GB1573931A - Azetidionones and process for preparation thereof - Google Patents

Azetidionones and process for preparation thereof Download PDF

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Publication number
GB1573931A
GB1573931A GB5271476A GB5271476A GB1573931A GB 1573931 A GB1573931 A GB 1573931A GB 5271476 A GB5271476 A GB 5271476A GB 5271476 A GB5271476 A GB 5271476A GB 1573931 A GB1573931 A GB 1573931A
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carboxypropoxy
phenyl
amino
tert
butoxycarbonylamino
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Fujisawa Pharmaceutical Co Ltd
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Fujisawa Pharmaceutical Co Ltd
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Priority claimed from JP49077091A external-priority patent/JPS51125061A/en
Priority claimed from JP49085526A external-priority patent/JPS51125062A/en
Priority claimed from JP49088452A external-priority patent/JPS51125064A/en
Priority claimed from JP50002650A external-priority patent/JPS5175056A/en
Priority claimed from JP15851175A external-priority patent/JPS5283451A/en
Priority claimed from JP51000190A external-priority patent/JPS6042237B2/en
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of GB1573931A publication Critical patent/GB1573931A/en
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    • 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
    • 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
    • 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
    • C07D205/09—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 sulfur atom directly attached in position 4
    • C07D205/095—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 sulfur atom directly attached in position 4 and with a nitrogen atom directly attached in position 3

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

(54) AZETIDINONES AND PROCESS POR PREPARATION THEREOF (71) We, FUJISAWA PHARMACEUTICAL CO. LTD., a Japanese Company of 3, Doshomachi, 4-chome, Higashiku, Osaka, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- Our British Patent Specification No. 1,519,495 describes and claims: A compound of the formula:
or its salt wherein R, is amino or acylamino, A is hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon residue, which is substituted by at least one substituent of carboxy or its derivatives, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy, or its derivatives, cyano, hydroxy and amino, or an aliphatic hydrocarbon residue which is substituted by carboxy or its derivatives at the first position thereof and by phenyl at the first position thereof whose ring may be substituted by one or more substituents selected from hydroxy, amino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen and sulfo; provided that when R1 is 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] 2 - hydroxyiminoacetamido, A is hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon residue, which is substituted by at least one substituent of carboxy or its derivatives, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivatives, cyano, hydroxy and amino, or an aliphatic-hydrocarbon residue which is substituted by carboxy or its derivatives at the first position thereof and by phenyl at the first position thereof whose ring may be subs;ituted by one or more substituents selected from hydroxy other than 4-hydroxy, amino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen and sulfo, when R, is 2-(2-nitrophenoxy)acetamido or 2-(2-nitrophenoxy)-2 methyipropionamido, A is a saturated or unsaturated normal aliphatic hydrocarbon residue which is substituted by at least one substituent of carboxy or its derivatives, cyano, hydroxy and amino, an unsaturated branched aliphatic hydrocarbon residue, which is substituted by at least one substituent of carboxy or its derivatives, cyano, hydroxy and amino, or an aliphatic hydrocarbon residue which is substituted by carboxy or its derivatives at the first carbon thereof and by phenyl at the first carbon thereof, whose ring may be substituted by one or more substituents selected from hydroxy, amino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen and sulfo, and when R1 is phenylacetamido, A is hydrogen, a saturated or unsaturated normal aliphatic hydrocarbon residue, which is substituted by at least one substituent of carboxy or its derivatives, cyano, hydroxy and amino, or an aliphatic hydrocarbon residue which is substituted by carboxy or its derivatives at the first position thereof and by phenyl at the first position thereof, whose ring may be substituted by one or more substituents selected from hydroxy, amino, nitro, alkyl, alkoxy, aralkoxy, alkylthio, halogen and sulfo, when A is hydrogen, R, is not formamide, benzyloxycarbonylamino or phthalimido.
This invention relates to new azetidinones which are modifications of the compounds disclosed in the aforementioned parent application and which have antimicrobial activities.
More particularly, this invention provides new azetidinones, especially ones which are characterized by having an acyloxy function in the substituent of the 1st position of the azetidinone nucleus and characterized by having a-(N-substituted or unsubstituted imino)acylamino group at the 3rd position thereof, which have antimicrobial activities against various pathogenic microorganisms and are useful as antibiotics for treatment of microbial infections in mammal including human beings and animals.
With regard to the states of the arts in this field, the following compounds are known to the public in the literatures.
(U.S.P. 3,487,072)
(Journal of Organic Chemistry, Vol. 38, p. 940-943, 1973)
(U.S.P. 3,487,072) (Tetrahedron, Vol. 23, p. 4769, 1967) (Tetrahedron, Vol 23, p. 4769, 1967) (Tetrahedron, Vol. 23, p.4769, 1967) (molecular modification in DRUG DESIGN, page 22-23, 1964, published by the American Chemical Society)
HOOC- C H (cn2) 20 C-CO N H (German Offenlegungsschrift 2242699) NH2 N-OH CHw9OH Coox 0 SCH3 f 0/CH3 (Tetrahedron Letters, No. 9, O c; \ COOCH3 CH3 It is one object of this invention to provide new azetidinones which have antimicrobial activity.
This invention provides a compound of the formula:
wherein R' is amino or acylamino, and R2 is hydrogen, or a group of the formula:
in which R4' is phenyl substituted by acyloxy, R5 is carboxy or its ester, R6' is alkyl bearing carboxy or its ester and R7 is substituted or unsubstituted aryl, provided that 1) when R'2 is hydrogen, then R1 is amino; 2) when R2' is a group of the formula:
then R' is phenylglyoxyloylamino, 2-(2-furyl)glycoloylamino, bromopyruvoylamino, 2-(2-thienyl)-2-(2-azidoacetamino)acetamido, 2-benzyloxyimino-2-(4-methoxyphenyl)acetamido, 2 - benzoyloxyimino - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - methoxy- carbonylpropoxy)phenyl] acetamido, 2 - - (2,2,2 - trichloroethoxycarbonylaminomethyl)phenoxy]acetamido, 2 - [2 - {N - (2,2,2 - trichloroethoxycarbonyl) - 2 - (carboxymethoxy)benzyl aminomethyl}phenoxy]acetamido, 2 - benzyloxyimino - 2 - phenylacetamido, 4 - 3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl glyoxyloylamino, crotoylamino, 2 - methoxyimino - 2 - [2 - (2,2,2 - trifluoroacetamido) - 4 - thiazolyl]acet- amido, 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy) - 3 - chloro phenylglyoxyloylamino, 4- (3 - methoxycarbonylpropoxy)phenylglyoxyloylamino, 3 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl glyoxyloylamino, 3 - (3 - phthalimidopropoxy)phenylglyoxyloylamino, N - [N - (2 - nitrophenyl)oxamoyl] - 2 - phenylglycinamido, 2 - [2 - 12 - (4 - chloro - 2 - nitrophenoxy)acetamidomethyllphenoxy]acet- amido, 2 - [2 - (2 - bromoacetamidomethyl)phenoxy]acetamido, N-(N-benzyloxamoyl)amino.
2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (5 - chlorosalicyloyl amino)acetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (3 - phenylureido)acet amido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - oxo - 1 - imid- azolidinylcarboxamido)acetamido, 3 - (3 amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 2 - [4 (3 - amino - 3 - carboxypropoxy) - 3 - chlorophenyl] - 2 - hydroxyimino acetamido, 4 - (3 - amino - 3 - carboxypropoxy) - 3 - chlorophenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroazonoacetamido, 2 - [4 - 13 - carboxy - 3 - (2 - phenylglycinamido)propoxy}phenyl] - 2 - hydroxy- iminoacetamido, 2 - [4 - (3 - carboxy - 3 - glycinamidopropoxy)phenyl] - 2 - hydroxyimino- acetamido, 2 - (2 - aminoethoxyimino) - 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl]- acetamido, 2 - [2 - (2 - carboxymethoxybenzylaminomethyl)phenoxy]acetamido, 2 - (2 - aminomethylphenoxy)acetamido, 2 - methoxyimino - 2 - (2 - amino - 4 - thiazolyl)acetamido, 4 - (3 - aminopropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyli - 2 - (carboxymethoxyimino)acetamido, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino, 3 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino, 4 - (3 - carboxypropoxy)phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy) - 3 - chlorophenylglyoxyloylamino, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 (5 - chlorosalicyloylamino)acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - (2oxo - I - imidazolidinecarboxamido)acetamido, 2 - benzamido - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl]acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - (3 phenylureido)acetamido, 2 - (2 - aminoacetamido) - 2 - (2 - thienyl)acetamido, N - [N - (2 - hydroxyethyl)oxamoyl]amino, (2 - amino - 2 - carboxyethylthio)pyruvoyl, 2 - (4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - phenylacetamido)acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl]glycinamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy) - 3 - chlorophenyl] - 2 - hydroxyiminoacetamido, 2 - [3 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - 4 - (3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - methoxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - ethoxycarbonylethoxyimino)acetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - benzyloxyiminoacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydrazonoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - semicarbazonoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - thiosemicarbazonoacetamido, 2 - [4 - 13 - (2 - chloroacetamido) - 3 - carboxypropoxylphenyll - 2 - hydroxy- iminoacetamido, 2 - [4 - 13 - (2 - phthalimidoacetamido) - 3 - carboxypropoxylphenyl] - 2hydroxyiminoacetamido, 2 - [4 - 13 - (3 - amidinoureido) - 3 - carboxypropoxylphenyli - 2 - hydroxy- iminoacetamido, 2 - 4 - {3 - (2 - tert - butoxycarbonylaminoacetamido) - 3 - carboxypropoxyE- phenyl] - 2 - hydroxyiminoacetamido, or 2 - [4 - 13 - (2 - phenyl - 2 - tert - butoxycarbonylaminoacetamido - 3 - carboxy- propoxyiphenyli - 2 - hydroxyiminoacetamido, 3) when R2' is a group of the formula:
then R' is amino, phthalimido, 4 - [3 - tert - butoxycarbonylamino - 3 - (4 - methoxybenzyloxycarbonyl)pro poxy]phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl glyoxyloylamino, 4 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloyl amino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 hydroxyiminoacetamido or 2 - phenyl - 2 - hydroxyiminoacetamido, 4) when R2' is a group of the formula:
then R1 is amino or 4 - [3 - tert - butoxycarbonylamino - 3 - (4 - methoxybenzyloxy carbonyl)propoxy]phenylglyoxyloylamino, 5) when R2' is a group of the formula:
then R1 is 4 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyli - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyli - 2 - hydroxyacetamido, 2 - [4 (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyli - 2 hydroxyacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyli - 2 hydroxyiminoacetamido or 2 - [4 - (3 - carboxy - 3 - tert - butoxycarbonylaminopropoxy)phenyl] - 2 hydroxyiminoacetamido, 6) when R2' is a group of the formula:
then R' is 2 - (2 - thienyl) - 2 - (2,2,2 - trichloroethoxycarbonylamino)acetamido or 2 - (2 - thienyl) - 2 - [2 - (4 - chloro - 2 - nitrophenoxy)acetamido]acetamido, 7) when R2' is a group of the formula:
then R1 is phthalimido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido or 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydroxyiminoacetamido, 8) when R2' is a group of the formula:
then R1 is benzyloxycarbonylamino, phthalimido or 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl glyoxyloylamino, and 9) when R2' is a group of the formula:
in which R4' and R5 are each as defined above, then R' is acylamino of the formula:
in which Rf is phenyl substituted by alkoxy having at least one functional group selected from amino, protected amino, carboxy and protected carboxy, and Ro and Rh are each hydrogen, or combined together to form oxo, hydroxy imino or acyloxyimino.
With regard to the compounds (I), it is to be understood that there may be one or more stereoisomeric pair(s) such as optical and/or geometric isomers being due to the asymmetric carbon atom(s) and/or double bond(s) in that molecule, and such isomers are also included within the scope of the compounds (I).
Reaction Schemes of the Processes for the Preparation of the Object Compounds According to this invention, the object compounds (I) can be prepared by the processes according to the following reaction schemes: (1) Process 1:
H2N Ra Acylation (II) AcylPion R2a (Il) (III) wherein R' is acylamino, and R2 is defined as R2' above other than hydrogen.
(2) Process 2:
emotiaI minx, c . o hydroxy and/or 7 carboy ~Ns 2 carbon protective; group in Rb (IV) (V) wherein R' is acylamino of which acyl moiety bears at least one functional group selected from protected amino, protected hydroxy and protected carboxy, R' is acylamino of which acyl moiety bears at least one functional group selected from amino, hydroxy and carboxy, and R2b is a group of the formula: -CHR5-R or -CR5=C(CH3)2 in which Rb4 is phenyl which may be substituted by at least one substituent selected from hydroxy, phenylmethoxy and acyloxy, and R5 is as defined above.
(3) Process 3:
H2N RA cleavage or H2N N a mido linkage aN (VI) (VIr) (VI) (VII) wherein R' is phthalimido or aralkoxycarbonylamino, and R2C is hydrogen or a group of the formula -CHR5-C6H5 or -CR5=C(CH3)2 where R5 is as defined above.
(4) Process 4:
Ra CONY R8 Ra r!o 8 Reiu (IX) Rc OC R8 BedvcLion N R8 (VIII) CH < 5 Redectlon "t"" a Ra wherein R1 is alkoxy having at least one substituent selected from amino, protected amino, carboxy and protected carboxy, Rb is oxo or hydroxyimino, Rc is hydroxy or amino.
R5 is p-hydroxy or p-phenylmethoxy, and Ra5 is defined as R5.
(5) Process 5:
Rd-CoCaNH R3 Re-NH RdCCONH R3 ReNH2 or its II N salt N 0 R2j e ON\R2J wherein Rd is substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, R@ is hydroxy, amino, substituted or unsubstituted alkoxy, substituted or unsubstituted aralkoxy, ureido or thioureido, Rd2 is a group of the formula: -CHR5-Rc4 or -CR5=C(CH3)2 in which Rc4 is phenyl having at least one substituent selected from hydroxy and phenylmethoxy, and R5 is as defined above, and R3 is hydrogen.
(6) Process 6:
Rf-;CCONH\ R!3 \Rh OOH 0 fH < b Rb eOR9 (XII) R5a R9OH or its R5 reactlve derlvative a (XIII) wherein R' is phenyl substituted by alkoxy having at least one functional group selected from amino, protected amino, carboxy and protected carboxy, R@ and Rh are each hydrogen, or combined together to form oxo, hydroxyimino or acyloxyimino (e.g. preferably aroyloxyimino, etc.), R9 is acyl (e.g. preferably alkanoyl, aroyl, aralkanoyl, aralkoxycarbonyl, carbamoyl, N-(haloalkanoyl)carbamoyl, etc.), and Ra5 is defined as R5.
(7) Process 7:
R5-CH (CH2)20 C-CONH NH2 > II N 0 O no o OH (XIV) R5a Acylation R5b-CH(CH2)20 eCONNX NHRt II N Iv OH XeH o (XV) RaS wherein R' is acyl selected from haloalkanoyl, N-protected glycyl, N-protected-2 (substituted or unsubstituted aryl)glycyl and N-(amidino)-carbamoyl, Rb5 is carboxy or its derivative, and Ra5 is defined as R5.
(8) Process 8:
wherein R11, Ra, Ra5 and X are each as defined hereinabove.
(9) Process 9:
Re SR 12 Re Desulfvrdting agent P.
(X XIV) (X X V) 0 R2e (XXIV) (XXV) wherein Ra is acylamino (e.g. preferably phthalimido, aralkanoylamino, aryloxyalkanoylamino, etc.), R02 is a group of the formula -CHR5. C8H4R13 or CR5=C(CHs)2 in which R'3 is hydrogen, hydroxy or phenylmethoxy, and R12 is alkyl, benzene-fused heterocyclic-thio or a group of the formula:
in which Ra and Ra are each as defined hereinabove, and Ra6 and R7 are each alkyl.
Detailed Explanation of Various Substituent.
Various groups as defined hereinabove and the suitable examples thereof will be explained in details and be clear in the following descriptions.
(1) Re: Acyl moiety of the acylamino group [R, Ra, Rb and Rc]: The preferred acyl moiety of said acylamino group is illustrated in the following.
(i) phthaloyl,
wherein RA is carboxy, protected carboxy or protected amino, R5 is hydrogen; amino; protected amino; N-protected or unprotected glycinamido; N-protected or unprotected arylglycinamido; alkanoylamino whose alkane moiety may be substituted by at least one suitable substituent such as halogen, etc.; arylureido; amidinoureido; or aralkylamino, RC is hydrogen or halogen, and RD is oxo; hydroxyimino; alkoxyimino whose alkane moiety may be substituted by at least one suitable substituent such as amino, protected amino, carboxy, protected carboxy, etc.: aralkoxyimino; aroyloxyimino; alkanoyloxyimino; semicarbazono; or thiosemicarbazono,
wherein RE is is a 5-membered heterocyclic group containing at least one hetero-atom selected from nitrogen, oxygen, and sulfur atoms, RF is hydrogen: hydroxy: amino; protected amino; alkanoylamino whose alkane moiety may be substituted by at least one suitable substituent such as azido, etc.; or aryloxyalkanoylamino whose aryl moiety may be substituted by at least one suitable substituent such as halogen, nitro, etc.,
wherein RG is carboxy or protected carboxy, RH is amino or protected amino, and R' is hydroxy; amino: aralkanoylamino; aroylamino whose aryl moiety may be substituted by at least one suitable substituent such as hydroxy, halogen, etc.; 5-membered heterocyclecarboxamido which contains at least one hetero atom selected from oxygen, nitrogen and sulfur atoms and may be substituted by at least one suitable substituent such as oxo, etc.; or arylureido, (v) RJ--COCOO- wherein RJ is aryl: haloalkyl: or alkylthioalkyl in which alkyl moiety of the alkylthio radical may be substituted by at least one suitable substituent such as amino, carboxy, etc.; (vi) RKCO wherein RK is aralkoxy; 6-membered heterocyclic group which contains at least one nitrogen atom, and may be substituted by at least one suitable substituent such as oxo group, etc.: N-(hydroxyalkyl)carbamoyl; N-aralkylcarbamoyl; aryloxyalkyl; or a-iminoaralkylaminoalkyl,
wherein RL is hydrogen, hydroxy or alkoxy, and RM is hydroxyimino, alkoxyimino, aralkoxyimino or aroyloxyimino,
wherein RN is amino; protected amino; N-protected or unprotected (carboxyalkoxy)aralkylamino; haloalkanoylamino; or aryloxyalkanoylamino whose aryl moiety may be substituted by at least one suitable substituent such as halogen, nitro, etc.,
wherein RO is 5-membered heterocyclic group which contains at least one hetero atom selected from oxygen, nitrogen and sulfur atoms and may be substituted by at least one suitable substituent such as amino, protected amino, etc., and RP is is oxo, hydroxyimino or alkoxyimino,
wherein RX is hydrogen or N-aryloxamoylamino whose aryl moiety may be substituted by at least one suitable substituent such as nitro, etc.
Each of the radicals as mentioned above is more particularly exemplified for the detailed explanation of the acyl moiety in the following.
(a) As preferred examples of "alkyl" moiety, for example, of alkyl, alkoxy, aralkyl, alkanoyl, etc., there may be exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl and the like; (b) As suitable examples of "aryl" moiety, there may be exemplified by phenyl, tolyl, xylyl, naphthyl and the like; (c) As preferred examples of "aralkyl" moiety, there may be exemplified by benzyl, phenethyl, phenylpropyl, diphenylmethyl, trityl and the like; (d) As preferred examples of "5-membered heterocyclic group which contains at least one hetero-atom selected from oxygen, nitrogen, and sulfur atoms", there may be exemplified by furyl, thienyl, oxazolyl, thiazolyl, oxadiaZolyl, thiadiazolyl, triazolyl, tetrazolyl and the like; (e) As preferred examples of "6-membered heterocyclic group which contains at least one nitrogen atom, and may be substituted by at least one oxo group", there may be exemplified by 1,2,3,4 - tetrahydro - 2,4 - dioxopyrimidinyl and the like; (f) As preferred examples of "amino protective group" in the protected amino group, there may be exemplified by substituted or unsubstituted alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertbutoxycarbonyl, chloromethoxycarbonyl, bromoethoxycarbonyl, tribromoethoxycarbonyl, trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, diphenylmethoxycarbonyl, nitrobenzyloxycarbonyl, bromobenzyloxycarbonyl, methoxybenzyloxycarbonyl, dinitrobenzyloxycarbonyl, etc.), halogenated alkanoyl (e.g. trifluoroacetyl, etc.), substituted or unsubstituted aralkyl (e.g. benzyl, diphenylmethyl, trityl, bromobenzyl, nitrobenzyl, etc.), substituted or unsubstituted arylthio (e.g. phenylthio, nitrophenylthio, dinitrophenylthio, etc.), substituted or unsubstituted alkylidene (e.g. ethylene, isopropylidene, 2-carboxyisopropylidene, etc.) or its tautomeric 1-alkenyl (e.g. 2-methoxycarbonyl-l-methylvinyl, etc.), aralkylidene (e.g. benzylidene, salicylidene, etc.), phthaloyl and the like; g) As preferred examples of "hydroxy protective group" in the protected hydroxy, there may be substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, halogenated alkanoyl, and substituted or unsubstituted aralkyl, whose examples may be the same as exemplified above, and additionally, alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, etc.), substituted or unsubstituted aroyl (e.g. benzoyl, toluoyl, xyloyl, nitrobenzoyl, bromobenzoyl, salicyloyl, etc.), substituted or unsubstituted aroylmethyl (e.g. phenacyl, bromophenacyl, etc.), and the like; h) As preferred examples of "carboxy protective group" in the protected carboxy, there may be exemplified by an ester such as silyl ester, aliphatic ester, esters containing an aromatic or a heterocyclic group, esters with N-hydroxy compound, concrete examples of which are the same as those given in the explanation of the ester as the derivative of carboxy for R5 mentioned hereinafter. i) As preferred examples of "halogen" and "halo" moiety, there may be exemplified by chlorine, bromine, fluorine and the like; j) As preferred examples of "5-membered heterocyclecarboxamido which contains at least one hetero-atom and may be substituted by oxo", there may be exemplified by 2-oxoimidazolidinecarboxamido and the like.
Further preferred specific examples of the acyl moiety are explained hereinafter, respectively. As to the acylamino group [R']: As suitable examples for "acyl moiety" of the acylamino group [R'], there may be illustrated by phenylglyoxyloyl, 2 - (2 - furyl)glycoloyl, bromopyruvoyl, 2 (2 - thienyl) - N - azidoacetylglycyl, 2 - (4 - methoxyphenyl) - 2 - benzyloxyiminoacetyl, 2 - benzoyloxyimino - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 methoxy carbonylpropoxy)phenyl]acetyl, 2 - [2 - (2,2,2 - trichloroethoxycarbonylaminomethyl)phenoxy]acetyl, 2 - [2 - 2 - carboxymethoxy N - (2,2,2 - trichloroethoxy carbonyl)benzylaminomethyljphenoxyiacetyl, 2 - benzyloxyimino - 2 - phenylacetyl, 3- or 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloyl, orotoyl, 2 - methoxyimino - 2 - [2 - (2,2,2 - trifluoroacetamido) 4 - thiazolyl]acetyl, 3 - chloro - 4 - (3 - tert - butoxycarbonylamino - 3 - methoxy- carbonylpropoxy)phenylglyoxyloyl, 4 - (3 - methoxycarbonylpropoxy)phenylglyoxyloyl, 4 - (3 - phthalimidopropoxy)phenylglyoxyloyl, 4 - [3 - tert - butoxycarbonylamino - 3 - (4 - methoxybenzyloxycarbonyl)propoxy]phenylglyoxyloyl, 2 - (2 - thienyl) - N - (2,2,2 - trichloroethoxycarbonyl)glycyl, benzyloxycarbonyl, 2 - phenyl - N - (2 - nitrophenyloxamoyl)glycyl, 2 - [2 - {2 - (4 - chloro - 2 - nitrophenoxy)acetamidomethyllphenoxy]acetyl, 2 - [2 - (2 - bromoacetamidomethyl)phenoxy]acetyl, benzylaminooxamoyl, 2 - (2 - thienyl) - 2 - [2 - (4 - chloro - 2nitrophenoxy)acetamido]acetyl, phthalimido, 2 - phenylacetyl, 2 - acetoxyimino2 - [4 - (3 - acetamido - 3 - methoxycarbonylpropoxy)phenyliacetyl.
As to the acylamino groups [Rb and R']: (i) Re: R' As suitable examples for "acyl moiety which bears at least one functional group selected from amino, hydroxy and carboxy" of the acylamino group [R'], there may be exemplified by 3- or 4 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloyl, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (5 - chlorosalicyloylamino)acetyl, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyli - 2 - (3 - phenylureido)acetyl, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - oxo - 1imidazolidinecarboxamido)acetyl, 2 - [3 - chloro - 4 - (3 - amino - 3 - carboxypro poxy)phenyli - 2 - hydroxyiminoacetyl, 3 - chloro - 4 - amino - 3 - carboxypropoxy)phenylglyoxyloyl, 2 - hydroxy - 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] acetyl, 2 - hydrazono - 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl]acetyl, 2 - hydroxyimino - 2 - [4 - {3 - (2 - phenylglycinamido)propoxy}phenyl]acetyl, 2 - hydroxyimino - 2 - [4 - (3 - glycinamido - 3 - carboxypropoxy)phenyl]acetyl, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - aminoethoxyimino)acetyl, 2 - [2 - (2 - carboxymethoxybenzylaminomethyl)phenoxy]acetyl, 2 - (2 - aminomethylphenoxy)acetyl, 2 - hydroxyimino - 2 - [4 - (3 - carboxy - 3 - aminopropoxy)phenyl]acetyl, 2 - methoxyimino - 2 - (2 - amino -4 - thiazolyl)acetyl, 4 - (3 - amino- propoxy)phenylglyoxyloyl, 2 - hydroxyimino - 2 - [4 - (3 - glycinamido - 3 - car boxypropoxy)phenyliacetyl, 2 - carboxymethoxyimino - 2 - [4 - (3 - carboxy - 3 aminopropoxy)phenyl]acetyl, 3- or 4 - (3 - carboxy - 3 - tert - butoxycarbonylpropoxy)phenylglyoxyloyl, 4 - (3 - carooxypropoxy)phenylglyoxyloyl, 3 - chloro4 - (3 - carboxy - 3 - tert - butoxycarbonylaminoproxy)phenylglyoxyloyl, 2hydroxyimino - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy) phenyliacetyl, 2 - phenyl - 2 - hydroxyiminoacetyl, 2 - (5 - chlorosalicyloylamino)2 - [4 - (3 - carboxy - 3 - tert - butoxycarbonylaminopropoxy)phenyl]acetyl, 2 (2 - oxo - 1 - imidazolidinecarboxamido) - 2 - [4 - (3 - tert - butoxycarbonylamino3 - carboxypropoxy)phenyl]acetyl, 2 - benzamido - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyliacetyl, 2 - (3 - phenylureido) - 2 [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyliacetyl, 2 - (2thienyl) - 2 - (2 - aminoacetamido)acetyl, (2 - hydroxyethyl)oxamoyl, (2 - carboxy2 - aminoethylthio)pyruvoyl, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 (2 - phenylacetamido)acetyl, 2 - hydroxyimino - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyllacetyl, 4 - hydroxy - 2 - hydroxyiminoacetyl.
(ii) Re: Rb As suitable examples for "acyl moiety which bears at least one functional group selected from protected amino, protected hydroxy and protected carboxy" of the acylamino group [Rb], it is to be understood that suitable examples of the acylamino group [Rb] are substantially the same as those given for the acylamino group [R'], provided that at least one functional group of amino, hydroxy and carboxy in [R'] is read as the corresponding protected functional group of protected amino, protected hydroxy and protected carboxy, respectively.
And, preferred example of said acyl moiety may be 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloyl, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - (5 - chlorosalicyloylamino)acetyl, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 (3 - phenylureido)acetyl, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxy- propoxy)phenyl] - 2 - (2 - oxo - 1 - imidazolidinecarboxamide)acetyl, 2 - [3 - chloro4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - hydroxy- iminoacetyl, 3 - chloro - 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypro poxy)phenylglyoxyloyl, 2 - hydroxy - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 carboxypropoxy)phenyllacetyl, 2 - hydrazono - 2 - [4 - (3 - tert - butoxycarbonyl amino - 3 - carboxypropoxy)phenyliacetyl, 2- hydroxyimino - 2- [4 -{3 -(2 - phenyl- N - tert - butoxycarbonylglycinamido)propoxy}phenyl]acetyl, 2 - hydroxyimino2 - [4 - (3 - N - tert - butoxycarbonylglycinamido - 3 - carboxypropoxy)phenyl]acetyl, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - (2 - tert - butoxycarbonylaminoethoxyimino)acetyl, 2 - [2 - 12 (2 - carboxymethoxy) - N - (2,2,2 - trichloroethoxycarbonyl)benzylamino methyllphenoxy]acetyl, 2 - [2 - (2,2,2 - trichloroethoxycarbonylaminomethyl)phenoxy]acetyl, 2 - hydroxyimino - 2 [4 - (3 - carboxy - 3 - tritylaminopropoxy)phenyl]acetyl, 2 - methoxyimino - 2 - [2 - (2,2,2 - trifluoroacetamido) - 4 - thiazolyl]acetyl, 4 - (3 - phthalimidopropoxy)phenylglyoxyloyl, 2 - hydroxyimino - 2 - [4 - (3 - N - phthaloylglycinamido3 - carboxypropoxy)phenyl]acetyl, 2 - ethoxycarbonylmethoxyimino2 - [4 - (3 - carboxy - 3 - aminopropoxy)phenyl]acetyl, 3- or 4 - (3 - methoxycarbonyl - 3 - tert - butoxycarbonylpropoxy)phenylglyoxyloyl, 4 (3 - methoxycarbonylpropoxy)phenylglyoxyloyl, 3 - chloro - 4 - (3methoxycarbonyl - 3 - tert - butoxycarbonylaminopropoxy)phenylgyloxyloyl, 2 - hydroxyimino - 2 - [4 - (3 - tert - butoxycarbonylamino - 3methoxycarbonylpropoxy)phenyl]acetyl, 2 - phenyl - 2 - (2,2 - dichloroacetoxyimino)acetyl, 2 - (5 - chlorosalicyloylamino) - 2 - [4 - (3 - methoxycarbonyl - 3 - tert - butoxycarbonylaminopropoxy)phenyl]acetyl, 2 - (2oxo - 1 - - imidazolidinecarboxamido) - 2 - [4 - (3 - tert - butoxycarbonyl amino - 3 ethoxy - methoxycarbonylpropoxy)phenyl]acetyl, 2 - benzamido- 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy) phenyl]acetyl, 2 - (3 - phenylureido) - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl]acetyl, 2 - (2 - thienyl)2 - [2 - (2,2,2 - trichloroethoxycarbonylamino)acetamido]acetyl, (2acetoxyethyl)oxamoyl, (2 - tert - butoxycarbonylamino - 2 - methoxycarbonylethylthio)pyruvoyl, 2 - [4 - (3 - tert - butoxycarbonylamino - 3methoxycarbonylpropoxy)phenyl] - 2 - (2 - phenylacetamido)acetyl, 2 - (benzoyloxyimino) - 2 - [4 - (3 - tert - butoxycarbonylamino - 3methoxycarbonylpropoxy)phenyl]acetyl, 4-hydroxy - 2 - (2,2 - dichloroacetoxyimino)acetyl.
(2) Re: Amino, hydroxy and carboxy protective groups of protected amino, protected hydroxy and protected carboxy moieties [R'O, R8, R' and R']: It is to be understood that suitable examples of "amino, hydroxy and carboxy protected groups" may be the same as those given for the protective group in the acyl moiety as explained in the above para. (1).
(3) Re: Aralkoxycarbonyl group [R9], and the corresponding moiety of aralkoxycarbonylamino group [R3] and of aralkoxycarbonyloxy group [R4, Run4 and R4l: Suitable examples of "aralkoxycarbonyl moiety" may be benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropoxycarbonyl, diphenylmethoxycarbonyl, and the like.
(4) Re: Aralkanoyl group [R9], and the corresponding moiety of aralkanoylamino group [R' and R'f] and of aralkanoyloxy group [R4, and R,4,]: Suitable examples of said "aralkanoyl moiety" may be phenylacetyl, tolylacetyl, xylylacetyl, naphthylacetyl, biphenylylacetyl, phenylpropionyl, tolylpropionyl, naphthylpropionyl, 2 - methyl - 3 - phenylpropionyl, 2 - methyl - 2 - phenylpropionyl, 2 - methyl - 3 - naphthylpropionyl, phenylbutyryl, naphthylbutyryl, phenylvaleryl, tolylvaleryl, naphthylvaleryl, diphenylacetyl, diphenylpropionyl, and the like.
(5) Re: Substituted or unsubstituted aryl [R3, R7, R7a, Rd, R' and RJ] and the corresponding aryl moiety of substituted or unsubstituted arylthioalkyl [R4 and R4c] and of substituted or unsubstituted arylthio [R7 and Rc]: It is to be understood that suitable examples of "aryl moiety" may be phenyl, tolyl, xylyl, naphthyl and the like, and the preferable substitutents on "substituted aryl moiety" in the groups of R3, R4, R4c, R7, R7a, Rc and Rl may be hydroxy, amino, halogen, carboxy, cyano, nitro and the like, and preferable ones on "substituted aryl moiety" Rd may be alkoxy which may bear at least one functional group selected from amino, protected amino, carboxy, protected carboxy, halogen, alkanoylamino (e.g. formamido, acetamido etc.), hydroxy, protected hydroxy, 3arylureido (e.g. 3-phenylureido, 3-tolylureido, 3-naphthylureido, etc.) and the like.
(6) Re: Substituted or unsubstituted aralkenyl group [R3]: Suitable examples of "aralkenyl group" may be styryl, cinnamyl, tolylvinyl, xylylvinyl, naphthylvinyl, and the like, in which the aryl moiety may be substituted by at least one suitable substituent such as those exemplified in the above para. (5).
(7) Re: Alkoxy moiety [Ra and Rf]: Suitable examples of "alkoxy moiety" may be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy and the like.
(8) Re: Substituted or unsubstituted aralkyl groups [R4, R4C and R"], and aralkyl moiety of substituted or unsubstituted aralkoxy groups [R4, R4', R4b, R4c, Re, R13 and R9l: Suitable examples of "aralkyl group and moiety" may be benzyl, phenethyl, phenylpropoxy, tolylmethyl, xylylmethyl, naphthylmethyl, and the like, which may be optionally substituted by at least one suitable substituent such as hydroxy, protected hydroxy, alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, etc.), aralkoxy (e.g. benzyloxy etc.), amino, protected amino, nitro, carboxy, cyano, halogen (e.g. chlorine, bromine, etc.) and the like, and more preferable substituent on the alkane moiety of said aralkyl group may be alkoxy and one on the arene moiety may be hydroxy or protected hydroxy.
(9) Re: Alkanoyl moiety of alkanoyloxy groups [R4, and Ra4] and alkanoyl group [R9]: Suitable examples of alkanoyl moiety and group may be formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, palmitoyl, and the like.
(10) Re: Aroyl moiety of aroyloxy [R4 and R,4,] and of aroyloxyimino group [combination of Rg and Rh] and said group [R9]: Suitable examples of "aroyl group and moiety" may be benzoyl, toluoyl, xyloyl, naphthoxyl and the like, and accordingly, suitable aroyloxylmlno group may be benzoyloxyimino, toluoyloxyimino, xyloyloxyimino, naphthaloyloxyimino and the like.
(Il) Re: Haloalkanoyl moiety of N-(haloalkanoyl)carbamoyloxy [R4] and haloalkanoyl group [R']: Suitable examples of "haloalkanoyl moiety and group may be chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, trifluoroacetyl, and the like.
(12) Re: Substituted or unsubstituted heterocyclic group [R4, R4c, Rd and Rf] and heterocyclic moiety of substituted or unsubstituted heterocyclic-thioalkyl group IR7 and Rc]: Suitable examples of "heterocyclic group and moiety may be 5- or 6membered heterocyclic group containing at least one hetero-atom selected from nitrogen, oxygen and sulfur atoms, preferably such as thienyl, furyl, pyridyl, pyranyl, imidazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazoyl, tetrazolyl, and the like, which may bear at least one suitable substituent such as alkyl (e.g. methyl, ethyl, propyl, etc.) amino, protected amino, oxo and the like.
(13) Re: Alkyl group [R4, R", Rt, Re, R7, R", Rb, Rc, and R12] and alkyl moiety of substituted or unsubstituted arylthioalkyl (R4 and R4c), of alkyl having carboxy or its derivative (R5) and of substituted or unsubstituted heterocyclicthioalkyl [R7 and Rc7]: Suitable examples of"alkyl group and moiety" may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.
(14) Re: Derivative of carboxy group [R5, R5 and R,5] and derivative of carboxy moiety [R5]: Suitable example of "derivative of the carboxy group and moiety" include amides, esters, pharmaceutically acceptable salt with a base and the like, and suitable examples of which are illustrated as follows.
(a) Amides include unsubstituted amide, N-alkyl amide (e.g. N-methyl amide, N-ethyl amide, etc.), N,N-dialkyl amide (e.g. N,N-dimethyl amide, N,N-diethyi amide, N-ethyl-N-methyl amide, etc.), N-aryl amide (e.g. anilide, etc.), amide with pyrazole, imidazole or 4-alkylimidazole, and the like.
(b) Ester include; silyl esters, aliphatic esters, esters containing an aromatic or a heterocyclic group and esters with a N-hydroxy compound.
The suitable silyl esters include trialkylsilyl (e.g. trimethylsilyl, triethylsilyl, etc.) esters, halo-alkyl-silyl (e.g. chloro-dimethylsilyl, dichloromethylsilyl, etc.) ester, trihalosilyl (e.g. trichlorosilyl, etc.) ester, alkylalkoxysilyl (e.g. methyldiethoxysilyl, etc.) ester, trialkoxysilyl (e.g. tris(2-chloroethoxy silyl, etc.) ester, and the like.
Suitable examples of the aliphatic esters include: alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) esters; cycloalkyl (e.g. cyclopentyl, cyclohexyl, etc.) esters; and the like.
Suitable examples of the esters containing an aromatic ring include, for example, aryl (e.g. phenyl, tolyl, xylyl, etc.) esters; aralkyl (e.g. benzyl, phenethyl, etc.) esters; aryloxyalkyl (e.g. phenoxymethyl, phenoxyethyl, etc.) esters; aroylalkyl (e.g. phenacyl, toluoylethyl, etc.) esters: and the like.
Suitable examples of the esters containing an heterocyclic ring include: heterocyclic esters, heterocyclic-alkyl esters, etc.; in which the suitable heterocyclic ester include saturated or unsaturated, monocyclic or fused, 3 to 10membered heterocyclic group containing 1 to 4 heteroatom(s) such as an oxygen, sulfur and nitrogen atom, (e.g. pyridyl, piperidinyl, 2-pyridon-l-yl, tetrahydropyranyl, quinolyl, pyrazolyl, etc.) esters; and the like, and the suitable heterocyclic-alkyl esters include, for example, aforementioned heterocyclic groupsubstituted-alkyl (e.g. methyl, ethyl, propyl, etc.) esters; and the like.
Suitable examples of the esters with a N-hydroxy compound include esters with N,N-dialkylhydroxylamine (e.g. N,N-dimethylhydroxylamine, N,Ndiethylhydroxylamine, etc.), and the like.
In the silyl esters, the aliphatic esters, the esters containing an aromatic or heterocyclic ring and the esters with a N-hydroxy compound as mentioned above, the moiety of these esters may optionally have one or more appropriate substituent(s) such as alkyl (e.g. methyl, ethyl, etc.), cycloalkyl (e.g. cyclopropyl, cyclohexyl, etc.), alkoxy (e.g. methoxy, ethoxy, etc.), alkanoyloxy (e.g. acetoxy, etc., alkylthio (e.g. methylthio, etc.), halogen (e.g. chlorine, etc.), cyano, nitro, etc.
Examples of such substituted esters may be mono-(di or tri)haloalkyl (e.g. chloromethyl, bromoethyl, dichloromethyl, 2,2,2-trichloroethyl, 2,2,2tribromoethyl, 2,2,2-trifluoroethyl, etc.) esters, cyanoalkyl (e.g. cyanomethyl, cyanoethyl, etc.) esters, cycloalkyl-substituted-alkyl (e.g. l-cyclopropylethyl, etc.) ester, mono(di, tri, tetra or penta)halophenyl (e.g. 4-chlorophenyl, 3,5dibromophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, pentachlorophenyl, etc.) esters, and the like.
(c) Examples of pharmaceutically acceptable salt with a base may be a salt with an inorganic base such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt; magnesium salt, etc.), ammonium salt, with an organic base, such as methylamine salt, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, pyridine salt, ethanolamine salt, diethanolamine salt, N,N-dimethylaniline salt, etc.) salt, and with an amino acid, such as glycine salt, alanine salt, and the like.
(15) Re: Benzene-fused heterocyclic-thio group (R'2): Suitable examples of "benzine-fused heterocyclic-thio group" may be benzothienylthio, benzoxadiazolylthio, benzothiazolylthio, benzoxazolylthio, benzisoxasolylthio, benzotriazolylthio, and the like.
(16) Re: Substituted or unsubstituted alkoxy (era): It is to be understood that suitable "unsubstituted alkoxy" group may be the same as those given for the alkoxy group as explained in the above para. 7), and preferable substituents may be amino, protected amino, carboxy, protected carboxy and the like. Accordingly, preferable "substituted alkoxy" may be 2aminoethoxy, 2-phthalimidoethoxy, 2-tert-butoxycarbonylaminoethoxy, 2carboxyethoxy, 2-methoxycarbonylethoxy, 2-ethoxycarbonylethoxy, and the like.
(17) Re: Acid residue (X): "Acid residue" is intended to mean a residue derived from an acid such as an inorganic acid (e.g., hydrochloric hydrobromic, hydroiodic, sulfuric acid, etc.), an organic acid such as organic sulfonic acid (e.g., methanesulfonic, benzenesulfonic, p-toluenesulfonic acid etc.), an organic carbamic acid (e.g., dimethylcarbamic or diethylcarbamic acid, etc.), and the like.
(18) Re: Alkylene [A]: Suitable alkylene may be methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene and the like.
(19) Re: Acyl group [Ri] and the corresponding acyl moiety of acyloxy group [R4, R4', Ra4 and Rb4] and of acyloxyimino [R and Rh]: The above acyl group and the acyl moiety include alkanoyl, aroyl, aralkanoyl, aralkoxycarbonyl, carbamoyl, N-(haloalkanoyl)carbamoyl and the like, and suitable examples of each of the above groups are as given in the aforementioned paragraph.
(20) Re: -Acyl moiety of acylamino group [Re and Rf]: The above acyl moiety includes the same ones as exemplified in aforementioned para. (1), and additionally includes aralkanoyl, aryloxyalkanoyl and the like.
Suitable examples of the aralkanoyl group and alkanoyl moiety of the aryloxyalkanoyl group are as given for the explanation of R81 and Rrf in aforementioned paragraph.
(21) Re: Aryloxy moiety of aryloxyalkanoyl [R']: Suitable aryloxy moiety of the aryloxyalkanoyl group may be phenoxy, tolyloxy, xylyloxy, naphthoxy, and the like.
Starting Compounds of The Present Invention The starting compounds of this invention include known and in part new compounds. The new starting compounds can be prepared by the following methods or by the similar methods thereto.
(A) For Process 1: Preparation of new carboxylic acids to be used as acylating agent:
(B) For Process 3: Preparation of the starting compound (VI):
FHCOOCH3 HCNO [CH2=N-CH ]3 NH2 COOCH3 0 /N-CH2COC1 D)NcH2COCt 8F3 Et2O and Pyridine t\CH t0 COUCH3 (C) For Process 5: Preparation of the starting compound (X):
(D) For Process 6: Preparation of the starting compound (XII)
(E) For Process 9: Preparation of the starting compound (XXIV):
Detailed Explanation of Processes For Preparation of Azetidinones (1) Process 1: This process relates to a method for preparing 3-acylamino-2-azetidinones (Ill) by reacting 3-amino-2-azetidinones (II) with an acylating agent.
In this reaction, the starting 3-amino-2-azetidinones (II) can be used in an activated form, that is an activated derivative of the amino function at the 3rd position of the compound (II). Such activated functional derivative includes isocyanate or isothiocyanate; Shiff's base; a salt with an acid (e.g. hydrochloric acid, hydrobromic acid, etc.); and the other conventional reactive derivative as formed by the reaction with a silyl compound (e.g. trimethylsilyl chloride, bis(trimethylsilyl)acetamide, etc.), a phosphorus compound (e.g., phosphorus oxychloride, phosphorus trichloride, etc.) and the like.
An acylating agent includes an organic acid such as an organic carboxylic acid, an organic carbonic acid, and the like, which corresponds to those comprising the acyl moiety as mentioned in the above para. (1), and a salt or reactive derivative thereof. More particularly, the said organic carboxylic acid and organic carbonic acid are organic acids comprising aliphatic, aromatic, araliphatic, heterocyclic and heterocyclic-aliphatic acyl groups.
Suitable reactive derivative of the above-mentioned organic acid includes its acid an hydride, ester, acid halide, amide, azide and the like. i) The acid an hydroxide may be a mixed anhydride with an acid such as dialkylphosphoric acid, aryl- or diarylphosphoric acid, diaralkylphosphoric acid, halophosphoric acid, dialkylphosphorus acid, sulfuric acid, alkyl-carbonic acid aliphatic carboxylic acid, aromatic carboxylic acid or the symmetrical acid an hydride, and preferably, with an acid such as diethylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, ethyl carbonic acid, tert-butyl carbonic acid, trichloroethyl carbonic acid, pivalic acid, trichloroacetic acid, trifluoroacetic acid, benzoic acid and the like. ii) The suitable ester may be a conventional activated ester such as substituted alkyl ester (e.g. cyanomethyl ester, methoxymethyl ester, etc.), olefinic or acetylenic ester (e.g. allyl ester, propargyl ester, etc.), substituted aryl ester (e.g. 4nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, etc.), an silyl ester (e.g. trimethylsilyl ester, dimethyl methoxy silyl ester, etc.), an ester with Nhydroxy compound such as acetoxime, N-hydroxysuccinimide, N-hydroxyphthalimide, I-hydroxy-6-chlorobenzotriazole, etc., and the like. iii) The amide may be an activated amide such as pyrazolide, imidazolide, 4methylimidazolide, and the like. iv) Suitable acid halide may be the acid chloride, acid bromide, and the like.
The reaction may be preferably conducted especially in case of using the corresponding free acid as an acylating agent, in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)-carbodiimide, N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3dimethylaminopropyl)carbodiimide, N,N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1 -alkoxy- 1 -chloroethylene, 6-chloro- I -(4-chlorobenzene- sulfonyloxy)-lH-benzotriazole, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide, (chloromethylene dimethylammonium chloride, 2,2,4,4,6,6-hexachloro- 1,3,5 2,4,6-triazatriphos- phorine, or a mixed condensing agent such as triphenylphosphine and either carbon tetrahalide (e.g. carbon tetrachloride, carbon tetrabromide, etc.) or halogen (e.g. chlorine, bromine, etc.), and the like.
In case of using the acylating agent in a form of reactive derivative as mentioned above, the reaction may be conducted preferably in the presence of a base, for example, an inorganic base (e.g. sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), or an organic base such as trialkylamine (e.g. trimethylamine, triethylamine, tributylamine, etc.); N,N-dialkylaniline (e.g. N,N-dimethylaniline, N,N-diethylaniline, etc.); N,N-dialkylbenzylamine (e.g. N,N-dimethylbenzylamine, etc.); N-substituted or unsubstituted basic heterocyclic compound (e.g. Nmethylmorpholine, N-methylpiperidine, pyridine, dimethylaminopyridine, picoline, lutidine, quinoline, 1 ,5-diazabicyclo-[4,3,0]-5-nonene, 1 ,4-diazabicyclo [2,2,2]octane, 1,8-diazabicyclo-[5,4,0]-8-undecene, etc.) and the like.
The reaction is usually carried out in a conventional solvent which does not have an adverse influence on the reaction, e.g. water, acetone, dichloromethane, chloroform, N,N-dimethylformamide and the like, and a liquid condensing agent or base can also be used as the solvent.
The type of acylating agents to be used, such as free acid, salt or reactive derivative thereof, are usually selected according to kind of an organic acid as an acylating agent and a solvent to be used and the other reaction conditions applied for the individual preparation of specific object compound.
In this process including the reaction and past-treatment steps, there may take place occasionally side reactions, for example, between amino, hydroxy and/or mercapto function of the starting compound (II) and the acylating agent to give the 3-acylamino-2-azetidinones (III) bearing the corresponding acylated functional group(s). These cases of reactions are to be noted to be included within the scope of the present process.
(2) Process 2: This process relates to a method for preparing a 3-acylamino compound (V) in which acyl moiety (R') bears at least one functional group selected from amino, hydroxy and carboxy (V) by removing amino, hydroxy and/or carboxy protective group(s) of compound (IV).
The removal reaction of said protective groups is conducted by a conventional method such as hydrolysis, and other conventional method, e.g., reduction, a method of using a metal salt such as metal halide, metal mercaptide, metal cyanide and metal thiocyanate, and a successive method comprising iminohalogenation, iminoetherification and hydrolysis. By this reaction a protective group of the protected amino, protected hydroxy and/or protected carboxy function(s) in the acylamino (Rb) of the compound (IV) is removed off to provide the corresponding amino, hydroxy and/or carboxy function(s), respectively.
In each of the above methods, suitable reagents to be used are exemplified as follows.
(i) For hydrolysis which refers to the same meaning as solvolysis including, for example acidolysis, alcoholysis, aminolysis, hydrozinolysis, etc.
Hydrolysis is preferably carried out in the presence of an acid or base.
Suitable acid is an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), an organic acid (e.g. formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), an acidic ion-exchange resin and the like.
Suitable base is an inorganic base such as alkali or alkaline earth metal hydroxide, carbonate or bicarbonate (e.g. sodium hydroxide, potassium carbonate sodium bicarbonate, calcium hydroxide, magnesium hydroxide, etc.), ammonium hydroxide and the like; an organic base such as an alkoxide or phenoxide of the above metal (e.g. sodium ethoxide, sodium methoxide, lithium phenoxide, etc.), an amine such as mono-, di- or trialkylamine (e.g. methylamine, ethylamine, propylamine, isopropylamine, butylamine, N,N-dimethyl- 1 ,3-propanediamine, trimethylamine, triethylamine, etc.), unsubstituted, mono- or disubstituted arylamine (e.g. aniline, N-methylaniline, N,N-dimethylaniline, etc.) or a heterocyclic base (e.g. pyrrolidine, morpholine, N-methylmorpholine, Nmethylpiperidine, N,N-dimethylpiperazine, pyridine, etc.), hydrazines (e.g. hydrazine, methylhydrazine, ethylhydrazine, etc.), a basic ion exchange resin and the like.
The hydrolysis is preferably conducted under somewhat milder conditions such as cooling or warming and usually in any solvent which does not have an adverse influence on the reaction, e.g., water, hydrophilic solvent such as methanol, ethanol, propanol, N,N-dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, etc. or a mixture thereof and other hydropholic solvent such as benzene, diethyl ether, etc., may also be used as a solvent. A liquid abovementioned acid or base can also be used as a solvent.
(ii) For reduction: Reduction including chemical reduction and catalytic reduction is carried out in a conventional manner.
Suit steps and the last step (i.e. hydrolysis step) are most preferably conducted in onebatch system.
Suitable iminohalogenation agents includes a halogenated compound such as phosphorus compound (e.g. phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, etc.), thionyl chloride, phosgen, and the like.
Suitable iminoetherifying agent may be an alcohol such as an alkanol (e.g. methanol ethanol, propanol, isopropanol, butanol, tert-butanol, etc.) or an alkoxyalkanol (e.g. methoxyethanol, ethoxyethanol, etc.), a thiol such as alkane thiol (e.g. methane thiol, ethane thiol, etc.), the alkoxide or thiolate of a metal such as alkali metal, alkaline earth metal (e.g. sodium methoxide, potassium ethoxide, magnesium ethoxide, lithium methoxide, potassium methanethiolate, etc.), and the like. Thus obtained reaction product is, if necessary, hydrolyzed in a conventional manner.
The hydrolysis is preferably carried out at ambient temperature or under cooling by simply mixing the reaction mixture with water or a hydrous or moistened organic solvent such as alcohol (e.g. methanol, ethanol, etc.), acetone, etc. and if necessary, with addition of an acid or base as exemplified above.
In the course of the present process, some kinds of the substituent(s) (e.g. protected amino, protected hydroxy, protected carboxy, etc.) in the group for Rb of the compound (IV) may also occasionally be transformed into the corresponding amino, hydroxy or carboxy group etc. It is to be understood that all the cases of the reaction are included within the scope of the present process.
(3) Process 3: This process relates to a method for preparing 3-amino-2-azetidinones (VII) by cleaving the amido linkage at the 3rd position of the compound (VI).
The cleavage of the amido linkage is conducted by a conventional method such as hydrolysis, reduction, and the like. Suitable reagents to be used are the same as those given in the aforementioned Process 2, and reaction condition (e.g. temperature, solvent, etc.) may be referred to those in Process 2.
In case that an amido group comprises phthalimido, the cleavage can be preferably conducted by an aminolysis with an amine such as (N,N-dialkylamino)alkylenediamine (e.g. (N,N-dimethyl)aminopropylenediamine, etc.).
(4) Process 4: This process relates to a method for preparing a compound having hydroxy or amino function (IX) by reacting a compound (VIII) with a reducing agent.
The reduction is conducted by a conventional method, for example, using alkali borohydride (e.g. sodium borohydride, potassium borohydride), diborane, hydrazine compound (e.g. phenyl hydrazine, hydrazine), electrolytic reduction, and additionally the other conventional chemical or catalytic reduction as mentioned in Process 2. Suitable examples of solvent and the other reaction conditions (e.g. temperature) are substantially the same as those exemplified in Process 2.
(5) Process 5: This process relates to a method for preparing a 3-acylamino-2-azetidinone having an imino function (XI) by reacting a corresponding compound having a carbonyl function (X) with an amino compound of the formula: R8-NH2, or its salt.
Suitable salt of the amino compound (R"--NH,), includes an inorganic acid salt (e.g. hydrochloride, hydrobromide sulfate, etc.) or an organic acid salt (e.g. form ate acetate, 2.2,2-trifluoroacetate, p-toluenesulfonate, etc.). In such case, the reaction may be preferably conducted in the presence of a base. Suitable base may be an inorganic base such as alkali or alkaline earth metal hydroxide (e.g. sodium hydroxide potassium hydroxide, calcium hydroxide, sodium bicarbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali or alkaline earth metal carbonate (e.g. sodium carbonate, calcium carbonate, etc.) alkali metal phosphate (e.g. sodium dihydrogenphosphate, potassiu dihydrogenphosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate. etc.) or an organic base such as alkali metal alkoxide (e.g. sodium methoxide potassium ethoxide, etc.), amines (e.g. triethylamine, pyridine lutidine, etc.).
The reaction is usually conducted in conventional manner. For example, the reaction is preferably conducted at ambient temperature or under heating, and in conventional solvent which does not have an adverse influence on the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide or a mixture thereof. More preferably, the reaction is carried out in around neutral conditions.
In this reaction, the object compound (XI) may be obtained as a stereoisomer of syn isomer, anti isomer or a mixture thereof due to the imidoyl group, and it is to be understood that each of these geometric isomers is included within the scope of the present process.
(6) Process 6: This process relates to a method for preparing a 3-acylamino-2-azetidinone compound having an acyloxy group (XIII) by reacting a compound having an phenolic hydroxy group (XII) with an acid of the formula: R9-OH or its reactive derivative.
The acid (R9-OH) to be used in this process includes an organic acid such as an organic carboxylic, carbonic and carbamic acids.
Typical reactive derivative of the above-mentioned organic acid may be the same as those exemplified in the explanation of the reactive derivative of an organic acid as acylating agent in Process 1. And additionally, the reactive derivative of an organic carbamic acid includes the corresponding isocyanate.
This acylation reaction carried out in a conventional manner, and accordingly the reaction procedure and conditions (e.g. temperature, solvent, etc.) are substantially the same as those given in the aforementioned Process 1, and in case that isocyanate is used as an acylating agent for the reactive derivative of the corresponding carbamic acid, the reaction is preferably carried out under an anhydrous condition.
(7) Process 7: This process relates to a method for preparing a compound having an acyl group (XV) by reacting a compound (XIV) with an acylating agent.
The acylating agent includes preferably haloalkanecarboxylic acid, Nprotected glycine, N-protected-2-(substituted or unsubstituted aryl)glycine, Namidinocarbamic acid or its reactive derivative, and suitable examples of the reactive derivative are the same as those exemplified for the acylating agent used in Process 1, and additionally, hydrazide of the above acid.
The reaction conditions, for example, a solvent to be used and reaction temperature are also substantially the same as those explained for the acylation in Process 1.
(8) Process 8: This process relates to a method for preparing a compound having an aralkoxy group (XXIII) by reacting a compound (XXII) with an aralkylating agent of the formula: R11-X.
The mode of the reaction procedure and examples of the reagents, solvents and other reaction condition (e.g. temperature) are substantially the same as those given in foregoing Process 1, respectively.
(9) Process 9: This process relates to a method for preparing a compound (XXV) by desulfurating 4-substituted thio-3-acylamino-2-azetidinones (XXIV) under reductive condition.
The desulfuration is usually conducted by reducing the starting compound (XXIV) in a conventional manner. Preferred reduction may be a catalytic reduction using a catalyst such as Raney nickel, Raney cobalt and the like.
The reductive desulfuration is usually carried out in a solvent such as ether, dioxane, methanol, ethanol, propanol, tetrahydrofuran, ethyl acetate and the like.
There is no particular limitation to this reaction, and the reaction is usually carried out at ambient or somewhat elevated temperature.
In the course of the reactions and/or their post-treatment steps of all the aforementioned Processes 1 to 11 there may be occasionally accompanied by (i) some transformations between the functional group i.e. carboxy, amino, and/or hydroxy and the corresponding groups i.e. protected- or derivatives of-carboxy protected-or substituted-amino, and/or protected-or substituted-hydroxy (e.g. acyloxy), respectively; and additionally, by (ii) stereoisomerizations among possible stereoisomers such as aforementioned syn- and anti-isomers and other optical isomers due to the epimerization at the asymmetric carbon atom(s) in the molecule, according to the kinds of the compounds, reagents, solvents, other conditions of the reaction and/or post-treatment so far used in the individual Processes.
Each of the reaction products in the abovementioned processes can be isolated and purified in a conventional manner to the skilled in the arts and they may be occasionally used as a starting compound for the next processes without any isolation and purification.
The compounds (I) of this invention include useful antibiotics for the treatment of microbial infections in animals and human being and useful intermediates for preparing the useful antibiotics. That is, the 3-acylamino-2azetidinones have antimicrobial activities against various pathogenic-microorganisms, e.g. Escherichia coli, Pseudomonas aeruginosa, Staphlococcus aureus, Proteus vulgaris etc. and are useful as antibiotics for the treatment of microbial infections in animals and human being. And, for example, 3-phthalimido, 3-amino2-azetidinones, etc. are important intermediates for preparing the abovementioned 3-acylamino-2-azetidinones. That is, 3-phthalimido-2-azetidinones can be converted into 3-amino-2-azetidinones by a conventional method (e.g. Process 3) and then said 3-amino-2-azetidinones is acylated to provide new 3-acylamino-2azetidinones which has antimicrobial activities against various pathogenic microorganisms.
Example No. of the compound Microorganism M.I.C. (zlg/ml) 80 Escherichia coli NIHJ 60 85 Pseudomonas aeruginosa NCTC 10490 4 Staphylococcus aureus 209 P 60 97 Pseudomonas aeruginosa NCTC 10490 4 Staphylococcus aureus 209 P 3.75 101 Pseudomonas aeruginosa NCTC 10490 15 Bacillus subtilis 15 Proteus vulgaris 16 111 Pseudomonas aeruginosa NCTC 10490 16 The compounds (I) of the present invention may be formulated for administration in any convenient way by analogy with other antibiotic.
Thus, the composition of present invention can be used in the form of pharmaceutical preparation, for examples, in solid, semisolid or liquid form, which contains the active object compound (I) of the present invention in admixture with a pharmaceutical organic or inorganic carrier, or excipient suitable for external or parenteral applications. The active ingredient may be compounded, for example, with usual carriers into tablets, pellets, capsules, suppositories, solutions, emulsions, aqueous suspensions, and other form suitable for therapeutical administration. The carriers which can be used are glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing. thickening and coloring agents and perfumes. The compositions of the present invention can also contain preserving or bacteriostatic agents thereby keeping the active ingredient in the desired preparations stable in activity. The active objecting compound (I) of the present invention is included in the composition of the present invention in an amount sufficient to produce the desired therapeutic effect upon the bacterially infected process or condition. While the dosage or therapeutically effective quantity of the compound (I) of the present invention varies from and also depends upon the age and condition of each individual patient to be treated, a daily dose of about 0.5-5 g, preferably 1-2 g/day of the active ingredient is generally given.
The following Examples are given for the purpose of illustration of the present invention.
EXAMPLE 1.
2-(3-Amino-2-oxo-1-azetidinyl)-2-(4-hydroxyphenyl)acetic acid (0.944 g.) was suspended in dried dichloromethane (30 ml.), and to the suspension there were added N,O-bis(trimethylsilyl)acetamide (3.50 g.) and dimethylformamide (0.2 ml.), whereafter the mixture was stirred at ambient temperature for 4.5 hours. Triethylamine (0.404 g.) and then phenylglyoxyloyl chloride (0.672 g.) dissolved in dried dichloromethane (10 ml.) were added dropwise to the above-obtained solution at -10"C in the course of 20 minutes with stirring, whereafter the stirring was continued at the same temperature for additional 2.5 hours. The reaction mixture was washed with dilute hydrochloric acid and water, and then dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give an oil (1.57 g.), which was subjected to column chromatography on silica gel (25 g.). Elution was carried out with ethyl acetate and the fractions containing a desired compound were collected. The solvent was distilled off from the eluate under reduced pressure to give an oil of 2 - (4 - hydroxyphenyl) - 2 - (2 - oxo 3 - phenylglyoxyloylamino - 1 - azetidinyl)acetic acid. This oil was crystallized from ethyl acetate to give the pure product (404 mg.), mp 190.5 to 1920C (dec.).
The following compounds (Examples 2 to 31) were obtained by reacting 3 amino - 2 - azetidinones with the corresponding acylating agent in substantially the same manner as described in Example 1.
EXAMPLE 2.
Sodium 2 - [3 - 12 - (2 - furyl)glycoloylamino) -2 - oxo - 1 - azetidinyl] - 2 (4 - hydroxyphenyl)acetate.
Infrared absorption spectrum (hereinafter referred to merely IR). v cam~' (KBr): 3350, 1735, 1615, 1380, 1240, 743 EXAMPLE 3.
2 - (3 - Bromopyruvoylamino - 2 - oxo - 1 - azetidinyl) - 2 - (4 - hydroxyphenyl)acetic acid, mp 188 to 1920C.
EXAMPLE 4.
2 - [3 - 12 - (2 - Azidoacetamido) - 2 - (2 - thienyl)acetamidol - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 120 to 125"C (dec.).
EXAMPLE 5.
2 - [3 - 12 - Benzyloxyimino - 2 - (4 - methoxyphenyl)acetamidol - 2 - oxo1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 138 to 1480C (dec.).
EXAMPLE 6.
2 - [3 - [2 - Benzoyloximino- 2 - 14 - (3 - tert - butoxycarbonylamino - 3 methoxycarbonylpropoxy)phenylEacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4hydroxyphenyl)acetic acid.
IR v cm-' (film): 3400, 1750, 17201700, 1680, 1660 EXAMPLE 7.
2 - (4 - Hydroxyphenyl) - 2 - [2 - oxo - 3 - [2 - 12 - (2,2,2 - trichloroethoxycarbonylaminomethyl)phenoxylacetamido] - 1 - azetidinyl] acetic acid.
IR V cm-l (KBr): 3275, 1740, 1715, 1660 EXAMPLE 8.
2 - [3 - [2 - [2 - 12 - Carboxymethoxy - N - (2,2,2 - trichloroethoxycarbonyl) benzylaminomethyllphenoxy]acetamido] - 2 - oxo - I - azetidinyl] - 2 - (4hydroxyphenyl)acetic acid, mp 141.5--144"C (dec.).
EXAMPLE 9.
Sodium 2 - [3 - (2 - benzyloxyimino - 2 - phenylacetamido) - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetate. mp 210 to 2130C (dec.).
EXAMPLE 10.
2 - [3 - {4 - (3 - tert - Butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloylamino - 2 - oxo - 1 - azetidinyl] - 2 - (4 -hydroxyphenyl)acetic acid.
NMR absorption spectrum (hereinafter referred to merely NMR) # ppm (D2O + NaHCO3): 1.26 (9H, s), 2.14 (2H, m), 3.06 (1H, q, J = 5,2 Hz), 3.4 to 4.4 (4H, m), 3.60 (3H, s), 5.04 (1H, q J = 5,2 hz), 5.34 (1H, s), 6.84, 7.24 (4H, ABq, J = 8 Hz), 6.82, 7.86 (4H, ABq, J = 8Hz).
EXAMPLE 11.
Sodium 2 - (4 - hydroxyphenyl) - 2 - (3 - crotoylamino - 2 - oxo - 1 - azetidinyl)acetrate, 164 to 171.50C.
EXAMPLE 12.
2 - (4 - Hydroxyphenyl) - 2 - [3 - [2 - methoxyimino - 2 - 12 - (2,2,2 - trifluoroacetamido) - 4 - thiazolyllacetamido] - 2 - oxo - 1 - azetidinyl]acetic acid.
NMR # ppm [(CD3)2CO]: 3.24 3.32 (1H, d, d, J = 2,5Hz), 3.84 (3H, s), 3.98 (1H, t, J = 5Hz), 5.14 to 5.32 (1h, m), 5.52 (1H, s) 6.82 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8Hz), 7.96 (1H, s), 8.20 (1H, broad s), 8.44 (1H, d, J = 8Hz) EXAMPLE 13.
2 - [3 - [4 - (3 - tert - Butoxycarbonylamino - 3 - methoxycarbonylpropoxy)3 - chlorophenylglyoxyloylamino] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid.
IR v cm-1 (film): 3320, 1760 to 1720, 1670 EXAMPLE 14.
2- [3 - [4 - (3 - Methoxycarbonylpropoxy)phenylglyoxyloylamino} - 2 - oxo1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 139 to 142 C.
EXAMPLE 15.
2 - [3 - {3 - (3 - tert - Butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid. (NUJOL is a Registered Trade Mark).
IR # cm-1 (Nujol); 3350, 1740, 1730, 1670 EXAMPLE 16.
2 - (4 - Hydroxyphenyl) - 2 - [3 - {4 - (@ - phthalimidopropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl]acetic acid, mp 173 to 175.5 C (dec.).
EXAMPLE 17.
Methyl 2 - [3 - [4 - {3 - tert - Butoxycarbonylamino - 3 - (4 - methoxybenzyloxycarbonyl)propoxy}phenylglyoxyloylamino] - 2 - oxo - 1 - azetidinyl] - 2 phenylacetate.
NMR a ppm (CDCl3): 1.49 (9H, s), 2.28 to 2.46 (2H, m), 3.02 to 4.12 (4H, m), 3.73 (3H. s), 4.39 to 4.70 (1H, m), 5.11 (2H, s), 5.22 to 5.33 (1H, m), 5.67 and 5.70 (1H, each s), 6.76 to 8.36 (13H, m), 7.74 and 7.93 (1H, each d, J=8Hz) EXAMPLE 18.
2 - [3 - 14 - (3 - tert - Butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloylamino) - 2 - oxo - 1 - azetidinyl] - 2 - phenyl acetic acid.
NMR # ppm (CDCl3): 1.42 (9H, s) 2.20 to 2.38 (2H, m), 3.10 to 4.20 (4H, m), 4.32 to 4.52 (1H, m), 5.01 to 5.16 (1H, m), 5.64 (1H, broad s), 6.82 to 8.30 (9H, m) EXAMPLE 19.
2 - 13 - 12 - (2,2,2 - Trichloroethoxycarbonylamino) - 2 - (2 - thienyl)acet amidoi - 2 - oxo - 1 - azetidinyl] - 3 - methylbutyric acid.
IR v cm-1 (KBr): 3300 to 3200, 1735, 1715, 1700, 1660 EXAMPLE 20.
Methyl 2 - (3 - benzyloxycarbonylamino - 2 - oxo - 1 - azetidinyl) - 3 - methyl2 - butenoic acid, mp 135 to 1370C.
EXAMPLE 21.
2 - (4 - Hydroxyphenyl) - 2 - [3 - [N - {N - (2 - nitrophenyl)oxamoyl} - 2phenylglycinamido] - 2 - oxo - 1 - azetidinyl]acetic acid, mp 155 to 159 C (dec.).
EXAMPLE 22.
Sodium 2 - [3 - [2 - [2 - {2 - (4 - chloro - 2 - nitrophenoxy)acetamidomethyl}- phenoxy]acetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetate, mp 117.5 to 122 C.
EXAMPLES 23.
2 - [3 - [2 - {2 - (2 - Bromoacetamidomethyl)phenoxy}acetamido] - 2 - oxo 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 152 to 155.5 C.
EXAMPLE 24.
2 - [3 - {N - (N - Benzyloxamoyl)amino} - 2 - oxo1 - azetidinyl] - 2 - (4 hydroxyphenyl)acetic acid, mp 125 to 129 C (dec.).
EXAMPLE 25.
Sodium 2 - [3 - [2 - {2 - (4 - chloro - 2 nitrophenoxy)acetamido} - 2 - (2thienyl)acetamido] - 2 - oxo - 1 - azetidinyl] - 3 methylbutyrate.
IR # cm-1 (Nujol): 3400, 3300, 1740, 1670, 1610 EXAMPLE 26.
2 - Phenyl - 2 - (3 - phthalimido - 2 - oxo - 1 - azetidinyl)acetic acid, mp 191.5 C.
EXAMPLE 27.
Ethyl 3 - phenyl - 2 - [3 - (2 - phenylacetamido) - 2 - oxo - 1 - azetidinyl]acrylate.
NMR # ppm (CDCl3): 1.28 (3H, t, J = 6Hz), 3.53 (2H, s), 4.24 (2H, q, J = 6Hz), 3.40, 3.44 (1H, d, d, J = 2, 4Hz), 3.73 (1H, t, J = 4Hz), 4.96 to 5.12 (1H, m), 6.92 (1H, d, J = 8Hz), 7.26 to 7.52 (11H, m) EXAMPLE 28.
3 - Phenyl - 2 - [3 - (2 - phenylacetamido) - 2 - oxo - 1 - azetidinyl]acrylic acid.
NMR # ppm (CD3OD): 3.42, 3.46 (1H, d, d, J = 2, 4Hz), 3.54 (2H, s), 3.68 (1H, t), 7.20 to 7.53 (11H, m) EXAMPLE 29.
Methyl 2 - [3 - [2 - {4 - (3 - acetamido - 3 - methoxycarbonylpropoxy)phenyl}2 - acetoxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - acetoxyphenyl)acetate, mp 120 to 123 C (dec.).
EXAMPLE 30.
2 - [3- [4 - {3 - tert - Butoxycarbonylamino - 3 - (4 - methoxybenzyloxycarbonyl)propoxy}phenylglyoxyloylamino] - 2 - oxo - 1 - azetidinyl] - 2 - phenylacetic acid.
IR v cm-1 (film): 3400 to 3300, 1760, 1740, 1710, 1680 to 1660 EXAMPLE 31.
Methyl 2 - [3 - {4 - ( 3 - tert-butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 3 - methyl - 2butenoate.
NMR # ppm (CDCl3): 1.42 (9H, s), 2.04 (3H, s), 2.24 (3H, s), 2.20 to 2.37 (2H, m), 3.72 (3H, s), 3.76 (3H, s), 3.63, 3.70 (1H, q, J = 2,5 Hz), 3.88 (1H, t, J = 5Hz), 4.14 (2H, t, J = 6Hz), 4.40 to 4.60 (1H, m), 5.02 to 5.20 (1H, m), 5.28 (1H, d, J = 8Hz), 6.93 (2H, d, J = 9Hz), 7.82 (1H, d, J = 8Hz), 8.37 (2H, d, J = 9Hz) EXAMPLE 32.
* 2 - (3 - Benzyloxycarbonylamino - 2 - oxo - 1 - azetidinyl) - 2 - (4 - benzyloxycarbonyloxyphenyl)acetic acid (1.55 g.) was obtained by reacting 2 - (3 - amino 2 - oxo - I - azetidinyl) - 2 - (4 - hydroxyphenyl)acetic acid (1.20 g.) with benzyl chloroformate (2.50 g.) in substantially the same manner as one described in Example 1, mp 138 to 141 C (dec.).
EXAMPLE 33.
2 - [3 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - phenylacetic acid (0.42 g.) was suspended in benzene (4 ml.), and to the suspension there was added anisole (0.4 ml.) to dissolve it. 2,2,2 - Trifluoroacetic acid (1 ml) was added to the solution obtained above under ice-cooling, whereafter the mixture was stirred at the same temperature for 5.5 hours. Diethyl ether (about 55 ml.) was added to the reaction mixture and the precipitating materials were collected by filtration. The materials were suspended in acetonitrile (30 ml.) and the suspension was stirred at ambient temperature for 50 minutes. The insoluble powder was collected by filtration, washed with acetonitrile and diethyl ether to give 2-[3 - {4 - (3 - amino - 3 - carboxy propoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - phenylacetic acid.
NMR # ppm (D2O+NaHCO3): 2.24 to 2.48 (2H, m), 3.12 to 4.02 (3H, m), 4.20 to 4.36 (2H, m), 4.98 to 5.08 (1H,m), 5.36 and 5.43 (1H, each s), 7.00 to 8.06 (9H, m).
The following compounds (Examples 34 to 49 were obtained by reacting the corresponding 3-acylamino-2-azetidinone compounds having tert-butoxycarbonylamino group with 2,2,2-trifluoroacetic acid in substantially the same manner as one described in Example 33.
EXAMPLE 34.
2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - (5 - chlorosalicyloylamino)acetamido] - 2 - oxo - 1 - azetidinyl] - 2 -(4 - hydroxyphenyl)acetic acid, mp 22 to 226 C (dec.).
EXAMPLE 35.
2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - (3 - phenylureido)acetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid.
NMR # ppm [(CD3)2SO+D2O]: 2.20 (2H, m), 2.96 (1H, m), 4.83 (1H, m), 5.23 (1H,s), 5.39 (1H, s), 6.8 to 7.6 (13H, m) EXAMPLE 36.
2 - 13 - [2 - (4 - (3 - Amino - 3 - carboxypropoxy)phenyll - 2 - (2- oxo - 1 - imid- azolidinylcarboxamido)acetamido] - 2 - oxo - I - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 200 to 2030C (dec.).
EXAMPLE 37.
2 - [3 - {3 - (3 - Amino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 182 to 183 C.
EXAMPLE 38.
2 - 13 - [2 - (4 - (3 - Amino - 3 - carboxypropoxy) - 3 - chlorophenyll - 2hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 175 (dec.).
EXAMPLE 39.
2 - [3 - [4 - (3 - Amino - 3 - carboxypropoxy) - 3 - chlorophenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 190 to 192 C (dec.).
EXAMPLE 40.
2 - [3 - {4 - (3 - Amino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo1-azetidinyl] - 2 - (4 - benzyloxyphenyl)acetic acid, mp 170 to 175 C (dec.).
EXAMPLE 41.
2 - 13 - [2 - (4 - (3 - Amino - 3 - carboxypropoxy)phenyll - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - benzyloxyphenyl)acetic acid, mp 164 to 167.5.
EXAMPLE 42.
2 - 13 - [2 - (4 - (3 - Amino - 3 - carboxypropoxy)phenyl( - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 3 - methyl - 2 - butenoic acid.
NMR # ppm (D2O+NaHCO3): 1.84 (3H, s); 1.96 (3H, s), 2.08 to 2.40 (2H, m), 3.68, 3.75 (1H, q, J = 2.5Hz), 3.88 (1H, t, J = 5Hz), 4.12 (2H, t, J = 5Hz), 5.09, 5.16 (1H, q, J = 2, 5Hz), 6.98 (2H, d, J = 8Hz), 7.50 (2H, d, J = 8Hz) EXAMPLE 43 2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - hydroxyacet]amido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - benzyloxyphenyl)acetic acid, mp 149 to 154 C (dec.).
EXAMPLE 44.
2 - [3 - {4 - (3 - Amino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 oxo - 1 - azetidinyl] - 2 - (4 - benzoyloxyphenyl)acetic acid, mp 181.5 to 184 C (dec.).
EXAMPLE 45.
2-[3-{4-(3 - Amino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo1 - azetidinyl] - 2 - (4 - carbamoyloxyphenyl)acetic acid.
IR v cm-' (Nujol): 3500 to 3200, 1730, 1720, 1660, 1600 EXAMPLE 46.
2 - [3 - {4 - (3 - Amino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo1 - azetidinyl] - 2 - (4 - benzyloxycarbonyloxyphenyl)acetic acid, mp 133 to 139 C (dec.).
EXAMPLE 47.
2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - hydrazonoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid.
NMR # ppm (D2O+NaHCO3): 2.30 to 2.48 (2H, m), 2.88 to 3.12 (1H, m), 3.64 to 3.76 (1H, m), 3.88 to 4.60 (3H, m), 4.71 and 4.72 (1h, each s), 6.84 to 7.40 (8H, m) EXAMPLE 48.
2 - [3 - [2 - [4 - {3 - (2 - phenylglycinamido) - 3 - carboxypropoxy)phenyl} - 2hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 -hydroxyphenyl)acetic acid.
NMR # ppm (D2O+NaHCO3): 2.18 to 2.40 (2H, m), 3.12, 3.18 (1H, q, J = 2, 5Hz), 3.78 to 4.00 (3H, m), 4.32 to 4.56 (1H, m), 5.02, 5.08 (1H, q, J = 2, 5Hz), 5.16 (1H, s), 5.36 (1H, s), 6.75 to 7.40 (13H, m) EXAMPLE 49.
2 - [3 - [2 - {4 - (3 - Glycinamino - 3 - carboxypropoxy)phenyl} - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid.
NMR # ppm (D2O+NaHCO3): 2.18 to 2.32 (2H, m), 3.09, 3.15 (1H, q, J = 2, 5Hz), 3.76 (2H, s), 3.96 (1H, t, J = 5Hz), 4.10 (2H, t, J = 6Hz), 4.35 to 4.52 (1H, m), 5.01, 5.07 (1H, q, J = 2, 5Hz), 5.36 (1H, s), 6.88 to 7.51 (8H, m) EXAMPLE 50.
2 - [3 - {4 - (3 - Amino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2oxo - 1 - azetidinyl] - 2 - phenylacetic acid (260 mg.) was obtained by reacting 2 - [3 - [4 - {3 - tert - butoxycarbonylamino - 3 - (4 - methoxybenzyloxycarbonyl)propoxy}phenylglyoxyloylamino] - 2 - oxo - 1 - azetidinyl] - 2 - phenylacetic aacid (0.870 g.) with 2,2,2 - trifluoroacetc acid (2 ml.) in substantiall under reduced pressure on a water bath. The residue was powdered with acetone to give 2 - [3 - [2 - {2 - (2 - carboxymethoxybenzylaminomethyl)phenoxy}acetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 159.5 to 164.5 C.
EXAMPLE 53.
2 - [3 - {2 - (2 - Aminomethylphenoxy)acetamido} - 2 - oxo - 1 - azetidinyl]2 - (4 - hydroxyphenyl)acetic acid (0.09 g.) was obtained by reacting 2 - 3 - [2 [2 - (2,2,2 - trichloroethoxycarbonylaminomethyl)phenoxy}acetamido] - 2 - oxo1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (0.25 g.) with 90% acetic acid (3 ml.) and zinc powder (0.45 g.) in substantially the same manner as one described in Example 52.
IR v cm-' (Nujol): 1725, 1650, 1600.
EXAMPLE 54.
2 - [4 - (2 - Phenylacetoxy)phenyl] - 2 - [3 - [2 - {4 - (3 - carboxy - 3 - tritylaminopropoxy)phenyl} - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl]acetic acid (0.5 g.) was dissolved in 80% acetic acid (10 ml.) and the mixture was stirred for 45 minutes. Insoluble materials were filtered off from the reaction mixture and the filtrate was evaporated to dryness under reduced pressure. The residue obtained was triturated with ethyl acetate to give a powder (0.27 g.). This powder (0.2 g.) was dissolved in an aqueous sodium bicarbonate and the solution was adjusted to pH 3 with 10% hydrochloric acid to give crystals of 2 - [3 - [2 - {4 (3 - amino - 3 - carboxypropoxy)phenyl} - 2 - hydroxyiminoacetamido] - 2 - oxo1 - azetidinyl] - 2 - [4 - (2 - phenylacetoxy)phenyl]acetic acid (0.14 g.).
IR v cm-1 (Nujol): 3250, 1750, 1730, 1670 EXAMPLE 55.
2 - [3 - {2 - (2 - Amino - 4 - thiazolyl) - 2 - methoxyiminoacetamido} - 2oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (110 mg.) was obtained by reacting 2 - (4 - hydroxyphenyl) - 2 - [3 - [2 - methoxyimino - 2 - {2 - (2,2,2 - trifluoroacetamido) - 4 - thiazolyllacetamido] - 2 - oxo - 1 - azetidinyl]acetic acid (240 mg.) with sodium acetate (340 mg.) in water (4 ml.) in substantially the same manner as one described in Example 54.
NMR # ppm (D2O+NaHCO3): 3.12, 3.20 (1H, d, d, J = 2, 5Hz), 3.88 (4H, m), 5.02, 5.10 (1H, d, d, J = 2, 5Hz), 5.32 (1H, s), 6.82 (1H, s), 6.90 (2H, d, J = 8Hz), 7.28 (2H, d, J = 8Hz) EXAMPLE 56.
A methanol solution (17 ml.) containing 2 - [3 - {4 - (3 - phthalimidopropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (1.13 g.), triethylamine (0.41 g.) and N,N - dimethylamino - 1,3 - propanediamine (0.45 g.) was stirred at 0 C for 72 hours. The reaction mixture was evaporated to dryness under reduced pressure to give a residue, to which water (10 ml.) was added. The aqueous solution was adjusted to pH 4.8 with 10% hydrochloric acid and the solution was subjected to column chromatography on an adsorption resin, Amberlite XAD-4 (Trade Mark, maker; Rohm & Haas Co.) (100 ml.). Elution was carried out with water and then with methanol, and the fractions containing a desired compound were collected. The eluate was evaporated to dryness under reduced pressure to give a residue, which was powdered with acetone. The powder (480 mg.) was crystallized with water to give 2 - 3 - {4 - (3 - aminopropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl]2 - (4 - hydroxyphenyl)acetic acid, mp 221 to 223 C.
EXAMPLE 57.
2 - 13 - 12 - 14 - (3 - Carboxy - 3 - glycinamidopropoxy)phenyll - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (80 mg.) was obtained by reacting 2 - [3 - [2 - [4 - {3 - (N - phthaloylglycinamido) - 3carboxypropoxy}phenyl] - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl]2 - (4 - hydroxyphenyl)acetic acid (300 mg.) with N,N - dimethylamino - 1,3propanediamine (200 mg.) in substantially the same manner as one described in Example 56.
NMR # ppm (D2O+NaHCO3): 2.18 to 2.32 (2H, m), 3.09, 3.15 (1H, q, J = 2, 5Hz) 3.76 (2H, s), 3.96 (1H, t, J = 5Hz), 4.10 (2H, t, J = 6Hz), 4.35 to 4.52 (1H, m), 5.01, 5.07 (1H, q, J = 2, 5Hz), 5.36 (1H, s), 6.88 to 7.51 (8H, m) EXAMPLE 58.
To a methanol (3 ml.) solution containing 2 - [3 - [2 - 14 - (3 - amino - 3 - car boxypropoxyphenyli - 2 - (ethoxycarbonylmethoxyimino)acetamido] - 2 - oxo - 1azetidinyl] - 2 - (4- hydroxyphenyl)acetic acid (280 mg.), there was added 1N sodium hydroxide (2 ml.) under ice-cooling. The mixture was stirred at the same temperature for an hour and at ambient temperature for additional 4 hours. The methanol was distilled off from the reaction mixture under reduced pressure to give an aqueous residue which was washed with ethyl acetate.
The aqueous solution was adjusted to pH 3.5 with dilute hydrochloric acid, and the precipitating material was collected by filtration, washed with water and acetone, and then dried to give crystalline 2 - [3 - 12 - (4 - (3 - amino - 3 carboxypropoxy)phenylj - 2 - (carboxymethoxyimino)acetamido] - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (160 mg.), mp 178 to 1800C (dec.).
The following compounds (Examples 59 to 63) were obtained by hydrolyzing the corresponding 3-acylamino-2-azetidinone compounds having methyl ester bond with IN sodium hydroxide in substantially the same manner as one described in Example 58.
EXAMPLE 59.
2 - 13 - [4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid.
NMR # ppm (D2O+NaHCO3): 1.34 (9H, s), 2.20 (2h, m), 3.07 (1H, q, J = 5, 2Hz), 3.83 (1H, t, J = 5Hz, 4.0 to 4.3 (3H, m), 4.98 (1H, q J = 5, 2Hz), 6.92, 7.26 (4H, ABq, J = 9Hz), 6.94, 7.88 (4H, ABq, J = 9Hz) EXAMPLE 60.
2 - [3 - {3 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 123 to 127 C (dec.).
EXAMPLE 61.
2 - [3 - {4 - (3 - Carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 157 to 158 C (dec.).
EXAMPLE 62.
2 - 13 - 14 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy) - 3 - chloro phenylglyloxyloylaminol - 2 - oxo - I - azetidinyl] - 2 - (4- hydroxyphenyl)acetic acid.
IR v cm~l (film): 3350, 1740 to 1720, 1680 EXAMPLE 63.
2 - [3 - 14 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylaminol - 2 - oxo - 1 - azetidinyl] - 2 - phenylacetic acid.
NMR # ppm [(CD3)2]: 1.40 (9H, s), 2.24 to 2.38 (2H, m), 3.33 to 4.52 (5H, m), 5.20 to 5.32 (1H, m), 5.62 and 5.66 (1H, each s), 7.04 to 8.28 (9H, m) EXAMPLE 64.
A dichloromethane (10 ml.) solution containing 2 - (2,2 - dichloroacetoxyimino) - 2 - phenylacetyl chloride, prepared by reacting the corresponding acetic acid (0.96 g.) with phosphorus pentachloride (0.79 g.) in conventional manner, was added dropwise to a dichloromethane (15 ml.) solution containing 2 - (3 - amino2 - oxo - I - azetidinyl) - 2 - phenylacetic acid (0.50 g.) and N,O - bis(trimethylsilyl)acetamide (2.33 g.) at -25 to -20 C in the course of 5 minutes. The mixture was stirred at the same temperature for an hour and at 0 C for additional half an hour. The reaction mixture was extracted with an aqueous sodium bicarbonate and the aqueous extract was washed with ethyl acetate. After adjusting the aqueous solution to pH I to 2 with 10% hydrochloric acid, the solution was extracted with ethyl acetate. The extract was washed with water and then dried over magnesium sulfate. The resultant solution was evaporated to dryness under reduced pressure to obtain an oily residue, which was crystallized with a mixture of diethyl ether and ethyl acetate to give 2 - [3 - (2 - hydroxyimino - 2 - phenylacetamido) - 2 - oxo - I - azetidinyl] - 2 - phenylacetic acid (195 mg.), mp 145 to 1490C.
The following compounds (Examples 65 to 75) were obtained by reacting 3 - amino - 2 - azetidinone compounds with the corresponding acylating agent, and then subjecting the resultant product, without isolation thereof, to removal protective group for amino, hydroxy and/or carboxy group in conventional manner.
H2N Rlc t) Acylating agent + XN 2 li) Removing amino, N \R2 hydroxy and/or o\R2 a carboxy protective b group.
lxaripIe Aylating Agent R Rb' mp (0C) L C-CONH r; 65 1 II 161-163 N- -u H CH2COoCH3 I (Cfl2)20 CHCOOH Cl nooc-cH(c2)2o CHCONH- CI 66 NHcoOc(CH;)NHCO NHcOoc(CH3)3 NHCO CIflOfHOH 218-223 (dec.) OH OH 0 67 I m\ ,, (Nujol): 33()() :h NHCON NH NHcOoC(CHa)i NHCOn NH 1730, 1660 4/ = zO 1610 CH3ooC-CH (cn2)2o Q O sJ L 8 (o 8 Q ;' ; &verbar; &verbar; ^ B ~ 9 2 t T t
NHCocK2 NNCOOCH2CCt 3 ClHcoc22 IRivom ' (KBr): 71 CHCOOCHCHNHCOCOOH HOCHCH2NHCOCONH- 3300, 1735 322 2 1660, 1510 CH3OOC-CHCH2SCH2COCOOH HOOC-C11CH2SCH2COCONH 72 N1Hcooc(C11), N111, ,' 162-169 (dec.) 73 CH3OOC(jH(Ctt2)20 CHCOOH ooc-c(cn2)2o CHCoNH- ,, 178-182 l 49 ~ S ~ e O o H H sD X V) E l E otoe ~ ~ < X NHCOcH2 NH2 NHCOCH2 74 CH3OOC-CH(cH2 )20 C-CO0H Hooc-cH(cH)o C1-CONii- ,, 193-197 (dec.) I II I NOCO NHCOoc(CHs)3 OH 75 C1-C0ON , w D O E N-OH CH2 COOH D l l l [ t o > N F t EXAMPLE 76.
Methyl 2 - (3 - phthalimido - 2 - oxo - 1 - azetidinyl) -2- phenylacetate (0.36 g.) and N,N - dimethyl - 1,3 - propanediamine (0.22 g.) were added to a mixed solution of methanol (5 ml.) and chloroform (5 ml.), whereafter the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was evaporated to dryness under reduced pressure, and ethyl acetate (20 ml.) and water were poured into the residue obtained. The ethyl acetate layer was separated from the mixture and the remaining aqueous layer was further extracted with ethyl acetate (10 ml.). The combined ethyl acetate solution was extracted with 1N hydro chloric acid (3 ml.) and water (10 ml.) respectively. The combined aqueous extracts were adjusted to pH 8.6 with an aqueous sodium bicarbonate. The aqueous solution was extracted with two 10 ml. portions of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give oily methyl 2 - (3 - amino - 2 oxo - I - azetidinyl) - 2 - phenylacetic acid (0.13 g.).
I.R. absorption spectrum v cam~' (film): 3400, 1750, 1710 The following compounds (Examples 77 and 78) were obtained by reacting 3 - phthalimido - 2 - azetidinone compounds with N,N - dimethylamino - 1 - propanediamine in substantially the same manner as one described in Example 76.
EXAMPLE 77.
2 - (3 - Amino - 2 - oxo - 1 - azetidinyl) - 2 - phenylacetic acid, mp 143 to 147"C (dec.).
EXAMPLE 78.
Methyl 3 - (3 - amino - 2 - oxo - 1 - azetidinyl) - 3 - phenylpropionate.
IR v cm-' (film): 3400, 1755, 1740, 1715 EXAMPLE 79.
A mixture of 3-benzyloxycarbonylamino - 2 - azetidinone (770 mg.), acetic acid (250 mg.), 10% palladium on carbon (350 mg.) and ethanol (70 ml.) was subjected to catalytic reduction in a stream of hydrogen gas at ordinary temperature and at ordinary atmospheric pressure. After a calculated volume of the hydrogen gas was absorbed into the reaction mixture, the catalyst was filtered off from the reaction mixture and washed with ethanol. The washings and the filtrate were combined and evaporated to dryness under reduced pressure to give a residue (490 mg.), which was washed with ether. The resultant residue (380 mg.) was dissolved in ethyl acetate (60 ml.) under warming, and then the solution was concentrated to a volume of about 3 ml. The precipitating crystals were collected by filtration to give acetate of 3 - amino - 2 - azetidinone (286 mg.), mp 130 to 131.5"C (dec.).
EXAMPLE 80.
Sodium borohydride (25 mg.) was added to an aqueous solution containing 2 - (4 benzyloxyphenyl) - 2 - [3 - 14 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylaminol - 2 - oxo - 1 - azetidinyl]acetic acid (330 mg.) and sodium bicarbonate (95 mg.), whereafter the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was adjusted to pH 2.5 to 3 with dilute hydrochloric acid and the precipitating crystals were collected by filtration to give 2 - (4 - benzyloxyphenyl) - 2 - [3 - [2 - 14 - (3 - tert - butoxycarbonylamino - 3carboxypropoxy)phenyl} - 2 - hydroxyacetamido] - 2 - oxo - 1 - azetidinyl]acetic acid (260 mg.).
NMR # ppm [(CD3)2CO]: 1.40 (9H, s), 2.20 to 2.40 (2H, m), 3.16, 3.23 (1H, d, d, J=2.5Hz), 3.80 (lH, t, J=5Hz), 4.10 (2H, t, J=6Hz), 4.28 to 4.30 (1H, m), 4.97 and 4.99 (1H, each s). 5.12 (2H, s), 5.28 (1H, s), 6.22 (1H, d, J = 8Hz), 6.80 to 7.54 (13H, m), 5.28 (1H, s), 8.12 (1H, d, J=8Hz) EXAMPLE 81.
2 - [3 - [2 - 14 - (3 - Amino - 3 - carboxypropoxy)phenyll - 2 - hydroxyacetamidol - 2 - oxo - I - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (0.47 g.) was obtained by reacting 2 - [3 - 14 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylaminol - 2 - oxo - I - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (0.97 g.) with sodium borohydride (0.08 g.) in substantially the same manner as one described in Example 80.
EXAMPLE 82.
2 - [3 - [2 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenyli- 2 - hydroxyiminoacetamido] - 2 - oxol - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (12.0 g.) and sodium bicarbonate (3.36 g.) were dissolved in water (75 ml.). 10% Palladium on carbon (3.0 g.) as a catalyst was added to the aqueous solution, and the mixture was stirred under conditions of ambient temperature and 3.5 atmospheric pressure for 4 hours in a stream of a hydrogen gas. After a calculated volume of the hydrogen gas was absorbed into the mixture, the catalyst was filtered off from the reaction mixture. The filtrate was concentrated to 20 ml under reduced pressure and the concentrate was adjusted to pH 4 with 5% hydrochloric acid. Acetone was added slowly to the solution until the powder was not come out in the solution. The powder was collected by filtration to give 2 - [3 [2 - {4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl}glycinamido]2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (10.05 g.), mp 255 to 258 C (dec.).
EXAMPLE 83.
2 - [3 - (4 - (3 - Carboxy - 3 - tert - butoxycarbonylaminopropoxy)phenyl- glyoxyloylaminol - 2 - oxo - 1 - azetidinyl] - 2 - (4 - benzyloxyphenyl)acetic acid (320 mg.) was suspended in water (5 ml.), and to the suspension, there was added hydroxylamino hydrochloride (75 mg.). The mixture was adjusted to pH 7 to 7.5 with sodium bicarbonate (170 mg.), whereafter the resultant mixture was stirred at 45 to 50 C for 4 hours. The reaction mixture was adjusted to pH 2 with dilute hydrochloric acid, whereafter the precipitating solid was collected by filtration, washed with water and then dried to give 2 - [3 - [2 - (4 - (3 - carboxy - 3 - tertbutoxycarbonylaminopropoxy)phenyl} - 2 - hydroxyiminoacetamido] - 2 - oxo - 1azetidinyl] - 2 - (4 - benzyloxyphenyl)acetic acid (280 mg.), mp 149.5 to 153 C (dec.).
The following compounds (Examples 84 to 97) were obtained by reacting a compound having a carbonyl group (II) with hydroxylamine hydrochloride in substantially the same manner as one described in Example 83.
EXAMPLE 84.
2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 215 to 217 C.
EXAMPLE 85.
2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - phenylacetic acid.
N.M.R. X ppm (D2O+NaHCO3): 2.30 to 2.48 (2H, m), 3.12 to 3.99 (3H, m), 4.10 to 4.24 (2H, m), 4.98 to 5.08 (1H, m), 5.34 and 5.43 (1H, each s), 6.92 to 7.56 (9H, m) EXAMPLE 86.
2 - [3 - [2 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenyll- 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - phenylacetic acid.
N.M.R. a ppm [(CD3)2CO]: 1.41 (9H, s), 2.20 to 2.36 (2H, m), 3.28 to 4.46 (5H, m), 5.10 to 5.24 (1H, m), 5.56 and 5.60 (Ih, each s), 6.22 (1H, broad d, J = 8Hz), 6.90 to 7.60 (9H, m), 8.26 (1H, broad d, J=8Hz) EXAMPLE 87.
2 - [3 - [2 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy) - 3chlorophenyll - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4hydroxyphenyl)acetic acid.
I.R. v cm-l (Nujol): 3350, 1740, 1700, 1640 EXAMPLE 88.
2 - [3 - [2 - {3 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl) - 2 - (4 - hydroxyphenyl)acetic acid, mp 179 to 1800C (dec.).
EXAMPLE 89.
2 - [3 - [2 - f4 - (3 - Carboxypropoxy)phenyl} - 2 - acetamido] - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 154 to 156 C (dec.).
EXAMPLE 90.
2 - [3 - [2 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)pheny}2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 193 to 197 C (dec.).
EXAMPLE 91.
2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy) - 3 - chlorophenyl} - 2hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 175 (dec.).
EXAMPLE 92.
2 - 13 - 12 - Hydroxyimino - 2 - (4 - hydroxyphenyl)acetamido) - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid.
I.R. # cm-1 (Nujol): 1740, 1695 EXAMPLE 93.
2 - [3 - [2 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)pheny} - 2hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 3 - methyl - 2 - butenoic acid.
I.R. # cm-1 (film): 3400 to 3300, 1760, 1720 to 1700, 1670 to 1650 EXAMPLE 94.
Erythro - 2 - [3 - (2 - Hydroxyimino - 2 - phenylacetamino) - 2 - oxo - 1azetidinyl] - 3 - methoxy - 3 - phenylpropionic acid.
N.M.R. # ppm [(CD3)2CO]: 3.27 (3H, s), 3.70 (1H, m), 4.10 (1H, t, J = 6Hz), 4.56 (1H, d, J = 5Hz), 4.93 (1H, d, J = 5Hz), 5.20 (1H, m), 7.2 to 7.8 (10H, m), 8.18 (1H, m) EXAMPLE 95.
2 - [3 - (2 - Hydroxyimino - 2 - phenylacetamido) - 2 - oxo - 4 - styryl - 1azetidinyl] - 2 - phenylacetic acid.
I.R. # cm-1 (Nujol): 3250, 2600 to 2500, 1760, 1740, 1690 EXAMPLE 96.
2 - [3 - (2 - Hydroxyimino - 2 - phenylacetamido) - 2 - oxo - 4 - hydroxymethyl1 - azetidinyl] - 2 - phenylacetic acid, mp 187 to 188 C (dec.).
EXAMPLE 97.
3 - [3 - (2 - Hydroxyimino - 2 - phenylacetamido) - 2 - oxo - 1 - azetidinyl]- 3 - phenylpropionic acid, mp 157 to 1580C.
The following compounds (Example 98 to 106) were obtained by reacting a compound having a carbonyl group with the corresponding amine of the formula: R6-NH2, in substantially the same manner as one described in Example 83.
EXAMPLE 98.
Sodium 2 - [3 - [2 - {4 - (3 - amino - 3 - carboxypropoxy)phenyl} - 2 - methoxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetate, mp 210 to 215 C (dec.).
EXAMPLE 99.
2 - [3 - {2 - Methoxyimino - 2 - (4 - methoxyphenyl)acetamidol - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 156 to 1610C (dec.).
EXAMPLE 100.
2 - [3 - {2 - (3 - Amino - 4 - thiazolyl) - 2 - methoxyiminoacetamido} - 2 - oxo 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid.
N.M.R. # ppm (D2O+NaHCO3): 3.12, 3.20 (1H, d, d, J = 2, 5Hz), 3.88 (4H, m), 5.02, 5.10 (1H, d, d, J = 2, 5Hz), 5.32 (1H, s), 6.82 (1H, s), 6.90 (2H, d, J = 8Hz), 7.28 (2H, d, J = 8Hz) EXAMPLE 101 2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - benzyloxyximinoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 180 to 184 C (dec.).
EXAMPLE 102.
Sodium 2 - [3 - (2 - Benzyloxyimino - 2 - phenylacetamido) - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetate, mp 210 to 2130C (dec.).
EXAMPLE 103.
2 - [3 - {2 - Benzyloxyimino - 2 - (4 - methoxyphenyl)acetamido} - 2 - oxo - 1azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 138 to 148 C (dec.).
EXAMPLE 104.
2 - [3 - [2 - {4 - (3 - tert -Butoxycarbonylamino - 3 - carboxypropoxy)phenyl}2 - hydrazonoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - hydroxyphenyl)acetic acid.
N.M.R. # ppm [(CD3)2SO]: 1.36 (9H, s), 2.00 to 2.12 (2H, m), 3.04 to 3.14 (1H, m), 3.58 to 3.70 (1H, m), 3.94 to 4.12 (2H, m), 4.84 to 4.94 (2H, m), 5.31 (1H, s), 6.76 to 7.36 (8H, m), 8.66 (1H, d, J = 8Hz) EXAMPLE 105.
2 - [3 - [2 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - (carbamoylhydrazono)acetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid.
N.M.R. # ppm (D2O+NaHCO3):2.24 to 2.36 (2H, m), 3.14, 3.20 (1H, d, d, J = 2, 5Hz), 3.72 to 4.08 (2H, m), 4.19 (2H, t, J = 6Hz), 4.93, 4.99 (1H, d, d, J = 2, 5Hz), 5.30 (1H, s), 6.84 to 7.50 (13H, m) EXAMPLE 106.
2 - [3 - {4 - (3 - Amino - 3 - carboxypropoxy)phenyl} - 2 - (thiocarbamoylhydrazono)acetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid, mp 206 to 207 C (dec.).
EXAMPLE 107.
2 - [3 - {2 - (2 - Thienyl)acetamido} - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (480 mg.) was suspended in water (10 ml.), and to the suspension, there was added sodium bicarbonate (520 mg) to dissolve it. Acetone (10 ml.) was added to the solution, whereafter a dried acetone solution (5 ml.) containing benzoyl chloride (560 mg.) was added dropwise thereto under icecooling with stirring. The stirring was continued at the same temperature for about 4.2 hours and then at ambient temperature for additional 5 hours. The acetone was removed by distillation from the reaction mixture under reduced presure to give an aqueous solution, which was washed with ethyl acetate. The aqueous solution was adjusted to pH 1 to 2 with dilute hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water and then dried over magnesium sulfate.
The solution was evaporated to dryness under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (20 g.). Elution was carried out with ethyl acetate and the fractions containing a desired compound were collected. The solvent was removed by distillation from the solution under reduced pressure to give a residue, which was crystallized from ethyl acetate to give 2 - (4 - benzoyloxyphenyl) - 2 - [2 - (2 - thienyl)acetamido} - 2 - oxo - 1azetidinyl]acetic acid (240 mg), mp 129 to 131 C.
Example 107 is outside the scope of this invention. The following compounds (Examples 108 and 109) were obtained by reacting 2 - (4 - hydroxyphenyl) - 2 - (3acylamino - 2 - oxo - 1 - azetidinyl)acetic acid with the corresponding acylating agent in substantially the same manner as one described in Example 107.
EXAMPLE 108.
2 - (4 - Benzyloxycarbonyloxyphenyl) - 2 - [3 - {4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl]acetic acid.
N.M.R. # ppm [(CD3)2CO]: 1.39 (3H, s), 2.20 to 2.44 (2H, m), 3.37, 3.43 (1H, d, d, J = 2Hz, 5Hz), 3.81 (1H, t, J = 5Hz), 4.25 (2H, t, J = 6Hz), 5.12 to 5.26 (1H, m), 5.28 (2H, s), 5.64 (1H, s), 6.24 (1H, d, J = 8Hz), 7.00 to 7.60 (11H, m), 8.20 (1H, d, J = 8Hz), 8.68 (1H, d, J = 8Hz) EXAMPLE 109.
2 - (4 - Benzoyloxyphenyl) - 2 - 13 - (4 - (3 - tert - butoxycarbonylamino - 3carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl]acetic acid.
N.M.R. # ppm[CD3)2CO]: 1.38 (3H,s), 2.26 to 2.44 (2H, m), 3.39, 3.45 (1H, d, d, J = 2Hz, 5Hz), 4.00 (2H, t, J = 5HZ), 4.24 (2H, t, J = 6Hz), 4.38 (1H, m), 5.06 to 5.30 (1H, m), 5.68 (1H, s), 6.24 (1H, d, J = 8Hz), 7.00 to 8.24 (13H, m), 8.72 (1H, d, J = 8Hz) EXAMPLE 110.
2 - [3 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - [4 - {N - (2,2,2 - trichloroacetyl)carbamoyloxy}phenyl]acetic acid (610 mg.) was obtained by reacting 2 - [3 - {4 - (3tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyoylamino}2 - oxo1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (585 mg.) with 2,2,2 - trichloroacetyl isocyanate (1.0 g.) in substantially the same manner as one described in Example 107.
N.M.R. # ppm [(CD3)2CO]: 1.55 (3H, s), 2.36 to 2.62 (2H, m), 3.38, 3.44 (1H, d, d, J = 2Hz, 5Hz), 3.99 (1H, t, J = 5Hz), 4.20 to 4.42 (3H, m), 5.10 to 5.30 (1H, m), 5.64 (1H, s), 6.96 to 7.60 (6H, m), 8.16 (2H, d, J = 8Hz), 8.68 (1H, d, J = 8Hz) EXAMPLE 111.
2- 13 - [2 - (4 - (3 - Acetamido - 3 - carboxypropoxy)phenyli -2- acetoxyimino- acetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - acetoxyphenyl)acetic acid (0.66 g.) was obtained by reacting 2 - [3 - [2 - {4 - (3 - amino - 3 - carboxypropoxy)phenyl} - 2hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (1.0 g.) with acetic anhydride (2 ml) in substantially the same manner as o
EXAMPLE 116.
2 - [3 - [2 - [4 - {3 - Carboxy - 3 - (2 - phenyl N - tert- butoxycarbonylglycinamido)propoxy}phenyl] - 2 - hydroxyiminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 (4 - hydroxyphenyl)acetic acid.
NMR # ppm [(CD3)2SO]: 1.38 (9H, s), 2.12 to 2.32 (2H, m), 3.12, 3.18 (2H, q, J = 2, 5Hz), 3.83 (1H, t, J = 5Hz), 4.03 (2h, t, J = 6Hz), 4.36 to 4.52 (1H, m), 4.96 to 5.08 (1H, m), 5.24 (1H, d, J = 8Hz), 5.48 (1H, s), 6.78 to 7.48 (13H, m), 8.48 (1H, d, J = 8Hz), 9.16 (1H, d, J = 8Hz) EXAMPLE 117.
2 - [3 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - {N - (2,2,2 - trichloroacetyl)carbamoyloxy}phenyl]acetic acid (550 mg.) was suspended in water (5 ml.), and to the suspension there were added sodium bicarbonate (250 mg.) and methanol (1 ml.). The mixture was stirred at ambient temperature for 7 hours. The reaction mixture was adjusted to pH 2 with dilute hydrochloric acid and the precipitating material was collected by filtration. The material was washed with water and then dried to give 2 - [3 - (4- (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)pheny glyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2- (4 - carbamoyloxyphenyl)acetic acid.
IR V cm-' (Nujol): 3300 to 3150, 1750, 1730, 1660 EXAMPLE 118.
2 - [3 - {4 - (3 - tert - Butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino} - 2 - oxo - 1 - azetidinyl] - 2 - (4 - hydroxyphenyl)acetic acid (585 mg.) was dissolved in dioxane (5 ml.), and to the solution, there were added 1N aqueous sodium hydroxide and additionally benzyl bromide (680 mg.) under icecooling. The mixture was stirred at the same temperature for an hour, and then at 10 to 15 C for additional 16 hours. Water (about 80 ml.) was added to the reaction mixture and the resultant solution was washed with ethyl acetate. The aqueous solution was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and then dried over magnesium sulfate. The solvent was removed by distillation from the solution under reduced pressure to give 2 - [3 - (4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy) phenylglyoxyloylaminol - 2 - oxo - 1 - azetidinyl] - 2 - (4 - benzyloxyphenyl)acetic acid (590 mg.).
NMR # ppm [(CD3)2CO]: 1.42 (3H, s), 2.28 to 2.54 (2H, m), 3.32 to 3.38 (1H, d, d, J = 2Hz, 5Hz), 3.93 (1H, t, J = 5Hz), 4.26 (2H, t, J = 6Hz), 4.32 to 4.52 (1H, m), 5.14 (2H, s), 5.55 (1H, s), 6.26 (1H, d, J = 8Hz), 7.02 to 7.46 (11H, m), 8.24 (2H, d, J = 8Hz), 8.70 (1H, d, J = 8Hz) EXAMPLE 119.
Sodium 2 - [4 - (2 - benzothiazolyldithio) - 3 - phthalimido - 2 - oxo - 1 - azetidinyl] - 3 - methyl - 2 - butenoate (2.0 g.) was dissolved in dioxane (20 ml.), and to the solution, there was added Raney nickel (20 ml.), whereafter the mixture was stirred at 50 to 600C for 35 minutes. Raney nickel was collected by filtration and washed with dioxane. The washings and the filtrate were combined and evaporated to dryness under reduced pressure to give a residue, which was dissolved in saturated aqueous sodium bicarbonate. The aqueous solution was washed with ethyl acetate and then adjusted to pH 2. The solution was extracted twice with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by distillation to give a residue (1.1 g.), which was subjected to column chromatography on silica gel (40 g.). Elution was carried out with ethyl acetate and the fractions containing a desired compound were collected. The eluate was evaporated to dryness under reduced pressure to give 2 - (3 - phthalimido - 2 - oxo - 1 - azetidinyl)3 - methyl - 2 - butenoic acid (240 mg.).
NMR # ppm (CD3OD): 2.20 (3H, s), 2.40 (3H, s), 4.00 to 4.18 (2H, m), 5.37, 5.83 (1H, d, d, J = 5Hz), 8.13 (4H, s) EXAMPLE 120.
Methyl 2 - (3 - phthalimido - 2 - oxo - 1 - azetidinyl) - 3 - methyl - 2 - butenoate (14.6 g.) was obtained by reacting methyl 2 - [4 - (2 - benzothiazolyldithio) - 3phthalimido - 2 - oxo - 1 - azetidinyl] - 3 - methyl - 2 - butenoate (47 g.) with Raney nickel (470 ml.) in substantially the same manner as one described in Example 119, mp 127 to 1280C.
EXAMPLE 121.
2 - [3 - [2 - (4 - (3 - Carboxy - 3 - tritylaminopropoxy)phenyl - 2 - hydroxy- iminoacetamido] - 2 - oxo - 1 - azetidinyl] - 2 - [4 - (2 - phenylacetoxy)phenyl]acetic acid (0.44 g) was obtained by reacting 2 - [3 - [2 - 14 - (3 - carboxy - 3 - tritylamino propoxy)phenyl} - 2 - hydroxyiminoacetamido] - 2 - (4 - hydroxyphenyl)acetic acid (0.75 g) with 2 - phenylacetyl chloride (0.16 g) in substantially the same manner as one described in Example 107.
IR V cm-l (Nujol): 3240, 1750, 1730, 1655 Our copending application No. 40893/75, a cognate of applications including 21507/76 (1,519,495) describes and claims inter alia a compound of the following formula:
wherein R is amino, acylamino, aralkylamino or substituted methyleneamino; A is a group represented by the following formula:
in which R' is aryl, aralkyl, arylthioalkyl or heterocyclic group, wherein the aryl, alkyl and heterocyclic moiety may bear at least one suitable substituent, provided that, when R is amino or acylainino, R' is aryl selected from phenyl bearing N substituted or unsubstituted alkanesulfonamido and naphthyl, aralkyl, arylthioalkyl or heterocyclic group; R2 is alkyl, haloalkyl, heterocyclic-thioalkyl or arylthio, wherein the heterocyclic and aryl moieties may bear at least one suitable substituent, R3 is hydrogen, alkyl, haloalkyl or heterocyclic-thioalkyl, wherein the heterocyclic moiety may bear at least one suitable substituent provided that, when R is amino or acylamino, R2 is alkyl and R3 is haloalkyl or heterocyclic-thioalkyl; and R4 is carboxy, its pharmaceutically acceptable salt or esterified carboxy, together with methods of preparation thereof.

Claims (12)

WHAT WE CLAIM IS:
1. A compound of the formula:
wherein R' is amino or acylainino, and R2' is hydrogen, or a group of the formula:
in which R4' is phenyl substituted by acyloxy, R5 is carboxy or its ester, R5' is alkyl bearing carboxy or its ester and R7 is substituted or unsubstituted aryl, provided that, 1) when R2' is hydrogen, then R1 is amino; 2) when R2' is a group of the formula:
then Rl is phenylglyoxyloylamino, 2-(2-furyl)glycoloylamino, bromopyruvoylamino, 2-(2-thienyl)-2-(2-azidoacetamino)acetamido, 2-benzyloxyimino-2-(4-methoxyphenyl)acetamido, 2 - benzoyloxyimino - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - methoxy- carbonylpropoxy)phenyl]acetamido, 2 - ]2 - (2,2,2 - trichloroethoxycarbonylaminomethyl)phenoxy]acetamido, 2 - [2 - {N - (2,2,2 - trichloroethoxycarbonyl) - 2 - (carboxymethoxy)benzyl aminomethyl lphenoxy] acetamido, 2 - benzyloxyimino - 2 - phenylacetamido, 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl glyoxyloylamino, crotoylamino, 2 - methoxyimino - 2 - [2 - (2,2,2 - trifluoroacetamido) - 4 - thiazolyl]acet amido, 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy) - 3 - chloro phenylglyoxyloylamino, 4 - (3 - methoxycarbonylpropoxy)phenylglyoxyloylamino, 3 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl- glyoxyloylamino, 3 - (3 - phthalimidopropoxy)phenylglyoxyloylamino, N - [N - (2 - nitrophenyl)oxamoyl] - 2 - phenylglycinamido, 2 - [2 - {2 - (4 - chloro - 2 - nitrophenoxy)acetamidomethyl}phenoxy]acet amido, 2 - [2 - (2 - bromoacetamidomethyl)phenoxy]acetamido, N-(N-benzyloxamoyl)amino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (5 - chlorosalicyloyl amino)acetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (3 - phenylureido)acet amido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - oxo - 1 - imid azolidinylcarboxamido)acetamido, 3 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy) - 3 - chlorophenyl] - 2 - hydroxyimino acetamido, 4 - (3 - amino - 3 - carboxypropoxy) - 3 - chlorophenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroazonoacetamido, 2 - [4 - (3 - carboxy - 3 - (2 - phenylglycinamido)propoxylphenyl] - 2 - hydroxy- iminoacetamido, 2 - [4 - (3 - carboxy - 3 - glycinamidopropoxy)phenyl] - 2 - hydroxyimino- acetamido, 2 - (2 - aminoethoxyimino) - 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] acetamido, 2 - [2 - (2 - carboxymethoxybenzylaminomethyl)phenoxy]acetamido, 2 - (2 - aminomethylphenoxy)acetamido, 2 - methoxyimino - 2 - (2 - amino - 4 - thiazolyl)acetamido, 4 - (3 - aminopropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (carboxymethoxyimino) acetamido, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloyl amino, 3 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloyl amino, 4 - (3 - carboxypropoxy)phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy) - 3 - chlorophenylglyoxyloylamino, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 (5 - chlorosalicyloylamino)acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - (2oxo - 1 - imidazolidinecarboxamido)acetamido, 2 - benzamido - 2 - [4 - (3 - tert - butocycarbonylamino - 3 - carboxypropoxy)phenyl]acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - (3phenylureido)acetamido, 2 - (2 - aminoacetamido) - 2 - (2 - thienyl)acetamido, N - [N -(2 - hydroxyethyl)oxamoyl]amino, (2 - amino - 2 - carboxyethylthio)pyruvoyl, 2 - (4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - phenylacetamido)acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl]glycinamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy) - 3 - chlorophenyl] - 2 - hydroxyiminoacetamido, 2 - [3 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - 4 - (3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - methoxyiminoacetamido, 2 - [4- (3 - amino - 3 - carboxypropoxy)phenyll -2- (2- ethoxycarbonylethoxyimino)acetamido, 2- [4 - (3 - amino - 3 - carboxypropoxy)phenyl] -2- benzyloxyiminoacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydrazonoacetamido, 2 - [4- (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - semicarbazonoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - thiosemicarbazonoacetamido, 2 - [4 - (3 - (2 - chloroacetamido) - 3 - carboxypropoxylphenyl] - 2 - hydroxy- iminoacetamido, 2 - [4 - (3 - (2 - phthalimidoacetamido) - 3 - carboxypropoxylphenyl] - 2hydroxyiminoacetamido, 2 - [4 - (3 - (3 - amidinoureido) - 3 - carboxypropoxy)phenyll - 2 - hydroxy- iminoacetamido, 2 - 4 - (3 - (2 - tert - butoxycarbonylaminoacetamido) - 3 - carboxypropoxy)- phenyl] - 2 - hydroxyiminoacetamido, or 2 - [4- (3 - (2 - phenyl - 2 - tert - butoxycarbonylaminoacetamido - 3 - carboxy- propoxyiphenyli - 2 - hydroxyiminoacetamido, 3) when R2' is a group of the formula:
then R1 is amino, phthalimido, 4 - [3 - tert - butoxycarbonylamino - 3 - (4 - methoxybenzyloxycarbonyl)pro poxy]phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl glyoxyloylamino, 4 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloyl amino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 hydroxyiminoacetamido or 2 - phenyl - 2 - hydroxyiminoacetamido, 4) when R2' is a group of the formula:
then R1 is amino or 4 - [3 - tert - butoxycarbonylamino - 3 - (4 - methoxybenzyloxy carbonyl)propoxy]phenylglyoxyloylamino, 5) when R2, is a group of the formula:
then R' is 4 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)pheny1] - 2 - hydroxyacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 hydroxyacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 hydroxyiminoacetamido or 2 - [4 - (3 - carboxy - 3 - tert - butoxycarbonylaminopropoxy)phenyl] - 2 hydroxyiminoacetamido, 6) when R2' is a group of the formula:
then R1 is 2 - (2 - thienyl) - 2 - (2,2,2 - trichloroethoxycarbonylamino)acetamido or 2 - (2 - thienyl) - 2 - [2 - (4 - chloro - 2 - nitrophenoxy)acetamido]acetamido, 7) when R2, is a group of the formula:
then R1 is phthalimido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido or i 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 hydroxyiminoacetamido, 8) when R2' is a group of the formula:
then R1 is benzyloxycarbonylamino, phthalimido or 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenyl glyoxyloylamino, and 9) when R2' is a group of the formula:
in which R4' and R5 are each as defined above, then R' is acylamino of the formula:
in which Ref is phenyl substituted by alkoxy having at least one functional group selected from amino, protected amino, carboxy and protected carboxy, and Ro and Rh are each hydrogen, or combined together to form oxo, hydroxyimino or acyloxyimino.
2. A compound according to claim 1, wherein
in which R' is phenyl substituted by alkoxy having at least one functional group selected from amino, protected amino, carboxy and protected carboxy, and R9 and Rh are each hydrogen, or combined together to form oxo, hydroxyimino or acyloxyimino, and R2' is a group of the formula:
in which R4' is phenyl substituted by acyloxy selected from alkanoyl, aroyl, aralkanoyl, aralkoxycarbonyl, carbamoyl and N-(haloalkanoyl)carbamoyl, and R5 is carboxy or its ester.
3. A compound according to claim 1, wherein R1 is acylamino and R2 is a group of the formula:
in which R5' is alkyl bearing carboxy or its ester.
4. A compound according to claim 1, wherein R' is acylamino and R2' is a group of the formula:
in which R7 is phenyl and R5 is carboxy or its ester.
5. A compound according to claim 1, wherein R' is amino and R2' is hydrogen.
6. A compound according to claim 1, wherein R' is phenylglyoxyloylamino, 2-(2-furyl)glycoloylamino, bromopyruvoylamino, 2-(2-thienyl)-2-(2-azidoacetamino)acetamido, 2-benzyloxyimino-2-(4-methoxyphenyl)acetamido, 2 - benzoyloxyimino - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - methoxy- carbonylpropoxy)phenyl]acetamido, 2 - [2 - (2,2,2 - trichloroethoxycarbonylaminomethyl)phenoxy]acetamido, 2 - [2 - IN - (2,2,2 - trichloroethoxycarbonyl) - 2 - (carboxymethoxy)benzylaminomethyl Sphenoxy]acetamido, 2 - benzyloxyimino - 2 - phenylacetamido, 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloylamino, crotoylamino, 2 - methoxyimino - 2 - [2 - (2,2,2 - trifluoroacetamido) - 4 - thiazolyl]acet- amido, 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy) - 3 - chlorophenylglyoxyloylamino, 4 - (3 - methoxycarbonylpropoxy)phenylglyoxyloylamino, 3 - (3 tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloylamino, 3 - (3 - phthalimidopropoxy)phenylglyoxyloylamino, N - [N - (2 - nitrophenyl)oxamoyl] - 2 - phenylglycinamido, 2 - [2 - (2 - (4 - chloro - 2 - nitrophenoxy)acetamidomethyllphenoxy]acet- amido, 2 - [2 - (2 - bromoacetamidomethyl)phenoxy]acetamido, N-(N-benzyloxamoyl)amino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (5 - chlorosalicyloylamino)acetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (3 - phenylureido)acetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - oxo - 1 - imid- azolidinylcarboxamido)acetamido, 3 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy) - 3 - chlorophenyl] - 2 - hydroxyiminoacetamido, 4 - (3 - amino - 3 - carboxypropoxy) - 3 - chlorophenylglyoxyloylamino, 2 - [4 - (3 - amino - 3-- carboxypropoxy)phenyl] - 2 - hydrazonoacetamido, 2 - [4 - (3 - carboxy - 3 - (2 - phenylglycinamido)propoxyjphenyl] - 2 - hydroxy- iminoacetamido, 2 - [4 - (3 - carboxy - 3 - glycinamidopropoxy)phenyl] - 2 - hydroxyimino- acetamido, 2 - (2 - aminoethoxyimino) - 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl]acetamido, 2 - [2 - (2 - carboxymethoxybenzylaminomethyl)phenoxy]acetamido, 2 - (2 - aminomethylphenoxy)acetamido, 2 - methoxyimino - 2 - (2 - amino - 4 - thiazolyl)acetamido, 4 - (3 - aminopropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)pheny1] - 2 - (carboxymethoxyimino)acetamido, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloyl- amino, 3 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloyl- amino, 4 - (3 - carboxypropoxy)phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy) - 3 - chlorophenylglyoxyloylamino, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 (5 - chlorosalicyloylamino)acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - (2oxo - 1 - imidazolidinecarboxamido)acetamido, 2 - benzamido - 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2 - (3phenylureido)acetamido, 2 - (2 - aminoacetamido) - 2 - (2 - thienyl)acetamido, N - [N - (2 - hydroxyethyl)oxamoyl]amino, (2 - amino - 2 - carboxyethylthio)pyruvoyl, 2 - (4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - (2 - phenylacetamido)acetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl]glycinamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy) - 3 - chlorophenyl] - 2 - hydroxyiminoacetamido, 2 - [3 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - 4 - (3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - methoxyiminoacetamido, 2 - [4- (3 - amino - 3 - carboxypropoxy)phenyl] - 2- (2- ethoxycarbonylethoxyimino)acetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - benzyloxyiminoacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydrazonoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - semicarbazonoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - thiosemicarbazonoacetamido, 2 - [4 - {3 - (2 - chioroacetamido) - 3 - carboxypropoxyiphenyl] - 2 - hydroxy- iminoacetamido, 2 - (4 - {3 - (2 - phthalimidoacetamido) - 3 - carboxypropoxy}phenyl] - 2 hydroxyiminoacetamido, 2 - [4 - {3 - (3 - amidinoureido) - 3 - carboxypropoxy]phenyl] - 2 - hydroxy- iminoacetamido, 2 - 4 - {3 - [2 - tert - butoxycarbonylaminoacetamido) - 3 - carboxypropoxy}phenyl] - 2 - hydroxyiminoacetamido, or 2 - [4 - 13 - (2 - phenyl - 2 - tert - butoxycarbonylaminoacetamido - 3 - carboxy propoxyiphenyl] - 2 - hydroxyiminoacetamido, and R2' is a group of the formula:
7. A compound according to claim 1, wherein R1 is amino, phthalimido, 4 - [3 - tert - butoxycarbonylamino - 3 - (4 - methoxybenzyloxycarbonyl)propoxy]phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloylamino, 4 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydroxyiminoacetamido or 2 - phenyl - 2 - hydroxyiminoacetamido, and R2' is a group of the formula:
8. A compound according to claim 1, wherein R is amino or 4 - [3 - tert - butoxycarbonylamino - 3 - (4 - methoxybenzyloxycarbonyl)propoxy]phenylglyoxyloylamino, and R2' is a group of the formula:
9. A compound according to claim 1, wherein R1 is 4 - (3 - amino - 3 - carboxypropoxy)phenylglyoxyloylamino, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyiminoacetamido, 2 - [4 - (3 - amino - 3 - carboxypropoxy)phenyl] - 2 - hydroxyacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyll - 2hydroxyacetamido, 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydroxyiminoacetamido, or 2 - [4 - (3 - carboxy - 3 - tert - butoxycarbonylaminopropoxy)phenyl] - 2hydroxyiminoacetamido, and R2' is a group of the formula:
10. A compound according to claim 1, wherein R' is 2 - (2 - thienyl) - 2 - (2,2,2 - trichloroethoxycarbonylamino)acetamido or 2 - (2 - thienyl) - 2 - [2 - (4 - chloro - 2 - nitrophenoxy)acetamido]acetamido, and R2' is a group of the formula:
I I. A compound according to claim 1, wherein R1 is phthalimido, 2 - [4- (3 - amino - 3 - carboxypropoxy)phenyl] - 2- hydroxyiminoacetamido or 2 - [4 - (3 - tert - butoxycarbonylamino - 3 - carboxypropoxy)phenyl] - 2hydroxyiminoacetamido, and R2' is a group of the formula:
12. A compound according to claim 1, wherein R1 is benzoyloxycarbonylamino, phthalimido or 4 - (3 - tert - butoxycarbonylamino - 3 - methoxycarbonylpropoxy)phenylglyoxyloylamino, and R2' is a group of the formula:
GB5271476A 1974-07-04 1976-12-17 Azetidionones and process for preparation thereof Expired GB1573931A (en)

Applications Claiming Priority (6)

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JP49077091A JPS51125061A (en) 1974-07-04 1974-07-04 A process for 3-acylaminoazetidinone derivatives
JP49085526A JPS51125062A (en) 1974-07-24 1974-07-24 A process for preparing 3-aminoazetidinone
JP49088452A JPS51125064A (en) 1974-07-31 1974-07-31 A process for preparing 1-substituted-3- acylaminoazetidinone derivati ves
JP50002650A JPS5175056A (en) 1974-12-23 1974-12-23 33 chikanazejinonjudotaino seizoho
JP15851175A JPS5283451A (en) 1975-12-30 1975-12-30 Preparation of 3-imino-substituted acylamino-2-azetidinone derivative
JP51000190A JPS6042237B2 (en) 1976-01-01 1976-01-01 Azetidinone derivatives

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US6541466B2 (en) 1996-12-23 2003-04-01 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6569851B1 (en) 1998-06-22 2003-05-27 Elan Pharmaceutials, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
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US6632811B2 (en) 1996-12-23 2003-10-14 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US7153847B2 (en) 1996-12-23 2006-12-26 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6541466B2 (en) 1996-12-23 2003-04-01 Athena Neurosciences, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6569851B1 (en) 1998-06-22 2003-05-27 Elan Pharmaceutials, Inc. Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6696438B2 (en) 1998-06-22 2004-02-24 Elan Pharmaceuticals, Inc. Cyclic amino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6774125B2 (en) 1998-06-22 2004-08-10 Elan Pharmaceuticals, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds
US6838455B2 (en) 1998-06-22 2005-01-04 Athena Neurosciences, Inc. Deoxyamino acid compounds, pharmaceutical compositions comprising same, and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds
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