Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
  • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• This invention concerns novel 2-azetidinone compounds having antimicrobial activity.
• R 20 is a Z-oximino-acyl moiety of the formula II wherein R 40 is as defined above, R 41 is t-butyl, diphenylmethyl or benzyl, R 50 is t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz) or triphenylmethyl (trityl), and R 60 is a moiety of the formula III; and compounds of the formula A-6 wherein n is 1 or 2, R 14 is -C(-O)H or t-butyloxycarbonyl (BOC) , R 21 is a Z-oximino-acyl moiety of the formula II wherein R 40 is as defined above, R 41 is tbutyl, diphenylmethyl or benzyl, R 50 is t-butyloxycarbonyl (BOC), benz
• R 31 is -(C 1 -C 8 )alkyl or -(CH 2 ) 2 X wherein X is -NH- (t-butyloxycarbonyl) [- NHBOC], -N(CH 3 )- (t-butyloxycarbonyl) [-N(CH 3 )BOC] , -OC(-O)NH 2, -Cl, -O- CH 3 or -NHC(-O)H, and R 60 is a moiety of the formula III;
• R 20 is Z-oximinoacyl a moiety of the formula II wherein R 40 is defined as above, R 41 is t-butyl, diphenylmethyl or benzyl, R 50 is t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz) or triphenylmethyl (trityl), R 30 is -(C 1 -C 8 )- alkyl or -(CH 2 ) 2 X wherein X is -NH-(t-butyloxycarbonyl) [ -NHBOC], -N-
• the carbon atom content of various hydrocarbon-containing moieties as indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety i.e., the prefix (C i -C j ) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
• (C 1 -C 3 ) alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl.
• alkyl of one to eight carbon atoms, inclusive are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl and isomeric forms thereof.
• the oximino compounds of this invention are in the Z-isomer form.
• pharmaceutically acceptable salts includes those compounds created by salt formation with the sulfonylaminocarbonyl group at the N-1 position as well as those formed with the amino, amide or carboxyl moieties of substituents on positions C-3 and C-4. These include salts with acids, and with alkali methal bases. Internal salts, zwitterionic compounds are also part of this invention. Such salts are made by known methods. Acid salts are formed by reacting the compounds described herein with the appropriate acid in a suitable solvent.
• Suitable acids for this purpose include hydrochloric, sulfuric, phosphoric, hydrobromic, hydroiodic, acetic, lactic, citric, succinic, benzoic, salicylic, pamoic, cyclohexansulfamic, methanesulfonic, naphthalenesulfonic, ptoluenesulfonic, maleic, fumaric, oxalic and the like.
• Metal salts are formed by suspending the compounds in water or other suitable solvent and adding a dilute metal base such as sodium or potassium bicarbonate until the pH is between 6 and 7.
• Metal salts include sodium and potassium salts. It will be recognized by those skilled in the art that carbon atoms C 3 and C 4 of the 4-membered ring of compounds of formula I of this invention are asymmetrically substituted and can independently possess the R or S-configuration. There are thus 4 stereoisomers which comprise two pairs of enantiomers; each enantiomeric pair is termed a racemate.
• the compounds of the formula I of this invention and their respective pharmaceutically acceptable salts have valuable antibiotic activity against a variety of gram-negative bacteria including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa.
• the compounds are useful for treating bacterial infections in animals, including and most preferably humans.
• MIC minimum inhibitory concentration
• the various bacteria used for testing are grown overnight on MHA at 35°C and transferred to Tryptiease Soy Broth (TSB) until a turbidity of 0.5 McFarland standard is obtained.
• the bacteria are diluted one to twenty in TSB and inoculated on the plates (1 ⁇ l using a Steers replicator). The plates are incubated at 35oC for 20 hours and the MIC is read to be the lowest concentration of drug that completely inhibits visible growth of the bacterium.
• the MIC test results of a compound of this invention (Compound A) is given in Table I.
• trialkylsilyl for example, trimethylsilyl ((CH 3 ) 3 Si-) or tertiary butyldimethylsilyl ((CH 3 ) 3 Si(CH 3 ) 2 -) and the like,
• benzyloxycarbonyl (Cbz) trifluoroalkanoyl, e.g., trifluoroacetyl, trifluoropropionyl, and
• the Cbz and BOC protecting groups can be used in this way, the Cbz group being removable in the presence of the BOC group and vice versa.
• Chart A the starting compound cis-( ⁇ ) -4-(methoxycarbonyl)-3- [[(benzyloxy)carbonyl]amino]-2-azetidinone (A-1) is known. J. Org.Chem., 47:2765-2767 (1982).
• the trans compound A-1 is known or is made by known methods. Thus compound A-1 is either cis or trans with respect to the substituents on C-3 and C-4.
• alkoxycarbonyls of from 1-5 carbon atoms, inclusive or aralkoxycarbonyls of from 5-14 carbon atoms, inclusive, either unsubstituted or substituted by 1-4 groups of halogen, nitro, or (C 1 -C 4 ) alkyl could be used in place of the benzyloxycarbonyl group of compound A-l. See also, W. F. Huffman et al., J. Am. Chem. Soc, 99:2352 (1977); D. B. Bryan et al., J. Am. Chem. Soc, 99:2353 (1977).
• the C-4-carbomethoxy group of compound (A-1) is reduced to the C- 4-hydroxymethyl group of compound (A-2) by use of metal hydride reducing reagents, such as sodium borohydride or zinc borohydride, in ether solvents, such as diethyl ether or tetrahydrofuran, at a temperature range of 0° to 80°C.
• metal hydride reducing reagents such as sodium borohydride or zinc borohydride
• ether solvents such as diethyl ether or tetrahydrofuran
• the sequence A-2 ⁇ A-7 of Chart A is used to produce the C-4- glycinoyloxymethyl-substituted compounds (A-7) of the present invention.
• the benzyloxycarbonyl group of compound (A-2) is removed catalytic hydrogenolysis using palladium metal supported on carbon or palladium metal itself under a hydrogen gas atmosphere in various kinds of organic solvents, such as alcoholic solvents, ether solvents or ethyl acetate solvent, at ambient temperature.
• the compound (A-3) is obtained by filtration of the solid catalyst followed by concentration under reduced pressure.
• the C-3-amino group of compound (A-3) is acylated with a suitably protected known acid, R 21 -OH wherein R 21 is a Z-oximino-acyl moiety of formula II wherein R 40 is defined as above, R41 is t-butyl, diphenylmethyl or benzyl, and R 50 is BOC, Cbz or trityl, to produce compound (A-4).
• R 21 is a Z-oximino-acyl moiety of formula II wherein R 40 is defined as above, R41 is t-butyl, diphenylmethyl or benzyl, and R 50 is BOC, Cbz or trityl
• This conversion may be carried out by any of a number of amide or peptide forming reaction sequences such as described in Methoden der Organischem Chemie, Vieri Auflage, Band XV/2, E. Wunch ed., Georg Thieme Verlag, Stuttgart, p.l.
• a preferred acylation process is the use of approximately equimolar quantities of a desired acid, 1-hydroxy- 1-benzotriazole (HOBT), and a carbodiimide, such as dicyclohexylcarbodiimide (DCC).
• HOBT 1-hydroxy- 1-benzotriazole
• DCC dicyclohexylcarbodiimide
• the choice of solvents is methylene dichloride, dimethylformamide or a combination of both solvents and the reaction is carried out in general at the temperature range of 0oC to ambient temperature.
• the desired compound (A-4) is obtained after filtration of precipitated dicyclohexylurea and removal of HOBT by treating with aqueous sodium bicarbonate solution and then column chromatography on silica gel.
• the compound (A-4) can be made by methods known in the art, i.e., J. Am. Chem. Soc, 95:2401-2404 (1973).
• the hydroxymethyl group of compound (A-4) is reacted with HOC(-O)- CH 2 NHR 14 wherein R 14 is -C(-O)H or BOC to produce compound A-5 using the DCC/HOBT method in the presence of a catalytic amount of 4-dimethylamino-pyridine in solvents, such as methylene dichloride, dimethylformamide or a combination of both solvents, at a temperature range of 0°C to ambient temperature.
• solvents such as methylene dichloride, dimethylformamide or a combination of both solvents
• the compound (A-5) is treated with approximately 1.2 to 1.6 equivalents of chlorosulfonyl isocyanate at -20° to 0oC in organic solvents, such as methylene dichloride, acetonitrile or a combination of both solvents to produce compounds (A-6) with n-1 and 2, which are used directly in the next step.
• organic solvents such as methylene dichloride, acetonitrile or a combination of both solvents.
• organic solvents such as methylene dichloride, acetonitrile or a combination of both solvents
• the imidazolidinone of Formula IV is silylated by reaction with N- methyl-N-(trimethylsilyl)-trifluoroacetamide or bis-(trimethylsilyl)- trifluoroacetamide in organic solvents, such as acetonitrile, methylene dichloride or tetrahydrofuran, at ambient temperature.
• organic solvents such as acetonitrile, methylene dichloride or tetrahydrofuran
• the crude product is obtained after a normal aqueous work-up procedure and then deprotected by treatment with trifluoroacetic acid (or deprotected otherwise as appropriate) followed by purification, e.g., by column chromatography on Diaion HP-20 resin (Mitsubishi Chemical Co.) or XAD- resin (Rohm and Haas Co.) to produce the final N-1-sulfonyl-aminocarbonyl activated compound (A-7).
• the sequence A-2 ⁇ A-7' of Chart A is used to produce the C-4 R 30 - oxycarbonyloxymethyl-substituted compounds (A-7') of the present invention.
• the reaction conditions involve the use of an inert solvent such as methylene dichloride, tetrahydrofuran, or dimethylformamide at -20oC to 30oC in the presence of a slight excess of organic base, such as pyridine, 2,4-lutidine, or triethylamine.
• organic base such as pyridine, 2,4-lutidine, or triethylamine.
• Ashburm et al. J. Am. Chem. Soc, 60, 2933 (1938). Briefly, the process described in these references is to contact an alcohol with an excess of phosgene either neat or in an organic solvent. After workup, the product is usually isolated by vacuum distillation.
• Compound (A-2) is placed in a solvent such as methylene dichloride, ethyl acetate, tetrahydrofuran, or acetonitrile containing a slight excess of an organic base, such as pyridine, triethylamine, or 2,4-lutidine, and is reacted at -20oC to 30oC with a solution of phosgene in an inert solvent, such as toluene, benzene or methylene dichloride.
• a solvent such as methylene dichloride, ethyl acetate, tetrahydrofuran, or acetonitrile containing a slight excess of an organic base, such as pyridine, triethylamine, or 2,4-lutidine
• R 31 OH suitably protected desired alcohol
• the compound (A-3') is treated with chlorosulfonyl isocyanate at -15° to 25°C in organic solvents, such as methylene dichloride, acetonitrile or a combination of both solvents to produce compound (A-4') which is used in the next step without purification.
• organic solvents such as methylene dichloride, acetonitrile or a combination of both solvents.
• the imidazolidinone of Formula IV is silylated by reaction with N-methylN-(trimethylsilyl)-trifluoroacetamide or bis-(trimethylsilyl)-trifluoroacetamide in organic solvents, such as ethyl acetate, acetonitrile, methylene dichloride or tetra-hydrofuran, at ambient temperature.
• This silylated imidazolidinone is reacted with compound (A-4') at 0oC, and the mixture is slowly warmed to room temperature over a period of 1 to 5 hours.
• the crude product is purified by conventional methods to produce the N-1-sulfonylaminocarbonyl activated compound (A- 5').
• the benzyloxycarbonyl group of compound (A-5') is removed by catalytic hydrogenolysis using palladium metal supported on carbon or palladium metal itself under a hydrogen gas atmosphere in various kinds of organic solvents, such as dimethylformamide, alcoholic solvents, ether solvents or ethyl acetate solvent, at ambient temperature.
• the compound (A-6') is obtained by filtration of the solid catalyst followed by concentration under reduced pressure.
• the C-3-amino group of compound (A-6') is acylated with a suitably protected known acid R 21 -0H, wherein R 21 is as defined above, followed by deprotection as appropriate to produce compound (A-7'). This conversion may be carried out by any of a number of amide or peptide forming reaction sequences as described above for the conversion of compound A-3 to A-4.
• Optically active compounds of the formula I of this invention are prepared by the use in the processes of Chart A of the appropriate optically active form of compound (A-1), which is prepared by known methods.
• the resolving agents are any of the known resolving agents such as optically active camphorsulfonic acid, bis-o-toluoyltartaric acid, tartaric acid, and diacetyl tartaric acid which are commercially available and which are commonly used for resolution of amines (bases), as for example in Organic Synthesis, Coll. Vol. V., p. 932 (1978), resolution of R- (+) and S-(-)- ⁇ -phenylethylamine with (-) -tartaric acid.
• the preferred starting compound for making optically active compounds of Formula I cis-( ⁇ )-1-[(2',4'-dimethoxyphenyl)methyl]- 4-(methoxycarbonyl)-3-phenylmethoxycarboxyamino-2-azetidinone, is known. Chem. Pharm. Bull., 32:2646-2659 (1984). The C-3 protecting group is removed by hydrogenolysis to produce the corresponding free amine. An appropriate substituted tartaric acid enantiomer is then added such as (+)-di-p-toluoyl-D-tartaric acid and reaction conditions altered to facilitate precipitation of the appropriate azetidinone diastereomeric salt. The tartaric acid is removed by treating the compound with inorganic base such as aqueous sodium bicarbonate to produce the desired resolved C-3-amino-azetidinone.
• the compounds of this invention are administered to human and other animal subj ects by parenteral (including intravenous and intramuscular) and rectal routes.
• unit dosage form refers to physically discrete units suitable as unitary dosages for human subj ects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired pharmaceutical effect in association with the required pharmaceutical diluent, carrier or vehicle.
• the specifications for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for use in humans and animals.
• suitable unit dosage forms in accord with this invention are ampoules, vials, suppositories, segregated multiples of any of the foregoing, and other forms as herein described.
• fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred.
• the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
• the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
• adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the. liquid prior to use.
• Parenteral suspensions can be prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
• the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• a rectal suppository can be employed to deliver the active compound.
• This dosage form is of particular interest where the mammal cannot be treated conveniently by means of other dosage forms, as in the case of young children or debilitated persons.
• the active compound can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycols (carbowaxes), polyethylene sorbitan monostearate , and mixtures of these with other compatible materials to modify the melting point or dissolution rate. These rectal suppositories can weigh from about 1 to 2.5 gm.
• the dosage of the compound of this invention for treatment depends on many factors that are well known to those skilled in the art. They include for example, the route of administration and the potency of the particular compound.
• a dosage schedule for humans having an average weight of 70 kilograms is from about 50 to about 3,000 mg of compound in a single dose, administered from 1 to 4 times per day parenterally in the compositions of this invention.
• Equivalent dosages are employed for other routes of administration. More specifically, the preferred single dose is from about 100 mg to 2,000 mg of compound.
• the rectal dose is from about 100 mg to about 4,000 mg in a single dose.
• TLC One spot, slower than starting material, is observed on TLC (cyclohexane-acetone, 1:1).
• N-Methyl-N-(trimethylsilyl)trifluoroacetamide (1.35 ml) is added to a stirred suspension of 476 mg 1-(5-hydroxy-4-pyridone-2-yl)carbonylamino-2-imidazolidinone in 20 ml of ethyl acetate. Solution is complete in about 50 min.
• To this solution is added the title product (C-3) of Preparation 6 (prepared from 2 mmol of the title product (C-2) of Preparation 5 and dissolved in 5 ml of ethyl acetate).
• 0.4 ml of triethylamine is added, followed by water (10 ml) with good shaking. The aqueous layer is separated and acidified. The solids which precipitated are collected by filtration and dried. 805 mg of the title product (C-4) is obtained. Physical characteristics are as follows:
• Example 1 cis-( ⁇ )-3-[2-(2-Amino-4-thiazolyl)-2-(1-carboxymethoxy)- imino] acetamido-4-N-formylglycinoyloxymethyl-1-[(5-hydroxy-4-pyridone-2-yl)carbonylamino-1-(2-imidazolidinone-3-yl)sulfonylaminocarbonylazetidine-2-one (B-7: n-1, R 40 -1-carboxymethyl, R 4 -C(-O)H).
• R 40 1-t-butoxycarbonylmethyl, R 4 -C(-O)H).
• the N-potassium salt of the title product (C-4) of Preparation 7 (310 mg) is dissolved in 1 0 ml of dimethylformamide and 150 mg of palladium black is added. The mixture is stirred under an atmosphere of hydrogen for 2 hours. The catalyst is removed by filtration to give a solution of the title product (C-5) of Preparation 8 in dimethylformamide.
• a portion of crude product (500 mg) is dissolved in 15 ml of acetonitrile and 15 ml of water. This solution is passed through a column of 110 ml of HP-20 resin. The column is eluted with 300 ml of water and then with water-acetonitrile solutions containing an increasing percentage of acetonitrile. The fraction eluted with almost 100% acetonitrile is evaporated to yield 101 mg of residue.
• This material is dissolved in 1 ml of methylene dichloride and 0.5 ml of trifluoroacetic acid added. After 40 min this solution is added to 40 ml of 1:1 Skellysolve B-ether. The precipitate is collected by filtration and dried.
• Compound A is cis-( ⁇ )-3-[2-(2-Amino-4-thiazolyl)-(Z)-2-(carboxymethoxyimino)acetamido]-1-[(5-hydroxy-4-pyridon-2-yl)carbonylamino-1- (2-imidazolidone-3-yl)sulfonylaminocarbonyl]-4-[(methoxycarbonyl)- oxymethyl]-2-azetidinone, dipotassium salt.
• Compound B is 2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1- sulfo-3-azetidinyl)amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, also known as aztreonam.
• Novel 2-azetidinone compounds as shown in formula (I), which are useful as antibacterial agents to eradicat control susceptible microbes. These compounds have a (5-hydroxy-4-pyridone-2-yl)carbonylamino-l-(2-imidazolidon yl)sulfonylaminocarbonyl group at the N-1 position, and a carbonate-type substituent or an amino acid derivative at C-4 position via an ester linkage. Intermediates and processes for making these compounds are also disclosed.

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• 1987
  • 1987-05-08 EP EP87903769A patent/EP0308416A1/de not_active Withdrawn
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  • 1987-05-08 WO PCT/US1987/001047 patent/WO1987007273A2/en not_active Application Discontinuation
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• 1988
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