EP0000656B1 - 4"-ureido-oleandomycin derivatives, process for their preparation and their use in pharmaceutical compositions - Google Patents

4"-ureido-oleandomycin derivatives, process for their preparation and their use in pharmaceutical compositions Download PDF

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Publication number
EP0000656B1
EP0000656B1 EP78300186A EP78300186A EP0000656B1 EP 0000656 B1 EP0000656 B1 EP 0000656B1 EP 78300186 A EP78300186 A EP 78300186A EP 78300186 A EP78300186 A EP 78300186A EP 0000656 B1 EP0000656 B1 EP 0000656B1
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EP
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Prior art keywords
deoxy
acetyl
oleandomycyl
urea
formula
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Application number
EP78300186A
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German (de)
English (en)
French (fr)
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EP0000656A1 (en
Inventor
Gene Michael Bright
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Pfizer Corp SRL
Pfizer Inc
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Pfizer Corp SRL
Pfizer Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • This invention relates to novel antibacterial agents and, in particular, to a series of 11-0-alkanoyl-4"-deoxy-4"-ureido-oleandomycins and their pharmaceutically acceptable acid addition salts.
  • the invention also relates to key intermediates leading to the 4"-ureido compounds and to other 4"-amino derived antibacterial agents.
  • Oleandomycin its production in fermentation broths and its use as an antibacterial agent were first described in U.S. Patent 2,757,123.
  • the naturally occurring compound is known to have the following structure: The conventionally accepted numbering scheme and stereochemical representation for oleandomycin and similar compounds is shown at a variety of positions.
  • Preferred antibacterials related to the compounds of formula 1 are those wherein R is acetyl.
  • Especially preferred species within this group are N-(11-O-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(p-methoxybenzyl)urea, N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(p-chlorobenzyl)urea; N-(11-0- acetyl-4"-deoxy-4"-oleandomycyl)-N'-(o-chlorobenzyl)urea, N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N' -(m-methylbenzyl)urea, N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(m-tolyl)urea and N-
  • Preferred antibacterials related to the compounds of formula 2 are those wherein R is acetyl.
  • Especially preferred species within this group are N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(m-methylbenzoyl)urea and N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(p-methoxybenzoyl)urea.
  • Preferred within the compounds of formula 3 are those wherein R is acetyl. Especially preferred as an intermediate is 11-0-acetyl-4"-deoxy-4"-isocyanato-oleandomycin.
  • reaction-inert solvent a reaction-inert solvent
  • solvents should appreciably solubilize the reactants while not reacting to any significant extent with either the starting reagents or the products formed.
  • aprotic, polar solvents which are immiscible with water.
  • methylene chloride and chloroform are especially preferred.
  • one mole of the isocyanate is contacted with up to four moles of the requisite amine.
  • one to two moles of the amine can be employed in conjunction with the balance of the four moles being a tertiary amine, such as triethylamine or pyridine.
  • Reaction time is not critical and is dependent on reaction temperature, concentration and inherent reactivity of the starting reagents.
  • concentration concentration of the starting reagents.
  • the reaction on completion, is worked-up by the addition of additional solvent and water.
  • the water layer is made strongly basic with an aqueous sodium hydroxide solution and the water immiscible organic phase separated, dried and evaporated to dryness.
  • the crude product can, if desired, be further purified by chromatographing on silica gel, a procedure well known in the art.
  • An alternative method according to the invention for synthesising compounds related to 1 comprises the reaction of the appropriate 11-0-alkanoyl-4"-deoxy-4"-amino-oleandomycin with the requisite isocyanate as illustrated:
  • This alternative method for preparing compounds related to 1 is conducted in a similar manner to the initial route.
  • the reactants are contacted in the same type of reaction-inert solvents at ice-bath temperature. It is convenient, in employing this alternative method, to allow the reaction temperature to warm to room temperature after the reactants have initially been brought into contact with one another. The reaction at ambient temperatures is complete in 30-60 minutes.
  • the ratio of 4"-amino-oleandomycin to isocyanate is about one to one with as much as a 10-20% excess of the isocyanate.
  • the antibacterial agents of formula 2 are prepared according to the invention through the reaction of the appropriate 11-0-alkanoyl-4" -deoxy-4" -amino-oleandomycin and benzoyl isocyanate as illustrated: wherein R and X are as previously defined.
  • reaction is conducted in a reaction-inert solvent similar to that employed in the routes leading to compounds of formula 1.
  • one mole of the 4"-amino compound is contacted with one mole of phosgene plus as much as a 10-20% excess in the presence of three to four moles of a hydrogen chloride scavenger such as pyridine or triethylamine.
  • a hydrogen chloride scavenger such as pyridine or triethylamine.
  • the reaction is best carried out under anhydrous conditions in a chlorinated hydrocarbon solvent such as methylene chloride or chloroform.
  • the product is isolated by removal of the solvent and excess acid scavenger, followed by redissolution in fresh solvent, washing with water to remove scavenger amine hydrochloride and removing the solvent in vacuo. No further purification of the intermediate is necessary.
  • reaction is substantially complete in 10-20 minutes.
  • the starting 4"-amino compounds used in the synthesis of antibacterial agents of the present invention are synthesized by oxidation of the natural oleandomycin followed by a reductive amination of the resultant ketone as hereinafter described.
  • the isocyanates employed in the processes for preparing compounds of formulae 1 and 2 are either commercially available or are synthesized according to the procedures as taught by Speziale et al., J. Org. Chem., 30, 4306 (1965) and Wagner and Zook, "Synthetic Organic Chemistry", John Wiley and Sons, New York, N.Y., 1956, p. 640.
  • the chemotherapeutic activity of those compounds of the present invention which form salts it is preferred, of course, to use pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts water- insolubility, high toxicity, or lack of crystalline nature may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the water insoluble or toxic salts can be converted to the corresponding pharmaceutically acceptable bases by decomposition of the salt as described above, or alternatively they can be converted to any desired pharmaceutically acceptable acid addition salt.
  • acids which provide pharmaceutically acceptable anions are hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, sulphurous, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, gluconic and aspartic acids.
  • novel 4"-deoxy-4"-amino-oleandomycin derivatives described herein exhibit in vitro activity against a variety of Grampositive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes and against certain Gram-negative microorganisms such as those of spherical or ellipsoidal shape (cocci).
  • Grampositive microorganisms such as Staphylococcus aureus and Streptococcus pyogenes
  • certain Gram-negative microorganisms such as those of spherical or ellipsoidal shape (cocci).
  • Their activity is readily demonstrated by in vitro tests against various microorganisms in a brain-heart infusion medium by the usual two-fold serial dilution technique.
  • Their in vitro activity renders them useful for topical application in the form of ointments, creams and the like; for sterilisation purposes, e.g. sick-room utensils; and
  • a pharmaceutically-acceptable carrier such as vegetable or mineral oil or an emollient cream.
  • a pharmaceutically-acceptable carrier such as vegetable or mineral oil or an emollient cream.
  • they may be dissolved or dispersed in liquid carriers or solvent, such as water, alcohol, glycols or mixtures thereof or other pharmaceutically-acceptable inert media; that is, media which have no harmful effect on the active ingredient.
  • concentrations of active ingredients of from 0.01 percent to 10 percent by weight based on total composition.
  • mice are active versus Gram-positive microorganisms via the oral and/or parenteral routes of administration in animals, including man.
  • Their in vivo activity is more limited as regards susceptible organisms and is determined by the usual procedure which comprises infecting mice of substantially uniform weight with the test organism and subsequently treating them orally or subcutaneously with the test compound.
  • the mice e.g. 10 are given an intraperitoneal inoculation of suitably diluted cultures containing approximately 1 to 10 times the LD 100 (the lowest concentration of organisms required to produce 100% deaths).
  • Control tests are simultaneously run in which mice receive inoculum of lower dilutions as a check on possible variation in virulence of the test organism.
  • the test compound is administered 0.5 hour post-inoculation, and is repeated 4, 24 and 48 hours later. Surviving mice are held for four days after the last treatment and the number of survivors is noted.
  • these novel compounds When used in vivo, these novel compounds can be administered orally or parenterally, e.g., by subcutaneous or intramuscular injection at a dosage of from 5 mg./kg. to 200 mg./kg. of body weight per day.
  • the favoured dosage range is from 25 mg./kg. to 100 mg./kg. of body weight per day and the preferred range from 50 mg./kg. to 75 mg./kg. of body weight per day.
  • Vehicles suitable for parenteral injection may be either aqueous such as water, isotonic saline, isotonic dextrose, Ringers' solution, or non-aqueous such as fatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame), dimethylsulfoxide and other non-aqueous vehicles which will not interfere with therapeutic efficiency of the preparation and are non-toxic in the volume of proportion used (glycol, propylene glycol, sorbitol). Additionally, compositions suitable for extemporaneous preparation of solutions prior to administration may advantageously be made.
  • aqueous such as water, isotonic saline, isotonic dextrose, Ringers' solution
  • non-aqueous such as fatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame), dimethylsulfoxide and other non-aqueous vehicles which will not interfere with therapeutic efficiency of the preparation and are non-toxic in the volume of proportion used (glycol, propylene glycol, sorb
  • compositions may include liquid diluents, for example, propylene glycol, diethyl carbonate, glycerol, sorbitol, etc.; buffering agents, hyaluronidase, local anaesthetics and inorganic salts to afford desirable pharmacological properties.
  • liquid diluents for example, propylene glycol, diethyl carbonate, glycerol, sorbitol, etc.
  • buffering agents hyaluronidase, local anaesthetics and inorganic salts to afford desirable pharmacological properties.
  • hyaluronidase hyaluronidase
  • local anaesthetics and inorganic salts to afford desirable pharmacological properties.
  • inert carriers including solid diluents, aqueous vehicles, non-toxic organic solvents in the form of capsules, tablets, lozenges, troches, dry mixes, suspensions, solutions elixirs and parenter
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula 1 or 2 or 3 wherein R 2 is -NHCN; or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • a cold (0°C) solution of 3.0g. (4.11 mmoles) of 11-0-acetyl-4" -deoxy-4" -amino-oleandomycin and .99 ml. of pyridine in 60 ml. of dry methylene chloride is rapidly stirred while 10.98 mi. of a .41M solution of phosgene in chloroform is added rapidly. After 5 min. 1.8 ml. of benzylamine is added and the stirring continued in the cold for an additional 15 min.
  • the reaction is diluted with 150 ml. of methylene chloride, layered with 150 ml. of water and the pH of the aqueous layer adjusted to 9.5 with aqueous 6N sodium hydroxide solution.
  • a .3M solution of phosgene in chloroform (10 mi.) is added rapidly with stirring to a solution of 2.0 g. (2.7 mmoles) of 11-0-acetyl-4"-deoxy-4"-amino-oleandomycin and .65 mi. of pyridine in 50 ml. of dry methylene chloride cooled to 0°C in an ice bath. The solvent is removed under reduced pressure, and the residual yellow foam dissolved in 50 mi. of dry methylene chloride. The solution is cooled with an ice bath and treated with 1.08 ml. of o-chlorobenzylamine.
  • reaction solution is washed with water (2 x 100 ml.), the pH being adjusted to 9.5 with 6N aqueous sodium hydroxide solution during the final washing.
  • the methylene chloride layer is separated, dried over sodium sulphate and concentrated in vacuo to give 3.3 g. of the desired product as a yellow foam.
  • the product is further purified by chromatographing on a 3.25 x 38 cm., silica gel-acetone packed column, using acetone as the eluate. Fractions 201-300, comprising 5 ml. each, are combined and concentrated to dryness to give 1.9 g. of the pure product.
  • the product is further purified by chromatographing on silica gel using acetone as the elutent. Fractions, which are comprised of 5 ml. each, 221-395 are combined and concentrated in vacuo to dryness to give 1.4 g. of the product.
  • Example 9 The procedure of Example 9 is repeated, starting with the requisite reagents, to give the following compounds:
  • reaction mixture is concentrated under reduced pressure, and the residual yellow foam dissolved in 50 ml. of dry methylene chloride.
  • the solution is cooled in an ice bath and is then treated with 2.5 mi. of triethylamine followed immediately by 1.8 g. of o-aminobenzylamine dihydrochloride.
  • the reaction is quenched with water (75 ml.) and the pH of the aqueous wash adjusted to 9.5 with 1N aqueous sodium hydroxide solution.
  • the organic phase is separated, dried over sodium sulphate and concentrated in vacuo to dryness to give 3.0 g. of the product as a yellow foam.
  • Example 11 The procedure of Example 11 is employed, starting with the appropriate reagents, to give the following compounds:
  • the reaction mixture is concentrated in vacuo to a foam, which is dissolved in 50 ml. of methylene chloride.
  • the solution is subsequently cooled to ice bath temperatures and treated with .93 ml. of 4-aminomethylpryidine.
  • After one hour of stirring in the cold the reaction mixture is treated with 100 ml. of methylene chloride and 75 ml. of water.
  • the water is separated and fresh water mixed with the methylene chloride.
  • the pH of the aqueous layer is adjusted to 9.5 with 6N aqueous sodium hydroxide solution.
  • the organic phase is separated, dried over sodium sulphate and concentrated to dryness to give 2.3 g. of the product as a yellow foam.
  • N-(11-O-propionyl-4"-deoxy-4"-oleandomycyl)-N'-(2-furylmethyl)-urea and N-(11-0-acetyl-4"-deoxy-4"-oleandomycyl)-N'-(3-furylmethyl)urea starting from, respectively, 11-0-propionyl-4"-deoxy-4"-amino-oleandomycin and 2-furylmethylamine, and 11-0- acetyl-4"-deoxy-4'iamino-oleandomycin and 3-furylmethylamine.
  • Example 13 The procedure of Example 13 is repeated, starting with the requisite reagents to give the following compounds:
  • the sample is further purified by chromatographing over silica gel using acetone eluate. Combined fractions (5 ml. each) 115-770 are concentrated in vacuo to give 800 mg. of pure product.
  • a reaction mixture comprising 25 g. (3.4 mmoles) of 11-0-acetyl-4"-deoxy-4"-amino-oleandomycin and .41 ml. (3.8 mmoles) of phenylisocyanate in 25 ml. of dry methylene chloride at 0°C . is stirred for one hour and warmed to room temperature.
  • the reaction mixture is treated with 100 ml. of methylene chloride and 100 ml. of water.
  • the pH of the water layer is adjusted to 9.9 with 1N aqueous sodium hydroxide and the methylene chloride layer separated, dried over sodium sulphate and concentrated in vacuo to dryness.
  • the residual product is further purified by chromatographing on silica gel, the fraction 5 ml. each, being monitored by thin layer chromatography (CHCI 3 /CH 3 0H/NH 4 0H 9:1:0.1 by volume). Fractions 115-155 are combined and stripped under reduced pressure to give 716 mg. of the product as a white foam.
  • Example 19 The procedure of Example 19 is again repeated, starting with the requisite reagents, to provide the following compounds:
  • the residual yellow foam is chromatographed over silica gel using acetone as the eluate.
  • the fractions which are comprised of 5 ml. each, are monitored with thin layer chromatography. Those fractions containing the pure product are combined and concentrated to give 440 mg. of the product as a colourless amorphous solid.
  • reaction mixture is stirred at 0°C for 15 min., and is subsequently poured into 500 ml. of water.
  • the pH is adjusted to 9.5 with 1N aqueous sodium hydroxide and the organic layer separated, washed with water and a brine solution and dried over sodium sulphate. Removal of the solvent in vacuo gives 4.9 g. of the desired product as a foam.
  • the aqueous layer after a further extraction with 500 ml. of chloroform, is treated with 500 mi. of ethyl acetate and the pH adjusted to 9.5 with 1N sodium hydroxide.
  • the ethyl acetate layer is separated and the aqueous layer extracted again with ethyl acetate.
  • the ethyl acetate extracts are combined, dried over sodium sulphate and concentrated to a yellow foam (18.6 g.), which on crystallisation from diisopropyl ether, provides 6.85 g. of the purified product, m.p. 157.5-160 0 C.
  • the other epimer which exists in the crude foam to the extent of 20-25% is obtained by gradual concentration and filtration of the mother liquors.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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EP78300186A 1977-07-25 1978-07-24 4"-ureido-oleandomycin derivatives, process for their preparation and their use in pharmaceutical compositions Expired EP0000656B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US05/818,907 US4098993A (en) 1977-07-25 1977-07-25 Semi-synthetic 4-ureido-oleandomycin derivatives
US818907 1977-07-25

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EP0000656A1 EP0000656A1 (en) 1979-02-07
EP0000656B1 true EP0000656B1 (en) 1981-02-11

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US (1) US4098993A (enrdf_load_stackoverflow)
EP (1) EP0000656B1 (enrdf_load_stackoverflow)
JP (3) JPS5463094A (enrdf_load_stackoverflow)
DE (1) DE2860469D1 (enrdf_load_stackoverflow)
DK (1) DK329078A (enrdf_load_stackoverflow)
IE (1) IE47714B1 (enrdf_load_stackoverflow)
IT (1) IT1097329B (enrdf_load_stackoverflow)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4133950A (en) * 1978-01-03 1979-01-09 Pfizer Inc. 4"-Deoxy-4"-carbamate and dithiocarbamate derivatives of oleandomycin and its esters
US4124755A (en) * 1978-01-03 1978-11-07 Pfizer Inc. 11-Alkanoyl-4"-deoxy-4"-isonitrilo-oleandomycin derivatives
US4166901A (en) * 1978-01-03 1979-09-04 Pfizer Inc. 4"-Deoxy-4"-arylglyoxamido- and aroylthioformamido derivatives of oleandomycin and its esters
US4427663A (en) 1982-03-16 1984-01-24 Merck & Co., Inc. 4"-Keto-and 4"-amino-4"-deoxy avermectin compounds and substituted amino derivatives thereof
JPH0384727U (enrdf_load_stackoverflow) * 1989-12-15 1991-08-28
JPH07115113B2 (ja) * 1991-03-04 1995-12-13 三菱製鋼株式会社 有機質粘結材系鋳物砂に含有される酸化鉄の再利用方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3022219A (en) * 1958-03-07 1962-02-20 Pfizer & Co C Acyl esters of oleandomycin
US4069379A (en) * 1976-07-08 1978-01-17 Pfizer Inc. Semi-synthetic oleandomycins
US4036853A (en) * 1976-08-06 1977-07-19 Pfizer Inc. Semi-synthetic oleandomycin derivatives-C8 modifications

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DE2860469D1 (en) 1981-03-26
IT7826036A0 (it) 1978-07-24
JPS564560B2 (enrdf_load_stackoverflow) 1981-01-30
IE781467L (en) 1979-01-25
US4098993A (en) 1978-07-04
JPS5463095A (en) 1979-05-21
JPS5463094A (en) 1979-05-21
EP0000656A1 (en) 1979-02-07
JPS5715120B2 (enrdf_load_stackoverflow) 1982-03-29
IE47714B1 (en) 1984-05-30
IT1097329B (it) 1985-08-31
DK329078A (da) 1979-01-26
JPS5424887A (en) 1979-02-24
JPS5628919B2 (enrdf_load_stackoverflow) 1981-07-04

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