DE2057190A1 - N-arylidene derivatives of erythromycylamine - Google Patents

Description

P ATENTA NWALTE

Π R. f. Γ = Ί Λ AS DR-W. Ρΐ · ^; "'· ^; " R. R DR.F. VOITK ^ iLiSITNE

8 MUNICH 23 REGERERSTf ?. 25 - TEL 39 02 33

83 834

El i Lilly and C ompany, Indianapolis, India na, V.St.A, N-arylidene derivatives of Erythrom yc ylamine

The invention provides N-arylidene derivatives of erythromycylamine represented by the following formulas Marked are:

HO

R'-CH = N _ ·

CH,
^ R

CH

OH

-0.

CH,

I '

CH;

VX4

CH

OH

0-CH,

R'-CH = N ····

CH,

0-CH,

10 9 8 2 3/2231 II

where R is hydrogen or the hydroxy group and R ^{1 is} a phenyl, naphthyl or pyridyl radical or substituted phenyl, substituted ilaphthyl or substituted pyridyl radicals which are mono- or polysubstituted by C 1 -C 6 -alkyl radicals, halogen atoms, Cj-Cj-alkyloxy radicals , lower alkanoyl groups, hydroxyl groups, carboxy groups, phenyl groups, nitro groups or trifluoromethyl groups are substituted. Formula I designates normal erythromycylamine or erythromycyl u-amine derivatives and formula II the corresponding Lpi derivatives.

If in the above formulas R is hydrogen, the compounds are derivatives of erythromycin B, and when R is hydroxy the compounds are Derivatives of erythromycin (sometimes also referred to as lythromycin A).

The collective term "N-Arylidenerythromycylamine" such as As used herein, it is intended to encompass derivatives of both the normal and the epi-amines, which differ from Krythromycin and derived from Erythromycin D.

The groups which are designated by "R 'in the above formulas include, for example, phenyl, alpha- and beta-naphthyl, 2-pyridyl, 3-pyridyl and 4-pyridyl. To the permissible within the scope of the invention Substituents on these rings include, for example, C 1 -C alkyl groups such as methyl, ethyl, n-propyl and isopropyl, C -C -j-alkoxy groups such as methoxy, ethoxy, n-propoxy or isopropoxy, lower alkanoyl groups such as formyl and acetyl or halogen atoms such as chlorine, bromine, fluorine or Iodine. Typical compounds that fall under the formulas given above are, for example:

10 9 8 2 3/2231

BAD ORiGIHAL

N- (4-ethylbenzylidene) -epi-erythromycylamine N- (2-bromobenzylidene) -erythromycylamine

N- (4-isopropoxy-i-naphthylmethylene) erythromyeylamine

N- (5-fluoro-2-pyridylmethylene) -erythromycy 1 -B-amih

N- (3-methyl-2-pyridylmethylene) -epi-erythromycy 1-B-amine N - ^ - trifluoromethyl ^ -pyrldylmethylene) -epi-ery thromycylamine

N- (5-ethyl-3-pyridylmethylene) -erythromycylamine N- (4-Methoxy-2-pyridylmethylene) -erythromycyl-B-amine N- / 3- (n-Propoxy) benzylidene / epi-erythromycylamine N- (2-isopropylbenzylidene) -epi-ery tliromycyl-B-amine N- (2-iodobenzylidene) -erythromycyl-B-amine N- (1-Ethoxy-2-naphthylmethylene) -erythromycy1-B-amine N- (5-chloro-1-naphthylmethylene) epi-erythromycylamine

N- (2,6-dimethyl-1-naphthylmethylene) -epi-erythromycylamine

N- (2-phenylbenzylidene) -erythromycylamine N- (8-Hydroxy-1-naphthylmethylene) erythromycylamine

N- (2-methyl-4-meth, oxy-1-naphthylmethylene) -erythromycyl-B-amine

N- (2,5-dimethoxybenzylidene) erythromycylamine N- (3,4-dichlorobenzylidene) -epi-erythromycy1-B-amine N- (2-chloro-4-methylbenzylidene) -erythromycyl-B-amine

N- (3-methyl-5-chloΓ-2-pyΓidylmethylene) -epi-erythromyeylamine

N- (2-nitrobenzylidene) epi-erythromycylamine

N- (3-Hydroxy-4-methoxy-2-pyridylmethylene) -epi-erythromycyl-B-amine

N- (3-trifluoromethylbenzylidene) -erythromycylamine N_ (4_Acetylbenzylidene) -erythromycylamine

205 '/ 1 9 0

H- (4-trifluoromethyl-1-naphthylmethylene) erythromycylamine N- (5-Kltro "2-naphthylmethylene) -erythroniycylaruin. N- (5-trifluoromethyl-3 - chloro ~ 2 - pyridylmethylene) -epi-

erythromycylamine
N ~ (5-nitro-2-pyridylwethylene) -erythromycylamine.

The compounds mentioned are prepared by reacting the corresponding aldehyde (R ¹ -CHO) with erythromycylamine, erythromycyl B-amine or epierythromycylamine.

Erythromycylamine and erythromycyl B-amine are produced by the catalytic hydrogenation of brythrornycin oxime, Erythromycin B oxime or related derivatives of erythromycin or erythromycin B obtained. Erythromycylamine and erythromycyl B-amine both have pronounced antibiotic activity on the order of magnitude of the strain antibiotic and are, when administered parenterally or orally, to mice infected with gram-positive Microorganisms are infected.

The invention has for its object to derivatives of erythromycylamine and of erythromycyl B-amine with better antibiotic activity and increased absorption in the intestinal tract when administered by the oral route create.

The compounds according to the invention have compared to erythromycin, erythromycin B, erythromycylamine or Erythromycyl B-amine in vitro or in vivo comparable or superior antibiotic activity. For example the compounds according to the invention are effective agents for the therapy of infections

109823/2231

Mammals caused by gram positive microorganisms. To demonstrate this activity, each animal was injected with a culture of S. pyogenes from a group of mice. Treated mice received two doses of the antibiotic 1 and 5 hours after injection. Untreated mice were given the pharmaceutical carrier only. To determine the EDc ₀ (dose which lightens 50% of the infected animals), different doses were used for different groups of mice. The following Table I shows the ED ₅₀ values for 4 compounds which come under the formulas given above. In column 1 of the table is the name of the compound, in column 2 the ED ^ ₀ for oral administration, in column 3 the ED ₅₀ for subcutaneous administration and in column 4 the minimum inhibitory concentration (MIC) in micrograms / milliliter that is associated with a Routine test tube test determined. For comparison purposes, the table also contains corresponding values for iSrythromycylamine.

109823/2 231

Table I. link

ED _c . _n (mg / kgX2)

Orally

Sc

MIG mcg / ml

N-benzylidene erythromycylamine

N-salicylidene erythromycylamine

N- (1-naphthylmethylene) erythromycylamine

N- (3-Hydroxy-4-methoxybenzylidene) erythromycylamine

Erythromycylamine

15.6

33.8

26.0

3.6

10.4 2.4 28.6 2.6

1.3

2.6

0.2 0.6 0.6

0.6 0.2

he »ι

Like the ED ₁ . Values in the table above show that the compounds of the present invention are equivalent to or better than erythromycylamine for curing S. pyogenes infections in mice.

never higher effectiveness of the N-Arylidenerythromycylamine according to the invention when administered by the oral route in comparison to erythromycylamine is also shown in the greater antibiotic activity of blood serum from dogs administered with the compounds. at carrying out these blood concentration determinations ^ .ri each compound in a capsule to groups of 6 chicken dogs (beagle), each weighing between 6 and 9 kg. The connection is made in a Amount of 25 mg / kg is administered, and the concentration of Antibio ti curtis in the blood is in a range of Time intervals, starting half an hour after the administration up to 6 hours, determined. The antibiotic Cum concentration in the blood is obtained by examining the Blood sera determined in a standard antibiotic test against Sarcina lutea. Similar research are for comparison purposes with erythromycin and Erythromycylamine carried out. The results of this Determinations are shown in Table II below. In Table II column 1 gives the name of the compound, and columns 2 to 8 give the blood concentrations antibiotic activity for the compounds in question in the respective time interval that is in the head of the respective Column is indicated, called. All numbers are averages from sera from six dogs.

109823/2231

Table II

Blood Concentrations of Antibiotic Activity in Dogs (Oral Doa ie - 25 mg / kg)

Mean value for 6 dogs (mcg / kg) Hours after administration link

N-benzylidene erythromycylamine

Erythromycin

Erythromycylamine

, 0.5

0.5

2.4

0.4

1.5

2.3. 1.6

2.7

1.0

1.2

1.4

1.0
1.2

0.6

1.2 0.4

0.6

0.7

0.2

0.6

CD

CD CD

As can be seen from the table, the blood concentrations for the tJ-benzylidene erythromycylamine are In each tested time interval higher than with erythromycylamine itself. Furthermore, the maximum occurs the blood concentration in the compound according to the invention later on than erythromycin and lasts considerably longer.

The N-arylidenerythroinycylamines are a matter of course Effective in vitro against both gram-negative and gram-positive bacteria. The following table III shows the antiblotic spectrum of two tJ-arylidenerythroraycylamines in vitro, the according to the agar disc diffusion method using trypticase soy agar as the culture medium was determined. In Table III, column 1 gives the name of the test organism, column 2 the minimal one Heroma concentration (MIC) in micrograms / milliliter, in which N-Benzylidenerythromycylarain inhibits the growth of the microorganisms mentioned in column 1, and Column 3 corresponding values for N-salicylidene erythromycylamine at.

109823/2231

- ίο -

Table III

Microorganism MIC in mcg / ml for MIC in mcg / ml for N-benzylidene- N-salicylidene erythromycylamine erythromycylamine

Pseudomonas sp. X-239 100.00 100.00 E. coli EC-0127 6.25 6.25 E. coli EC-H 6.25 6.25 Proteue sp. (Indole) PR-6 100.00 50.00 Proteus sp. (Indole +) PR-9 100.00 100.00

K. aerobacter K-1 12.5 K. aerobacter KA-H 6.25 S. aureus PS-3055 0.2 S. aureus MR-3130 6.25 S. typhimurium S-4 6.25 S. typhosa T-36 6.25 Salmonella sp. SA-12 6.25 Shigella sp. SH-3 6.25

12.5

6.25

0.1

6.25

6.25

6.25

6.25

3.13

■ «ΛΙΊΛΙ JUA1

- ■ "- 2G57190

As can be seen from Tables I to III, the N-arylidenerythromycylamines have antibiotic activity in vitro and in vivo against both gram-positive and gram-negative microorganisms. The compounds can therefore be used to combat populations of staphylococci or streptococci _f that occur on devices, furnishings, walls and floors in practice of doctors and dentists and in hospitals. For this sweck, the N-Arylidenerythromycy1-amine is dissolved in water, preferably with the addition of a surface-active agent, and the solution is applied to the surfaces like an ordinary washing solution. The N-Arylidenerythromycylamine may further z ^ x Eöhandlung be used by infections in mammals and birds, caused by various microorganisms. When used for this purpose, the methods customary for the administration of lrythromycin, its salts or its derivatives to animals and humans can be applied directly to the application of the N-arylidenerythromycylamines. In other words, the η-arylidenerythromycylamines can be used to treat infections caused by pathogenic microorganisms, for example the staphylococci, pneumococci, streptococci (including hemolytic streptococci) and also by strains of Reisseria, Hemphilus, Corynebacterium, Brucella and Clostridium When the N-arylidenerythromycylamines are used to treat infections in mammals or birds, they are administered in divided doses at doses of 0.5 to 2 grams per day.

Usually the N-arylidene erythromycylamines are used administered to mammals by the oral route in either capsule or tablet form. This pharmaceutical Dosage forms can be made according to the methods be prepared that are used to produce similar

10 9 8 2 3/2231 ^ßAD ORIGINAL

pharmaceutical dosage forms for erythromycin even be applied.

The N-Arylidenerythromycylamines offer in their application for therapeutic purposes besides their increased oral activity the further advantage that with them not only is there virtually no danger of them inducing abnormal liver function, as is the case with erythromycin may be the case itself, but rather that it is nonexistent in comparison to erythromycin or its salts fc or practically no increased motility of the intestinal

cause tracts.

The weakened motility of the intestinal tract Use of Ιϊ-Arylidenerytrlionycylainine in comparison to erythromycin is illustrated by the following experiment, in which erythromycin and H-arylidenerythromycylamine were administered to dogs with induction coils permanently implanted on the intestinal walls. The antibiotic was given orally to the dogs in every case administered at a dosage of 25 rag / kg. The number of dogs that vomited was recorded. the The results of this experiment are shown in Table IV. In

W Table IV gives column 1 the name of the compound, column 2 the number of dogs tested and column 3 the number of dogs that vomited.

2L »Jl_? -L-l · ®? Y.

Number of dogs, connection number 1 of dogs that vomited

N-benzylidene

erythromycylamine 6 O

N-salicylid

erythromycylamine 6 O

Erythromycin 6 3

109823/2231

BAD CBiGiNAt

A summary of the results of the examination of the antibiotic activity of the N-arylidenerythromycylamines according to the invention thus shows that the compounds have an activity in vitro that of the of erythromycylamine or of erythromycin equivalent is. When used in vivo, they stimulate the gastrointestinal tract less than erythromycin and give no indication of liver toxicity. The compounds exhibit better oral activity against Infections in mice referred to as erythromycylamine. relation borrowed the blood concentrations in fasting dogs, the H-Arylidenerythromycylamine give a higher and longer lasting blood levels than erythromycylamine or erythromycin.

The preparation of the compounds according to the invention is explained in more detail by the following examples.

example

About 1.5 g of benzaldehyde are added to a hot solution of 10.0 g of erythromycylamine in 50 ml of leopropanol given. The reaction mixture is heated to the boil for about 1.5 hours. Then water is added until Crystallization of H-benzylidene erythromycylamine, which has arisen in the reaction described above, begins. The reaction mixture is cooled and N-benzylerythromycylamine is filtered off. Enamel point 142 - 146 degrees C.

The following examples show compounds which, according to the procedure of Example 1 described above by reacting the aldehydes in question with erythromycylamine.

10 9 8 2 3/2231

Example

- H connection

N-salicylidene erythromycylamine N-4-methylbenzylidene erythromycylamine N-4-carboxybenzylidene erythromycylamine N-4-methoxybenzylidene erythromycylamine N- (3-pyridylmethylene) erythromycylamine N-4-chlorobenzylidene erythromycylamine

N-3-hydroxy-4-methoxybenzylidene erythromycylamine N-4-phenyl-benzylidene erythromyoylamine N-4-bromobenzylidene erythromycylamine N-4-nitrobenzylidene erythromycylamine N-4-formylbenzylidene erythromycylamine *

N-2,4,6-trimethoxybenzylidene erythromycylamine

N-2,4,6-trimethylbenzylidene erythromycylamine M.p.

124 ~ 26 ° C.

141-43 ⁰ C

212-15 ⁰ C amorphous amorphous amorphous

144-46 ⁰ G. amorphous 142-15O ⁰ G. '151-162 ⁰ C. amorphous

202.5-204 ° C.

136.5-14O ⁰ G.

134-138 ⁰ C.

amorphous

N-2-methoxybenzylidene erythromycylamine U-2,4-dimethoxybenzylidene erythromycylamine

N- (2-Pyridylmethylene) -erythromycylamine 146-156 ⁰ C. N- (4-Pyridylmethylene) -erythromycylamine 160-163 C.

* The procedure described is used to produce this derivative preferably modified so that equimolar amounts of amine and aldehyde are used.

109823/2231

Example 19 N- (1-Haphthylmethylene) -erythrpn ^ cylami ^ n.

Following the procedure of Example 1, alpha-naphthylaldehyde and erythromycylamine in isopropanol solution to N- (lHtfaphthylmethylene) -erythromycylamine implemented. To isolate the compound, the reaction mixture is diluted with water and the aqueous Solution extracted with methylene chloride. When evaporating the separated methylene chloride extracts are left with U- (1-naphthylmethylene) erythromycylamine. the Compound is made from a methanol-water-solvent- mixture recrystallized. Melting point 140 to 146 degrees C.

The N-benzylidene and N-salicylidene derivative of Erythromycyl B-amine or epi-erythromycylamine and similar Schiff bases are used according to the procedure from Example 1 or Example 19 obtained.

Erythromycylamine, and Erythromycyl B-amine are through catalytic hydrogenation of erythromydnoxiin, Erythromycin B-Oxiin or similar derivatives.

Epierythromycylamine itself is obtained from the reduction mixture that occurs during catalytic hydrogenation of erythromycin oxime, erythroraycin hydrazine adduct or similar derivatives is obtained. Epierythromycyl B-amine is also formed together with erythromycyl B-AmIn, when erythromycin B-oxime is hydrogenated and can also be isolated from the hydrogenation mixture.

109823/2231

Claims (5)

P ate η ta η s ρ r ü ch _e_ / l / IJ-arylidene derivatives of erythromycylamine, characterized by the formula HO R'-CH = N OH O-CH, HO CH ₃ ^and 3 O-CH, II wherein R is hydrogen or the hydroxy group and R ^{1 is} a phenyl, naphthyl or pyridyl radical or substituted phenyl, substituted naphthyl or substituted pyridyl radicals, the 109823/2231 one or more times by C-C alkyl radicals, halogen atoms, C. -C - ^ - alkyloxy groups, lower alkanoyl radicals, Hydroxy groups, carboxyl groups, phenyl groups, nitro groups or trifluoromethyl radicals are substituted. 2. Erythromycylamine compound according to claim 1, characterized in that R ^{1 is} a phenyl, naphthyl or pyridyl radical or a phenyl, ilaphthyl which is monosubstituted or polysubstituted by CC ₃ alkyl radicals, halogen atoms, C -C_ ~ alkyloxy radicals, hydroxy groups or trifluoromethyl radicals or is a pyridyl radical. 3. Erythromycylamine compound according to claim 1, characterized in that R ^{1 is} a niecleralkanoy 1-carboxy, phenyl or nitro-substituted radical. 4. erythromycylamine compound according to claim 1, characterized by the chemical name il-benzylidene erythromycylamine or N-salicylidene erythromycylamine. 5. Compound according to claim 1 _f, characterized by the chemical name N-4-Forinylbenzylidenerythromycylamin. 109823/2231