1-yl M2 4-Phenylpiperidin-1-yl M3 hexahydroazepin-1-yl M4 octahydroazocin-1-yl M5 octahydro-1H-azonin-1-yl M6 azacyclotridecan-1-yl M7 1,2,3,4-tetrahydroisoquinolin-2-yl M8 3-Azabicyclo [3.2.2] nonan-3-yl M9 3,5-dimethylpiperidin-1-yl M10 cis-3,5-dimethylperidin-1-yl WE trans-3,5-dimethylpiperidin-1-yl

dream ₃

R ² = H; and R ³ = MHKapo3n.TOKCH

Table IV

Compound # C-20-Modified lactenocin derivatives R LI L2 L3 L4 L5 L6 L7 L8 L9 LIO LI 1 LI 2 L13 pyrrolidin-1-yl piperidin-1-yl 4-Phenylpiperidin-1-yl hexahydroazepin-1-yl octahydroazocin-1-yl octahydro-1H-azonin-1-yl azacyclotridecan-1-yl 1,2,3,4-tetrahydroisoquinolin-2-yl 3-Azabicyclo [3.2.2] nonan-3-yl 1,3,3-trimethyl-6-azabicyclo [3.2.1] octan-6-yl 3,5-dimethylpiperidin-1-yl cis-3,5-dimethylpiperidin-1-yl trans-3,5-dimethylpiperidine- 1-il

R ^ H; and R ³ = OH

CH ₃

Table V

Compound # C-20-Modified DOMMa derivatives R C1 C2 NW C4 C5 C6 pyrrolidin-1-yl 4-Phenylpiperidin-1-yl hexahydroazepin-1-yl octahydroazocin-1-yl azacyclotridecan-1-yl 3,5-dimethylpiperidin-1-yl

R ² = H; E ³ = mycarosyloxy

Table VI

C-20-Modified DOML Derivatives "

Compound No. R

N1 pyrrolidin-1-yl N2 4-Phenylpiperidin-1-yl N3 hexahydroazepin-1-yl N4 octahydroazocin-1-yl N5 octahydro-1H-azonin-yl N6 azacyclotridecan-1-yl N7 1,2,3,4-tetrahydroquinolin-1-yl N8 3,5-dimethylpiperidin-1-yl

RMi; R ³ = OH

Table VII

C-20-Modified tylosin derivatives Compound # R R ² (2 ') ^b E1 hexahydroazepin-1-yl propionyl E2 octahydroazocin-1-yl propionyl EU piperidin-1-yl acetyl E4 3,5-dimethylpiperidin-1-yl acetyl

R ³ = mycarosyl ^b- position number of the esterified hydroxyl group in parentheses

Table VIII

C-20-Modified desmicosin ester derivatives

Compound # R R ² (2 ') ^b R '(4') ^b E42 hexahydroazepin-1-yl propionyl OH E5 hexahydroazepin-1-yl propionyl propionyloxy E6 octahydroazocin-1-yl acetyl OH E7 octahydroazocin-1-yl acetyl acetoxy E8 piperidin-1-yl propionyl OH E9 3,5-dimethylpiperidin-1-yl acetyl OH E10 3,5-dimethylpiperidin-1-yl acetyl acetoxy EN cis-3,5-dimethylpiperidin-1-yl acetyl OH E12 cis-3,5-dimethylpiperidin-1-yl acetyl nitric oxide E13 trans-3,5-dimethylpiperidin-1-yl acetyl OH E14 trans-3,5-dimethylpiperidin-1-yl acetyl acetoxy

^{b is the} number of the esterified hydroxyl group in parentheses

The derivatives of the invention inhibit the growth of pathogenic bacteria, in particular Gram-positive bacteria of the Mycoplasma species and Gram-negative bacteria of the Pasteurella species. The derivatives are particularly active against Pasteurella species, such as P. multocida and P. hemolitica, and against Mycoplasma species, such as M. gallisepticum and M. hyopneumoniae (an agent causing microplasma pneumonia in pigs).

The minimum inhibitory concentrations (MICs) at which the compounds of the invention inhibit certain bacteria are listed in Tables IX and X. The MICs in Table IX were determined by standard agar dilution assay. The MICs in Table X are determined by conventional microtiter dilution tests.

Table IX

Antibiotic activity of C-20-modified derivatives

Tested compound ”

Tested organism DI D4 D5 D5a D6 D10 D14 M3 L5 Staphylococcus aureus XI. 1 2 0.5 0.5 0.5 0.5 0.25 0.25 4 1 Staphylococcus aureus V4P 2 0.5 0.5 0.5 0.5 0.25 0.25 8 1 Staphylococcus aureus X400 ¹¹ 2 0.5 1 1 0.5 0.25 0.5 32 2 Staphylococcus aureus S13E 2 0.5 0.25 0.5 0.5 0.25 0.25 8 / Staphylococcus epidermis EPI1 2 0.5 0.5 0.5 0.5 0.25 0.5 8 1 Staphylococcus epidermidis 222 1 0.25 0.12 0.25 0.25 0.12 0.12 2 0.5 Streptococcus pyogenes C203 1 0.25 0.5 0.25 0.5 NT ¹ NT 4 0.5 Streptococcus pneumoniae Park I 0,5 0.25 0.5 0.25 0.5 0.25 0.5 2 0.5 Staphylococcus Group D X66 32 1 3 2 4 4 4 - 16

Streptococcus Group D 2041 16 2 ^h 8 2 8 ^h 4 4 - 16 ^h Haemophilus influenzae C. L. ' 16 8 16 8 16 4 4 128 32 Haemophilus influenzae 76 ^s 16 8 128 8 16 8 8 128 6 Escherichia coli N10 _g 64 128 64 64 32 32 - - Escherichia coli EC 14 - 64 4 128 64 64 32 - - Escherichia coli TEM 128 32 8 8 16 8 16 - 16 Klebsiella X 26 16 32 _g 8 16 16 8 - 16

Tested organism Test Compound® M4 L4 T6 T13 D2 D3 D7 DI 1 D12 Staphylococcus aureus XI. 1 4 2 4 4 0.5 8 0.5 0.5 0.5 Staphylococcus aureus V4E 4 2 4 4 0.5 8 0.5 0.5 0.5 Staphylococcus aureus X400 ^J 8 2 8 8 1 16 0.5 0.5 0.5 Staphylococcus aureus S13E 4 2 4 4 0.5 8 0.5 0.5 0.5 Staphylococcus epidermis EPI1 4 2 4 4 1 8 0.5 0.5 0.5 Staphylococcus epidermidis 222 2 1 2 2 0.5 4 0.25 0.25 0.25 Streptococcus pyogenes C203 2 1 2 4 0.25 1 0.06 0.5 0.5 Streptococcus pneumoniae Park I 32 8 8 16 0.25 8 0.5 2 1 Streptococcus Group D X66 - 32 - 128 16 128 4 8 4 Streptococcus Group d 2041 - 16 - - 16 32 8 8 8 Haemophilus influenzae C.L. ' 128 16 64 128 16 64 16 64 16 Haemophilus influenzae 76 ^f 128 16 128 16 64 16 8 8 Escherichia coli N10 - - - - - 64 - - Escherichia coli EC 14 - - - - - 64 - 128 Escherichia coli TEM - - - 16 - 16 - 64 Klebsiella X26 - 16 - 16 64 - - 32

Antibiotic activity of C-20-modified derivatives Tested organism Test Compound® D13 D15 D19 D20 D21 D22 D23 D24 D25 Staphylococcus aureus Xl.l 0.5 2 1 0.5 1 1 0.5 0.5 0.5 Staphylococcus aureus V4T 1 2 1 0.5 1 0.5 0.5 0.5 0.5 Staphylococcus aureus X400 ^d 1 4 1 0.5 1 1 1 1 1 Staphylococcus aureus S13E 1 2 1 0.5 1 0.5 0.5 0.5 0.5 Staphylococcus epidermis EPI1 1 2 1 0.5 1 0.5 0.5 0.5 0.5 Staphylococcus epidermidis 222 0.25 1 0.25 0.25 0.5 0.25 0.5 0.25 0.25 Streptococcus pyogenes C203 2 0.5 0.5 0.25 0.5 0.25 0.5 0.25 0.25 Streptococcus pneumoniae Park I 2 1 0.25 0.12 0.5 1 0.5 1 0.5 Streptococcus Group D X66 2 32 16 8 4 8 4 4 4 Streptococcus Group D 2041 2 32 16 8 8 8 8 8 4 Haemophilus influenzae C.L. ' 16 32 16 16 32 16 16 32 16 Haemophilus influenzae 76 ^s 8 32 16 16 16 8 8 8 8 Escherichia coli N10 - - 128 128 64 - 64 64 128 Escherichia coli EC 14 - - 128 128 64 - 64 64 128 Escherichia coli TEM - 64 32 32 32 64 32 32 32 Klebsiella X26 16 32 32 16 64 64 128 128 128

Tested compound ”

Tested organism D26 D27 D28 D29 D34 D40 D41 D42 D Staphylococcus aureus XI. 1 0.5 1 2 0.5 1 0.5 8 0.5 1 Staphylococcus aureus V4F 0.5 1 2 0.5 1 0.5 8 0.25 1 Staphylococcus aureus X400 ^d 0.5 1 4 0.5 1 0.5 8 0.5 1 Staphylococcus aureus S13E 0.5 1 2 0.5 0.5 0.5 8 0.5 1 Staphylococcus epidermis EPI1 0.5 I 2 0.5 0.5 0.5 8 0.5 0.5 Staphylococcus epidermidis 222 0.25 0.25 1 0,125 th most common 0.25 0.25 2 0.25 0.5 Streptococcus pyogenes C203 0.25 0.25 0.5 0.5 0.5 0.25 I 0.5 0.5 Streptococcus pneumoniae Park / 0,25 0.5 2 0.5 2 2 1 0.25 2 Streptococcus Group D X66 1 2 8 2 4 4 32 2 8 Streptococcus Group D 204 J 2 4 8 8 8 8 32 2 16 Haemophilus influenzae C.L. '' 32 32 32 4 16 4 64 16 NT Haemophilus influenzae 7 &amp; 8 16 32 4 4 8 64 8 NT Escherichia coli N10 128 128 - 64 128 64 - - NT Escherichia coli EC 14 128 128 - 64 128 64 - - NT Escherichia coli TEM 32 32 64 16 32 16 - - NT Klebsiella X26 64 64 64 32 64 16 128 64 -

a MIC mcg / ml b Number of compounds of Tables I-IV with Penicillin Resistant Strain d Methicillin Resistant Strain Ampicillin Sensitive / Ampicillin Resistant Strain g inactive at 128 mcg / ml highest tested h level tested used a precursor from Group D strain 9960 i not tested

Table X

Antibiotic activity of C-20 Modified derivatives

Test Compound ⁶

Tested organism DI D2 D3 D4 D5 D6 D7 D10 Dll D12 Staphylococcus aureus 0.78 0.78 12.5 0.39 1.56 0.78 1.56 0.39 1.56 1.56 Streptococcus sp. 19 F 6.25 6.25 12.5 0.09 3.12 0.78 3.12 0.78 3.12 3.12 Pasteurella midtocida 17EF 6.25 25 50 6.25 3.12 3.12 6.25 1.56 12.5 6.25 Pasteurella midtocida 6 () A ^d 6.25 6.25 50 6.25 3.12 6.25 6.25 3.12 50 12.5 Pasteurella hemolytica 22C 6.25 3.12 50 6.25 1.56 1.56 3.12 1.56 25 3.12 Mycoplasma gallisepticum 29C 12.5 3.12 25 0.39 1.56 1.56 0.39 0,097 <0,048 <0,048 Mycoplasma synoviae 40A 0.39 0.78 6.25 <0.05 0.39 0.78 0.39 <0,048 0.78 0.39 Mycoplasma hyorhinis 29E 50 > 50 50 50 50 50 25 12.5 6.25 12.5 Mycoplasma hyopneumonie S5972 12.5 12.5 6.25 0.78 1.56 1.56 1.56 0.78 1.56 3.12

Test compound ¹¹

Tested organism D13 F14 D15 D19 D20 D21 D22 D23 D24 D25 Staphylococcus aureus 3.12 0.78 6.25 0.78 0.78 0.78 1.56 3.12 3.12 3.12 Streptococcus sp. 19F 6.25 1.56 12.5 3.12 3.12 1.56 3.12 1.56 3.12 3.12 Pasteurella multocida 17EF 12.5 3.12 12.5 3.12 3.12 3.12 12.5 6.25 12.5 12.5 Pasteurella multocida 60A ^d 12.5 3.12 12.5 3.12 3.12 3.12 12.5 12.5 6.25 12.5 Pasteurella hemolytica 22C 12.5 1.56 25 3.12 3.12 3.12 3.12 3.12 6.25 3.12 Mycoplasma gallisepticum 29C 6.25 1.56 3.12 1.56 0.78 1.56 0.78 0,097 0.39 0.39 Mycoplasma synoviae 40A 1.56 0.39 1.56 0.39 0,195 0.39 0.78 0,097 0.097 0,097 Mycoplasma hyorhinis 29 E 50 50 > 50 > 50 50 - 25 6.25 25 12.5 Mycoplasma hyopneumonie S5972 3.12 0.78 3.12 3.12 0.78 0,195 1.56 0.78 0.78 0.39

Test Compound ⁶

Tested organism D5 D26 D27 D28 D5a L4 T6 T13 M3 M4 Staphylococcus aureus 1.56 3.12 3.12 3.12 0.39 6.25 12.5 6.25 12.5 12.5 Streptococcus sp. 19F 0.78 0.78 0.78 3.12 0.78 6.25 50 50 50 12.5 Pasteurella multocida I7E 6.25 6.25 6.25 6.25 6.25 12.5 > 50 > 50 > 50 > 50 Pasteurella multocida 60 A ^d 12.5 12.5 12.5 25 3.12 12.5 > 50 > 50 > 50 > 50 Pasteurella hemolytica 22C 12.5 12.5 12.5 25 3.12 25 50 50 50 > 50 Mycoplasma gallisepticum 29C 6.25 <0,048 <0,048 0,097 0.78 12.5 3.12 1.56 6.25 3.12 Mycoplasma synoviae 40A 3.12 0.78 <0,048 0,195 0,195 1.56 0.78 1.56 25 6.25 Mycoplasma hyorhinis 29E 50 25 25 25 3.12 50 > 50 > 50 > 50 > 50 Mycoplasma hyopneumonie S5972 N'T * 0.78 0.39 1.56 0,195 1.56 12.5 25 12.5 6.25

Test Compound ⁶

Tested organism D29 D34 D41 D42 D43 D44 D46 Staphylococcus aureus 19C 1.56 3.12 6.25 0.78 1.56 3.12 3.12 Streptococcus sp. 19F 1.56 3.12 6.25 0.78 1.56 1.56 1.56 Pasteurella multocida I7E7 3.12 12.5 25 12.5 6.25 12.5 6.25 Pasteurella multocida 60A ^d 6.25 12.5 50 25 6.25 12.5 12.5 Pasteurella hemolytica 22C 6.25 6.25 > 50 50 6.25 12.5 6.25 Mycoplasma gallisepticum 29C 0,195 0,195 6.25 0,097 0,195 1.56 0,195 Mycoplasma synoviae 40A <0,048 0.78 1.56 0,195 <0,048 0,097 1.56 Mycoplasma hyorhinis 29E 6.25 12.5 50 3.12 25 50 25 Mycoplasma hyopneumonie S5972 0,195 0.78 3.12 0,097 0.78 0.39 3.12

and MIC in mcg / ml

B The numbers of the compounds in Tables I-IV with Bovine isolate d Avian isolate have not been studied

The C-20 modified derivatives of the invention show antimicrobial activity in vivo against experimentally induced infections in laboratory animals. When two doses of test compound were administered to mice experimentally infected with S. pyogenes C02H3, the observed activity was measured as ED _{5 (|} value [effective dose in mg / kg protecting 50% of the animals tested (Warren Wick et al., J. Bacteriol 81. 233-235, 1961) The observed ED _5II values for the illustrative compounds are shown in Table XI.

Table XI

Tested ED _{S (1} values of C-20-modified derivatives vs Streptococcus pyogenes C203 in mice · ' Oral compound ” Subcutaneously D1 1,2 > 50 D2 0.9 50 D4 6.0 19 D5 1.3 50 D5a 1.5 34 D6 0.7 14 D7 1.6 12 D10 <10 68 DI1 7.5 19 D12 2.0 <6.3 D14 1.0 50 DI9 2.9 46 D20 1.7 34 D21 1.0 10 D22 0.8 40 D26 5.61 12.5 D27 3.81 16.5 D28 0.75 77 D29 1.56 10.3 D34 <0.625 7.98 D35 0.88 10.93 D41 2.04 > 100 D43 1.34 8 D44 0.69 37,9 D48 7.53 25 L5 1.8 100 M3 > 10 > 100 T6 > 10 44 T13 > 10 30 a mg / kg x 2; doses 1 and 4 hours after infection

b the numbers of the compounds of Tables 1-IV.

Many of the C-20 modified derivatives. included in the invention also exhibit antibacterial activity in vivo against infections caused by gram-negative bacteria. Tables XI and XIII summarize the results of tests in which illustrative compounds are evaluated against Pasteurella infection in chickens one day old. The compounds were administered parenterally or orally after infection of the chickens with Pasteurella multocida (0.1 ml of a 20-h culture was subcutaneously injected into the tryptose culture medium of avian P. multocida at dilution 10 ⁴ ). In these tests, unless otherwise indicated, all infected and untreated chickens die within 24 hours of infection with Pasteurella. In the tests summarized in Table XII, the compounds were administered by subcutaneous injection at doses of 30 mg / kg, 1 and 4 h after infection with P. multocida chickens. In the tests summarized in Table XIII, the compounds were administered in therapeutic drinking water (at a dosage of 0.53 g / l) in Table XII 4 to 20 h before infecting the chickens with P. multocida and during the 3-day test period.

Activity of C-20-modified derivatives administered subcutaneously to Pasteurella multocida infected chickens · '

Test Compound ⁶

Number of deaths / Number of treatments

D1

D2

D4

D5 d6 d7 dlO Dll D12 D14 D19

D21

D22

D23

D24

D25

D26

D27

D28

D34

D45

D47

L5

0/10

0/10

9/10

0/10

0/10

3/10 10/10 10/10

9/10

2/10

0/10

7/10

0/10

8/10

2/10

0/10 10/10

8/10

0/10

3/10

0/10

0/10

0/10 and subcutaneous administration; 30 mg / kg χ 2;

b the numbers of the compounds of Tables II and IV

Table XIII

Activity of C-20-modified derivatives administered orally to Pasteurella multocida infected chicks "

Test Compound ⁶

Number of deaths / Number of treatments

D1

D2

D4

D5

D6

D7

DI 1

D12

9/10

5/10

6/10

2/10

1/10

2/10

8/10

8/10

D14 0/10 D19 3/10 D20 0/10 D21 3/10 D22 5/10 D23 4/10 D25 7/10 D28 7/10 D34 3/10, 0/10, 1/10. 6/10 D45 1/10 D46 3/10 D47 6/10

and applied to the drinking water at a concentration of 0.53 g / 1b the compound numbers of Table II

The invention also encompasses methods of controlling infections caused by bacterial and mycoplasma species. An effective amount of a compound of formula I or 2 is administered parenterally or orally to an infected or susceptible warm-blooded animal. The compounds may also be administered by insufflation, i.e., inhalation of the compound in the form of a powder in an enclosed space or room where animals or birds are kept. The healing dust is breathed in from the air and absorbed through the eyes, a process called intraocular injection.

The effective dose control varies depending on the degree of infection and the age, weight and condition of the animal. The total dose required for protection in parenteral administration is generally in the range of about 0.1 to 100 mg / kg, preferably from about 0.5 to about 50 mg / kg. The dose required for oral administration is generally from 1 to 300 mg / kg, preferably in the range of from about 1 to about 100 mg / kg. Suitable dosage regimens may be formulated.

An advantage of the invention is that some of the compounds are effective when administered as a single injection. For example, a single injection of 20-dihydro-20-deoxy- (cis-3,5-dimethylpiperidin-1-yl) desmycosin provides prolonged, measurable blood and tissue levels of the drug over a 7-day period.

Often, the most practical way to administer the compounds is to mix them with food or drinking water. Different types of food can be used - plain dry, liquid and granular.

The invention relates to compositions used for the control of infections caused by bacterial and mycoplasma species. These compositions consist of compounds of formula 20 or formula 1 together with a suitable carrier. Formulations for parenteral or oral administration may be formulated by methods known in the art.

Methods for mixing medicines with animal foods are well known. It is preferable to prepare a pre-concentrated drug mixture for the preparation of medicinal foods. Typical premixes contain from about 2.22 to about 444.44 g of drug per kilogram of the mixture. The premix can be liquid or solid.

The final nutritional forms for animals or birds depend on the amount of medicine prescribed. For the preparation of foods containing compounds of formula 1 or 2, conventional mixing and granulation methods may be used.

Effective injectable compositions containing the compounds may be in the form of suspensions or solutions. In the preparation of suitable forms, it is apparent that the solubility of the acid addition salts in water is greater than that of the free bases. Also, the bases are more soluble in dilute acids or in acidic solutions than in neutral or alkaline solutions.

When in solution form, the compound is dissolved in a physiologically acceptable complex solvent which includes a suitable solvent, preservatives such as benzyl alcohol, if necessary, and buffers. Convenient solvents are water, alcoholic aqueous solutions, glycols and carbonate esters such as diethyl carbonate.

Injectable suspension formulations require a liquid suspending medium, with or without additives, as a carrier. The suspending medium may be, for example, an aqueous solution of polyvinylpyrrolidone. inert oils such as vegetable oils or highly refined mineral oils or an aqueous solution of carboxymethylcellulose.

Physiologically acceptable additives are required to keep the compound suspended. The additives may be selected from thickeners such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates. Many surfactants are also used as suspending agents. Suitable suspending agents are lecithin, alkylphenol polyethylene oxide adducts, naphthalenesulfonates, alkylbenzenesulfonates and polyoxyethylene sorbitan esters.

In individual cases, many substances that affect the hydrophilicity, density and surface tension of the liquid suspending medium may be helpful in the preparation of injection suspensions. For example, suitable suspending agents may be silicone antifoams, sorbitol and sugars.

The invention is further illustrated by the following examples in which the abbreviation 20DH-DO means 20-dihydro-20-deoxy.

Comparative Example 1. Preparation of 20-dihydrothylosine (Relomycin)

A solution of tylosin base (30.0 g, 32.8 mmol) in 2-propanol (300 ml) and water (200 ml) was treated with sodium borohydride (315mg, 8.2 mmol) in portions for 5 min. 30 min after completion of the addition, the pH of the reaction solution was adjusted to 7.0 by the addition of 1N sulfuric acid solution. The neutralized solution was evaporated in vacuo to remove 2 propanol, and the remaining aqueous solution was treated with saturated sodium bicarbonate solution (500 ml). The mixture was extracted with dichloromethane (3 x 300 ml) and the combined extracts extracted with saturated sodium chloride solution (200 ml) and dried with sodium sulfate. Filtration, followed by evaporation, gave a glassy mass which is destroyed in n-hexane, collected on a filter and air dried to give 28.5 g (95%) of 20-dihydrothylosine.

Comparative Example 2. Preparation of 20-dihydrodesmycosin

Desmicosin (10 g, 13 mmol) was dissolved in isopropanol: water (1: 1, 175 ml) and stirred at room temperature until NaBH ₄ (125 mg, 3.3 mmol) was added. After 0.5 h, the pH of the reaction mixture was adjusted to 7.0 with INH ₂ SO ₄ . Alcohol is released under reduced pressure. A saturated solution of NaHCO ₃ was added to the aqueous solution and the product was extracted into CH ₂ Cl ₂ . The organic layer was dried (Na ₂ SO ₄ ) and the solvent removed under reduced pressure to give 9.65 g of 20-dihydrodesmicosin (12.5 mmol, 96% yield) as a white foam.

Comparative Example 3. Preparation of 20-OH-PO-20-iododemicosine (Method 1)

20-Dihydrodesmycosin (2.0 g, 2.6 mmol) and tetra n-butylammonium iodide (1.5 g, 3.9 mmol) were dissolved in CH ₂ Cl (30 ml) with the addition of s-colidine (0, 6 ml, 4.5 mmol). This solution was cooled to -78 ° C under a nitrogen atmosphere and treated with trifluoromethanesulfonic anhydride (0.6 ml, 3.9 mmol) dropwise via syringe. The reaction mixture was stirred for 5 min at -78 ° C, then allowed to reach room temperature (for about 30 min). Saturated NaHCO ₃ solution was added and the product was extracted with CH ₂ Cl ₂ . The organic layer was dried (Na ₂ SO ₄ ) and evaporated to give a red oil, which was purified by flash chromatography on silica gel, eluting first with CH ₂ Cl ₂ (400 ml) and then successively with CH ₂ Cl ₂ : CH ₃ OH solutions as follows: 98: 2 (250 ml); 96: 4 (500 ml); 95: 5 (250 ml); 94: 6 (750 ml) and 92: 8 (250 ml). The fractions containing the desired product were identified by TLC, combined and evaporated to dryness to give 20-PN-00-20-iododesmicosin (595 mg, 0.67 mmol, yield 26%) as a white foam.

Comparative Example 4. Preparation of 20-OH-OO-20-Iododesmicosin (Method 2)

20-Dihydrodesmycosin (5.0 g, 6.5 mmol) and triphenylphosphine (2.54 g, 9.70 mmol) were dissolved in dimethylformamide (DMF) (10 ml). This mixture was stirred at room temperature in N ₂ while iodine (2.46 g, 9.70 mmol) in DMF (5ml) was added dropwise. The reaction mixture was stirred for 2 h, then poured into cold saturated NaHCO ₃ solution. The product was extracted with 2 parts CHCl ₃ and the combined CHCl ₃ extracts were shaken with 0.1 M sodium thiosulphate to remove unreacted iodine. The organic layer was dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give a pale yellow oil which was purified by flash chromatography on silica gel. The column was eluted initially with CH ₂ Cl ₂ (500 ml) and then with 250 ml portions of CH ₂ Cl ₂ : CH ₃ OH mixtures as follows: 98: 2; 96: 4; 95: 5; 94: 6; 92: 8; 88:12 and 86:14. The fractions containing the desired product were identified as in Preparation 3 and mixed to give 1.78 g (2.0 mmol, 31% yield) of 20-DH-DO-20 iododimesicosin as a white foam.

Example 1

20-DH-DO-20- (octahydroazocin-1-yl) desmicosine

20-OH-OO-20-iododesmicosine (575 mg, 0.65 mmol) was dissolved in acetonitrile (10 ml) and heptamethylenimine (0.37 g, 0.41 ml, 3.3 mmol) was added to this solution. The reaction mixture was stirred at reflux for 1.5 h. The volatiles are then removed in vacuo. The residue was dissolved in CH ₂ Cl ₂ and extracted with saturated NaHCO ₃ solution. The organic layer was dried (Na ₂ SO ₄ ) and then evaporated under reduced pressure to give a light brown foam. This foam was purified by flash chromatography on silica gel, eluting with 250 ml of each of the following CH ₂ Cl ₂ : CH ₃ OH mixtures: 98: 2; 96: 4; 94: 6; 9: 1; 88:12; 82:18; 65:35; 1: 1; 1: 3 and finally with 300 ml CH ₃ OH. The fractions containing the desired product were identified by TLC, combined and evaporated to dryness to give 397 mg (0.46 mmol, yield 71%) of 20-DH-DO-20- (octahydroazocin-1-yl) desmicosin in kind of white foam.

Example 2

20-DH-DO-20- (hexahydroazepin-1-yl) desmicosine

Desmicosin (10 g, 13 mmol) dissolved in anhydrous methanol (100 ml) was added rapidly to a solution of NaBH ₃ CN) (3.3 g, 52 mmol) and hexamethylenimine (6.5 g, 7.5 ml, 65 mmol) in anhydrous methanol (50 ml) in the presence of NJ. The reaction mixture was stirred in N ₂ at room temperature for about 3 hours and then evaporated under reduced pressure. The resulting precipitate was dissolved in CH ₂ Cl ₂ in the presence of an amount of ethyl acetate sufficient to dissolve the precipitate. This solution was extracted with saturated NaHCO ₃ solution. The organic layer was separated, dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to give a pale yellow foam. This foam was purified by flash chromatography on silica gel, eluting initially with CH ₂ Cl ₂ (1 L) and then successively with 500 ml portions of CH ₂ Cl ₂ : CH ₃ OH mixtures as follows: 98: 2; 96: 4; 94: 6; 92: 8 and 9: 1 and finally with

CH ₂ C1 ₂ : CH ₃ OH: NH ₄ OH mixtures as follows: 90: 10: 0,5 (500 ml) and 75: 25: 0,5 (2 1). The fractions containing the desired product were identified by TLC, combined and evaporated to dryness to give 6.035 g (7.07 mmol) of 20-OH-OO-20-hexahydroazepin-1 yl) desmicosin as a white foam . The other fractions containing the impure product were combined, redissolved in CH ₂ Cl ₂ , re-extracted with saturated NaHCO ₃ solution and purified as before using a silica gel column filled with CH ₂ Cl ₂ : CH ₃ OH (9: 1) and eluting with CH ₂ Cl ₂ : CH ₃ OH: NH ₄ OH as follows: 90: 10: 0,5 (500 ml) and 80: 20: 0,5 (11), to obtain another 1.372 g (1.61 mmol) of product. The total yield of 20-DH-DO-20- (hexahydroazepine-Pyl) desmycosin was 7.407 g (8.68 mmol, 67%).

Example 3

20-DH-DO-20 - (4-phenylpiperidin-1-yl) desmicosine

Desmicosin (1.5 g, 2 mmol) was dissolved in absolute methanol (60 ml) and treated with 4phenylpiperidine (640 mg, 4 mmol) in the presence of Linde 4A molecular sieves. After 0.5 h, NaBH ₃ CN (500 mg, 8 mmol) was added and the mixture was stirred at room temperature for 2.5 h. The mixture was poured into a saturated solution of NaHCO ₃ (200 ml) and extracted with CH ₂ Cl ₃ (3 x 200 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and evaporated under reduced pressure. The precipitate (3.6 g) was purified by flash chromatography on silica gel, eluting with a gradient of 1 1 CH ₂ Cl ₂ to 1 1 MeOH: CH ₂ Cl ₂ (5:95) and then with 1 1 MeOH: CH ₂ Cl ₂ (5:95). The fractions containing the desired product were detected by TLC, combined and evaporated to dryness to give 680 mg of 20-DH-DO21

2O- (4-phenylpiperidin-1-yl) desmicosine

Example 4

20-DH-DO-20- (hexahydroazepin-1-yl) 4'-deoxydesmicosin

A solution of 4'-deoxydesmicosin (565 mg, 0.75 mmol) in methanol (15 ml) was stirred in the presence of argon and activated Linde 3a molecular sieves (2.2 g) for 30 min, then hexamethylenimine (0 was added) (25 ml, 2.25 mmol). 1 h later, sodium cyanoborohydride (141 mg, 2.25 mmol) was added to the reaction mixture. After another 45 min, the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were shaken with saturated sodium chloride solution, dried with sodium sulfate, filtered and evaporated to give 600 mg of crude product. This product was purified by silica gel TLC, eluting with dichloromethane / methanol / concentrated ammonium hydroxide (90: 15: 2) to give 150 mg (yield 24%) of 20-DHDO-20- (hexahydroazepin-1-yl ) -4'-deoxydesmicosin.

Examples 5-6

20-DH-DO-20- (octahydroazocin-1yl) desmycosin was prepared by the method of Example 2.

20-DH-DO-20- (hexahydroazepin-1-yl) desmycosin was prepared by the method of Example 1.

Example 7

20-DH-DO-20- (octahydroazocin - 1 yl) desmicosin (Method 3)

Desmicosin (4.0 g, 5.2 mmol) was dissolved in absolute methanol (30 ml) and treated with heptamethylenimine (1.2 g, 1.3 ml, 10.4 mmol) in the presence of 3A molecular sieves. After stirring the reaction mixture for 1 h at room temperature, a solution of NaBH ₄ (60 mg, 1.6 mmol) in absolute methanol (10 ml) was rapidly added by pipette. The reaction mixture was stirred for 1.5 h at room temperature and then 30 mg of NaBH ₄ (one portion of solid) was added. The reaction mixture was stirred for a further 75 min and then filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml) and this solution was extracted with water (150 ml) and saturated NaHCO ₃ solution (100 ml). The ethyl acetate solution was then extracted with 0.5 M NaH ₂ PO ₄ buffer (150 ml) at pH 6.5. The buffer extract was evaporated in vacuo to remove the precipitated ethyl acetate and then stirred rapidly until NaOH was slowly added to give a thick white precipitate. The white solid was filtered off, washed with a small amount of water and dried to give 3.55 g of 20-OH-OO-20- (octahydroazocin-1-yl) desmycosin

Example 8

20-DH-DO-20- [1-Azaspiro [4.5] decan-1yl] desmicosin

Desmicosin (5.0 g, 6.5 mmol) was dissolved in absolute methanol (50 ml) and treated with 1-azaspiro [4.5] decane (1.36 g, 9.8 mmol) in the presence of 3a molecular sieves. After 15 min NaBH ₃ CN (620 mg, 9.8 mmol) was added and the mixture was stirred for 17 h at room temperature. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The precipitate was dissolved in ethyl acetate (300 ml) and extracted with water (300 ml and 100 ml). The product was then extracted from the ethyl acetate solution with 0.5 M NaH ₂ PO ₄ buffer (300 ml and 100 ml) at pH 6.5. The phosphate buffer extracts were combined and evaporated in vacuo to remove the precipitated ethyl acetate. The phosphate buffer solution was then stirred until 5N NaOH was slowly added to give a thick white precipitate. The white solid was removed by filtration, washed with water and dried to give 20DH-DO-20- [1-azaspiro [4.5] decan-1-yl] desmycosin (3.52 g).

Example 9

20-DH-DO-20- (1,2,3,4-tetrahydroquinolin-1-yl) desmicosin

Desmicosin (11.6 g, 15 mmol) was dissolved in dry methanol (100 ml) and 1,2,3,4-tetrahydroquinoline (3.8 ml, 30 mmol) was added. The mixture was then stirred for 30 min at room temperature and sodium cyanoborohydride (1.25 g, 20 mmol) was added. The mixture was stirred overnight and then evaporated under reduced pressure. The precipitate was partitioned between ethyl acetate and water (100 ml each). The organic layer was then extracted sequentially with aqueous phosphate buffer (100 ml) at pH 6.5 and aqueous phosphate buffer (100 ml) at pH 4.5. The ethyl acetate layer was dried (sodium sulfate), filtered and evaporated; and the precipitate (4.6 g) was separated by chromatography on silica gel (Waiters Prep 500). The column was eluted by a linear gradient of dichloromethane (4 I) and 5% methanol with 0.5% concentrated ammonium hydroxide in dichloromethane (4 L). The fractions containing the desired product were identified by TLC, collected and evaporated to dryness to give 3.4 g of the title compound.

Example 10

20-DH-D0-20- (1,2,3,4-tetrahydroisoquinolin-2-yl) desmycosin

Desmicosin (11.6 g, 15 mmol) was dissolved in dry methanol (100 ml) and 1,2,3,4-tetrahydroisoquinoline (3.8 ml, 30 mmol) was added. The mixture was then stirred for 30 min at room temperature and sodium cyanoborohydride (1.25 g, 20 mmol) was added. The mixture was stirred overnight and then evaporated under reduced pressure. The precipitate was partitioned between ethyl acetate and water (150 ml each). The organic layer was then extracted sequentially with phosphate buffer (100 ml) at pH 6.5 and phosphate buffer (100 ml) at pH 4.5. After evaporation of the buffer extract at pH 4.5 under reduced pressure to remove the ethyl acetate, the pH was adjusted to 10 with 5N sodium hydroxide. The precipitate formed was collected and air-dried to give 5.6 g of the title compound.

Example 11

20-DH-DO-20-U, 2,3,6-tetrahydropyridin-1-yl) desmicosin

Desmicosin (11.6 g, 15 mmol) was dissolved in dry methanol (100 ml) and 1,2,3,6-tetrahydropyridine (2.8 ml, 30 mmol) was added. The mixture was then stirred for 30 min at room temperature and sodium cyanoborohydride (1.2 g, 20 mmol) was added. The mixture was stirred overnight and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml). This solution was extracted with water (150 ml) and then with an aqueous solution of phosphate buffer (2 x 100 ml) at pH 6.5. The buffer solutions were evaporated separately under reduced pressure to remove the ethyl acetate and then the pH was adjusted to 10 with 5N sodium hydroxide. The precipitates formed were collected by filtration and air-dried to give 5.4 g (of the first extract) and 3.2 g (of the second extract) of the title compound.

Examples 12-32

The following compounds were prepared by the methods of Examples 1,2,7 or 8:

20-DH-DO-20- (3,3-dimethylpiperidin-1-yl) desmicosine

20-DH-DO-20- (octahydroazocin-1-yl) lactenocin

20-OH-OO-20- (pyrrolidin-1-yl) desmycosin

20-OH-OO-20- (azacyclotridecan-1-yl) desmicosine

20-DH-DO-20- (4-hydroxypiperidin-1-yl) desmycosin

20-DH-DO-20- (hexahydroazepin-1-yl) macrocin

20-DH-DO-20- [3-azacyclo [3.2.2] -nonan3-yl] desmicosin

20-OH-OO-20- (piperidin-1-yl) desmycosin

20-DH-DO-20- [3-N-N-diethylcarbamoyl) piperidin-1-yl] desmicosin

20-DH-DO-20 - [(4-piperidino) piperidin-1-yl] desmicosin

20-OH-OO-20- (octahydro-1H-azonin-1yl) desmicosin

20-DH-DO-20- (decahydroquinolin-1 yl) desmicosine

20-DH-DO-20- [1,3,3-trimethyl-6-azabicyclo [3.2.1] octan-6-yl) desmicosin

20-OH-OO-20- (dodecahydrocarbazol-9yl) desmicosine

20-DH-DO-20- (octahydroazocin-1-yl) tylosin

20-OH-OO-20- (3-azabicyclo [3.2.2] nonan-3-yl) tylosin

20-OH-OO-20- (4-phenyl-1,2,3,6-tetrahydropyridin-1-yl) desmycosin

20-DH-DO-20- (4-benzyl-piperidin-1-yl) desmicosine

20-DH-DO-20- [4- (ethylenedioxy) piperidin-1-yl) desmicosin

20-DH-DO-20- (octahydroazocin-1-yl) macrocin

20-DH-DO-20- (hexahydroazepin-1-yl) actenocin

Examples 33-36

20-OH-OO-20- (3,3,5-trimethylhexahydroazepin-1-yl) desmicosine was prepared by the method of Example 8 and then separated into isomers 1 and 2 by flash chromatography on silica gel.

20-OH-OO-20- (dodecahydrocarbazol-9-yl) desmicosin (compound D25) is a mixture of two isomers. The mixture was separated into two fractions, each of which was rich in one of the isomers by flash chromatography on its lycagel. Each of these fractions has an activity similar to that of the mixture.

Examples 37-38

20-OH-OO-20- (octahydroazocin-1-yl) desmycosin

The dihydrochloride and tartrate salts are prepared from 20-OH-OO-20- (octahydroazocin-1-yl) desmicosin using standard procedures.

Example 39

A. Purification of cis-3,5-dimethylpiperidine

A solution containing 3,5-dimethylpiperidine (40 ml, 4: 1 mixture of cis: trans isomers), triethylamine (42 ml) and dichloromethane (250 ml) was stirred while adding chlorobenzoyl chloride dropwise at a rate sufficient to allow maintains low reflux. After the addition was complete, the solution was stirred for an additional 0.5 h; then 10% aqueous ammonium chloride solution (200 ml) and enough concentrated HCl were added to make the aqueous layer acidic. The organic layer was separated, washed with brine, dried and concentrated. The resulting solid was recrystallized twice from CH ₂ Cl ₂ and hexane to give a perfectly pure cisamide, mp 99 '' - 103'C.

The amide (17 g) was dissolved in ethylene glycol. Potassium hydroxide granules are added and the solution is refluxed. After 1 h the flask was prepared for distillation and fractions boiling between 100C and 195C were collected. This material was partitioned between water and ether, dried and concentrated to give pure cis-3,5-dimethylpiperidine.

B.

Alternative purification of cis-3,5dimethylpiperidine

48 ml (0.36 mmol) of technically 3,5 dimethylpiperidine (80-85% cis) and 600 ml of anhydrous ether are placed in a one-liter, three-necked flask. HCl gas was bubbled through the solution with vigorous stirring until no free amine remained. The resulting product was separated by filtration and air-dried to give 47 g of the hydrochloride salt, mp 160-180C.

The salt was suspended in acetone (600 ml) and refluxed for 1 h. The reaction mixture was cooled to 50C and filtered. The separated solid was air-dried to give 25.6 g of the product, mp 226-228C. Part of this material (18 g) was dissolved in water (100 ml) and the solution was adjusted to pH 10 with granular sodium hydroxide. The free amine was extracted into diethyl ether, dried over magnesium sulfate, filtered and carefully concentrated to give 8.5 ml of cis-3,5-dimethylgperidine with a contamination of <5% transisomer.

S.

Preparation of cis-20-OH-OO-20- (3,5-dimethylpiperidin-1-yl) desmicosin

Desmicosin (10 g, 12.9 mmol) was dissolved in dry methanol (100 ml) and cis 3,5,5-dimethylpiperidine (4g, 35 mmol) was added. After stirring at room temperature for 30 min, sodium cyanoborohydride (0.8 g, 12.9 mmol) was added. The solution was stirred overnight and then evaporated under reduced pressure. The precipitate was partitioned between ethyl acetate and water (150 ml each). The organic layer was extracted sequentially with phosphate buffer (100 ml) at pH 6.5 and phosphate buffer (100 ml) at pH 4.5.

The latter solution was adjusted to pH 10 with 5N sodium hydroxide and the free amine was re-extracted into ethyl acetate. The solution was dried with magnesium sulfate, filtered and concentrated to give 6.0 g of 20-OH-OO-20- (cis-3,5-dimethylpiperidin-1-yl) desmycosin. Analysis of the product by reverse phase HPLC did not detect a transisomer.

Example 40

Separation of cis-and trans-20-OH-OO-20- (3,5-dimethylpiperidin-1-yl) desmicosin

20-OH-OO-20- (3,5-dimethylpiperidin-1-yl) desmicosine was prepared using 3,5-dimethylpiperidine and which is a mixture of cis: trans isomers (4: 1). The product was chromatographed on silica gel using the solvent system methanolchloromethane: ammonium hydroxide (49.5: 49.5: 1). A single, large peak elutes. The first 10% of this peak consists of the pure isomer, and the next 10% includes the enriched transisomer (cis: the trans material is 16:84).

Tables X1V-XVI summarize certain physical data of exemplary compounds.

Table XIV

Physical characteristics of C-20-modified Desmicosin derivatives 20 substitute Compound · ' No FDMS Main ion (pg + 1) HC Xmax (£) ^b Titled groups' pyrrolidin-1-yl D1 827 7.9,9.5 4-Phenylpiperidin-1-yl D4 917 283 (21,800) hexahydroazepin-1-yl D5 855 282 (21,500) 7.9,9.6 hexahydroazepin-1-yl D5a 839 282 (21,500) octahydroazocin-1-yl D6 869 282 (21,750) 7.9,9.4 azacyclotridecan-1-yl D10 939 282 (19,500) 8.0,9.5 4-Piperidinopiperidin-1-yl D13 924 282 (18,600) 6.0,9.2 3-Azabicyclo [3.2.2] nonan-3-yl D14 881 282 (20,500) 7.9,9.2 piperidin-1-yl D2 841 282 (24,500) 7.8,9.1 4-hydroxypiperidin-1-yl D3 857 282 (20,750) 7.1,8.7 octahydro-1H-azonin-1-yl D7 883 282 (20,000) 7.9,9.0 1,2,3,4-tetrahydroquinolin-1-yl D11 888 281 sh (24,500) 1,2,3,4-tetrahydroisoquinolin-2-yl D12 888 283 (24,600) 3- (N, N-Diethylcarbamoyl) piperidine-1 -or D15 940 282 (20,500) 7.4,8.6 1-Azaspiro [4.5] decan-1-yl D19 894 281 (24,500) 7.9,9.8 decahydroquinolin-1-yl D20 895 281 (21,500) 7.9,9.4 1,3,3-trimethyl-6-azabicyclo- [3.2.1] octan-6-yl D21 908 282 (21,100) 8.0,9.7 1,2,3,6-tetrahydropyridin-1-yl D22 839 282 (21,100) 3,3,3-trimethylhexahydroazepin-1-yl, (isomer 1) D23 896 282 (21,130) 7.7,9.0 3,3,5-trimethylhexahydroazepin-1-yl, (isomer 2) D24 897 283 (21,390) 7.9,9.4 dodohydro ca rbazol-9-yl D25 935 282 (22,500) 7.95,9.95 octahydroazocin-1-yl D6e @ 7.9,9.4 octahydroazocin-1-yl D6f @ 869,151 282 (19,500) 5.4,7.3, 9.2 cis-3,5-dimethylpiperidin-1-yl D34 869 282 (20,000) trans-3,5-dimethylpiperidin-1-yl D35 869 282 (20,000) 3,3-dimethylpiperidin-1-yl D40 869 282 (18,900)

a The numbers of the compounds of Table II

B In methanol or ethanol with B 66% aqueous dimethylformamide d Silica gel tiles 60; CH ₂ Cl ₂ MeOH / NH ₄ OH (90: 10: 0.5) solvent is the dihydrochloride salt f tartrate salt

Table XV

Physical characteristics of C-20-modified Macrocin derivatives

20 substitute Compound ³ no FDMS Main ion (m * + 1) UV .lambda.max (£) ^L Titled groups' TCX ^d R, hexahydroazepn-1-yl M3 985 6.91,9.40 0.26 octahydroazocin-1-yl M4 999 282 (24,000) 6.90,9.25

a The numbers of the compounds of Table III b b in methanol with B 66% aqueous DMF d plates of silica gel 60; CH ₂ Cl ₂ MeOH / NH ₄ OH (90: 10: 0.5) solvent 5

Table XVI

Physical characteristics of C-20-modified Lactenocin derivatives

20 substitute

FDMS Compound No. Base ion

UV

? Max (f) ^b

T etated groups' (yyy + 1)

Hectahydroazepin-1-yl octahydroazocin-1-yl a Compound numbers of Table IV b In ethanol with B methanol d 66% aqueous DMF was added

Example 41-64

The following compounds may be prepared by the methods of the foregoing examples.

20-DH-DO-20 - (octahydroazocin-1yl) tylosin

20-DH-DO-20- (piperidin-1-yl) lactenocin

20-OH-OO-20- (4-hydroxypiperidine-1h.t) DOML

20-OH-OO-20- (decahydroazecin-1-yl) desmycosin

20-OH-OO-20- (octahydroazocin-1yl) macrocine

20-DH-DO-20- (azacyclotridecan-1-yl) lactenocin

20-OH-OO-20- (hexahydroazepin-1-yl) lactenocin

20-DH-DO-20- (1,2,3,4-tetrahydroisoquinolin-1-yl) macrocine

20-DH-DO-20- (1,2,3,4-tetrahydroquinolin-1-yl) macrocine

20-OH-OO-20- (azacycloundecan-1-yl) desmicosine

20-DH-DO-20- (4-methylpiperidin-1-yl) desmycosin

20-DH-DO-20- (pyrrolidin-1-yl) lactenocin

20-DH-DO-20- (octahydro-1H-azonin-1 yl) tylosin

20-DH-DO-20- (octahydroazocin-1-yl) DO MM

20-DH-DO-20- (octahydroazocine - 1 L4 841 282 (21,500) 8.0,9 = 70

L5 855 282 (21,500G 7.8,9.3 on) DOML

20-DH-DO-20- (4-phenyl-piperidin-1-yl) lactenocin

20-DH-DO-20- (4-phenyl piperidin-1-yl) -4'-deoxydesmicosin

20-DH-DO-20- (octahydroazocin-1-yl) 4'-deoxydesmicosin

20-DH-DO-20- (3-azabicyclo [3.2.2] nonan-3-yl) -4'-deoxydesmicosin 20-DH-D0-20- (1,2,3,4-tetrahydroisoquinolin-2-yl) ) lactenocin

20-OH-OO-20- (3,3,5-trimethylhexahide55 roazepin-1-yl) macrocine

20-DH-DO-20- (decahydrocyclopent [c] azepin-1-yl) desmicosine

20-OH-OO-20- (7-azabicyclo [2.2.1] heptan-7-yl) desmicosine

20-OH-OO-20- (decahydroisoquinolin-2yl) desmycosin

20-DH-DO-20- (3,5-dimethylpiperidin-1-yl) -4'-deoxydesmicosin

20-OH-OO-20- (3,4-dimethoxypiperidin45 1-yl) desmicosin

20-OH-OO-20- (3,5-dimethylpiperidin-1-yl) macrocine

Example 65

Injectable composition and (A) A compound of formula I as a base is added to propylene glycol. Water and benzyl alcohol are added so that the solution contains 50% vol. propylene glycol. 4% vol. benzyl alcohol and 200 mg / ml of the compound of formula 1.

(B) Prepare a solution as described in section A, except that the solution contains 50 mg / ml of compound of formula 1 as a base.

(C) Prepare a solution as described in section A except that the solution contains 350 mg / ml of compound of formula 1 as a base.

(D) Prepare a solution as described in section A except that the solution contains 500 mg / ml of the tartrate salt of a compound of formula 1.

(E) Suspension is prepared by adding a finely divided compound of formula 1 to carboxymethylcellulose, gently mixing to form a suspension containing 200 mg / compound of formula 1 as a base of ml suspension.

Example 66

Microplasma control ration of chickens

The following recipe prepares a balanced, high-energy ration designed to feed the chickens and rapidly increase their weight:

Component 7 / o kg Ground yellow corn 50 2.22 Soya flour, solvent extracted, cleaned, finely ground, 50% protein 31.09 1381,77 Animal fat (beef tallow) 6.5 288,88 Fishmeal, soluble (60% protein) 5.0 222,22 Soluble maize distillates 4.0 177.77 Dicalcium phosphate for feeding 1.8 80 Calcium carbonate 0.8 35.55 Vitamin mixture (containing vitamins A, D, E, K and B ₂ , choline, niacin, pantothenic acid, riboflavin. biotin with glucose as a swelling agent) 0.5 22,22 Trace mineral mixture (containing MnSO ₄ , ZnO, KI, FeSO ₄ , CaCO ₃ ) 0.2 8.8 2-amino-4-hydroxybutyric acid (hydroxy anal of methionine) 0.1 4.4 Compound of Formula 1 or 2 0.01 0.4

These substances are mixed in accordance with standard food mixing technologies. Chickens fed with such ration and water ad libitum are protected from the effects of micro-plasma infections. Claims

Claims (63)

A compound of formula wherein R is a saturated or unsaturated secondary amino group of formula wherein the atom atom is part of a carbocyclic ring system selected from a monocyclic ring containing from 5 to 16 atoms or from a bicyclic or tricyclic ring system containing from 8 to 20 an atom or such group wherein one or more carbon atoms are substituted by C 1 -C ₄ alkyl, C ₂ C, alkenyl, C-C, alkynyl, C 1 -C _x alkoxy, 4 414 C 1 -C ₄ alkoxycarbonyl, hydroxyl, C 1 -C ₄ alkanoyloxy, halogen, halogen-C _1-4 alkyl, C 1 -C 4 -C 1-4 alkyl-, -N (CH ₂ ) _in , OO 11 -C-N (C 1 -C ₄ -alkyl) ₂ , -C-N (CH ₂ ) _m cyano, ethylenedioxy, benzyl, phenyl or phenyl substituted with 1 to 3 substituents such as nitro. halogen. C _| -C ₄ -alkyl. C ₍ -C ₄ alkoxy. 10 hydroxy, amino or mono or di-C 1 -C 4 alkyl) amino; m is an integer from 4 to 7; R 'is dream ₃ dream ₃ dream ₃ R ² is hydrogen; C 1 -C ₅ alkanoyl or C 1 -C 3 alkanoyl with 1 to 3 halogen substituents; benzoyl, phenylacetyl or phenylpropionyl or benzoyl, phenylacetyl or phenylpropionyl having 1 to 5 halogens or methyl group or 1 or 2 methoxy, nitro or hydroxyl ^J substituents; R ³ is hydroxy; C 1 -C ₅ alkanoyloxy; C 1 -C 6 alkanoyloxy with 1 to 3 halogen substituents; benzyloxy, phenylacetoxy or phenoxyacetoxy or benzoyloxy, phenylacetoxy or phenoxyacetoxy having from 1 to 40 5 halogens or methyl group or from 1 to 2 methoxy, nitro or hydroxyl substituents; or or the corresponding acid addition salts thereof. A compound according to claim 1, wherein R is a monocyclic ring. Compound according to claim 1, characterized in that R is a bicyclic or tricyclic ring system. A compound according to claim 1 wherein R is unsaturated. 5. A compound according to claim 1 wherein R is saturated. A compound according to claim 1, wherein R ¹ is CH ₃ CH ₃ A compound according to claim 6 wherein R ³ is hydroxy. A compound according to claim 2, wherein R is octahydroazocin-1-yl, hexahydroazepin-1-yl, octahydro-1H-azonin-1-yl, piperidin-1-yl or 1,2,3,6 -tetrahydropyridin-1-yl. A compound according to claim 8 characterized in that it is 20-dihydro20-deoxy-20- (3,3,5-trimethylhexahydroazepin-1-yl) desmycosin. A compound according to claim 8, which is 20-dihydro20-deoxy-20- (3,5-dimethylpiperidin-1-yl) desmicosine. Compound according to claim 10, characterized in that it is in the cisconfiguration. A compound according to claim 10, which is in the transconfiguration. A compound according to claim 8 characterized in that it is 20-dihydro20-deoxy-20-deoxy-20- (3,3-dimethylpiperidin-1-yl) desmicosine. A compound according to claim 3, wherein R is 1,2,3,4tetrahydroisoquinolin-1-yl; 1-azaspiro [4.5] decan-1-yl; 3-azaspiro [5.5] undecan-3yl; azabicyclononanil; decahydroquinolin-5-yl; 1,8,8-trimethyl-3-azabicyclo [3.2.1] octan-3-yl; 1,3,3-trimethyl-6-azabicyclo [3.2.1] octan-6-yl or dodecahydrocarbazol9-yl. A compound according to claim 14, 10 wherein it is 20-dihydro- 20-deoxy-20- [3-azabicyclo [3.2.2] nonan-3yl] desmicosine. A compound according to claim 3, wherein R is 2,3- 15 dihydroindol-1-yl, octahydroisoindol-2-yl or octahydroindol-1-yl. 17. Compound of formula: Q ² is hydrogen or a hydroxy protecting group; Q ³ is hydrogen or iodine; R is a saturated or unsaturated secondary amino group of formula -OH alkoxycarbonyl, hydroxyl, C 1 -C ₄ alkanoyloxy, halogen, halogen-C 1 -C 6 alkyl, -N (C 35 C 1-4 alkyl), -N (CH 3), 4 22 m οο IIII-C-N (C-C-alkyl), -C-N (CH,) 1 4 22 m 40 cyano, ethylenedioxy, benzyl, phenyl or phenyl substituted with 1 to 3 substituents selected from nitro, a halogen, C ^ C ^ alkyl, C ₄ alkoxy, hydroxy, amino, or mono or di- (C ₁ -C ₍ alkyl) amino; m is an integer of 4 45 to 7; R ² is hydrogen; C 1 -C 5 alkanoyl or C 1 -C ₅ alkanoyl with 1 to 3 halogen substituents; wherein the nitrogen atom is part of a carbocyclic ring system, such as a monocyclic ring containing 5 to 16 atoms or of bicyclic benzoyl, phenylacetyl or phenylpropionyl or benzoyl, phenylacetyl or phenylpropionyl having 1 to 5 halogens or methyl group of flax or tricyclic ring or tricyclic group from 1 to 2 methoxy, nitro or hydride containing from 8 to 20 atoms or such group in which one or more carbon atoms are substituted by C 1 -C. alkyl, C1-C6. alkenyl, C 1 -C, alkynyl, C 1 -C 4 alkoxy, C 1 -C, 2 4 14 14 roxyl substituents; and the corresponding acid addition salts. A compound according to claim 17 wherein R is a monocyclic ring. A compound according to claim 17, wherein R is a bicyclic or tricyclic ring system. A compound according to claim 17, wherein R is unsaturated. 21. A compound according to claim 17, wherein R is saturated. A compound according to claim 17 wherein Q ² and Q ³ are hydrogen. A compound according to claim 18 wherein R is octahydroazocin-1-yl, hexahydroazepin-1-yl, octahydro-1H-azonin-1-yl, piperidin-1-yl or 1,2,3, 6-tetrahydropyridin-1-yl. A compound according to claim 23, which is 20-dihydro20-deoxy-20- (3,5-dimethylpiperidin-1-yl) 4'-deoxydesmicosin. A compound according to claim 19, wherein R is 1,2,3,4tetrahydroisoquinolin-1-yl; 1-azaspiro [4.5] decan-1-yl; 3-azaspiro [5.5] undecan-1yl; 3-azabicyclo [3.2.2] nonan-3-yl; decahydroquinolin-1-yl; 1,8,8-trimethyl-3-azabicyclo [3.2.1] octan-3-yl; 6-azabicyclo [3.2.1] octan-6-yl or dodecahydrocarbazol-9-yl. A compound according to claim 1, wherein R is selected from (a) a saturated monocyclic amino group; (c) a saturated monocyclic amino group which is substituted at one or more carbon atoms by C 1 -C 6 alkyl, hydroxyl, -N (R ⁴ ) ₂ , Oh II-C-N (R ⁴ ) ₂ carbomethoxy, carboethoxy or phenyl group; or (c) a bicyclic or tricyclic ring system, such as 1,2,3,4-tetrahydroquinoline- 1-yl; decahydroquinolin-1-yl; 1,2,3,4-tetrahydroisoquinolin-2-yl; decahydroquinoline- 2-yl; indolin-1-yl; isoindolin-2-yl; decahydrocyclohepta [b] pyrrol-1-yl; decahydrocyclohepta [c] pyrrol-2-yl; decahydrocyclopent [c] azepin-2-yl; decahydrocyclopent [<1] azepin-3-yl; 2,3,4,5-tetrahydro-1H-2-benzazepin-2-yl; 2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl; azabicycloheptanyl; azabicyclooctanyl; azabicyclononanil; azabicyclodecanyl or azatricyclodecanyl; and R ⁴ is methyl, ethyl, n-propyl or isopropyl or the R ⁴ groups taken together form a polymethylene moiety such that -N (R ⁴ ) ₂ includes a cyclic amino group selected from pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazocinyl; and the corresponding acid addition salts. A compound according to claim 26. wherein R is octahydroazocin-1-yl or substituted octahydroazocin-1-yl. A compound according to claim 27, wherein R is octahydroazocin-1-yl. A compound according to claim 26, wherein R is hexahydroazepin-1-yl or substituted hexahydroazepin-1-yl. 30. A compound according to claim 29, wherein R is hexahydroazepin-1-yl. The compound of claim 26, wherein R is piperidin-1-yl or substituted piperidin-1-yl. A compound according to claim 31, which is 20-dihydro20-deoxy-20- (4-hydroxypiperidin-1-yl) desmycosin. A compound according to claim 31, which is 20-dihydro20-deoxy-20- (4-piperidinopiperidin-1-yl) desmycosin. A compound according to claim 31, wherein R is piperidin-1-yl. A compound according to claim 26, wherein R ² is C 1 -C 5 alkanoyl or substituted C 1 -C ₅ alkanoyl. A compound according to claim 35, wherein R ² is acetyl or propionyl. The compound of claim 17, wherein R is (a) a saturated monocyclic amino group; (c) a saturated monocyclic amino group which is substituted in one or more of the carbon atoms by C, -C ₃ -alkyl, hydroxy, -N (R ⁴⁾ _2. II -CN (R ⁴ ) ₂ carbomethoxy, carboethoxy or phenyl group; or (c) a bicyclic or tricyclic ring system such as 1,2,3,4-tetrahydroquinolin-yl; decahydroquinolin-1-yl; 1,2,3,4-tetrahydroisoquinolin-2-yl; decahydroisoquinolin-2-yl; indolin-1-yl; isoindolin-2-yl; decahydrocyclohepta [b] pyrrol-1-yl; decahydrocyclohepta [c] pyrrol-2-yl; decahydrocyclopent [c] azepin-2-yl; decahydrocyclopent [C1] azepin-3-yl; 2,3,4,5-tetrahydro-1H-2-benzazepin-2-yl; 2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl; azabicycloheptanyl; azabicyclooctanyl; azabicyclononanil; azabicyclodecanyl or azatricyclodecanyl; and R ⁴ is a methyl, ethyl, n-propyl or isopropyl group or the R ⁴ groups taken together form a polymethylene moiety such that -N (R ⁴ ) ₂ includes a cyclic amino group such as pyrrolidinyl, piperidinyl, hexahydroazepinyl or octahydroazocinyl; and the corresponding acid addition salts. A compound according to claim 37, wherein R is octahydroazocin-1-yl or substituted octahydroosacin-1-yl. 39. A compound according to claim 37, wherein R is hexahydroazepin-1-yl or substituted hexahydroazepin-1-yl. A compound according to claim 37 wherein R ² is C 1 -C ₅ alkanoyl or C 1 -C ₅ alkanoyl. A compound according to claim 40, wherein R ² is acetyl or propionyl. A compound according to claim 28, which is 20-dihydro-20-deoxy-20- (octahydroazocin-1-yl) desmicosine. A compound according to claim 30, which is 20-dihydro20-deoxy-20- (hexahydroazepin-1-yl) desmicosine. A compound according to claim 34, which is 20-dihydro20-deoxy-20- (piperidin-1-yl) desmicosine. The compound of claim 31, which is 20-dihydro20-deoxy-20- (4-phenylpiperidin-1-yl) des mycosin. A compound according to claim 38, which is 20-dihydro20-deoxy-20- (octahydroazocin-1-yl) -4'-deoxydesmicosin. A compound according to claim 39, characterized in that it is 20-dihydro20-deoxy-20- (hexahydroazepin-1-yl) -4'deoxydesmicosin. A composition for treating bacterial and mycoplasma infections comprising an effective amount of a compound according to claim 1 or the corresponding pharmaceutically acceptable acid addition salt and a suitable pharmaceutical carrier. A composition for treating bacterial and mycoplasma infections comprising an effective amount of a compound according to claim 17 or the corresponding pharmaceutically acceptable acid addition salt and a suitable pharmaceutical carrier. A method for treating infections caused by Mycoplasma, characterized in that it is administered parenterally to infected or susceptible warm-blooded animals an effective amount of a composition according to claim 48. A method for treating infections caused by Mycoplasma, characterized in that it is administered parenterally to infected or susceptible warm-blooded animals an effective amount of a composition according to claim 49. 52. A method for treating infections caused by gram-positive bacteria, characterized in that an effective amount of a composition according to claim 48 is administered to infected or susceptible warm-blooded animals. 53. A method for treating infections caused by gram-positive bacteria, characterized in that an effective amount of a composition according to claim 49 is administered to infected or susceptible warm-blooded animals. 54. A method of treating infections caused by Pasteurella, characterized in that an effective amount of a composition according to claim 48 is administered to infected or susceptible warm-blooded animals. 55. A method of treating infections in31 caused by Pasleurella, characterized in that an effective amount of a composition according to claim 49 is administered to infected or susceptible warm-blooded animals. 56. A composition for treating bacterial and mycoplasma infections comprising an effective amount of a compound according to claim 26 or a corresponding pharmaceutically acceptable acid addition salt and a suitable pharmaceutical carrier. A composition for treating bacterial and mycoplasma infections comprising an effective amount of a compound according to claim 37 or the corresponding pharmaceutically acceptable acid addition salt and a suitable pharmaceutical carrier. 58. A method of treating infections caused by Mycoplasma, characterized in that an effective amount of a composition according to claim 56 is administered to infected or susceptible warm-blooded animals. 59. A method of treating infections caused by Mycoplasma, characterized in that a parenterally effective amount of a composition according to claim 57 is administered to infected or susceptible infected warm-blooded animals. 60. A method of treating infections caused by gram-positive bacteria, characterized in that an effective amount of a composition according to claim 56 is administered to infected or susceptible warm-blooded animals. 10 A method for treating infections caused by gram-positive bacteria, characterized in that an effective amount of 15 formulations according to claim 57 is administered to infected or susceptible warm-blooded animals. 62. A method of treating infections caused by Pasteurella, characterized in that the infected or susceptible to infection of warm-blooded animals is effectively 20 administers an amount of composition according to claim 56. 63. A method of treating infections caused by Pasteurella, characterized in that it is infected or susceptible to infection. The sowing of warm-blooded animals effectively administers an amount of composition according to claim 57.