 |
Description  |
|
|
The present invention relates to 9a-N-(N'-carbamoyl) and
9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin
A, novel semisynthetic macrolide antibiotics of the azalide series having
an antibacterial action of the general formula (I)
##STR2##
wherein R represents a C.sub.1 -C.sub.3 alkyl, aryl or aralkyl group and X
represents O or S, to pharmaceutically acceptable addition salts thereof
with inorganic or organic acids, to a process for the preparation thereof,
to a process for the preparation of the pharmaceutical compositions as
well as to the use of pharmaceutical compositions obtained in the
treatment of bacterial infections.
Erythromycin A is a macrolide antibiotic, whose structure is characterized
by a 14-member macrolactone ring having a carbonyl group in C-9 position.
It was found by McGuire in 1952 (Antibiot. Chemother., 1952; 2:281) and
for over 40 years it has been considered as a reliable and effective
antimicrobial agent in the treatment of diseases caused by Gram-positive
and some Gram-negative microorganisms. However, in an acidic medium it is
easily converted into anhydroerythromycin A, an inactive C-6/C-12
metabolite of a spiroketaI structure (Kurath P. et al., Experientia 1971;
27:362). It is well-known that spirocyclisation of aglycone ring of
erythromycin A is successfully inhibited by a chemical transformation of
C-9 ketones or hydroxy groups in a C-6 and/or C-12 position. By the
oximation of C-9 ketones (Djokic S. et al., Tetrahedron Lett., 1967; 1945)
and by subsequently modifying the obtained 9(E)-oxime into
9-[O-(2-methoxyethoxy)-methyloxime] erithromycin A (ROKSITROMICIN)
(Ambrieres, G. S., FR 2,473,525/1981) or 9(S)-erithromycylamine (Egan R.
S. et al., J. Org. Chem., 1974; 39:2492) or a more complex oxazine
derivative thereof,
9-deoxo-11-deoxy-9,11-{imino[2-(2-methoxyethxyethylidene]-oxy}-9(S)-erythr
omycin A (DIRITROMICIN) (Lugar P. et al., J. Crist. Mol. Struct., 1979;
9:329), novel semisynthetic macrolides were synthetized, whose basic
characteristic, in addition to a greater stability in an acidic medium, is
a better pharmacokinetics and a long half-time with regard to the parent
antibiotic erythromycin A. In a third way for modifying C-9 ketones use is
made of Beckmann rearrangement of 9(E)-oxime and of a reduction of the
obtained imino ether (Kobrehel G. et al., U.S. Pat. No. 4,328,334, 5/1982)
into 11-aza-10-deoxo-10-dihydroerythromycin A
(9-deoxo-9a-aza-9a-homoerythromycin A) under broadening the 14-member
ketolactone ring into a 15-member azalactone ring. By reductive
N-methylation of 9a-amino group according to Eschweiler-Clark process
(Kobrehel G. et al., BE Pat. No. 892,357, 7/1982) or by a preliminary
protection of amino group by means of conversion into the corresponding
N-oxides and then by alkylation and reduction (Bright G. M., U.S. Pat. No.
4,474,768, 10/1984) N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A
(9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A, AZITROMICIN) was
synthetized, a prototype of azalide antibiotics, which, in addition to a
broad antimicrobial spectrum including Gram-negative bacteria and
intracellular microorganisms, are characterized by a specific mechanism of
transport to the application site, a long biological half-time and a short
therapy period. In EP A 0 316 128 (Bright G. M.) novel 9a-allyl and
9a-propargyl derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A are
disclosed and in U.S. Pat. No. 4,492,688, 1/1985 (Bright G. M.) the
synthesis and the antibacterial activity of the corresponding cyclic
ethers are disclosed. In the Croatian patent application 381-03/93-05/041
(559-93-1) there are further disclosed the synthesis and the activity
spectrum of novel 9-deoxo-9a-aza-11-deoxy-9a-homoerythromycin A
9a,11-cyclic carbamates and O-methyl derivatives thereof.
According to the known and established Prior Art, 9a-N-(N'-carbamoyl) and
9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin
A and pharmaceutically acceptable addition salts thereof with inorganic or
organic acids, a process for the preparation thereof as well as the
preparation methods and use an pharmaceutical preparations have not been
disclosed as yet.
It has been found and it is an object of the present invention that
9a-N-(N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of
9-deoxo-9a-aza-9a-homoerythromycin A, novel semisynthetic macrolide
antibiotics of the azalide series and pharmaceutically acceptable addition
salts thereof with inorganic or organic acids may be prepared by reacting
9-deoxo-9a-aza-9a-homoerythromycin A with isocyanates or isothiocyanates
and optionally by reacting the obtained 9a-N-(N'-carbamoyl) and
9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin
A with inorganic and organic acids.
It has been found that novel 9a-N-(N'-carbamoyl) and
9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin
A of the formula (I)
##STR3##
wherein R represents a C.sub.1 -C.sub.3 alkyl, aryl or aralkyl group and X
represents O or S, and pharmaceutically acceptable addition salts thereof
with inorganic or organic acids may be prepared by reacting
9-deoxo-9a-aza-9a-homoerythromycin A with isocyanates or isothiocyanates
of the general formula (II)
R-N.dbd.C.dbd.X(II)
wherein R and X have the above meanings, in toluene, xylene or some other
aprotic solvent, at a temperature of 20.degree. to 110.degree. C., the
isocyanates of the general formula (II) wherein R represents a phenyl
group, 1-naphthyl group or unsubstituted or substituted aromatic 5-member
and 6-member rings having one or two hetero atoms being prepared in situ
by means of Curtius rearrangement of the corresponding acid azide at
elevated temperature.
Pharmaceutically acceptable acid addition salts, which also represent an
object of the present invention, are obtained by reacting
9a-N-(N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of
9-deoxo-9a-aza-9a-homoerythromycin A with an at least equimolar amount of
the corresponding inorganic or organic acid such as hydrochloric acid,
hydroiodic acid, sulfuric acid, phosphoric acid, acetic acid,
trifluoroacetic acid, propionic acid, benzoic acid, benzene sulfonic acid,
methane sulfonic acid, lauryl sulfonic acid, stearic acid, palmitic acid,
succinic acid, ethylsuccinic acid, lactobionic acid, oxalic acid,
salicylic acid and similar acids, in a solvent inert to the reaction.
Addition salts are isolated by evaporating the solvent or, alternatively,
by filtration after a spontaneous precipitation or a precipitation by the
addition of a non-polar cosolvent.
9a-N-(N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of
9-deoxo-9a-aza-9a-homoerythromycin A of the formula (I) and
pharmaceutically acceptable addition salts with inorganic or organic acids
thereof possess an antibacterial activity in vitro. Minimum inhibitory
concentrations (MIC, mcg/ml) are determined by dilution method on
microplates according to the recommendation of National Committee for
Clinical Laboratory Standards (NCCLS, M7-A2). It is evident from Table 1
that standard strains and clinical isolates tested are susceptible to
newly synthetised compounds. Thus they may be used for disinfection of
rooms, chirurgical instruments and humans and as therapeutic agents in the
treatment of infective diseases in animals, especially mammals and humans,
caused by a broad spectrum of Gram-positive bacteria, mycoplasmas and
generally patogenic microorganisms that are susceptible to the compounds
of the formula (I). To this purpose the above compounds and
pharmaceutically acceptable acid addition salts thereof may be
administered orally in usual doses from 0.2 mg/kg body weight daily to
about 250 mg/kg/day, most preferably from 5-50 mg/kg/day, or parenterally
in the form of subcutaneous and intramuscular injections.
TABLE 1
______________________________________
Antibacterial in vitro activity of novel 9a-N-(N'-carbamoyl) and
9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homo-
erythromycin A in comparison with the starting amine
MIC (mcg/ml)
Test 9a-
organism NH* 1 4 5 6 7**
______________________________________
Staphylococcus
3.12 6.25 25.0 3.12 6.25 6.25
epidermidis ATCC
12228
Staphylococcus
3.12 1.56 12.5 6.25 3.12 3.12
aureus ATCC
6538P
Micrococcus flavus
1.56 3.12 12.5 6.25 3.12 1.56
ATCC 10240
Streptococcus
3.12 3.12 6.25 3.12 3.12 1.56
faecalis ATCC
8043
Bacillus subtilis
12.5 1.56 25.0 6.25 3.12 1.56
NCTC 8236
B. pumilus NCTC
12.5 6.25 12.5 6.25 3.12 1.56
8241
B. cererus ATCC
3.12 6.25 12.5 12.5 6.25 6.25
11778
Pseudomonas
25.0 25.0 50.0 50.0 50.0 50.0
aeruginosa NCTC
10490
Esherichia coli
3.12 12.5 12.5 12.5 25.0 12.5
ATCC 10536
Salmonella 3.12 6.25 25.0 25.0 >100.0 >100.0
Panama 6117
BHS-A Strepto-
3.12 12.5 3.12
coccus pyogenes
J-21
BHS-B Strepto-
1.56 12.5 1.56
coccus Agalactiae
J-22
______________________________________
*9-deoxo-9a-aza-9a-homoerythromycin A
**numbers designate newly synthetised compounds from the corresponding
Examples
Process for the preparation of 9a-N-(N'-carbamoyl) and
9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin
A of this invention is illustrated by the following Examples which should
in no way be construed as a limitation of the scope thereof.
EXAMPLE 1
9-deoxo-9a-N-(N'-isopropyl-carbamoyl)-9a-aza-9a-homoerythromycin A
A mixture of 9-deoxo-9a-aza-9a-homoerythromycin A (7.27 g; 0.01 mole),
isopropylisocyanate (0.94 g; 0.011 mole) and toluene (40 ml) was stirred
for 1 hour at the temperature of 30.degree. C. The reaction mixture was
evaporated at reduced pressure (40.degree. C.) to dryness to give crude
9-deoxo-9a-N-(N'-isopropyl-carbamoyl)-9a-aza-9a-homoerythromycin A (7.0 g;
86.2%), m.p. 128.degree.-136.degree. C. By recrystallization of the
obtained product from a methanol-water mixture a chromatographically
homogenous substance having the following physico-chemical constants was
obtained:
m.p. 135.degree.-144.degree. C.
TLC, EtAc-(n-C.sub.6 H.sub.6)-NHEt.sub.2 (100:100:20), Rf 0.351.
CHCl.sub.3 --CH.sub.3 OH-conc. NH.sub.4 OH (6:1:0.1), Rf 0.553.
IR (KBr) cm.sup.-1 1730, 1625, 1515, 1455, 1380, 1270, 1165, 1050, 950.
.sup.1 H NMR (300 MHz, CDCl.sub.3).delta. 5.00 (1H, H-13), 4.85 (1H, H-1"),
4.47 (1H, H-1'), 4.02 (1H, H-3), 3.91 (1H, --CH(CH.sub.3).sub.2), 3.50
(1H, H-5), 3.43 (1H, H-9a), 3.28 (3H, 3"-OCH.sub.3), 2.49 (1H, H-9b), 2.32
[6H, 3'-N(CH.sub.3).sub.2, 2.31 (1H, H-8), 1.62 (1H, H-7a), 1.29 (3H,
10-CH.sub.3), 1.14 [6H,--CH(CH.sub.3).sub.2 ], 1.13 (1H, H-7b), 1.04 (3H,
8-CH.sub.3).
.sup.13 C NMR (75 MHz, CDCl.sub.3).delta. (175.5 (C-1), 158.2 (9a-NCONH),
103.8 (C-1'), 96.0 (C-1"), 87.9 (C-5), 78.8 (C-3), 48.8 (3"-OCH.sub.3),
45.5 (C-2), 42.2 [--CH(CH.sub.3).sub.2 ], 39.9 [3'-N(CH.sub.3).sub.2 ],
27.4 (C-8), 22.9 [--CH(CH.sub.3).sub.2, 20.5 (8-CH.sub.3), 12.2
(10-CH.sub.3).
EXAMPLE 2
9-deoxo-9a-N-{N'-[(4-methyl-5-oxazole)-carbamoyl]}-9a-aza-9a-homoerythromyc
in A
A mixture of 9-deoxo-9a-aza-9a-homoerythromycin A (4.8 g; 0.0065 mole),
4-methyl-5-oxazole-carboxylic acid azide (1.0 g; 0.0066 mole) and dry
toluene (30 ml) was heated for 15 minutes at the boiling temperature and
then, by distillation at reduced pressure (40.degree. C.), evaporated to
dryness. The obtained residue was suspended in acetone (20 ml), stirred at
room temperature and then the obtained crystals were filtered to give
9-deoxo-9a-N-{N'-[(4-methyl-5-oxazole)-carbamoyl]}-9a-aza-9a-homoerythromy
cin A (5.4 g; 93.3%), m.p. 174.degree.-177.degree. C. By recrystallization
from hot acetone, a chromatographically homogenous product having the
following physico-chemical constants was obtained:
m.p. 181.degree.-183.degree. C.
TLC, EtAc-(n-C.sub.6 H.sub.6)-NHEt.sub.2 (100:100:20), Rf 0.149.
CHCl.sub.3 --CH.sub.3 OH-conc. NH.sub.4 OH (6:1:0.1), Rf 0.491.
IR (KBr) cm.sup.-1 1730, 1680, 1655, 1490, 1460, 1380, 1170, 1050, 755,
660.
.sup.1 H NMR (300 MHz, Py d.sub.5, 50.degree. C.).delta. 9.02 (9a-N-CONH),
7.95 (--CH.dbd.N) 5.71 (1H, H-13), 5.15 (1H, H-1"), 4.94 (1H, H-1'), 4.77
(1H, H-3), 4.07 (1H, H-5), 3.96 (1H, H-9a), 3.44 (3H, 3"-OCH.sub.3), 2.50
(1H, H-9b), 2.32 [6H, 3'-N(CH.sub.3).sub.2 ], 2.34 (1H, H-8), 2.35 (1H,
H-7a), 1.68 (3H, 10-CH.sub.3), 1.97 (1H, H-7b), 1.09 (3H, 8-CH.sub.3).
.sup.13 C NMR (75 MHz, Py d.sub.5, 50.degree. C.).delta. 177.2 (C-1), 157.2
(9a-NCONH), 104.2 (C-1'), 96.9 (C-1"), 86.6 C-5), 80.5 (C-3), 50.1
(3"-OCH.sub.3), 46.5 (C-2), 42.2 (C-4), 41.0 [3"-N(CH.sub.3).sub.2 ], 29.1
(C-8), 21.2 (8-CH.sub.3), 14.1 (10-CH.sub.3), 149.9, 142.2, 128.2 and 12.2
(4-methyl-5-oxazole).
EXAMPLE 3
9-deoxo-9a-N-[N'-(2-furyl)-carbamoyl]-9a-aza-9a-homoerythromycin A
Analogously to the process disclosed in Example 2, from
9-deoxo-9a-aza-9a-homoerythromycin A (2.18 g; 0.003 mole),
2-furancarboxylic acid azide (0.5 g, 0.0036 mole) and toluene (15 ml) a
resinous residue (2.1 g) was obtained, wherefrom by chromatography on a
silica gel column using the solvent system CHCl.sub.3 --CH.sub.3 OH (7:3)
9-deoxo-9a-N-[N'-(2-furyl)-carbamoyl]-9a-aza-9a-homoerythromycin A (1.7 g;
77.0%) having the following physico-chemical constants was obtained:
m.p. 155.degree.-159.degree. C.
TLC, EtAc-(n-C.sub.6 H.sub.6)-NHEt.sub.2 (100:100:20), Rf 0.262.
CHCl.sub.3 --CH.sub.3 OH-conc. NH.sub.4 OH (6:1:0.1), Rf 0.574.
IR (CHCl.sub.3) cm.sup.-1 1730, 1655, 1520, 1460, 1380, 1270, 1165, 1050,
1000, 955, 900, 830, 730.
.sup.1 H NMR (300 MHz, DMSO).delta. 8.51 (9a-N-CONH), 7.24 (--O--CH.dbd.)
6.34 (--O--CH.dbd.CH--), 6.00 (--CH.dbd.C--NH), 5.04 (1H, H-13), 4.77 (1H,
H-1"), 4.47 (1H, H-1'), 4.01 (1H, H-3), 3.42 (1H, H-5), 3.47 (1H, H-9a),
3.35 (3H, 3'-OCH.sub.3), 3.25 (1H, H-9b), 2.50 [6H, 3'-N(CH.sub.3).sub.2
], 2.07 (1H, H-8), 1.45 (1H, H-7a), 1.20 (1H, H-7b), 1.15 (3H,
10-CH.sub.3), 0.90 (3H, 8-CH.sub.3).
.sup.13 C NMR (75 MHz, DMSO).delta. 175.5 (C-1), 155.4 (9a-NCONH), 101.9
(C-1'), 95.3 (C-1"), 84.4 (C-5), 78.6 (C-3), 48.8 (3"-OCH.sub.3), 44.6
(C-2), 40.0 (C-4), 40.1 [3'-N(CH.sub.3).sub.2 ], 27.7 (C-8), 19.7
(8-CH.sub.3), 13.2 (10-CH.sub.3), 147.7, 136.5, 118.9, 98.0 (5-furanoyl).
EXAMPLE 4
9-deoxo-9a-N-[N'-(4-pyridyl)-carbamoyl]-9a-aza-9a-homoerythromycin A
Analogously to the process disclosed in Example 2, from
9-deoxo-9a-aza-9a-homoerythromycin A (2.18 g; 0.003 mole), isonicotinic
acid azide (0.53 g, 0.0036 mole) and toluene (15 ml) a resinous residue
(2.26 g) was obtained, wherefrom by recrystallization from a
methanol-water mixture
9-deoxo-9a-N-[N'-(4-pyridyl)-carbamoyl]-9a-aza-9a-homoerythromycin A (1.9
g; 74.8%) having the following physico-chemical constants was obtained:
m.p. 149.degree.-153.degree. C.
TLC, EtAc-(n-C.sub.6 H.sub.6)-NHEt.sub.2 (100:100:20), Rf 0.089.
CHCl.sub.3 --CH.sub.3 OH-conc. NH.sub.4 OH (6:1:0.1), Rf 0.441.
IR (CHCl.sub.3) cm.sup.-1 1730, 1650, 1590, 1510, 1460, 1380, 1330, 1280,
1165, 1050, 1000, 955, 900, 830, 730.
.sup.1 H NMR (300 MHz, DMSO).delta. 8.66 (9a-N--CONH), 8.25, 7.35
(4-piridyl), 5.16 (1H, H-13), 4.89 (1H, H-1"), 4.52 (1H, H-1'), 4.15 (1H,
H-3), 3.53 (1H, H-5), 3.51 (1H, H-9a), 3.33 (3H, 3"-OCH.sub.3), 3.28 (1H,
H-9b), 2.34 [6H, 3'-N(CH.sub.3).sub.2 ], 2.28 (1H, H-8), 1.62 (1H, H-7a),
1.23 (1H, H-7b), 1.36 (3H, 10-CH.sub.3), 1.04 (3H, 8-CH.sub.3).
.sup.13 C NMR (75 MHz, DMSO).delta. 176.1 (C-1), 155.5 (9a-NCONH), 102.2
(C-1'), 95.5 (C-1"), 84.3 (C-5), 78.7 (C-3), 48.9 (3"-OCH.sub.3), 44.8
(C-2), 40.2 (C-4), 40.4 [3'-N(CH.sub.3).sub.2 ], 27.8 (C-8), 20.2
(8-CH.sub.3), 14.4 (10-CH.sub.3), 149.8, 148.0, 113.9 (4-pyridyl).
EXAMPLE 5
9-deoxo-9a-N-(N'-phenyl-carbamoyl)-9a-aza-9a-homoerythromycin A
Analogously to the process disclosed in Example 2, from
9-deoxo-9a-aza-9a-homoerythromycin A (2.0 g; 0.0027 mole), benzoic acid
azide (0.5 g, 0.0034 mole) and toluene (15 ml) a resinous residue (2.43 g)
was obtained, wherefrom by chromatography on a silica gel column using a
solvent system CH.sub.2 Cl.sub.2 --CH.sub.3 OH (85:15),
9-deoxo-9a-N-(N'-phenyl-carbamoyl)-9a-aza-9a-homoerythromycin A (1.4 g;
61.4%) having the following physico-chemical constants was obtained:
m.p. 126.degree.-130.degree. C.
TLC, EtAc-(n-C.sub.6 H.sub.6)-NHEt.sub.2 (100:100:20), Rf 0.345.
CHCl.sub.3 --CH.sub.3 OH-conc. NH.sub.4 OH (6:1:0.1), Rf 0.637.
IR (KBr) cm.sup.-1 1730, 1645, 1600, 1539, 1510, 1455, 1380, 1315, 1240,
1165, 1045,950, 895, 755, 690.
.sup.1 H NMR (300 MHz, DMSO).delta. 8.11 (9a-N--CONH), 7.30, 7.35 (phenyl),
5.05 (1H, H-13), 4.79 (1H, H-1"), 4.46 (1H, H-1'), 4.04 (1H, H-3), 3.46
(1H, H-5), 3.28 (1H, H-9a), 3.23 (3H, 3"-OCH.sub.3), 3.16 (1H, H-9b), 2.34
[6H, 3'-N(CH.sub.3).sub.2 ], 2.16 (1H, H-8), 1.58 (1H, H-7a), 1.15 (1H,
H-7b), 1.25 (3H, 10-CH.sub.3), 0.90 (3H, 8-CH.sub.3).
.sup.13 C NMR (75 MHz, DMSO).delta. 175.6 (C-1), 156.1 (9a-NCONH), 102.0
(C-1'), 95.4 (C-1"), 84.4 (C-5), 78.5 (C-3), 48.9 (3"-OCH.sub.3), 44.6
(C-2), 39.4 (C-4), 40.1 [3'-N(CH.sub.3).sub.2 ], 27.3 (C-8), 20.0
(8-CH.sub.3), 14.0 (10-CH.sub.3), 140.6, 127.9 and 114.4 (phenyl).
EXAMPLE 6
9-deoxo-9a-N-(N'-benzyl-carbamoyl)-9a-aza-9a-homoerythromycin A
Analogously to the process disclosed in Example 1, from
9-deoxo-9a-aza-9a-homoerythromycin A (7.27 g; 0.01 mole), benzylisocyanate
(1.33 g, 0.01 mole) and toluene (15 ml) a resinous residue (8.4 g) was
obtained, wherefrom by chromatography on a silica gel column using a
solvent system CHCl.sub.3 --CH.sub.3 OH (7:3),
9-deoxo-9a-N-(N'-benzyl-carbamoyl)-9a-aza-9a-homoerythromycin A (6.5 g,
75.6%) having the following physico-chemical constants was obtained:
m.p. 142.degree.-144.degree. C.
TLC, EtAc-(n-C.sub.6 H.sub.6)-NHEt.sub.2 (100:100:20), Rf 0.355.
CHCl.sub.3 --CH.sub.3 OH-conc. NH4OH (6:1:0.1), Rf 0.621.
IR (KBr) cm.sup.-1 1730, 1630, 1525, 1410, 1380, 1270, 1165, 1045, 950,
895, 755, 700.
.sup.1 H NMR (300 MHz, CDCl.sub.3).delta. 7.30, 5.00, 4.40 (--CH.sub.2
--C.sub.6 H.sub.5), 5.04 (1H, H-13), 4.83 (1H, H-1"), 4.48 (1H, H-1'),
4.00 (1H, H-3), 3.52 (1H, H-5), 3.48 (1H, H-9a), 3.28 (3H, 3"-OCH.sub.3),
2.51 (1H, H-9b), 2.56 [6H, 3'-N(CH.sub.3).sub.2 ], 2.34 (1H, H-8), 1.66
(1H, H-7a), 1.10 (1H, H-7b), 0.99 (3H, 10-CH.sub.3), 1.36 (3H,
8-CH.sub.3). .sup.13 C NMR (75 MHz, CDCl.sub.3).delta. 175.7 (C-1), 159.3
(9a-NCONH), 103.8 (C-1'), 96.5 (C-1"), 88.8 (C-5), 78.8 (C-3), 48.9
(3"-OCH.sub.3), 45.9 (C-2), 40.4 (C-4), 40.2 [3'-N(CH.sub.3).sub.2 ], 27.3
(C-8), 20.5 (8-CH.sub.3), 12.3 (10-CH.sub.3), 139.1, 128.3, 127.2 and
126.8, 45.9 (--CH.sub.2 --C.sub.6 H.sub.5).
EXAMPLE 7
9-deoxo-9a-N-(N'-benzyl-thiocarbamoyl)-9a-aza-9a-homoerythromycin A
Analogously to the process disclosed in Example 1, from
9-deoxo-9a-aza-9a-homoerythromycin A (7.27 g; 0.01 mole),
benzylisothiocyanate (1.50 g, 0.01 mole) and toluene (30 ml) under
stirring of the reaction mixture for 8 hours at the temperature of
30.degree. C., a resinous residue (8.6 g) was isolated, wherefrom by
chromatography on a silica gel column using the solvent system CHCl.sub.3
--CH.sub.3 OH (7:3),
9-deoxo-9a-N-(N'-benzyl-thiocarbamoyl)-9a-aza-9a-homoerythromycin A (7.2
g; 82.1%) having the following physico-chemical constants was obtained:
m.p. 119.degree.-122.degree. C.
TLC, EtAc-(n-C.sub.6 H.sub.6)-NHEt.sub.2 (100:100:20), Rf 0.370.
CHCl.sub.3 --CH.sub.3 OH-conc. NH.sub.4 OH (6:1:0.1), Rf 0.689.
IR (KBr) cm.sup.-1 1730, 1630, 1525, 1410, 1380, 1270, 1165, 1045, 950,
895, 755, 700.
.sup.1 H NMR (300 MHz, CDCl.sub.3).delta. 7.36, 4.85, 4.72 (--CH.sub.2
--C.sub.6 H.sub.5), 4.75 (1H, H-13), 4.87 (1H, H-1"), 4.4 (1H, H-1'), 4.10
(1H, H-3), 3.81 (1H, H-11), 3.49 (1H, H-5), 3.30 (3H, 3"-OCH.sub.3), 3.03
(1H, H-4"), 2.34 [6H, 3'-N(CH.sub.3).sub.2 ], 2.31 (1H, H-8), 1.52 (1H,
H-7a), 1.26 (1H, H-7b), 1.31 (3H, 10-CH.sub.3), 0.96 (3H, 8-CH.sub.3).
EXAMPLE 8
9-deoxo-9a-N-[N'-(1-naphthyl)-carbamoyl]-9a-aza-9a-homoerythromycin A
Analogously to the process disclosed in Example 1, from
9-deoxo-9a-aza-9a-homoerythromycin A (7.27 g; 0.01 mole),
1-naphthylisocyanate (1.7 g, 0.01 mole) and toluene (40 ml) by stirring
the reaction mixture for 1 hour at the temperature of 20.degree. C. a
resinous residue (9.0 g) was isolated, wherefrom by chromatography on a
silica gel column using the solvent system CHCl.sub.3 --CH.sub.3 OH-conc.
NH.sub.4 OH (6:1:0.1)
9-deoxo-9a-N-[N'-(1-naphthyl)-carbamoyl]-9a-aza-9a-homoerythromycin A (7.8
g; 86.6%) having the following physico-chemical constants was obtained:
m.p. 134.degree.-137.degree. C.
TLC, EtAc-(n-C.sub.6 H.sub.6)-NHEt.sub.2 (100:100:20), Rf 0.335.
CHCl.sub.3 --CH.sub.3 OH-conc. NH4OH (6:1:0.1), Rf 0.658.
IR (CHCl.sub.3) cm.sup.-1 1740, 1635, 1530, 1500, 1455, 1380, 1340, 1265,
1160, 1050, 1010, 960, 890, 795, 775, 735; 700.
* * * * *
|
|
 |
|
 |
Description |
|
