JPS62289593A - Novel antibiotic retinoic acid esters, manufacture, skin disease treating medicine and cosmetic composition - Google Patents

Abstract

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

Description

Detailed Description of the Invention 3. Detailed Description of the Invention The present invention provides novel esters of antibiotics, retinoin esters of lincomycin and clindamycin, a method for producing them, and their use as active ingredients. It relates to medicines for treating skin diseases, as well as for the treatment of skin conditions.

The novel retinoic acid ester according to the present invention has been found to exhibit antitumor activity, and has been shown to exhibit antitumor activity. 1! The present invention is also useful as a horse medicine.The present invention essentially addresses the need to treat infectious or non-infectious bacteria associated with the transplantation of pathogenic yeasts of the genus Mycobacterium and/or of certain horses. The purpose of this invention is to use the retinoic acid ester of the above antibiotic in the treatment of infectious scaly disease.

In particular, the antibiotic retinoic acid ester is used in the treatment of acne.Although it may appear suddenly during adolescence, the majority of cases occur naturally at the age of 20 years. It is a degenerative polymorphic skin disease (more than one type of disease exists in one person). The disease occurs in the Xf-region, indicating that this anti-Imi disease is related to the BL sebaceous gland, ie, the sebaceous gland molecules y and qm.

There is no locus memory without sebum pain. Although seborrhea is one of the rapid hormonal excretion phenomena that occurs suddenly during adolescence, it does not appear that seborrhea is related to any kind of hormonal disorder.

Although the etiology of Zayu is not yet clear, it is believed to be the culprit behind the characteristic disorder called cornedon. This occurs as a young fruit of duct obstruction due to dehorning of the host gland duct.

This blockage? The main shadow 4 that is more closely related to this is the viscosity of the inverse quantity and the '?' of the medium. This is the point at which special characteristics (pH, phosphorus vapor, etc.) occur.

This deformity can lead to severe proliferation of the cephalic cephalic tract present within the skin.

In any case, this anti-oil disease is not related to the transplantation of pathogenic bacteria (footwear), and it is also contagious. It's something that doesn't exist.

Finally, the advancement to increase the amount of food is to increase the number of sac folliculair+s in the body as its mechanism.
It then releases into the dermis a protease or hyaluronidase of bacterial origin that causes an inflammatory-type reaction of the proboscis-like tissue in the dermis.

Although the nature of these inflammatory compounds has not yet been practically identified, there is little doubt that they are of bacterial origin. This explains why the treatment of inflammatory acne using antibiotics is well tolerated both by oral and topical administration.

Among the antibiotics, erythromycin and clindamycin are very often recommended, but relatively high concentrations (particularly for erythromycin) are required to obtain a satisfactory effect.

On the other hand, as shown in recent studies, it has been demonstrated that treatment with these antibiotics is less effective, progressively increasing resistance to probiothromycin, lincomycin and hytalindamycin, and especially erythromycin. Topical administration of drugs has also caused problems of penetration into the stratum corneum, which limits their effectiveness.

Novel antibiotic retinoic acid-ester according to the invention,
In particular, the retinoic acid esters of erythromycin A1 clindamycin and lincomycin can satisfactorily solve the problems encountered with these antibiotics themselves. In other words, according to the cooking tests conducted by the present inventors on these new esters, these esters showed only low activity against Staphylococcus aeruginosa, but showed selective action against acne, which is a cause of inflammation. , thus confirming that these skin diseases can be treated without disturbing the skin's equilibrium, and that these new antibiotic retinoic acid esters, especially all-trans- erythromycin A and lincomycin,
It should be noted that the novel antibiotic retinoic acid esters according to the present invention exhibit the disadvantages of retinoic acid. It was recognized that it was effective without any problems.

It has been found that the novel ester of the invention is better tolerated by the skin and kidney than the antibiotic/retinoic acid combination and exhibits significantly lower toxicity upon oral administration.

Antibiotic retinoic acid esters that comply with unexploited t#4'IC have keratolytic activity in the case of all-trans-retinoic acid esters and 13-cis-retinoic acid esters, in contrast to other known antibiotic esters. In the case of esters, they have the advantage of exhibiting potential antidiabetic activity, which gives these esters the image of "prodrugs".

The novel retinoin minister according to the present invention exhibits higher efficacy, thereby improving the ability of the epidermis to penetrate the skin.

Current technology regarding the combination of retinoic acid and antibiotic A water 3 from Laboratoires CILAG -
An is a standard product sold under the name "bio-Abersl".

The current state of the art regarding erythromycin esters is erythromycin A, such as erythromycin A monostearate and erythromycin A monooleate.
This is exemplified by the description of US Pat. No. 2-62-21 regarding the preparation of saturated and monounsaturated fatty acid esters.

The current state of the art regarding esters of clindamycin and lincomycin is typified by the description in German Patent Application No. 2077003 regarding the preparation of esters of lincomycin and clindamycin with acyl chains of t and it carbon atoms. Ru.

The present invention is directed to retinoic acid esters of antibiotics, particularly all-trans- and 13-cis-retinoic acid esters of erythromycin A1, lincomycin, and clindamycin, and salts of these esters.

The antibiotic retinoin nystyl according to the invention can optionally be in the form of a mixture, but preferably the 2' retinoic acid ester of erythromycin A and the 3' retinoic acid ester of lincomycin and hiclindamycin. It's ester.

Retinoic acid ester (17) at position 2' of erythromycin A can be represented by the following formula: (wherein,
R is a total tra/thretinoyl group or a 13-cis-retinoyl group t-[retinoyl group has the formula: %formula%) The retinoic acid ester at the 3-position of lincomycin and clindamycin can be represented by the following formula. : CH5 OH CH.

(wherein R has the same meaning as defined above) The invention further provides a process for preparing all-trans- and 13-cis-retinoin constructs of erythromycin A1, lincomycin, and clindamycin.

Various esterification methods are available for the production of lithinoin sapon ester according to the invention, but one method is preferred.
A mixed anhydride of all-trans- or 13-cis retinoin precipitate (e.g. chloroformic acid) in an anhydrous solvent, either A1 or tetrahydrofuran alone or a mixture of tetrahydrofuran and other organic solvents such as pyridine. An excess of erythromycin, lincomycin or clindamycin in the base form and an organic or inorganic base, e.g. It consists of annealing in the presence of pyridine and/or sodium bicarbonate.

The method of using this mixed anhydride is the isomerism f of the retinoyl group.
Retinoic acid esters at the 2'-position of erythromycin and at the 3-position of lincomycin and clindamycin are generated and removed without causing a reaction.

Another preferred esterification method is preferably applied to the esterification of lincomycin and tocimycin in the presence of a base such as sodium or 13-butyrate. In an anhydrous solution such as P, retinoic acid imidazolyte P
This method uses This method usually yields a mixture of these antibiotic tinoic acid esters.

According to the latter method, therefore, a mixture of esters of lincomycin is obtained, which is predominantly an ester at position 7 of lincomycin and also contains esters at positions 2.3 and Uμ.

Similarly, clindamycin 2. A mixture of monoesters at position 14 and 14 is obtained.

However, this latter method often gives rise to isomerism of the retinoyl groups.

The invention further provides that erythromycin A, lincomycin or clindamycin all-trans-
or? '113-cis-retinoic acid ester or at least one of its salts @0.0/based on the total weight of the parabolite
, 10 weight pots, more preferably o, os, i weight potions. or f
A cosmetic composition is provided.

For the preparation of the pharmaceutical or cosmetic composition of the present invention, which contains at least one kind of all-trans- or /3-cis-retinoic acid ester of erythromycin A1, lincomycin, or clindamycin as an effective medical ingredient. Bases and additives described in the literature in the fields of medicine, cosmetics and similar fields can be used.

For the preparation of solution type cleavage, one or more organic solvents that are acceptable from a physiological point of view may be used, for example, such as acetone, isopropyl alcohol, fats, etc. 71 to liglyceride r1 glyco-A/ x
- selected from the group consisting of C1-C4 alkyl esters of chloro, short hos and ethers of polytetrahyP-furan.

The pharmaceutical or cosmetic compositions according to the invention may also contain permeability agents such as cellulose and/or heptalulose derivatives of Q, 5 to 2 Q, relative to the total weight of the composition.

The composition according to the present invention may contain at least one other known anti-sedative agent in combination with at least one retinoic acid ester of an antibiotic according to the present invention.

If desired, conventional additives selected from the group consisting of antioxidants, preservatives, flavorings and colorants can be added.

Typical antioxidants that can be used include t-butylhydroxide. Roxyquinone, butyl? Roxyanisole, butyloxytoluene and α-tocopherol and their derivatives are among the pharmacological and herbal medicines according to the present invention.
transformation is carried out in a known manner.

The form of crude drug G'5 preparation is for local administration to the skin, so VC is cream, emulsion, gel, and more or less! Lotion, lotion-impregnated hole para 2 (tampon), pomer P% rod relative agent father can be an aerosol product in the form of a spray or foaming agent (mousse) + 1, for oral administration group VI,
The odor may be in the form of tablets, gelatin capsules, dragees, syrups, suspensions, emulsions, powders, granules or melts. Administration′j in oral administration! About o-iag~
J cape/moan/day, preferably about l cape ~ 2. It is J Misaki / Moan / Day. These compositions can also be in the form of herbal medicines.

Treatment of floaters using the topical composition according to the invention consists of applying a sufficient amount to the skin area to be treated two to three times daily;
This consists of a period of 6 to 30 weeks, preferably 12 to 24 weeks.

The composition according to the invention can also be used prophylactically, ie on areas of the skin susceptible to acne.

Test Erythromycin A1 A dilution method used for the purpose of determining the minimum inhibition (MIC) of the activity of the retinoic acid esters of lincomycin and hiclindamycin, i.e. G, A, DENYS et al., An mferob-1a
l Agents and Chemotherapy
(/ 5' Jr J) 2 j.

33! -337 and J-J, LEYDEN et al., 3,
Am.

Acad, Dermatol, (/ri1'3)1m,
The PJ7 strain provided by CUNLIFFE and HOLLAND was subjected to the tests described in the following publications: They are: J, GREENMAN, K, T, HOL.
LAND and W, 3-CUNLIFFE, Jour
nal of General~Iicrobiolo
gy<1yr3)iiri, /30/-1307:-E,
INGHAM, N, T, HOLLAND, G, GOWL
AND and w, J, CUNL I F'F':
, ibid. (iyro) iir.

! 9-43: AND-K, T, HOLLAND, 3, GREENMAN and W, 3.

CUNLIFFE,3ournal of Appli
ed Bacteriology (1979) lA7,
313-3944゜p37 strain has a minimum inhibitory concentration (MI
As shown in C=0.71r μg, y'go), it was FA-receptive to lithromycin.

On the contrary, the same medium (RCM/li/20°DM
SO/TA/λO volume ratio: *RCM = strong f-Hyclostridium medium (OXOID)) In order to gradually stabilize this strain in this medium, the following Progressive resistance to erythromycin developed as -rLfc was standardized on agar medium (RCM + furazolin) in Petri dishes and 7' (inoculum (D O = 1.r: 4C).
t Onm) g is the diameter in the center of this Petri dish after t? Remove one disc and place erythromycin jOg9 (as a solution in DMSO) on top of the disc.

- After culturing for 6 days at 36°C in an anaerobic environment (GAS-PAK system, B, B, L), the growth-inhibited area of the strain was clearly visible (total diameter = ≠ 21), and the colony The vast majority is present at the periphery of the blocking area.

On the other hand, some colonies are clearly visible inside it.

These two quantities of colonies are then collected by scraping the agar medium (with a sterile loop).

l) Inside the inhibition zone, the tS bed, synonymous with p37pQ, is retained because it has clear resistance to erythromycin.

2) From the periphery of the inhibition zone! A strain named P77E■ is held in a location 3 miles away.

After isolation and culturing, strains PJ7E■ and PJ7Eθ
show markedly different sensitivities to erythromycin as indicated by their respective MIC values below.

P77 P37E■ p77g■ >IIC (pW/'mt) o, yg o, qr
s.

This phenomenon is confirmed by a test of IC5o (jO winter 6 occlusion degree), which represents the concentration of erythromycin at which 304 of the test microorganisms were observed to survive during culture for a certain period of time.

PJ7 PJ7E■ pj7)i:θIC5o(
μ? 7'B Men! rO!
Minimum inhibitory concentration of the retinoic acid ester of erythromycin A1 lincomycin and hyclindamycin tested against 100 strains PJ7E and P37E
MIc) (μP/g) is shown in the following table.

(susceptible) (resistant) 2'-0-(all-trans)-retinoyl-erythromycin A /4c13
Erythromycin A 3-. 0-(13-cis)-retinoyl-lincomycin /2 evenings 2j
J-0-(all-trans)-retinoyl-clindamycin it t.

3-Q-(/3-cis)-retinoyl-clindamycin l-13! versus
Teru J-Q-oleyl-erythromycin A (Z-ta)
! 0 1003-0-oleyl-lincomycin lta 4L
2j-Q-oleyl-clindamycin
jtA”)/31 erythromycin A
/ > 60 Lincomycin 13 66 Clindamycin /
/θ Is it in the table below? Showing the minimum inhibitory concentration of the antibiotic retinoic acid ester against two strains of Staphylococcus:
(Staph, Eoi,)co'-o-(all-trans)-retinoyl-erythromycin A
7! r 10J' -0-(/J
-cis)-retinoyl-erythromycin A
llO1103-0-(13-cis)-retinoyl-clindamycin/
13 /13j-0-(/3-cis)-retinoyl-lincomycin 100
100 control erythromycin A/3
30 Clindamycin
7t lincomycin
Strain 3 of lμ 20 Staphylococcus was taken from a patient with seizures, while strain 6 of Staphylococcus sinensis was taken from a patient without seizures. Isolation of these strains is WI
LLIAMSON-KLIGMAN'S METHOD ("A n
ew method for th@quintlta is ve inves is ga is on of cuta-n*
ous baet*ria @P, WILLIAMSO
N and A.

KLIGMAN, J., 1. D, , Volume 6, Volume 6
I did it according to the No. 16. Perform decimal dilutions of the collected samples and make these dilutions 0. /go was inoculated into a selective medium capable of isolation of Streptococcus spp.

As can be seen in Table 1, erythromycin and lincomycin are more active against retinoin (ix) than their parent antibiotics. Furthermore, the oleyl ester at position 22 of erythromycin A (U.S. Pat.
A2. No. 21 Specification 8) and 3-position oleyl ester of clindamycin (West German Patent Application No. 2,07)
7,0 O3 Publication) was used as a control ester, but a susceptible strain (PJ7E) and a resistant strain (P
j7E■) is clearly lower in activity than the ester of the present invention;
In particular, the advantages of the retinoic acid esters of erythromycin A and clindamycin are demonstrated. The second table shows that although the retinoic acid esters of these antibiotics are significantly less active than their parent antibiotics against certain bacterial strains, the benefits of all these esters against skin ecology are shown. Enter.

For illustrative purposes, an example of the production of an antibiotic retinoic acid ester according to the invention and an example of the formulation of a pharmaceutical or cosmetic composition used for the treatment of skin diseases, especially acne are shown below.

Example 1 Preparation of Co'-0-(/J-cis)-Retinoyl-Erythromycin A In a flask under an atmosphere of inert 2HH, anhydrous tetrahydrochloride was prepared. 73-cis-retinoic acid jf (/4.A
Dissolve the IJ mol). The reaction mixture is cooled to fO<0>C and the anhydrous pyridine 3rd (31 mmol) and ethyl chloroformate/A d (/14 mmol) are separated off. Stir this solution for 3 minutes, then add sodium bicarbonate λ, yo? (30 mmol), and then add tetrahydrochloride (30 mmol) in advance. Erythromycin A dissolved in Lofuran 13Od≠
,? ? (4.7 mmol) is added. The reaction mixture is then stirred for io hours and returned to room temperature (silica gel thin layer chromatography: methylene chloride, methanol). The solution is poured with 14 ml of water and then extracted with ethyl acetate. The organic phase is dried over magnesium ester, P, ML and then concentrated under reduced pressure.

The crude parasitic product thus obtained was chromatographed (HPLC) on a silica gel column using ethyl acetate (7)/hexane (3) as the eluent to obtain pure J'-0-(/J
-cis)-retinoyl-erythromycin A <c,Q
L? (63 liters of straw) was collected in a single distillation.

Melting point = r2℃ (hexane/ethyl) [α) z
i 7° (c=6: Ig/-dichloromethane trace analysis "C57H95NO14" molecular weight = / 0 / A
, 4' calculated value: C, 67, 3t H, or 12 N,
/Jr4 actual value: C, 47, ulr H, 9, 32
N, /, 31% infrared: 1731 leap absorption band (ester) CNMR (CD0g3, internal standard T, bx,
s, )/' (-2,2 ppm) and 3' (--L
,/ppm) negative.

The r effect indicates the ester position of λ'. Retinoyl chain carbon C', o (20,4' ppm), C'14
(//7., Zlppn) and C10 (131, ppm) correspond to the 13-cis conformation of the retinoyl chain.

Example 2 In a flask under an inert atmosphere, (all-trans) retinoic acid 3?
(/4.6 mmol) and the reaction mixture was reduced to 0.
℃, and add anhydrous pyridine 3d (31 mmol) and 6-(/14 mmol) to ethyl chloroformate. The solution was stirred for a period of time, then added with sodium bicarbonate, λ, and ethyl chloroformate (30 mmol). ) Next, add tetrahydrofuran/!OB14, dissolved erythromycin A IA, and Rif (6.7 mmol), and then return the mixture to room temperature while stirring for 10 hours (silica gel thin layer chromatography). Graph: methylene chloride y71o
4 methanol). The solution is poured into AOmt water and then extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, then concentrated under reduced pressure, and the resulting Tomozo raw material was chromatographed on a silica gel column using ethyl acetate (7)/hexane (J) as eluent. (HPLC) pure λ'-07(all-trans)-retinoyl-erythromycin A4c,/? (Collection vehicle t!; 04) is isolated.

Melting point near 6℃ (ethyl acetate/hexane) (a) 22=-
47' (e=-2 curvature/'y+/dichloromethane) Trace analysis: C57H23NO14・μH20: Molecular weight: 10g, j Calculated value: C, Au, fta H, 9, 33N, /,
2. Actual measurement value: C, j2.71 H, t, ri Q N, /
, 2 seedlings 15CNMR (CDC/3 s, internal standard T, 'v1.S,)/' (-2 ppm) and j' (
-/, 2 ppm) indicates an ester in the 2-position. ”20 (/tA-1ppm)s C'14
(//ta, 3 4 ppm) and C'1
The carbons in □ (/#, /ppm) correspond to the all-trans conformation of the retinoyl chain.

Example 3 Preparation of J-0-(all-trans)-retinoyl-clindamycin In a flask under an inert atmosphere, all-trans retinoin @) 9 (/1.-A mmol) was dissolved in anhydrous tetrahydrofuran. do. The reaction mixture was cooled to 0° C. and then dissolved in Aln1 (/6.A ml) to anhydrous viridiy A ml (71, mmol) and ethyl chloroformate.
1 mol). The mixture was stirred for 5 minutes, and then added to sodium bicarbonate (xsw (is mmol)), and then dissolved in 100 g of a mixture of tetrahydrofuran (f)/pyridine (2) or 11 damycin 2. J j
? (33 mmol) to the 5th pot. The reaction mixture was then stirred for 70 hours and returned to room temperature (silica gel thin layer chromatography, methylene chloride ¥/!winter methanol). The solution is poured into a water tank and then extracted with pure ethyl 0.degree. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained was subjected to #exfoliation on a silica gel column with ethyl acetate (
Hexane (-t)? Using chromatography (f(P
LC) to isolate pure 3~o-(all-trans)-retinoyl-clindamycin λ,/j9 (yield jj壬).

Melting point: 62℃ [“]Otsu2=-)-jOo (e=100η/godichloromethane) Trace analysis: C3BH5qN2SObCb11
2. jH20: Molecular weight: 7 j 2. Calculation IB: C, 40, tAIA H, lr, Or
N, 3.23qb Actual value: C, 60,66H, L1
2 N, j, 7-2 easy” CN M R (CD C6
s, internal s潴T-M-8,): page r effect μ position (--Z
J pan ) and 2nd position (-/, Y ppm ).

ct14 (l171gμppm) and Coo (/
'A, / / pprl) single-digit shift confirms the all-trans stereochemistry of the retinoyl chain.

Example μ Preparation of 13-cis-retinoic acid 6? in a flask under an inert atmosphere. (/A, A mmol) is dissolved in 30 g of anhydrous tetrafluorocarbons. The reaction mixture is cooled to 0° C. and then anhydrous pyridine Ad (74 mmol) and 1.6 put (/4.489 mol) of ethyl chloroformate are added. After stirring the solution for 5 minutes, add 1.
27? (/j mmol), then add tetrahydrochloride in advance? Clindamycin λ, j j ? dissolved in 100 d of mixture of lofuran (g)/pyridine (2)? (j, j mmol) is added. Then, the scheelite mixture was returned to room temperature while stirring for flO hours (silica gel 4-layer chromatography: methylene chloride 1'/j 4 methanol). This solution was diluted with water.

- and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then parallelized under reduced pressure. The raw ash thus obtained was purified on a silica gel column with atf ethyl(j)/hexane<j)f as eluent.
Thoroughly processed by chromatography (HPLC) to make it pure! -0-(/J-cis)-retinoyl-clindamycin 2% P (yield jl) is isolated.

Melting point: 5r7℃ (hexane/ethyl acetate) [α) 20
=-)-///' (c =/jlq/-dichlormethane) Trace analysis: C3BH5qC6N2SOb: Molecular weight near 07. μ Calculated value: C, A4cJ2 ) (, f
J/1 actual value: C, 41qlA7 H, Ir, 14
jqb”CNMR (CD(1,, internal marking T, M-8,
) The ester position is 3-position (-)-/, 77 ppm)
It is shown by the positive j effect of , and the negative r effect of the second place (-1,'A ppm ) and the μ place (-1, jppm ). ,
/3-cis coordination is C,o(,10,riJ ppm)
and c′,4(iis,y4cppm).

Example Preparation of Mycin In a flask under an inert atmosphere, 13-cis retinoic acid j IF (/4j mmol) f anhydrous tetrahycin rK
Dissolve in 27 runs 30d. The anti-Y6 mixture was cooled to 0° C. and then anhydrous pyridine A rnt (7 A mmol) and ethyl chlorate 1.6 d (lt, b mmol)
Add. After stirring the solution for 5 minutes, sodium bicarbonate was added. (13 mmol) in advance with a fingernail of 100 d of a mixture of 20 furan (7)/bi-11 dine (3) on tetra
K fused t lincomycin λj ? (j, tA mmol) is added. The reaction mixture is then returned to room temperature while stirring for io hours (silica gel thin layer chromatography:
methylene chloride'#'7'104b methanol). Add this solution to water io.

- Inject it inside, then l! The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Chromatography (HPLC) using (r)/hexane (co)
Treated pure 3-Q-(/3-cis)-retinoyl-
The yield of lincomycin is reduced.

Melting point: Rijo (hexane/ethyl) [“]
/ Oj (e = 7q,, 'godichloromethane trace analysis: C58H5oN2S07・λ, j1 (20: molecule 7: 7J4C, j calculated value: C, l, 2./I H,?
, QJ Jin actual measurement 1st shift: C, AlI3 H, L64L4
”CNMR (CDC#6, internal standard T, M, S,) The ester positions are the positive β effect at the 3rd position (+/, 4 ppm) and the positive β effect at the 2nd position (-2-'A ppm) and the μ position (- to 2p
This is indicated by the negative r effect of (orn). The 13-cis coordination is C'20 (-Z o, 2r opm ) and C',
Example 6 confirmed by 4 (//t, RyoJ ppm) 7-0-(all-trans)-retinoyl-lincomycin, j-0-(all-trans)-retinoyl-lincomycin 02-0- Monoester of (all-trans)-retinoyl-lincomycin In a flask under an inert atmosphere, 1) lincomycin jO'? (7≠mmol) was dissolved in anhydrous N,N-dimethylformaminy3oo,1 and then potassium tert-butyrate rJOη (7,μ
mmol)-f was added, the temperature was brought to room temperature, and stirring was continued for 5'θ minutes. Next, anhydrous N, N-dimethylformamide
A solution of tJ)/-(all-trans)-retinoyl imidazole/jP (J 7817 mol) is added and the resulting medium is stirred at room temperature for 12 hours (
Silica gel thin non-chromatography: methylene chloride P/7J% methanol). Water this solution! 00r14,
injection and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure with a nail. The crude product thus obtained was chromatographed (HPLC) on a silica gel column using lid ethyl (7)/hexane (3) as eluent to obtain all-trans retinoic acid at positions 2,3 and 7 of lincomycin. Mixture of monoesters (774) 6 minutes.

” CNMR (CD C/s, internal standard T,
The negative r effect at the M, S, +- position (--2,-j ppm) and the 6-position (-3-r ppm) is due to the monoester's 7
The esterification site at position is shown.

The negative r effect at the 11th position (-4' pprn) also affects the monoester at the 2nd position (--2ppm) and the μ position (-
The negative r effect of 2.4 ppm) indicates the IQ of the monoester in the 3rd position. The position(s) of C1 is packed into r J-06 ppm for the monoester at position 2, r, r, μmt ppm for the monoester at position 7, and the monoester at position 3? ? ', 67 ppm K.

For the all-trans retinoyl chain configuration a a C'14 / / 7,7 r pom and for "20 l≠, shown in OI ppm: indicating 13-cis allomorph / / j, Traces of isomerism are recognized by the presence of the 2pprn (C', 4) peak.

Example 7 Preparation of damycin, 3-0-C all-trans)-retinoester mixture Clindamycin 20
? (μ7 mmol) fAnhydrous N,N-dimethylformamide? 2zOa AVCM is dissolved and then potassium tert-butyrate 276F (44.7 mmol) is added to the reaction medium and stirred for 2050+ minutes at ambient temperature.

Anhydrous N, N-dimethyl compound ♂ 130d
/-(all-trans)-retinoyl-imidazole L
A solution of 2j09 (2 Lj mmol) is added and the resulting reaction medium is stirred at room temperature for 12 hours (silica gel thin layer chromatography: methylene chloride y/z4 methanol).
. Next, add this solution to water! 00ml and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and then concentrated under reduced pressure. The crude product obtained was filtered on a silica gel column using ethyl acetate (j)/hexane (Cj) as eluent. Using Chroma Dog 5 Fee I
PLc) Treated with a mixture of lance retinoin monoester at the 2.3 and μ positions of clindamycin*-2r9
(25 width) branch.

”CN~IR(CDCI,,internal standard T,&i,S,
) -1 position (-'3 pprn ) negative r effect indicates two-way esterification.

1 μ position (-23 pprl) and 2 position (-8 ppm
) has a weak negative r effect on the 3rd-position monoester.
The effect center indicates the monoester at the η position.

Position of C1 (plural number is j for monoesters with λ position)
4A, t J ppm, Ir t for the 3-position monoester, 7ripan, r7. for the μ-position monoester. It is in rppm.

The all-trans configuration of the retinoyl chain predominates (
C) 4 is / / 7. ! ppm ic, mari c”2
0 is /'A, Orppm K-) is trace isomerization: r
It is clearly recognized in E special 'Ic e'20 &c', 4.

1. Human-roxybrobylcellulose /W-butyl-oxytoluene 0.0393-0-(13
-cis) Retinoyl- Lincomycin 0.
Including the impromptu tool, the total is 10091
, hypoxyprobylcellulose i, sv butylhypropylcellulose o, o jtj -0-
(all-trans)-retinoyl clindamycin
0.3? Add imbronozonol to total IQQW1, butylhyroxytoluene o, ozt2'-0-C all trans)-
Retinoyl-erythromycin A
Add Ifc a-c Zip Fat Triglyceride for a total of 100fi! In this example formulation, the active f is of course equivalent to 2'-Q-(/J
-Can be replaced by cistern-retinoyl erythromycin A.

2. Butyloxytoluene 0.0! ? J
-0-(13-cis)-retinoyl-clidamycin 0.7v (t'il, n=!
) polytetrahy? Lofuran dimethyl ether (viscosity 22
centiboise) f7JO and the total
1009 white petrolatum
12v vaseline oil ijt refined paraffin 3 Vλ/ -0-(all-trans)-retinoyl-erythromycin A
I9J'-0- (all transformer)
-Retinoyl-erythromycin A
O, Oj? C8-Cl2m fatty acid triglyceride 0.27 Add 11 half-artificial triglyceride for a total of 29g! 00q Capsule The walls of the capsule are shaped from glycerin, fulvit and gelatin.

1. Capsules 2'-0 containing 10 mg of active compound
-(/J-cis)-retinoyl-erythromycin A
30 ~ Vaseline oil
200789 Thick Vaseline Oil
260 Ki2, capsules containing the active compound 1oap 21-0-(/J-cis)retinoyl-erythromycin A 10mg butyl hyphrosyaminose 0. Q j 9 tribehenic acid 20 toluene 0.0 j 9 tribehenic acid glyceryl y 1 oot C6-C12 fatty cotriglyceride - added for a total of 100 ~ The wall of the capsule is formed from gelatin and di[f] triglyceride.

2'-0-(all-trans)-retinoyl-erythromycin A 20q coloi? 2η−2η Magnesium stearate.

Claims (1)

Claims: 1. All-trans- and 13-cis-retinoic acid esters of erythromycin A, lincomycin and clindamycin, and mixtures and salts of these esters. 2. Retinoic acid ester of erythromycin A is 2'
The compound according to claim 1, which is in the position 3. The retinoic acid ester of lincomycin and clindamycin is at the 3rd position.Claim 1
Compounds described in Section. 4, 2'-O-(all-trans)-retinoyl erythromycin A, 2'-O-(13-cis)-retinoyl erythromycin A, 3-O-(13-cis)-retinoyl lincomycin, 3- Any one of claims 1 to 3 which is a compound selected from the group consisting of O-(all-trans)-retinoylclindamycin and 3-O-(13-cis)-retinoylclindamycin. Compounds described. 5. In an anhydrous organic solvent, an excess of all-trans- or 13
- a complete preparation of erythromycin A, lincomycin or clindamycin consisting of reacting a mixed acid anhydride of cis-retinoic acid with erythromycin A, lincomycin or clindamycin in the base form in the presence of an organic or inorganic base; A process for producing trans- and 13-cis-retinoic acid esters, mixtures of the esters, or salts thereof. 6. The production method according to claim 5, wherein the anhydrous organic solvent is tetrahydrofuran alone or a mixture of tetrahydrofuran and pyridine. 7. The production method according to claim 5, wherein the organic or inorganic base is pyridine and/or sodium hydrogen carbonate. 8. All-trans-of lincomycin or clindamycin, consisting of reacting all-trans- or 13-cis-retinoic acid imidazolide with lincomycin or clindamycin in the base form in an anhydrous solvent in the presence of a base. and a method for producing 13-cis-retinoic acid ester, a mixture thereof, or a salt thereof. 9. The anhydrous solvent is N,N-dimethylformamide;
9. The method of claim 8, wherein the base is sodium or potassium tertiary butyrate. 10. Erythromycin A as an active ingredient in anhydrous base
, lincomycin or clindamycin all-trans-
or 13-cis-retinoic acid ester or a salt thereof, a pharmaceutical or cosmetic composition for treating skin diseases, particularly acne. 11. The composition according to claim 10, which contains 0.01 to 10% by weight of the active ingredient compound. 12. The base is acetone, isopropyl alcohol, fatty acid triglyceride, glycol ether, short chain acid C
The composition according to claim 10 or 11, which is a _1 to C_4 alkyl ester, an ether of polytetrahydrofuran, or a mixture thereof. 13. Claims 10 to 1 further contain a thickening agent such as cellulose and/or cellulose derivatives in an amount of 0.5 to 20% by weight based on the total weight of the composition.
The composition according to any one of Item 2. 14. A composition according to any of claims 10 to 13, further comprising antioxidants, preservatives, fragrances, colorants or other anti-acne agents.