前苏联专利SU1616517A3 Method of producing derivatives of aminomethyloxooxazolidinylaroyl benzene

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专利摘要:
Aminomethyl oxooxazolidinyl aroylbenzene derivatives, such as l -N-[3-[4-(2,4-difluorobenzoyl)phenyl]-2-oxooxazolidin-5-ylmethyl]aceta mide, possess useful antibacterial activity.
公开号:SU1616517A3
申请号:SU884356643
申请日:1988-10-14
公开日:1990-12-23
发明作者:Эделмэн Грегори Уолтер；Смиф Кэзар Ш Холлис
申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new chemical compounds, namely, derivatives of aminomethyl-oxooxazolidinyliloylbenzene in the form of 1-isomers, which have an antibacterial effect and can be used in medicine.
The aim of the invention is to provide a method for producing new aminomethyl oxooxazolidinyloylbenzene derivatives having increased activity against certain strains of microorganisms.
Example 1. Preparation of (1) -Y-Hz-4- (4-fluoro-benzoyl) phenyl -2-oxoxoxazalidin-5-yl-methyl acetamide.
To a solution of 7.45 g (43 mmol) of methanesulfonic anhydride, 14 mp of methanesulfonic acid and 2.0 g (9 mmol). 1) -H- (3-phenyl-2-oxooxazolidin-5-ylmethyl) acetamide, 4.8 g (34 mmol) of 4-fluorobenzoic acid are added.
CM
The mixture was stirred overnight at 50-60 ° C, the mixture was allowed to stand to room temperature, after which it was drunk on 120 ml of a mixture of ice and water. The resulting mixture was extracted with a mixture of chloroform and 2-propanap. The organic extract is washed with a saturated solution of sodium bicarbonate and saturated brine WG is dried with sodium sulfate. The solvent is then removed under vacuum, and the residue is purified by HPLC, followed by crystallization from ethyl acetate. 2.2 g (73%) of the title compound are obtained, with an I-temperature of 8), 5-1 70, 5 ° C.
The data of IR analysis (KBG), cm: 1752, 1652, 1600.
NMR analysis (dg-DKSO), o: 8.29 (m, 1H), 7.78 (m, 6H), 7.40 (m, 2H), 4.79 (m, 1H), 4, 20 (dd J 9.9 Hz, 1H), 3.83 (dd, J 6.5, 9.1 Hz, 1H), 3.45 (m, 2H), 1.83 (s, ZN).
Calculated,%: C 64.04; H 4.81; F 5.33; N 7.86.
Found,%: C 64,12; H 4.82; F 5.37; N /, 90.
-31 ° (C, 0.1, acetone). Examples 2-9. According to the method described in Example 1, (ar, yphenyl) -2-oxooxazolidin-5-Tsu1-methyl acetamides are obtained (tab, 1).
Example 10 Preparation of (1) -N- {(4-fluorophenyl) - (oxy) methyl Pheny 2-oxooxazolidin-5-yl-methyl acetamide.
To a solution of 1.50 g (4.2 mmol of (l) -N-f3-G4- (4-fluorobenzoyl) phenyl -2-oxoxoxazolidin-5-yl-methyl ace gamide in 30 nl of tetrahydrofuran was added 1.05 ml ( 2 M and THF, 2.1 mmol) lithium borohydride. The mixture is stirred at room temperature overnight, after which it is drastically saturated with water and 1 N. Hydrochloric acid. The solution is diluted with 1N hydrochloric acid and The mixture is extracted with a mixture of chloroform and 2-propanol. The organic extract is washed with a saturated solution of sodium bicarbonate and saturated brine, after which it is extracted; it is dissolved in sodium sulfate. solvent was removed in vacuo and the residue was purified resolved by flash chromatography. A 0.52 g (34%) tse1tevogo product of melting point 73-76 C.
Data IR-en, chisa (KBG),: 1745, 1655.

0
five
0
five
0
S
0
five
0
five
NMR analysis (d-DMSQ), 8.24 (m, 1H), 7.41 (m, 6H), 7.10 (m, 2I), 5.93 (d, J 4 Hz. 1H), 5.70 (d, J 4 Hz, 1H), 4.69 (m, 1H), 4.06 (m, 1H), 3.71 (m, 1H), 3.39 (m, 1H), 1 , 83 (s, ZN).
Mass spectrum: m / z 358, 1335 (tb, calculated for C ,, 5, q 358, 1329; -12 ° (C - 1.0, ethanol).
Examples 11-12. According to the method described in Example 10, L- (phenylhydroxymethyl) phenyl-2-oxo-oxacholidin-5-yl-netil1-petamides are obtained (Table 2). Bact ep1- (residues obtained according to the method described can be introduced by any standard methods of contacting the onset of action with the month, the effect of exposure in the field of medicine.They can be introduced by any known methods suitable for use with other pharmaceutical preparations, either as a single therapeutic agent or in combination of therapeutic agents.or may be administered alone, but are generally administered with a pharmaceutical carriers selected in accordance with the kind of administration chosen and accepted pharmaceutical practice.
The dose administered depends on such well-known iJiaKTopoH as f; The pharmacological characteristics of the particular agents, the method and type of administration, the age, state of health and weight of the patient, the nature and extent of the symptom, the type of concurrent treatment, the frequency of treatment and the target E11) effect. Typically, the daily dose of the active ingredient may be g, 5-20 mg / kg body weight. In the case of more potent compounds, the daily dose is usually 5-15, preferably 5-7.5 mg / kg, and it is taken 2-4 times a day or in the pide of a drug with a prolonged dose (division. Preparations can also be administered parenterally .
A deliberate therapeutic level in the human body should be provided by oral administration of a dose of 5–20 mg / kg body weight, taken 2–4 times a day. In case of acute, i.e. If you give birth to life infections, the dosage will be appropriately controlled.
51
Pose forms (compositions) suitable for internal use contain 1.0 mg to 500 mg of the active ingredient per preparation. In these pharmaceutical compositions, the active ingredient is usually in the amount of 0.5-95 PPC.%, Calculated on the total weight of the total body weight.
The active ingredient may be administered orally in solid dosage forms, for example in the form of capsules, tablets or powders, or in the form of liquid dosage forms, for example elixirs, syrups and suspensions. It can also be administered parenterally in sterile liquid dosage forms.
Gelatin capsules contain the active ingredient and powdered carriers, for example lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. The same diluents can be used to make tablets. Both tablets and capsules can be made in the form of preparations that ensure the long-term holding of the drug for several hours. Tablets may be coated with sugar or a film that masks the unpleasant taste and protects the tablet from exposure to the atmosphere or provides selective decomposition of the tablet in the gastrointestinal tract.
Liquid preparations for oral administration may contain opacifying and apomatisation opa e substances for ease of use by the patient.
Suitable carriers for parenteral solutions are generally water, suitable oil, physiological saline solution, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and (if necessary) buffering agents. Suitable stabilizers are antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid, or mixtures of these compounds. Citric acid and its salts and the sodium salt of ethylenediaminetetrauxus5176 are also used.
Noah acid. In addition, parenteral solutions may contain prophylactic agents, for example, benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
Useful pharmaceutical preparations for administering the compounds of the invention are illustrated as follows.
0 way.
Capsules A large number of cap-. Sul is prepared by filling in standard two-part hard gelatin capsules, 75 mg of powdered different active ingredient, 150 mg of lactose, 24 mg of talc and 6 mg of magnesium stearate.
Soft gelatin capsules. Prepare the active ingredient mixture in
20 soybean oil and inject it with a volumetric pump into a gelatin to form soft gelatin capsules containing 1x 75 mg of the active ingredient. The capsules are washed and dried.
Pills. A large number of tablets are prepared according to standard methods so that one tablet contains 75 mg of the active ingredient, 0.2 mg
30 colloidal silicon dioxide, 5 mg
magnesium stearate, 250 mg of microcrystalline cellulose, 11 mg of corn starch and 98.8 mg of lactose. Appropriate coatings may be used to improve palatability or delay absorption.
Injection solutions. A composition suitable for parenteral administration by injection is prepared by stirring 1.5% by weight of the active ingredient with water and 10% by volume of propylene glycol. The resulting solution is converted to an isotonic state with sodium chloride and it is sterilized.
d5 Suspensions. An aqueous suspension for oral administration is prepared so that each 5 ml contains 75 mg of finely dispersed active ingredient, 200 mg of sodium carboxymethylcellulose lulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 ml of vanillin.
The new compounds are biologically active against gram-like bacteria and harmful bacteria, including the nrrai MOB Staphylococci and Streptococci, which are multi-resistant against antibiotics. New compounds may be useful in treating
35
bacterial infections in humans and animals, including diseases of the respiratory, gastrointestinal and urogenital systems, blood, interstitial fluids and soft tissues.
Microdilution of bacteria in broth to determine the minimum bacteriostatic concentration (MBC) is given in Table 3.
As follows from Table 3, the compounds obtained by the proposed method have a bacteriostatic effect in vitro. The determination of the daily minimum bacteriostatic concentration (MBC) of the new compounds in the tested strains of Staphylococcus aureus and Escherichia coli is carried out according to the standard method of microdilution using Mypler-Hinton broth.
The effect of the tested compounds in vivo is illustrated by the data given in table 4.
It was determined by intraperitoneal administration to mice of cultures of an infecting microorganism diluted in order to achieve 100% mortality in control animals during the day. The culture of S. aureus, which was used to infect animals, was diluted to the desired density using a 5% solution of porcine stomach powder. Connect. ©
NIN was dissolved or weighed in a 25% aqueous solution of Metosel (Metosel Hydroxypropylmethylcellulose, E15 Premium, Dow Kem Cal Company) for oral administration or sterile distilled water containing 5% DMSO (Fisher Scientific Company, Feirlon, New Jersey) for subcutaneous administration. New compounds were introduced 1 and 4 hours after infection. Mortality was recorded daily until the end of the test 7 days after infection. To determine the effective dose of EDO, which protects 50% of the mice, we used the number of mice of each experimental group, which 7 days after infection turned out to be still alive.
Comparison of the results of the study of antibacterial activity shows that the effective doses of the compounds obtained according to the invention are surfactants (naturally lower).

compared with 3- (substituted phenyl) -5-acylamidomethyl oxazolidines, which are the closest analogues in structure and type of biological activity.

权利要求:
Claims (1)
[1]
The results of determining the activity of compounds in vivo against Staphylococcus aureus on a model of acute lethal infection in mice are listed in Table 4. I Formula of invention
The method of obtaining aminomethipoxooxazolidinyl derivatives of the formula
R, .RZ
about
SNG NSSOZhz
in the form of 1-isomers, where R is a hydrogen atom and R is a hydroxy group or R R together is OXYGEN;
R is C-C-alkyl;
X and Y are both hydrogen atoms and Z is nitrogen,
or ChiU independently of each other - a hydrogen atom, or a halogen atom, or C, -C.-alkoxy or a nitro group Z is a SI group,
characterized in that the compound of formula
CH -NHCR. II
OV in the form of a 1-isomer, where R has the indicated value, is reacted with a carboxylic acid of the formula
soon
where X, Y and Z have the indicated meanings,
in the presence of methanesulphonic acid and methanesulphonic anhydride 1slots and the target product is agglomerated, where K and R are oxygen, or in the case of non-Table 1
ABOUT
SNoKSSN.
table 2
about
CHoNHCCH.
II Oh
eleven
1616517
Table3
one
2 3 5 6 7 8 9 11
four
four
four
eight
one
32
one
eight
32
128 128 128 128 128 128 128 128
Editor A. Motl
Compiled by Y. Manaev Tehred L. Oliynyk
Order 3998
Circulation 322
VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5
Table4
1 2 3 5 6 7 8 9 11
40 47 41 42 30
p-120 90 90 65
20 60 15 25 26
120 90 59 52
Proofreader A. Obruchar
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法律状态:

优先权:

申请号 | 申请日 | 专利标题

US10903287A| true| 1987-10-16|1987-10-16|

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