CS235343B2 - Process for preparing 20-aminotylosine derivatives - Google Patents

Abstract

The subject of the invention is a method for producing new macrolide antibiotics from the group of 20-aminoderivatives of tylosin and similar macrolide substances which are effective against bacteria and mycoplasmas.

Description

The invention relates to a process for the production of a macrolide antibiotic, in particular to novel compounds which are similar to the known drug tylosin, which is described, for example, in Tetrahedron Letters, 2339 (1970) and U.S. Patent No. 3,178,341. In the novel compounds, the 20-position of the macrolide system is substituted with an amino group.

Although tylosin is a very valuable substance, there is still a need to develop other antibiotics, both because it would be necessary to obtain derivatives that are even more effective or have an even broader spectrum of activity, and because microorganisms easily develop resistance. However, chemical modifications of macrolide antibiotics of the tylosin type are very difficult. For this reason, most scientists are trying to find new microorganisms that would produce related compounds.

It has now been unexpectedly found that the aldehyde group at position 20 in systems similar to tylosin can be converted by reductive sensing amines into an amino group without concomitant destruction of the macrolide system. Furthermore, these derivatives have very good antibiotic activity.

The subject of the invention is therefore a method for producing a new macrolide antibiotic of general formula I

where

R represents a hydrogen atom, a hydroxyl group or a mycinosyloxy group, Q represents a hydrogen atom,

X denotes a group of the general formula

where (i) R ¹⁰ and R ¹¹ independently of each other represent a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a cycloalkyl radical of 3 to 10 carbon atoms or a group of the general formula (CH 2 ) -Ph where q represents an integer 0, 1 or 2a/

Ph represents a phenyl radical, optionally substituted by an alkoxycarbonyl group of 1 to 4 carbon atoms, an amino group, a halogen atom, an alkyl or alkoxy radical of 1 to 4 carbon atoms, (ii) a single substituent R ¹⁰ or R ¹ ' represents a group of the general formula

where r’2 represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms, the latter being defined according to paragraph i) or (iii)

^R10 and

R ¹¹ together with the nitrogen atom to which they are attached forms a heterocyclic ring of 5 to 7 atoms, the other heteroatom being oxygen or nitrogen, as well as pharmaceutically acceptable salts and acyl esters which are effective antibiotics.

Although no atereochemical configuration is given for the above structural formula, it is clear that the stereochemistry is the same as that of tylosin. The amino sugar is wylaminose.

The term cycloalkyl radical of 3 to 10 carbon atoms refers to groups with a carbon ring of 3 to 10 carbon atoms, such as cyclobutyl, cyclohexyl, cyclooctyl and adamantyl. Similarly, the term alkyl radical of 1 to 4 carbon atoms refers to straight-chain or branched alkyl radicals of 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl and isopropyl.

Preferred are compounds of general formula I in which R represents a myciaosyloxy group.

In the case where κ'θ and r'' form a heterocyclic ring of 5 to 7 atoms with oxygen or nitrogen as a further heteroatom, typical examples of these radicals are a piperazine or morpholine radical. The heterocyclic ring must contain two heteroatoms and is preferably saturated.

Another group of interesting compounds that can be mentioned are those in which X represents an amino group, a dimethylamino group, an aniline group, an H-methylaniline group, an o-ethoxycarbonylaniline group, a benzylamino group, an aminobenzylamino group, a halobenzylamino group, a cyclohexylamino group and a morpholine group.

The following substances may be mentioned as preferred compounds obtainable by the method according to the invention:

20-deoxo-20-(N-benzylamino)demycarosyltylosin a

20-deoxo-20-(N-morpholino)demycarosyltylosin and their pharmaceutically acceptable ^salts and acyl esters.

The hydroxylides of general formula I contain amino groups in the 20- and 3-positions and can form acid addition salts. These salts, if non-toxic, can be used in chemotherapy in warm-blooded animals, for example, pharmaceutically acceptable salts can be used as antibiotics.

Typical salts of this type are salts formed by common reactions with organic and inorganic acids, such as sulfuric, hydrochloric, phosphoric, acetic, oxalic, citric, lactic, maleic, fumaric, palmitic, bile, pamoic, mucinic, D-glutamic, d-camphoric, glutaric, glycolic, violet, tartaric, formic, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic and cinnamic acids.

Pharmaceutically acceptable acyl esters are preferably those derived from a monocarboxylic acid having 2 to 7 carbon atoms, for example acetic, propionic, butyric or isovaleric acid.

Compounds of general formula 1 in which Q' represents a mycarosyloxy group can be obtained by reductive amination of an aldehyde of general formula II.

where

R has the above meaning, and

Q' represents a mycarosyloxy group when using an amination agent of general formula III

HN' (III)

Where is it?

R ¹ ® and R ¹¹ have the above meaning, or some of its acid addition salts,

The reductive amination is preferably carried out using a cyanoborohydride of the general formula MBH3CN, in which U represents a metal from Group Ia or an ammonium ion, the most preferred substance being sodium cyanoborohydride.

The solvent used for the reaction is usually an inert polar organic solvent, for example an alkanol of 1 to 4 carbon atoms, preferably methanol. Typical reaction temperatures are in the range of 0 to 60°C, preferably 20 to 40°C. The reaction is usually carried out at a neutral pH in the range of 6 to 8.

The reaction is usually carried out using an excess of the reactant of general formula III, usually 2 to 3 equivalents. In carrying out the reaction, dehydrating agents are also preferably used, for example molecular sieve 4A or anhydrous sodium or magnesium sulfate.

Reductive amination can also be carried out by reducing the aldehyde function at position 20 to the corresponding hydroxymethyl derivative. The hydroxymethyl derivative obtained is then modified by converting the hydroxymethyl group to a -CHgL group, in which L is a readily removable group that can be readily removed by the action of an amination agent of general formula III. According to one embodiment of the invention, for example, the hydroxyl group at position 20 can be converted to a trifluoromethanesulfonyl group, which can optionally be further converted and replaced by an iodine atom. According to a second embodiment, the iodinated derivative can be formed directly by adding iodine dissolved in a suitable solvent such as dimethylformamide to a solution of the 20-hydroxymethyl derivative and triphenylphosphine under a nitrogen atmosphere.

The readily leaving group at position 20, i.e. iodine, trifluoromethanesulfonyl, and the like, can then be replaced by reaction with an amine-based reagent in a suitable organic solvent, e.g. acetonitrile, to give a compound of formula I.

The hydrolysis of compounds of formula I in which Q is mycarose and/or R is mycinoyloxy is carried out in a conventional manner as described in U.S. Patent No. 3,459,853.

For example, mycarose can be hydrolytically cleaved at a pH lower than 4, preferably at a pH of 0.5 to 2.0, at a temperature of 0 to 60°C, preferably at room temperature.

This hydrolytic cleavage can be carried out by treatment with a strong aqueous solution of an inorganic acid, for example hydrochloric or sulfuric acid, or with a strong organic acid, for example p-toluenesulfonic acid.

Similarly, the mycinose residue can also be hydrolytically cleaved, although less mild conditions must be used and care must be taken to avoid disruption of the macrolide system. Longer reaction times and a pH of 1.5 to 2.5 are required. Higher temperatures, in the range of 80 to 130°C, preferably 90°C to the reflux temperature of the reaction mixture, are also required. Since cleavage of the mycinose is more difficult, the compound of formula I, in which R is a hydroxyl group, is most preferably prepared by reductive amination of the starting material of formula II, in which R is a hydroxyl group.

If necessary, the compounds of general formula I can be esterified to acyl ester derivatives by the action of acylating agents in conventional manner. Suitable organic solvents for this purpose are pyridine and triethylamine.

The acylating agent may be an activated carboxylic acid derivative, for example an anhydride or halide of a carboxylic acid having 2 to 7 carbon atoms. Similarly, pharmaceutically acceptable salts of the above antibiotics may be obtained by converting them into these salts in a known manner.

The subject of the invention is therefore a process for the production of a macrolide antibiotic of general formula 1, its pharmaceutically acceptable salts or acyl esters, characterized in that

a) cleaving off the sugar mycarose from the macrolide antibiotic of general formula I', in which Q' represents mycarose, by hydrolysis in an acidic medium to form a compound of general formula 1, in which Q represents a hydrogen atom and

b) optionally esterifying and/or converting into a salt the resulting product thus obtained.

Aldehydes of the general formula are known compounds and their preparation is disclosed, for example, in U.S. Patent Nos. 3,177,341, 4,321,361 and 4,321,362.

The compounds produced by the method according to the invention are effective against gram-positive microorganisms, for example Streptococcus pyogenes and against Mycoplasmas. The compounds of general formula 1 are also effective against some gram-negative bacteria, for example Pasteurella sp. In addition, the compounds produced by the method according to the invention are well absorbed upon administration and provide good levels of the antibiotic in the blood. For these reasons, they can be used for the prevention and treatment of microbial infections in warm-blooded animals. For this purpose, a chemotherapeutically effective amount of the compounds of general formula I is administered parenterally or orally to an infected or endangered warm-blooded animal. In some cases, it is also possible to inject the compounds, for example in the form of a dust, into an enclosed space in which, for example, animals or poultry are kept. These animals or poultry then inhale the dust containing the active substance present in the air; in addition, this dust can also enter the body through the mucous membrane of the eye, thereby treating or protecting the animals against infection.

The dose required to control the infection varies depending on the severity of the infection and on the age, weight and general condition of the animal. The total dose for parenteral administration is usually in the range of 1 to 100 mg/kg. For oral administration, this dose is usually in the range of 1 to 300 mg/kg, preferably 1 to 100 mg/kg.

Antibiotics obtained by the method according to the invention can be processed into compositions for the treatment of infections caused by bacteria and mycoplasmas. These veterinary compositions contain as active ingredient a macrolide antibiotic of the general formula 1, a pharmaceutically acceptable salt or acyl ester thereof together with one or more physiologically acceptable carriers or diluents.

Often the most convenient way to administer these compounds is through incorporation into feed or drinking water. The compounds can be incorporated into a variety of feeds, including dry feeds, liquid feeds, and pelleted feeds.

The method of incorporating veterinary drugs into feed is well known. The most preferred method is to produce a concentrated pre-feed which is then added to the feed. A typical pre-feed contains 1 to 400 g of active ingredient per 1 kg and may be in liquid or solid form.

The resulting livestock or poultry feed will depend on the amount of antibiotic to be administered. Conventional methods are used to manufacture and pellet these feeds.

Injectable compositions containing compounds prepared according to the invention may be in the form of a suspension or solution. In the preparation of such compositions, it is understood that the acid addition salts have better solubility in water than the free compounds. The free compounds of formula I are more soluble in dilute acids or acidic solutions than in neutral or basic solutions.

The compounds prepared by the method according to the invention are dissolved in physiologically acceptable media. These may be suitable solvents, preservatives such as benzyl alcohol and buffers. The solvent which can be used is, for example, water, a mixture of water and alcohols, glycols and esters, for example diethyl carbonate. The aqueous solutions usually contain at most 50% by volume of organic solvent.

Injection suspensions are obtained using a liquid medium, optionally in the presence of an excipient. The medium may be, for example, aqueous polyvinylpyrrolidone, inert oils such as vegetable oils or highly purified mineral oils, or aqueous carboxymethylcellulose.

In order to keep the compounds in suspension, physiologically acceptable auxiliary agents are added. For example, thickeners such as carboxymethyl cellulose, polyvinylpyrrolidone, gelatin and alginates. Wetting agents can also be used as suspension aids. Other suitable suspension aids include lecithin, alkylphenol and polyethylene oxide adducts, naphthalene sulfonates, alkylbenzene sulfonates and polyoxyethylene sorbitan esters.

A number of substances affecting the hydrophilicity, density and surface tension of liquid suspensions can help in individual cases to create a suspension suitable for injection use. For example, antifoaming agents such as silicones, sorbitol and sugars can be used.

The invention will be illustrated by the following examples.

Example

20-deoxo-20-(N-benzylamino)tylosin g tylosin, 7.9 g benzylamine hydrochloride and 1.4 g sodium cyanoborohydride were dissolved in 50 ml methanol and the mixture was allowed to react under nitrogen atmosphere for 5 hours at room temperature. After the reaction was completed, the reaction mixture was poured into 600 ml of cold, saturated aqueous sodium bicarbonate solution and then extracted three times with 100 ml chloroform. The resulting chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give the crude product. This crude product was purified by chromatography on a silica gel column using a mixture of chloroform, methanol and concentrated ammonium hydroxide in the ratio 15:1:0.5 as eluent to give 3.8 g of the yellow final product in a yield of 71%.

Elemental analysis for 6 molecular weight 1.006:

calculated:

found:

63.22% C, 64.01% C,

8.55% H, 8.58% H,

2.78% N, 2.69% N,

25.45 # O; 24.72 » O.

Melting point: 103.5 to 107 °C

Specific rotation [n]^ ⁹ : » -55.8° (c 1, methanol)

Spectrum in ultraviolet light

LCH-jOH max

283 nm (S 22 900)

Mass spectrum (a/e) 673, 654, 175, 174, 145, 106, 91.

In a similar way, the compounds of the following examples can be obtained:

Example 2

20-deoxo-20-(K,N-dimethylamino)tylosin

Melting point 119.2 to 120.3 °C

Specific rotation at -40.4° (c 1, methanol)

Ultraviolet spectrum of .HeOH (O- 282.5 nm (12500)

Mass spectrum (m/e): 944, 700, 770, 419, 175.

NMR spectrum, ppm):

1.78 (and, 2.15 <8, _C20 -N(Me) ₂ ), 2.52 (.·, O ₃ , -N(Me) _a ) 3.43 (e, C ₂ ,,,-0lle), 3.60 (8, C ₃ ,,,-0Me), *.23 Cd, H,«), 4.52 Cd, ,»»)« 4.92 (bt ' ^H 15^' 5.05 (d, H,,,), 5.90 Cd, h, ₃ ), 6.26 Cd, ^0^ 7.33 Cd, H,,)>

Yield: 84%.

Example 1. a d 3

20-deoxo-20-(N-anilino)tyloain

Melting points: 111 to 113 °C

Optical rotation: M -86.0° (c 1, methanol)

Chaotic spectrum (m/e): 831, 658, 190, 175, 145.

•NMR spectrum (ppm):

1.77 (with, ^22^ ^- 2.46 (·, C ₃ , -N(Me.)g) 3.46 (e, C ₂ ,,,-Cbe), 3.56 (with, C ₃ ,,,-0Ke), 4.23 Cd, H,'), 4.54 Cd, H,,,,), 5.04 Cd, ,,), 4.97 (bt, - ^H 15 ^} ·

AND

5.84 (bd. • ^H ,3 ⁾ > 6.23 (d, ^H 10 ⁾ ' 6.57 (d, o-H-anilino) 6.67 (d, o-H-anilino) 7.10 (d, m-H-anilino) 7.23 (d, H,,).

Yield: 48%.

Example 4

20-deoxo-20- [N-(o-ethoxycarbonyl)anilinoj tylosin Melting point: 122.5 to 124 °C Ultraviolet spectrum i MeOH ^X aax ^{(C): 282.3} ““ ⁽² '^300> Yield: 34%.

Example 5

20-deoxo-20-(N-methylanilino)tylosin

Melting point: 106.5 to 109 °C

Mass spectrum (m/e): Γ 006, 862, 688, 481, 175, 145 HMK-spectrum, £ (ppm):

1.79 (with, Hggg), 2.40 (with, Cy-N(Me) ₂ ), 2.87 (with, _C20 -N-Ue), 3.46 (with, C ₂ ,,,-0Me), 3.59 (with, C ₃ ,,,-0Me), 4.27 (d, H,'>, 4.54 (d, «,,,,,,), 5.05 (d, «,,,>, 5.0 (b, h, ₅ ), 5.83 (bd , h, ₃ ), 6.21 (d, H, _o ), 6.7 (d, _C20 -N-(oH(gH)Ph), 7.27 (d, ».,>· 7.15 (d, _C20 -N-(bH)PH).

Yield: 34%.

Example

20-deoxo-20-(N,N-dibenzylamino)tylosin MMR spectrum <5 (ppm):

1.78 (s, Hg),

2.46 (s, C ₃ , -N(Me) ₂ ), that

3.46 (s, _C2 ,,,-0Me),

3.60 (s, _C3 ,,,-0Me),

4.57 (d, H,,,,),

5.88 (bd, H ₁₃ ),

6.23 (d, H, _o ),

7.3 (benzyl protons).

Yield: 70%.

Example 7

20-deoxo-20-(N-adamantylamino)tylosin

Melting point 108.5 to 10.5 °C

Optical rotation: {rotj -32.9° (o = 1, methanol)

Absorption spectrum in ultraviolet light:

, UeOH ^Z max 284 nm (9,800)

Mass spectrum (m/e): 1050, 732, 718, 543, 175, 157.

Yield: 82%.

Examples

20-deoxo-20-(M-cyclohexylamino)tylosin

Melting point: 111 to 114 °C.

Optical rotation: [o<] -48.9° (c1, methanol)

Absorption spectrum in ultraviolet light:

UeOH max (£.): 284 nm (20,000)

Mass Spectrum (m/e): 832, 664, 473, 175, 157, 145.

Yield: 50%.

Example 9

20-deoxo-20-(N-benzylamino)demycarosyltylosin g 20-deoxo-20-(N-benzylamino)tylosin was dissolved in 30 ml of 0.1 K hydrochloric acid and the mixture was allowed to react for 19 hours at room temperature. After the reaction was completed, the reaction mixture was washed with 30 ml of chloroform and the pH of the resulting aqueous layer was adjusted to 8.0 with 1 N sodium hydroxide. Then the solution was extracted three times with .00 ml of chloroform, the chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 820 mg of pale yellow crude material. This material was purified by chromatography on a silica gel column, using a mixture of chloroform, methanol and concentrated ammonium hydroxide in a ratio of 20:1:0.95 as the eluent? to give 620 mg of the title compound as a white solid, yield 72%.

Elemental analysis for (molecular weight 862):

calculated:

found:

64.10% C, 64.04% C,

8.60% H, 8.58% H,

3.20% N, 3.25% N,

24.10% 0; 24.13% 0.

Melting point 88.5 to 91.5 °C.

Optical rotation: [α] = -35.2° (c,= 1, methanol)

Spectrum in ultraviolet light:

, CH,OH ^max ^{= 264 ( C 22,000)} ·

Infrared absorption spectrum (KBr): 3440, 2980, 2950, 1710, 1680, 1590, 1460, 1350, 1165, 1090 cm ^-1 .

Mass spectrum (m/e): 756, 672, 565, 482, 174, 91.

The compound of the following example can be obtained in a similar manner.

Example

0-deoxo-2 0-(N-me thylanili.no)demycaro syltylo syn

Melting point: 95.5 to 98.5 °C.

Absorption spectrum in ultraviolet light:

MeOH max (C):

283 nm (20,600)

Mass spectrum (m/e): 862, 688, 190, 174. NMR spectrum (δ (ppm):

1 .77 (with, h ₂₂ ), 2.49 (with, C ₃ , -N(Me) ₂ 2.87 (with, _C20 -N-Me), 3 <46 (with, C ₂ ,,-OMe>, 3.59 (with, C ₃ ,,-C«e), 4.33 Cd, H, '), 4.56 (and, H,'), 5.00 (dt, 5.84 (bd, , h ₁₃ ), 6.63 Cd, ^H 10 ⁾ > 6.70 (and, o-H-aniline) 6.73 Ca, p-H-aniline) 7.20 Cd, m-H-aniline) 7.2 CH,, ).

Yield: 43 »

Example 11

20-deoxo-20-(N-morpholine)tylosin

A solution of 500 mg of tylosin, 480 mg of morpholine and .30 mg of sodium cyanoborohydride in 5 ml of methanol was allowed to stand at room temperature under nitrogen atmosphere for 24 hours. After completion of the reaction, the reaction mixture was poured into .50 ml of aqueous saturated sodium bicarbonate solution and then extracted three times with 80 ml of chloroform. The resulting chloroform layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give the resulting compound as a crude product. This material was purified by silica gel column chromatography, eluting with a mixture of chloroform, methanol and concentrated ammonium hydroxide in the ratio of 30:1:0.05, to give 430 mg of the resulting product as a white solid in 80% yield.

Elemental analysis for ^50^6^2^17 (molecular weight ’ 986):

calculated: 60.80% C, 8.75% H, found: 60.85% C, ' 8.72% H,

2.83% N, 27.62% O.

2.84% N, 27.59 » O.

Melting point: 122.5 to 124.5 °C.

Optical rotation:[a] = -39.6° (c = 1, methanol)

Absorption spectrum in ultraviolet light:

CH,0H ^А max ^{283.5 ( L} '9 500)

The compound from the following example can be obtained in the usual way:

Example 12

20-deoxo-20-(4-N-methylpiperazinylamino)tylosin

Melting point: 95.0 to 98.0 °C

Optical rotation: -55.4° (c 1, methanol)

Absorption spectrum in ultraviolet light:

> MeOH (t) 283 nm (17,700) n&x

Mass spectrum (m/e): 1014, 870, 680, 175, 157, 145

HMR spectrum $ (ppm);

1.79 (with, «22), 2.31 (e, 4-Me), 2.47 (with, C ₃ :-N(Me) ₂ ), 3.47 (e, Og’’’OMe), 3.60 (with, C ₃ ,,,-0Me), 4.27 <4, 4.56 <a. H,,,,), 5.07 (and, H,,,),

4.95 (b, H ₁₅ ), 5.86 (d, H _{) 3} ),

6.26 (d, H ₎₀ ),

7.27 (d, H,,).

Yield: 69 «.

The antibacterial activity of typical compounds of general formula 1 is shown in the following table, which shows the results of experiments with the determination of the minimum inhibitory concentration (HIC) in a standard solution on agar, the culture is grown for 24 hours at a temperature of 37 °C.

Table

Minimum inhibitory concentration (ug/ml) Example number ...... 9 .0 . Staphylococcus aureus PDA 209P 0.4 0.4 Bacillus subtilis PCI 219 0.4 0.4 Bacillus cereus IPC 300, 0.4 <0.1 Micrococcus leuteus PCI 1001 <0.1 <0.1 Mycobacterium smegmatis ATCC 607 3.12 25 Esterichia coli NIHJ 25 >100 Klebsiella pneumoniae PCI 602 50 50 Salmonella typhimurium KB 20 50 >100

In animal experiments, it was also shown that 20-deoxo-20-(N-benzylamino)demycarosyltylosin, when administered orally to mice infected with Streptococcus pyogenes, had an efficacy ED _{0 of} 39 mg/kg, which is almost twice that of demycarosyltylosin.

Claims (5)

SUBJECT OF THE INVENTION ,. A process for the preparation of 20-aminotylosine derivatives of the general formula I wherein H represents a hydrogen atom, a hydroxyl group or a mycinosyloxy group, Q represents a hydrogen atom, X is a radical of formula wherein (1) r'O and r '' are independently hydrogen, C 1 -C 4 alkyl or C 3 -C 10 cycloalkyl, or formula - < ^CH 2) _n -Ph wherein U is an integer of 0, 1 or 2a Ph represents a phenyl radical optionally substituted by a C 1 -C 4 alkoxycarbonyl, amino, halogen, C 1 -C 4 alkyl or alkoxy radical, (ii) a single substituent R c or r represents a group of the formula wherein, 12 ( iii) r 10a represents a hydrogen atom or a C 1 -C 4 alkyl radical, the latter as defined in (i) or (11), together with the nitrogen atoms to which they are attached, forms a 5- to 7-heteroatomic ring, the heteroatom is an alkali or a dical, as well as pharmaceutically acceptable salts and acyl esters, characterized in that a) cleaving off the mycarose sugar from an aacrolide of formula I corresponding to formula I wherein Q is replaced by Q * and Q * represents an acarose by acid hydrolysis to give a compound of formula I wherein Q is hydrogen b) optionally, the product obtained in step (a) is esterified and / or converted into a salt. 2. A process according to claim 1, starting from a compound of formula (I ') to form an acrolide of formula (I) wherein R is mycinoayloxy and the other formulas are as defined above, or salts or an acyl ester thereof, acceptable. from a pharmaceutical point of view. 3. A process according to claim 1, wherein the compound of formula (I) is formed to form a macrolide antibiotic of formula (1) in which X is amino, dimethylano, aniline, N-ethylaniline, o-ethoxycarbonylaniline. , benzylamino, aainobenzylaainoacin, halobenzylamino, cyclohexylaminoacin or an aphoroline group, or a pharmaceutically acceptable salt or acyl ester thereof. 2353 * 3 4. A process according to claim 1, starting from a compound of formula I 'to give 20-deoxo-20- (N-benzylamino) demycarosyltylosin. 5. A process according to claim 1, starting from a compound of formula I * to give 20-deoxo-20- (N-morpholino) demycarosyltylosin.