CA1051420A - ESTERS OF .alpha.-SUBSTITUTED AMIDINOPENICILLANIC ACIDS - Google Patents
ESTERS OF .alpha.-SUBSTITUTED AMIDINOPENICILLANIC ACIDSInfo
- Publication number
- CA1051420A CA1051420A CA165,831A CA165831A CA1051420A CA 1051420 A CA1051420 A CA 1051420A CA 165831 A CA165831 A CA 165831A CA 1051420 A CA1051420 A CA 1051420A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- process according
- penicillanate
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to new penicillanic acid derivatives which are effective in treatment of infectious diseases caused by bacterial microorganisms and to methods for their preparation. More precisely this invention relates to new esters of amidinopenicillanic acids of the formula:
I
and therapeutically acceptable salts thereof, wherein R1 and R2, which are the same or different, are alkyl groups containing from 1 to 10 carbon atoms R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring system; R3 is selected from the group consisting of and in which radicals R4 is selected from the group consisting of alkyl groups containing from 1 to 8 carbon atoms, or phenyl, R5 is selected from the group consisting of hydrogen, methyl and ethyl, with the proviso that when R1 and R2 together with the adjacent nitrogen atom form a hexahydro-1H-azepine ring R3 is
The present invention relates to new penicillanic acid derivatives which are effective in treatment of infectious diseases caused by bacterial microorganisms and to methods for their preparation. More precisely this invention relates to new esters of amidinopenicillanic acids of the formula:
I
and therapeutically acceptable salts thereof, wherein R1 and R2, which are the same or different, are alkyl groups containing from 1 to 10 carbon atoms R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring system; R3 is selected from the group consisting of and in which radicals R4 is selected from the group consisting of alkyl groups containing from 1 to 8 carbon atoms, or phenyl, R5 is selected from the group consisting of hydrogen, methyl and ethyl, with the proviso that when R1 and R2 together with the adjacent nitrogen atom form a hexahydro-1H-azepine ring R3 is
Description
~,oS~20 The present invention relates to new penicillanic acid derivatives which are effective in treatment of infectious diseases caused by bacterial microorganisms and to methods for their preparation.
More precisely this invention relates to new esters of amidino-penicillanic acids of the formula Rl N-CH=N - CH - CH / \ C / 3 H R2 / ¦ ~ ¦ \ CH3 CO - N CH -COOR
and pharmaceutically acceptable salts thereof, wherein Rl and R2, which are the same or different, are alkyl groups containing from 1 to 10 carbon atoms, Rl and R2 together with the adjacent nitrogen atom form a heterocyclic ring system; R3 is selected from the group consisting of _1~_0_CO_R4 and -CH-o-Coo-R4 in which radicals R4 is selected from the group consisting of alkyl groups containing from 1 to 8 carbon atoms, and phenyl; R5 is selected from the group consisting of hydrogen, methyl and ethyl, with the proviso that when Rl and R2 together with the adjacent nitrogen atom form a hexahydro-lH-azepine ring, R3 is -CH-o-CooR4 and R5 is methyl, R4 is not ethyl.
The compound in which Rl and R2 together with the adjacent nitrogen atom form a hexahydro-lH-azepine ring, R3 is -CH-o-CooR4, R5 is methyl and R4 is ethyl, i.e. 1'-ethoxycarbonyloxy-ethyl-6-~hexahydro-lH-azepin-l-yl)-methyleneamino penicillanate of formula N-CH=N-CH-CH C
vis;~n~JQ
is the subject of~pplication ~4~-ial Mo. divided out of this application.
'. ~
14~20 Illustrative examples of radicals included in the above definitions are: alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, 2-ethyl-hexyl -NRl, R2 forming a ring system:
/ 2 \ / CH2 - CH2 / CH2 - CH2 \
-N CH2 -H ¦ -N / CH2 CH2 - CH2 - CH2\
\ CH2 - 2 .:
i~
ij .~:
:~ .
i :
i _ la '( . .
1~51`~'~0 The above illustrative examples illustrate, where applicable, all the radicals Rl-R4 to the extent of the definition given to each radical and within the boundaries with regard to number of carbon atoms which may be prescribed for each radical.
The invention relates in a further aspect to such chemical intermediates which are new and useful in the preparation of the compounds of the formula I.
The compounds of the invention are of value in the treatment of infectious diseases in man or animal caused by bacterial organisms. They may be isolated and used as such but also, depending on the presence of basic groups in the molecule, in the form of salts with pharmaceutically acceptable organic or inorganic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid~ sulphuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, and fumaric acid.
The side chain of the structure in formula I may contain an asymmetric center. Depending on the configuration around this center the compound will occur in different diastereoisomeric forms which are all biologi-cally active. Likewise the ester groups may contain asymmetric atoms, e.g.
; when R5-CH3 or C2H5, giving rise to different diastereoisomeric forms which also all are biologically active. It is to be understood that the invention comprises the pure diastereoisomers as well as mixtures of them.
Penicillanic acid derivatives of the general fo~la 11 ~5~
`\ N-CH=N-CH - CH / \ C ~ 3 R2 / l l ¦ CH3 CO - N CH - COOH
are known to have strong antibacterial activity especially against gramnega-tive organisms ~Canadian Patent No. 914,165). They are, however, not well absorbed by the oral route and have to be given by injection. It is one pur-pose of the present invention to provide esters of compounds of formula II, which are well absorbed orally and hydrolysed within the body to give blood and organ levels of the compounds of formula II that are adequate for the treatment of infectious diseases caused by bacteria sensitive to penicillanic acids of the general formula II. To achieve the full antibacterial activity of the penicillanic acids II it is necessary to choose such ester groups that are rapidly hydrolyzed in vivo. It is an essential feature of the present invention to provide such ester groups that are rapidly hydroly2ed in the body after oral absorption.
The compounds of the invention with the formula I are well tolerated, give a low frequency of side-effects and may readily be used in pharmaceutical preparations, either as such or in the form of their salts, and they can be intermixed with solid carriers or adjuuants.or both. In such preparations the ratio between the therapeutic substance and the carriers and adjuvants may vary between 1 % and 95 %. The preparation may either be processed to for instance tablets, pills or dragees or can be supplied to medical contain-brs, such as capsules or as regards mixtures they can be filled on bottles.
Pharmaceutically acceptable, organic oriinoganic, solid or liquid carriers may be used, suitably for oral or enteral administration or for topical application, in manufacturing the preparations. Gelatine, lactose, starch, magnesium stearate, talc, vegetabilic and animalic fats and oils, vegetabilic rubber and polyalkylene glycol and other kno~n carriers for pharmaceuticals are all suitable or manufacturing preparations of said compounds. Moreover, the preparation may contain other pharmaceutical active~components, being 1~5~ .0 suitably adminstratable together with the compounds of the invention when treating infectious diseases. For instance other suitable antibiotical sub-stances, e.g. gentamycin and polymyxin.
In the treatment of bacterial infections in man, the compounds of invention are for example administered in amounts corresponding to 5 to 20 mg/kg/day, preferably in the range of 10 to 100 mg/kg/day in divided dosages, e.g. two, three or four times a day. They are administered in dosage~units containing e.g. 175, 350, 500 and 1000 mg of the compounds.
Examples of preferred compounds of the invention are given in Tables 10 1-5. The designations Me and Et in the tables mean methyl and ethyl, respectively.
Table I
Rl R2 R3 ethyl ethyl CH~Me)OCOMe propyl propyl "-ethyl isopropyl "-isopropyl isopropyl "-methyl n.butyl "-ethyl t.butyl "-n.heptyl n!heptyl "-methyl methyl "-RlR2N- R3 pyrrolidyl-l CH~Me)OCOMe
More precisely this invention relates to new esters of amidino-penicillanic acids of the formula Rl N-CH=N - CH - CH / \ C / 3 H R2 / ¦ ~ ¦ \ CH3 CO - N CH -COOR
and pharmaceutically acceptable salts thereof, wherein Rl and R2, which are the same or different, are alkyl groups containing from 1 to 10 carbon atoms, Rl and R2 together with the adjacent nitrogen atom form a heterocyclic ring system; R3 is selected from the group consisting of _1~_0_CO_R4 and -CH-o-Coo-R4 in which radicals R4 is selected from the group consisting of alkyl groups containing from 1 to 8 carbon atoms, and phenyl; R5 is selected from the group consisting of hydrogen, methyl and ethyl, with the proviso that when Rl and R2 together with the adjacent nitrogen atom form a hexahydro-lH-azepine ring, R3 is -CH-o-CooR4 and R5 is methyl, R4 is not ethyl.
The compound in which Rl and R2 together with the adjacent nitrogen atom form a hexahydro-lH-azepine ring, R3 is -CH-o-CooR4, R5 is methyl and R4 is ethyl, i.e. 1'-ethoxycarbonyloxy-ethyl-6-~hexahydro-lH-azepin-l-yl)-methyleneamino penicillanate of formula N-CH=N-CH-CH C
vis;~n~JQ
is the subject of~pplication ~4~-ial Mo. divided out of this application.
'. ~
14~20 Illustrative examples of radicals included in the above definitions are: alkyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, 2-ethyl-hexyl -NRl, R2 forming a ring system:
/ 2 \ / CH2 - CH2 / CH2 - CH2 \
-N CH2 -H ¦ -N / CH2 CH2 - CH2 - CH2\
\ CH2 - 2 .:
i~
ij .~:
:~ .
i :
i _ la '( . .
1~51`~'~0 The above illustrative examples illustrate, where applicable, all the radicals Rl-R4 to the extent of the definition given to each radical and within the boundaries with regard to number of carbon atoms which may be prescribed for each radical.
The invention relates in a further aspect to such chemical intermediates which are new and useful in the preparation of the compounds of the formula I.
The compounds of the invention are of value in the treatment of infectious diseases in man or animal caused by bacterial organisms. They may be isolated and used as such but also, depending on the presence of basic groups in the molecule, in the form of salts with pharmaceutically acceptable organic or inorganic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid~ sulphuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, and fumaric acid.
The side chain of the structure in formula I may contain an asymmetric center. Depending on the configuration around this center the compound will occur in different diastereoisomeric forms which are all biologi-cally active. Likewise the ester groups may contain asymmetric atoms, e.g.
; when R5-CH3 or C2H5, giving rise to different diastereoisomeric forms which also all are biologically active. It is to be understood that the invention comprises the pure diastereoisomers as well as mixtures of them.
Penicillanic acid derivatives of the general fo~la 11 ~5~
`\ N-CH=N-CH - CH / \ C ~ 3 R2 / l l ¦ CH3 CO - N CH - COOH
are known to have strong antibacterial activity especially against gramnega-tive organisms ~Canadian Patent No. 914,165). They are, however, not well absorbed by the oral route and have to be given by injection. It is one pur-pose of the present invention to provide esters of compounds of formula II, which are well absorbed orally and hydrolysed within the body to give blood and organ levels of the compounds of formula II that are adequate for the treatment of infectious diseases caused by bacteria sensitive to penicillanic acids of the general formula II. To achieve the full antibacterial activity of the penicillanic acids II it is necessary to choose such ester groups that are rapidly hydrolyzed in vivo. It is an essential feature of the present invention to provide such ester groups that are rapidly hydroly2ed in the body after oral absorption.
The compounds of the invention with the formula I are well tolerated, give a low frequency of side-effects and may readily be used in pharmaceutical preparations, either as such or in the form of their salts, and they can be intermixed with solid carriers or adjuuants.or both. In such preparations the ratio between the therapeutic substance and the carriers and adjuvants may vary between 1 % and 95 %. The preparation may either be processed to for instance tablets, pills or dragees or can be supplied to medical contain-brs, such as capsules or as regards mixtures they can be filled on bottles.
Pharmaceutically acceptable, organic oriinoganic, solid or liquid carriers may be used, suitably for oral or enteral administration or for topical application, in manufacturing the preparations. Gelatine, lactose, starch, magnesium stearate, talc, vegetabilic and animalic fats and oils, vegetabilic rubber and polyalkylene glycol and other kno~n carriers for pharmaceuticals are all suitable or manufacturing preparations of said compounds. Moreover, the preparation may contain other pharmaceutical active~components, being 1~5~ .0 suitably adminstratable together with the compounds of the invention when treating infectious diseases. For instance other suitable antibiotical sub-stances, e.g. gentamycin and polymyxin.
In the treatment of bacterial infections in man, the compounds of invention are for example administered in amounts corresponding to 5 to 20 mg/kg/day, preferably in the range of 10 to 100 mg/kg/day in divided dosages, e.g. two, three or four times a day. They are administered in dosage~units containing e.g. 175, 350, 500 and 1000 mg of the compounds.
Examples of preferred compounds of the invention are given in Tables 10 1-5. The designations Me and Et in the tables mean methyl and ethyl, respectively.
Table I
Rl R2 R3 ethyl ethyl CH~Me)OCOMe propyl propyl "-ethyl isopropyl "-isopropyl isopropyl "-methyl n.butyl "-ethyl t.butyl "-n.heptyl n!heptyl "-methyl methyl "-RlR2N- R3 pyrrolidyl-l CH~Me)OCOMe
2-methylpiperidyl-1 "-
3-methylpiperidyl-1 "-
4-methylpiperidyl-1 "-2, 6-dimethylp,iperidyl - l "-hexahydro-lH-azepin-l-yl "-hexahydro-lH-azepin-l-yl "-hexahydro-lC2H~-azocinyl CH(Me)OCOMe 1,2,3,4-tetrahydroisoquinolyl-2 "-4-methylpiperazinyl~
morfolinyl~4 "-~Table 2 _ _ 3 Rl R2 R
~s~o ethyl ethyl ~HCEt)OCOMe propyl propyl "-ethyl isopropyl "-isopropyl isopropyl "-methyl n.butyl "-ethyl t.butyl "-n.heptyl n.heptyl "-methyl methyl "-RlR2N- - ~ R3 pyrrolidyl-l CH(Et)OCOMe 2-methylpiperidyl-1 "-3-methylpiperidyl-1 "-4-methylpiperidyl-1 "-2,6-dimethylpiperidyl-1 "-hexahydro-lH-azepin-l-yl "-hexahydro-lH-azepin-l-yl "-hexahydro-lC2H)-azocinyl "-1,2,3,4-tetrahydroisoquinolyl-2 "-4-methylpiperizinyl-1 "-morfolinyl-4 "-Table 3 2 3 Rl R R
ethyl ethyl~ CH20C0OEt propyl propyl "-ethyl isopropyl "-isopropyl isopropyl "-methyl n.butyl "-ethyl t.butyl "-n.heptyl n.heptyl "-methyl methyl "-RlR N- R3-~ CH OCOOEt pyrrolldyl-l 2 2-methylpiperidyl^l ''-3-methylpiperidyl-1 4-methylpiperidyl-1 "_ 2,6-di~ethylpipe~idyl-1 "-hex~hydro-IH~azepin-l-yl "-hexahydro-lH-azepin-l-yl "-hexahydro-1(2H)-azocinyl "-
morfolinyl~4 "-~Table 2 _ _ 3 Rl R2 R
~s~o ethyl ethyl ~HCEt)OCOMe propyl propyl "-ethyl isopropyl "-isopropyl isopropyl "-methyl n.butyl "-ethyl t.butyl "-n.heptyl n.heptyl "-methyl methyl "-RlR2N- - ~ R3 pyrrolidyl-l CH(Et)OCOMe 2-methylpiperidyl-1 "-3-methylpiperidyl-1 "-4-methylpiperidyl-1 "-2,6-dimethylpiperidyl-1 "-hexahydro-lH-azepin-l-yl "-hexahydro-lH-azepin-l-yl "-hexahydro-lC2H)-azocinyl "-1,2,3,4-tetrahydroisoquinolyl-2 "-4-methylpiperizinyl-1 "-morfolinyl-4 "-Table 3 2 3 Rl R R
ethyl ethyl~ CH20C0OEt propyl propyl "-ethyl isopropyl "-isopropyl isopropyl "-methyl n.butyl "-ethyl t.butyl "-n.heptyl n.heptyl "-methyl methyl "-RlR N- R3-~ CH OCOOEt pyrrolldyl-l 2 2-methylpiperidyl^l ''-3-methylpiperidyl-1 4-methylpiperidyl-1 "_ 2,6-di~ethylpipe~idyl-1 "-hex~hydro-IH~azepin-l-yl "-hexahydro-lH-azepin-l-yl "-hexahydro-1(2H)-azocinyl "-
- 5 ~
r ~.~s~ o 1,2,3,4-tetrahydrosioquinolyl-2 "-4-methylpiperazinyl-1 "-morfolinyl-4 "-Table 4 - 3 Rl R2 R
ethyl ethyl CH(Me)OCOOEt propyl propyl "-ethyl isopropyl "-isopropyl isopropyl "-methyl n.butyl "-ethyl t.butyl CH ~le)OCOOEt n,heptyl n.heptyl "-methyl methyl ~-R R N- R
pyrrolidyl-l CH~Me)OCOOEt 2`methylpiperidyl-1 "-3-methylpiperidyl-1 "-4-methylpiperidyl-1 "-G 2,6-dimethylpiperidyl-1 "-llv~lly~lru-lH-~
l.vxal.~ v~
hexahydro-1(2H)-azocinyl "-1,2,3,4-tetrahydroisoquinolyl-2 "-4-methylpiperazinyl-1 "-morfolinyl-4 "-Table 5 ethyl ethyl CH20COOpropyl propyl propyl "-ethyl isopropyl "-isopropyl isopropyl CH(Me)OCOO-propyl methyl n.butyl "-ethyl t.butyl "
r ~.~s~ o 1,2,3,4-tetrahydrosioquinolyl-2 "-4-methylpiperazinyl-1 "-morfolinyl-4 "-Table 4 - 3 Rl R2 R
ethyl ethyl CH(Me)OCOOEt propyl propyl "-ethyl isopropyl "-isopropyl isopropyl "-methyl n.butyl "-ethyl t.butyl CH ~le)OCOOEt n,heptyl n.heptyl "-methyl methyl ~-R R N- R
pyrrolidyl-l CH~Me)OCOOEt 2`methylpiperidyl-1 "-3-methylpiperidyl-1 "-4-methylpiperidyl-1 "-G 2,6-dimethylpiperidyl-1 "-llv~lly~lru-lH-~
l.vxal.~ v~
hexahydro-1(2H)-azocinyl "-1,2,3,4-tetrahydroisoquinolyl-2 "-4-methylpiperazinyl-1 "-morfolinyl-4 "-Table 5 ethyl ethyl CH20COOpropyl propyl propyl "-ethyl isopropyl "-isopropyl isopropyl CH(Me)OCOO-propyl methyl n.butyl "-ethyl t.butyl "
- 6 -~ ~5~?,0 n.heptyl n.heptyl CH~Me)OCOOn-hexyl methyl methyl CHtMe)OCOOCH2CH2NH2 RlR2~1 R3 ._ - - - -pyrrolidyl-l CH(Me)OCOCH2CH2NHMe 2-met:hylpiperidyl-1 " ~
3-methylpiperidyl-1 " ~
4-methylpiperidyl-1 CH2OCOOCH2CH2NEt2 2,6-dimethylpiperidyl-1 " ~
hexahydro-lH-azepin-l-yl "~ ;~
hexahydro-lH-azepin-l-yl CH2OCOOCH2CH2NH2 hexahydro-1~2H)-azocinyl " ~
1,2,3,4-tetrahydroisoquinolyl-2 CH2OCOOCH2CH2NHMe 4-methylpiperazinyl-1 "~
morfolinyl-4 "~
The compounds of the invention are prepared by different methods ~ --such as by reacting a reactive derivative of an amide OT thioamide of the formula III
Rl N - CH = R6 III
R2~
where Rl and R2 are as defined above and R6 is O or S, with an ester of 6-aminopenicillanic acid with the formula IV
S \ / CH3 H N-CH - CH C IV
2 1 ¦ ¦ \ CH3 3 CO - N CH - COOR
where R3 is as defined above.
The reactive derivatives of the amides or thioamides of formula III are acid amide halogenides or dialkylsulphate complexes of acid b~;n~
amides or acid amide acetals. The former two reagents may be 4~usiuuul accord-ing to known methods by treatment of compounds of the formula III with halo-genating agents like phosgeneJ oxalyldichloride, thionyl chloride or thionyl omide or with a dialkylsulphate like dimethyl sulphate. The reactions with . ~ _ 7 _ i(~S14~0 the halogenating agents are performed in inert dry organic solvents like diethylether, toluene, benzene, chloroform or carbon tetrachloride. The halogenides are usuall~ obtained as ! :
i~ ' .1~
~ - 7a -:
~`i ~. ., . ' '' ' ' .: .. ': . -: .: . :. . . . . ' .
1~51~'~0 hygroscopic precipitates.
~reatment of the acid amide dialkylsulphate complexes with strong bases, e.g. sodium methoxide, convert them into acid amide acetals of the formula (V) 2,",N - CH(OR )2 V
where R7 is a lower alkyl group originating from the dialkylsulphate, which also can be reacted with the esters of 6-aminopenicillanic acid with the formula IV to give the compounds of the invention.
The esters of 6-aminopenicillanic acid with the general structure IV may be prepared by treatment of 6-APA with compounds R3-Y , where R3 has the same meaning as above and Y is halogen or a functionally equivalent group capable of reacting with a carboxy group under formation of an ester linkage, such as an organic sulphonic acid residue. The reaction is pref-erably performed in organic solvents like dimethylformamide, dimethyl-~ulphoxide or hexamethylphosphoramide.
Alternatively 6-acylaminopenicillanic acid~ with acyl groups that can be removed without destruction of the penicillin ring system are treated with R3-Y wherein R3 and Y have the meaning specified above, to give esters 1 of the 6-acylamino penicillanic acids from which the acyl groups then are re-t 20 moved to give the esters of 6-aminopenicillanic acid of the formula III. A
I ~ preferred method consists of reacting a salt, e.g. the sodium, potassium or tetraalkylammonium salt of 6-phenylacetamido penicillanic acid(benzyl-penicillin) with R3-Y in an organic solvent like chloroform, methylene-I :~
chloride, acetone, dimethylformamide, dimethylsulphoxide or hexamethyl-ph4sphoramide or in a mixture of an organic solvent and water, e.g. aqueous acetone or dioxane to give the corresponding ester of benzylpenicillin. The phenylacetyl side chain is then removed according to the method described 1:
in United States patent No. 3,697,515 or South African Patent publication 67/2g27 by treatment with phosphorous pentachloride in presence of a tertiary oreanic base to give an imino chloride which is reacted with an .
~ - 8 -.'~
~Si~O
alcohol like propanol to give the corresponding imino ether which is hydrolyzed by add:it.ion of water or alcoholized by addition of alcohol, to give the ester III. Alternatively the phenylacetyl side chain may be removed by enzymatic hydrolysis using an E.coli acylase according to the method described in ;
- 8a -r~;,.
. .
105~ 0 French Patent 1 576 027 In still another method N-protected 6-aminopenicillanic acids are reacted with R3-Yl to give the corresponding ester from which the protecting groups are removed to give the compounds of the general formula IV.
Examples of protecting groups which can be used are the benzyloxycarbonyl group which is removed by catalytic hydrogenation, the 0-nitro-phenyl-sulphenyl group which can be removed by treatment with nucleophilic agents at acid pH (Jap. Pat. 505 176), and the trityl group which can be removed by mild acid hydrolysis.
lD Alternative methods can be used for the preparation of the compounds of the invention. 6-formamidopenicillanic acid may be converted into esters of the formula (VI) / \ / 3 HCONHCH - CR ¦ \ CH3 VI
CO - N CH - COOR
where R3 is as defined above by reaction with R3Y under the conditions previously indicated. Treatment of an ester of 6-aminopenicillanic acid, i.e. a compound of formula IV,with an l,l-dihalogendimethyl ether, e.g.
l-dichlorodimethyl ether, in presence of a tertiary organic base, gives a reactive derivative of the compound of formula VI which reactive derivative reacts with an amine of the formula (VII):
1. ~ 1 R ~ NH VII
R2 "' where R and R are as defined a~ove, to give the compound of formula I.
~ A third method consists of reacting compounds of formula II, 1 suitable in form of a salt, e~gO a sodium, potassium, calcium, triethylammoni~m or tetraalkylammonium salt, with a compound R3 ~ wherein R and Y have the meaning specified above to give the compounds of the ~ _ 9 _ ;
.. . . .
~C~514'~
invention with the general formula I. The reaction s suitably performed in organic solvents like chloroform, methylenechloride, acetone, dimethylformamide~ dimethylsulphoxide or hexamethylphosphoramide or in aqueous organic solvents like aqueous dioxane.
H - 9a -1(~51~'~0 As described above the starting material may be in the form of a salt, for instance a sodium, potassium, calcium or trialkylammonium salt, in some of the ways for the preparation of the compounds of the invention.
In addition, tetraalkylammonium salts and other analogues salts such as salts where the cation has the formula AlA2A3A4N 1~) in which formula A is selected from the group consisting of straight and branched alkyl groups containing from 3 to 6 carbon atoms, substituted and unsubstituted aryl, and substituted and unsubstituted aralkyl, and wherein A , A3 and A , which are the same or different, are selected from the group consisting of straight and branched alkyl groups containing from 1 to 6 carbon atoms, provided that A , A3 and A are alkyl with 3-6 carbon atoms when A is alkyl, may be used.
Illustrative examples of suitable combinations of A , A , A3 and A in the quaternary ammonium ion A1A2A3A4N ~ are given below:
Table I. Examples of suitable combinations of the radicals A -A4 in the AlA2A3A4N ~ ion n-propyl n-propyl n-propyl n-propyl i-propyl i-propyl i-propyl i-propyl n-butyl n-butyl n-butyl n-butyl i-butyl i-butyl i-butyl i-butyl n-pentyl n-pentyl n-pentyl n-pentyl n-hexyl n-hexyl n-hexyl n-hexyl phenyl methyl methyl methyl phenyl ethyl ethyl ethyl p-tolyl ethyl ethyl ethyl p-chlorophenyl ethyl ethyl ethyl When the radicals A -A all are different the resulting ion :
contains an asymmetric centre and may occur in two enantiomeric forms. Epimeric forms can occur if A , A , A3 andtor A contain one or more asymmetric carbon atoms.
i , . . . . .
.. ..
~5~1~ZO
Examples of quaternary ammonium ions containing an asymmetric centre are given in Table II below:
Table II - Examples of quaternary ammonium ion AlA2A3A4N ~3 containing an asymmetric centre Al A2 A3 A4 benzyl n-propyl i-propyl n-butyl benzyl n-propyl i-propyl sec.butyl benzyl n-propyl n-butyl sec.butyl n-propyl n-propyl n butyl sec.butyl n-propyl n-propyl n-propyl sec.butyl n-propyl n-propyl n-propyl sec.pentyl n-propyl n-propyl n-propyl sec.hexyl n-propyl n-propyl n.butyl sec.hexyl -The use as describéd above of a quaternary salt form of the start-ing material for the preparation of the compounds of this inyention is not previously described in the literature pertaining to this technical field. In this method the preferred cation is the tetraalkylammonium ion, particularly the tetrabutylammonium ion. The preferred solvents are chloroform, methylene-chloride and acetone.
The quaternary ammonium salt form of the above described starting material may be prepared by reacting the starting material in question with a quaternary ammonium salt of the formula AlA2A3A4N ~ B Q
wherein Al, A2, A3 and A4 have the meanings specified above and B is a suitable anion such as HS04 ~ , CL ~ or CH3COO Q to the formation of a quaternary salt of the starting material.
The salts of the formula above which contains B as the anion may be prepared in known manner analogous as described in for instance Belgian patent 751,791. The anion B ~3 is in the preferred embodiment HS04 ~3 .
The following examples will further illustrate the invention.
1~51'~0 Example 1 illustrates the preparation of l'-ethoxycarbonyloxy ethyl-6-(hexahydro-lH-azepin-l-yl)methyleneamino penicillanate which is not within the claims of this application but is the subject of the divisional application mentioned above. It will readily be inferred that compounds with-in the claims of this application can be made by the procedures illustrated in Example 1. Likewise in Example 8 formulations (b), (g) and (i) contain the compound of the divisional application but it will be appreciated that compounds within the claims of this application could be substituted for that compound in the formulations shown.
- lla -P~.
. , .
1~514~0 Example 1. l-Ethoxycarbonyloxy-ethyl 6-(hexahydro-lH-azepin-l-yl)-methylene-amino penicillanate ,~ef~
l-Hexamethyleneiminocarboxaldehyde-dimcth~ t~G (3.1 g) in chloroform ~50 ml) was added dropwise at -30C to a solution of l-ethoxycar-bonyloxy-ethyl 6-amino-penicillanate (5 g) and triethylamine Cl.9 ml) in chloroform (150 ml) during 15 minutes. Then the temperature is allowed to rise to 0 during 30 minutes and the mixture is stirred at O for another 60 minutes. Water (120 ml) is added and stirring is continued for 10 minutes.
The water phase is separated and the organic layer is washed with water and stripped. The residue (5 g) showed a strong IR-absorption band at 1775 cm 1 (~-lactam ring).
Incubation of the product with human serum at 37C was found to cause a rapid formation of 6-(hexahydro-lH-azepin-l-yl)-methyleneamino pen-icillanic acid.
The l-ethoxycarbonyloxy-ethyl 6-aminopenicillanate was prepared as described in Canadian Patent No. 960,211.
Example 2 By substituting the l-ethoxycarbonyloxy-ethyl 6-aminopenicillanate in example 1 with l-acetoxy-ethyl 6-aminopenicillanate and ethoxycarbonyloxy-methyl 6-amino-penicillanate, ~-acetoxy-ethyl and ethoxycarbonyloxymethyl 6-~hexahydro-lH-azepin-l-yl)-methyleneamino penicillanates respectively were ', obtained. The compounds showed strong ~-lactam absorption in IR at 1775 cm 1 and were rapdily hydroly~ed by human serum to the corresponding penicillanic acids.
Example 3 l-Ethoxycarbonyloxyet,hyl 6-,~piperidyl-1-)-methyleneaminopenicillanate To phosphorus pentachloride ~1.7 g, 0.008 mole) and quinoline (1.8 g, 0.016 mole~ in dry methylene chloride (50 ml~ l-ethoxycarbonyloxyethyl ben-~ylpenicillanate C3.2 g, 0.007 mole) was added with stirring and chilling to -40C, the reaction was kept in dry iner~ gas Cargon~. After 1 hour dry me-thanol C2.24 g) was added dropwise and the temperature was adjustsd to -30.
~ - 12 -~Si4'20 After 1 hour brine ClS ml) was dropped to the solution while the temperature was allowed to rise to 0. After 15 min. the organic phase was dried and evaporated in vacuo, the residue was triturated with petroleum - 12a -~, .
1(~51'~'~0 ether and dried yielding a crystalline mass (2.8 g, 100%), IR 1790 cm 1 (~_ lactam). To a solution of this material (2.8 g, 0.007 mole) and triethyl-amine (o.84 ml, o.oo6 mole) in chloroform (50 ml) at -50 - -60 N-piperidylchloroformiminiumchloride (1.1 g, o.oo6 mole) in chloroform (20 ml) was added dropwise. The mixture was kept under dry argon for 1.5 h during which time the temperature rose to 0 . The solvent was removed in vacuo at 40 and the residue was slurried with dry acetone (100 ml) and filtered.
The flltrate was concentrated in vacuo and the remaining oil was triturated with petroleum ether until crystallisation, yield 1.2 g, IR-absorption 1760 cm (~-lactam), NMR: ringlet at 480 cps (methyleneimino), multiplet at 320 cps (5- and 6`position of penicillin nucleus).
Example 4 l'-Acetoxyethyl 6-(piperidyl-1)-meth~leneamino~enicillanate was _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ prepared as described in Example 3 from l'-acetoxyethyl benzylpenicillinate (2.94 g, 0.007 mole) and N-piperidylchloroformiminiumchloride (1.1 g, o.oo6 mole) yielding a half crystalline mass. IR-absorption at 1760 cm 1 (~-lactam).
Example 5 Ethoxy_a b_n~loxymethyl 6-(hexahyd_o_lH-_z~p_n-l-yl)_methylene_ amin_E~I c.LIanate was prepared as described in Example 3 from ethoxy-carbonyloxymethyl benzylpenicillinate (3. g, mole) and hexahydro-lH-azepin-l-ylchloroformiminium chloride (1.15 g, o,oo6 mole) yielding an oil; IR-absorption 1760 cm (~-lactam).
ExamPle 6 Phenox~carbonylo~ymethyl 6-(ethy_-isop_o~yl)-met~ylene~m_n~p_n_c_l-la_ate was prepared as described in Example 3 from phenoxycarbonyloxymethyl benzylpenicillinate (3.4 g, 0,007 mole) and N-ethyl-N-isopropylchloroformim-inium chloride (1.02 g, o.oo6 mole) yielding an oily product; IR-absorption 1775 cm 1 (~-lactam).
Example 7 _h_n_xycarbonyloxyme_hyl_ 6-(N,N-di - e_hyl_-methyleneaminopenicil-_anate was prepared as described in Example 3 from phenoxycarbonyloxymethyl benzylpenicillinate (3.4 g, 0.007 mole) and N,N-dimethylchloroformiminium chloride (0.77 g, o.oo6 mole) yielding a half crystalline mass; IR-absorption 1775 cm 1 (~-la-ctam).
' ' lQs~ o Example 8. Pharmaceutical formulations For preparation of tablets the following compositions were made:
a) 1'-Acetoxyethyl 6-hexahydro-lH-azepin-1-(yl)--methyleneamino penicillanate 325 mg Starch 100 mg Magnesium stearate lO mg b) l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH--azepin-l-(yl)-methyleneamino penicillanate 350 mg Starch 100 mg Magnesium stearate 10 mg c) Ethoxycarbonyloxymethyl 6-hexahydro-lH-azepin-l-(yl)-methyleneamino penicillanate 350 mg Calcium carbonate 100 mg Magnesium stearate lO mg d) 1'-Ethoxycarbonyloxyethyl 6-(piperidyl-1)--methyleneamino-penicillanate 350 mg Lactose lO0 mg Magnesium stearate 10 mg ~ ~ ~20 e) 1'-Acetoxyethyl 6-(piperidyl-1)-methylene-: amino-penicillanate 300 mg !~ Calcium carbonate lO0 mg ~:: Lactose lO0 mg Magnesium stearate 10 mg : For filling in capsules the following formulations were made:
f) 1'-Acetoxyethyl 6-hexahydro-lH-azepin-1-(yl)-methyleneamino penicillanate 350 mg Magnesium stearate 5 mg gj l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH-azepin-l-:30 -(yl)-methyleneamino penicillanate350 mg Lactose 40 mg Magnesium stearate 5 mg ~;~ - 14 -' , .. . . .. , , - -11~5~4;~0 For oral suspensions the following formulations were prepared:
h) 1'-Acetoxyethyl 6-(piperidyl-1)-methylene~mino penicillanate 35 mg Aluminium monostearate 50 mg Tween - 80 ~ 1.2 mg Peanut oil ad 1000 mg i) l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH-azepin-l-(yl)-methyleneamino penicillanate 36 g Sodium benzoate o.48 g Sodium chloride 0-75 g Flavouring agents 4.7 g Aerosil ~ 0.3 g Antifoam ~ o.o375 g Alkali salts of polysaccharide sulphates 4.0 g Sodium saccharinate 0.4 g Sorbitol ad 100 g l(~S14~0 SUPPLEMENTARY DISCLOSURE
Example 9 Preparation of l~(S)-Ethoxycarbonyloxyethyl 6~j(hexahydro-lH-azepin-l-yl)-methyleneaminopenicillanate hydrochloride A. Preparation of l~(S)-Ethoxycarbonyloxyethyl 6~-amino~enicillanate hydrochloride used as starting material A solution of l'(S)-ethoxycarbonyloxyethyl 6-phenylacetamido peni-cillanate (7.4 g, 0.016 mole) in 10 ml dry ethanol-free chloroform was added to a stirred mixture of phosphorus pentachloride (3.8 g, 0.018 mole) and quinoline (4.8 g, 0.037 mole) in 25 ml dry ethanol-free chloroform at -20C
under dry nitrogen. After stirring at this temperature for l h, the solution was cooled to -30C and dry propanol (12 ml) was added during 20 mins. The temperature was allowed to rise to -15C during 30 mins, then cold brine (25 ml) was added with vigorous stirring while the temperature rose to -50C.
The reaction mixture was poured into 50 ~1 ice-cold ligroin and stirred for 15 mins, then a further 55 ml ice-cold ligroin were added and the mixture stirred for a further 10 mins. The mixture was then allowed to separate and the oil-water phase collected and extracted with 30 ml chloroform. The chloro-form phase was dried at 0C over sodium sulphate. lR (CHC13) showed ~-lactam (1790 cm~l) and ester (1790 cm~l). NMR (CDCl3): C(6)H, lH, d at 5.68 ppm (J=4.0 Hz); C(s)H, lH, d at 5.20 ppm (J=4.0 Hz).
B. l~(S)-Ethoxycarbonyloxyethyl 6~-(hexahydro-lH-azepin-l-yl)-methyl-ideneaminopenicillanate hydrochloride To the above-described chloroform solution of l'(S)-ethoxycarbonyl-~;~ oxyethyl 6~-aminopenicillanate hydrochloride cooled to 10C, triethylamine (5.80 ml, 0.042 mole) was added with stirring. The temperature was allowed to rise to -25C and then a solution of hexahydro-lH-azepin-l-ylchloroform-iminium chloride (3.79 g, 0.021 mole) in 10 ml dry ethanol-free chloroform was added dropwise. The mixture was then stirred at 0C for 30 mins. After removal of the solvent u~der reduced pressure the resulting residue was ~30 slurried with dry acetone (50 ml) and filtered. The filtrate was stripped :~ F~
1~514~0 of solvent and leached with petroleum ether and the syrupy residue dissolved by stirring with 10 ml 2-pentanon. The solution was kept at ~5C overnight whereupon the crude product crystallized and was collected by filtration.
i The,crude product was dissolved in methylene chloride (12 ml) and washed with cold saturated brine (2xlS ml). After drying the organic phase over sodium sulphate, the solvent was removed under reduced pressure and the resulting residue slurried with dry acetone (S ml) affording the analytically pure crystalline product, m.p. 147-149C (decomposition). [~]D = +163.5 (c=l;
96 % ethanol). lR (KBr): 1795 cm~l (~)-lactam car~onyl); 1760 cm~l (ester ' 10 carbonyl); 1675 cm~l (-CH=NH-). '' ¦ A proton NMR spectrum of the product showed only one signal for ,~ the C-3 proton indicating the presence of only one stereoisomer. This was confirmed by a carbon-13 NMR spectrum in CDC13 since only one signal was seen for the 2~.-methyl carbon at 29.44 ppm (from TMS) whereas a mixture of the two , stereoisomers gave signals for this carbon at 29.51 and 30.50 ppm.
,, Found: C 50.21; H 6.62; C1 7.55; N 8.89; S 6.56; Calc. for ' C20~32C1N3C69~ CSC.25; ~ 6,75; ol 7.42; N 5.79; S 6.71.
t 1 ~
' 'j F :`
~ C -/7-( ~
, !, ~ ` ` `
1(~514;~0 MMR (D20): -CH2CH3 3 H t at 1.27 ppm (J=7.O HZ) -OCHO-C(2)(CH3)217 H m at 1.4-2.1 ppm ~H2'CH2 - c~
N 4 H m at 3.4-3.9 ppm ,CH2 _OCH2CH3 2 H q at 4.25 ppm (J=7.0 Hz) C(3)H 1 H s at 4.65 ppm C(5)H 1 H d at 5.56 ppm 1J=4.0 Hz) .
C(6)H 1 H d at 5.64 ppm (J=4.0 Hz) -OCH- 1 H q at 6.79 ppm (J=5.5 Hz) i: +
N-CH=N- 1 H s, at 8.05 ppm ~ H broad .~
,~ -1 ~ :
f ~
F
'~'!,``~ G - J~~
,. ~
~ . ~
..
3-methylpiperidyl-1 " ~
4-methylpiperidyl-1 CH2OCOOCH2CH2NEt2 2,6-dimethylpiperidyl-1 " ~
hexahydro-lH-azepin-l-yl "~ ;~
hexahydro-lH-azepin-l-yl CH2OCOOCH2CH2NH2 hexahydro-1~2H)-azocinyl " ~
1,2,3,4-tetrahydroisoquinolyl-2 CH2OCOOCH2CH2NHMe 4-methylpiperazinyl-1 "~
morfolinyl-4 "~
The compounds of the invention are prepared by different methods ~ --such as by reacting a reactive derivative of an amide OT thioamide of the formula III
Rl N - CH = R6 III
R2~
where Rl and R2 are as defined above and R6 is O or S, with an ester of 6-aminopenicillanic acid with the formula IV
S \ / CH3 H N-CH - CH C IV
2 1 ¦ ¦ \ CH3 3 CO - N CH - COOR
where R3 is as defined above.
The reactive derivatives of the amides or thioamides of formula III are acid amide halogenides or dialkylsulphate complexes of acid b~;n~
amides or acid amide acetals. The former two reagents may be 4~usiuuul accord-ing to known methods by treatment of compounds of the formula III with halo-genating agents like phosgeneJ oxalyldichloride, thionyl chloride or thionyl omide or with a dialkylsulphate like dimethyl sulphate. The reactions with . ~ _ 7 _ i(~S14~0 the halogenating agents are performed in inert dry organic solvents like diethylether, toluene, benzene, chloroform or carbon tetrachloride. The halogenides are usuall~ obtained as ! :
i~ ' .1~
~ - 7a -:
~`i ~. ., . ' '' ' ' .: .. ': . -: .: . :. . . . . ' .
1~51~'~0 hygroscopic precipitates.
~reatment of the acid amide dialkylsulphate complexes with strong bases, e.g. sodium methoxide, convert them into acid amide acetals of the formula (V) 2,",N - CH(OR )2 V
where R7 is a lower alkyl group originating from the dialkylsulphate, which also can be reacted with the esters of 6-aminopenicillanic acid with the formula IV to give the compounds of the invention.
The esters of 6-aminopenicillanic acid with the general structure IV may be prepared by treatment of 6-APA with compounds R3-Y , where R3 has the same meaning as above and Y is halogen or a functionally equivalent group capable of reacting with a carboxy group under formation of an ester linkage, such as an organic sulphonic acid residue. The reaction is pref-erably performed in organic solvents like dimethylformamide, dimethyl-~ulphoxide or hexamethylphosphoramide.
Alternatively 6-acylaminopenicillanic acid~ with acyl groups that can be removed without destruction of the penicillin ring system are treated with R3-Y wherein R3 and Y have the meaning specified above, to give esters 1 of the 6-acylamino penicillanic acids from which the acyl groups then are re-t 20 moved to give the esters of 6-aminopenicillanic acid of the formula III. A
I ~ preferred method consists of reacting a salt, e.g. the sodium, potassium or tetraalkylammonium salt of 6-phenylacetamido penicillanic acid(benzyl-penicillin) with R3-Y in an organic solvent like chloroform, methylene-I :~
chloride, acetone, dimethylformamide, dimethylsulphoxide or hexamethyl-ph4sphoramide or in a mixture of an organic solvent and water, e.g. aqueous acetone or dioxane to give the corresponding ester of benzylpenicillin. The phenylacetyl side chain is then removed according to the method described 1:
in United States patent No. 3,697,515 or South African Patent publication 67/2g27 by treatment with phosphorous pentachloride in presence of a tertiary oreanic base to give an imino chloride which is reacted with an .
~ - 8 -.'~
~Si~O
alcohol like propanol to give the corresponding imino ether which is hydrolyzed by add:it.ion of water or alcoholized by addition of alcohol, to give the ester III. Alternatively the phenylacetyl side chain may be removed by enzymatic hydrolysis using an E.coli acylase according to the method described in ;
- 8a -r~;,.
. .
105~ 0 French Patent 1 576 027 In still another method N-protected 6-aminopenicillanic acids are reacted with R3-Yl to give the corresponding ester from which the protecting groups are removed to give the compounds of the general formula IV.
Examples of protecting groups which can be used are the benzyloxycarbonyl group which is removed by catalytic hydrogenation, the 0-nitro-phenyl-sulphenyl group which can be removed by treatment with nucleophilic agents at acid pH (Jap. Pat. 505 176), and the trityl group which can be removed by mild acid hydrolysis.
lD Alternative methods can be used for the preparation of the compounds of the invention. 6-formamidopenicillanic acid may be converted into esters of the formula (VI) / \ / 3 HCONHCH - CR ¦ \ CH3 VI
CO - N CH - COOR
where R3 is as defined above by reaction with R3Y under the conditions previously indicated. Treatment of an ester of 6-aminopenicillanic acid, i.e. a compound of formula IV,with an l,l-dihalogendimethyl ether, e.g.
l-dichlorodimethyl ether, in presence of a tertiary organic base, gives a reactive derivative of the compound of formula VI which reactive derivative reacts with an amine of the formula (VII):
1. ~ 1 R ~ NH VII
R2 "' where R and R are as defined a~ove, to give the compound of formula I.
~ A third method consists of reacting compounds of formula II, 1 suitable in form of a salt, e~gO a sodium, potassium, calcium, triethylammoni~m or tetraalkylammonium salt, with a compound R3 ~ wherein R and Y have the meaning specified above to give the compounds of the ~ _ 9 _ ;
.. . . .
~C~514'~
invention with the general formula I. The reaction s suitably performed in organic solvents like chloroform, methylenechloride, acetone, dimethylformamide~ dimethylsulphoxide or hexamethylphosphoramide or in aqueous organic solvents like aqueous dioxane.
H - 9a -1(~51~'~0 As described above the starting material may be in the form of a salt, for instance a sodium, potassium, calcium or trialkylammonium salt, in some of the ways for the preparation of the compounds of the invention.
In addition, tetraalkylammonium salts and other analogues salts such as salts where the cation has the formula AlA2A3A4N 1~) in which formula A is selected from the group consisting of straight and branched alkyl groups containing from 3 to 6 carbon atoms, substituted and unsubstituted aryl, and substituted and unsubstituted aralkyl, and wherein A , A3 and A , which are the same or different, are selected from the group consisting of straight and branched alkyl groups containing from 1 to 6 carbon atoms, provided that A , A3 and A are alkyl with 3-6 carbon atoms when A is alkyl, may be used.
Illustrative examples of suitable combinations of A , A , A3 and A in the quaternary ammonium ion A1A2A3A4N ~ are given below:
Table I. Examples of suitable combinations of the radicals A -A4 in the AlA2A3A4N ~ ion n-propyl n-propyl n-propyl n-propyl i-propyl i-propyl i-propyl i-propyl n-butyl n-butyl n-butyl n-butyl i-butyl i-butyl i-butyl i-butyl n-pentyl n-pentyl n-pentyl n-pentyl n-hexyl n-hexyl n-hexyl n-hexyl phenyl methyl methyl methyl phenyl ethyl ethyl ethyl p-tolyl ethyl ethyl ethyl p-chlorophenyl ethyl ethyl ethyl When the radicals A -A all are different the resulting ion :
contains an asymmetric centre and may occur in two enantiomeric forms. Epimeric forms can occur if A , A , A3 andtor A contain one or more asymmetric carbon atoms.
i , . . . . .
.. ..
~5~1~ZO
Examples of quaternary ammonium ions containing an asymmetric centre are given in Table II below:
Table II - Examples of quaternary ammonium ion AlA2A3A4N ~3 containing an asymmetric centre Al A2 A3 A4 benzyl n-propyl i-propyl n-butyl benzyl n-propyl i-propyl sec.butyl benzyl n-propyl n-butyl sec.butyl n-propyl n-propyl n butyl sec.butyl n-propyl n-propyl n-propyl sec.butyl n-propyl n-propyl n-propyl sec.pentyl n-propyl n-propyl n-propyl sec.hexyl n-propyl n-propyl n.butyl sec.hexyl -The use as describéd above of a quaternary salt form of the start-ing material for the preparation of the compounds of this inyention is not previously described in the literature pertaining to this technical field. In this method the preferred cation is the tetraalkylammonium ion, particularly the tetrabutylammonium ion. The preferred solvents are chloroform, methylene-chloride and acetone.
The quaternary ammonium salt form of the above described starting material may be prepared by reacting the starting material in question with a quaternary ammonium salt of the formula AlA2A3A4N ~ B Q
wherein Al, A2, A3 and A4 have the meanings specified above and B is a suitable anion such as HS04 ~ , CL ~ or CH3COO Q to the formation of a quaternary salt of the starting material.
The salts of the formula above which contains B as the anion may be prepared in known manner analogous as described in for instance Belgian patent 751,791. The anion B ~3 is in the preferred embodiment HS04 ~3 .
The following examples will further illustrate the invention.
1~51'~0 Example 1 illustrates the preparation of l'-ethoxycarbonyloxy ethyl-6-(hexahydro-lH-azepin-l-yl)methyleneamino penicillanate which is not within the claims of this application but is the subject of the divisional application mentioned above. It will readily be inferred that compounds with-in the claims of this application can be made by the procedures illustrated in Example 1. Likewise in Example 8 formulations (b), (g) and (i) contain the compound of the divisional application but it will be appreciated that compounds within the claims of this application could be substituted for that compound in the formulations shown.
- lla -P~.
. , .
1~514~0 Example 1. l-Ethoxycarbonyloxy-ethyl 6-(hexahydro-lH-azepin-l-yl)-methylene-amino penicillanate ,~ef~
l-Hexamethyleneiminocarboxaldehyde-dimcth~ t~G (3.1 g) in chloroform ~50 ml) was added dropwise at -30C to a solution of l-ethoxycar-bonyloxy-ethyl 6-amino-penicillanate (5 g) and triethylamine Cl.9 ml) in chloroform (150 ml) during 15 minutes. Then the temperature is allowed to rise to 0 during 30 minutes and the mixture is stirred at O for another 60 minutes. Water (120 ml) is added and stirring is continued for 10 minutes.
The water phase is separated and the organic layer is washed with water and stripped. The residue (5 g) showed a strong IR-absorption band at 1775 cm 1 (~-lactam ring).
Incubation of the product with human serum at 37C was found to cause a rapid formation of 6-(hexahydro-lH-azepin-l-yl)-methyleneamino pen-icillanic acid.
The l-ethoxycarbonyloxy-ethyl 6-aminopenicillanate was prepared as described in Canadian Patent No. 960,211.
Example 2 By substituting the l-ethoxycarbonyloxy-ethyl 6-aminopenicillanate in example 1 with l-acetoxy-ethyl 6-aminopenicillanate and ethoxycarbonyloxy-methyl 6-amino-penicillanate, ~-acetoxy-ethyl and ethoxycarbonyloxymethyl 6-~hexahydro-lH-azepin-l-yl)-methyleneamino penicillanates respectively were ', obtained. The compounds showed strong ~-lactam absorption in IR at 1775 cm 1 and were rapdily hydroly~ed by human serum to the corresponding penicillanic acids.
Example 3 l-Ethoxycarbonyloxyet,hyl 6-,~piperidyl-1-)-methyleneaminopenicillanate To phosphorus pentachloride ~1.7 g, 0.008 mole) and quinoline (1.8 g, 0.016 mole~ in dry methylene chloride (50 ml~ l-ethoxycarbonyloxyethyl ben-~ylpenicillanate C3.2 g, 0.007 mole) was added with stirring and chilling to -40C, the reaction was kept in dry iner~ gas Cargon~. After 1 hour dry me-thanol C2.24 g) was added dropwise and the temperature was adjustsd to -30.
~ - 12 -~Si4'20 After 1 hour brine ClS ml) was dropped to the solution while the temperature was allowed to rise to 0. After 15 min. the organic phase was dried and evaporated in vacuo, the residue was triturated with petroleum - 12a -~, .
1(~51'~'~0 ether and dried yielding a crystalline mass (2.8 g, 100%), IR 1790 cm 1 (~_ lactam). To a solution of this material (2.8 g, 0.007 mole) and triethyl-amine (o.84 ml, o.oo6 mole) in chloroform (50 ml) at -50 - -60 N-piperidylchloroformiminiumchloride (1.1 g, o.oo6 mole) in chloroform (20 ml) was added dropwise. The mixture was kept under dry argon for 1.5 h during which time the temperature rose to 0 . The solvent was removed in vacuo at 40 and the residue was slurried with dry acetone (100 ml) and filtered.
The flltrate was concentrated in vacuo and the remaining oil was triturated with petroleum ether until crystallisation, yield 1.2 g, IR-absorption 1760 cm (~-lactam), NMR: ringlet at 480 cps (methyleneimino), multiplet at 320 cps (5- and 6`position of penicillin nucleus).
Example 4 l'-Acetoxyethyl 6-(piperidyl-1)-meth~leneamino~enicillanate was _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ prepared as described in Example 3 from l'-acetoxyethyl benzylpenicillinate (2.94 g, 0.007 mole) and N-piperidylchloroformiminiumchloride (1.1 g, o.oo6 mole) yielding a half crystalline mass. IR-absorption at 1760 cm 1 (~-lactam).
Example 5 Ethoxy_a b_n~loxymethyl 6-(hexahyd_o_lH-_z~p_n-l-yl)_methylene_ amin_E~I c.LIanate was prepared as described in Example 3 from ethoxy-carbonyloxymethyl benzylpenicillinate (3. g, mole) and hexahydro-lH-azepin-l-ylchloroformiminium chloride (1.15 g, o,oo6 mole) yielding an oil; IR-absorption 1760 cm (~-lactam).
ExamPle 6 Phenox~carbonylo~ymethyl 6-(ethy_-isop_o~yl)-met~ylene~m_n~p_n_c_l-la_ate was prepared as described in Example 3 from phenoxycarbonyloxymethyl benzylpenicillinate (3.4 g, 0,007 mole) and N-ethyl-N-isopropylchloroformim-inium chloride (1.02 g, o.oo6 mole) yielding an oily product; IR-absorption 1775 cm 1 (~-lactam).
Example 7 _h_n_xycarbonyloxyme_hyl_ 6-(N,N-di - e_hyl_-methyleneaminopenicil-_anate was prepared as described in Example 3 from phenoxycarbonyloxymethyl benzylpenicillinate (3.4 g, 0.007 mole) and N,N-dimethylchloroformiminium chloride (0.77 g, o.oo6 mole) yielding a half crystalline mass; IR-absorption 1775 cm 1 (~-la-ctam).
' ' lQs~ o Example 8. Pharmaceutical formulations For preparation of tablets the following compositions were made:
a) 1'-Acetoxyethyl 6-hexahydro-lH-azepin-1-(yl)--methyleneamino penicillanate 325 mg Starch 100 mg Magnesium stearate lO mg b) l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH--azepin-l-(yl)-methyleneamino penicillanate 350 mg Starch 100 mg Magnesium stearate 10 mg c) Ethoxycarbonyloxymethyl 6-hexahydro-lH-azepin-l-(yl)-methyleneamino penicillanate 350 mg Calcium carbonate 100 mg Magnesium stearate lO mg d) 1'-Ethoxycarbonyloxyethyl 6-(piperidyl-1)--methyleneamino-penicillanate 350 mg Lactose lO0 mg Magnesium stearate 10 mg ~ ~ ~20 e) 1'-Acetoxyethyl 6-(piperidyl-1)-methylene-: amino-penicillanate 300 mg !~ Calcium carbonate lO0 mg ~:: Lactose lO0 mg Magnesium stearate 10 mg : For filling in capsules the following formulations were made:
f) 1'-Acetoxyethyl 6-hexahydro-lH-azepin-1-(yl)-methyleneamino penicillanate 350 mg Magnesium stearate 5 mg gj l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH-azepin-l-:30 -(yl)-methyleneamino penicillanate350 mg Lactose 40 mg Magnesium stearate 5 mg ~;~ - 14 -' , .. . . .. , , - -11~5~4;~0 For oral suspensions the following formulations were prepared:
h) 1'-Acetoxyethyl 6-(piperidyl-1)-methylene~mino penicillanate 35 mg Aluminium monostearate 50 mg Tween - 80 ~ 1.2 mg Peanut oil ad 1000 mg i) l'-Ethoxycarbonyloxyethyl 6-hexahydro-lH-azepin-l-(yl)-methyleneamino penicillanate 36 g Sodium benzoate o.48 g Sodium chloride 0-75 g Flavouring agents 4.7 g Aerosil ~ 0.3 g Antifoam ~ o.o375 g Alkali salts of polysaccharide sulphates 4.0 g Sodium saccharinate 0.4 g Sorbitol ad 100 g l(~S14~0 SUPPLEMENTARY DISCLOSURE
Example 9 Preparation of l~(S)-Ethoxycarbonyloxyethyl 6~j(hexahydro-lH-azepin-l-yl)-methyleneaminopenicillanate hydrochloride A. Preparation of l~(S)-Ethoxycarbonyloxyethyl 6~-amino~enicillanate hydrochloride used as starting material A solution of l'(S)-ethoxycarbonyloxyethyl 6-phenylacetamido peni-cillanate (7.4 g, 0.016 mole) in 10 ml dry ethanol-free chloroform was added to a stirred mixture of phosphorus pentachloride (3.8 g, 0.018 mole) and quinoline (4.8 g, 0.037 mole) in 25 ml dry ethanol-free chloroform at -20C
under dry nitrogen. After stirring at this temperature for l h, the solution was cooled to -30C and dry propanol (12 ml) was added during 20 mins. The temperature was allowed to rise to -15C during 30 mins, then cold brine (25 ml) was added with vigorous stirring while the temperature rose to -50C.
The reaction mixture was poured into 50 ~1 ice-cold ligroin and stirred for 15 mins, then a further 55 ml ice-cold ligroin were added and the mixture stirred for a further 10 mins. The mixture was then allowed to separate and the oil-water phase collected and extracted with 30 ml chloroform. The chloro-form phase was dried at 0C over sodium sulphate. lR (CHC13) showed ~-lactam (1790 cm~l) and ester (1790 cm~l). NMR (CDCl3): C(6)H, lH, d at 5.68 ppm (J=4.0 Hz); C(s)H, lH, d at 5.20 ppm (J=4.0 Hz).
B. l~(S)-Ethoxycarbonyloxyethyl 6~-(hexahydro-lH-azepin-l-yl)-methyl-ideneaminopenicillanate hydrochloride To the above-described chloroform solution of l'(S)-ethoxycarbonyl-~;~ oxyethyl 6~-aminopenicillanate hydrochloride cooled to 10C, triethylamine (5.80 ml, 0.042 mole) was added with stirring. The temperature was allowed to rise to -25C and then a solution of hexahydro-lH-azepin-l-ylchloroform-iminium chloride (3.79 g, 0.021 mole) in 10 ml dry ethanol-free chloroform was added dropwise. The mixture was then stirred at 0C for 30 mins. After removal of the solvent u~der reduced pressure the resulting residue was ~30 slurried with dry acetone (50 ml) and filtered. The filtrate was stripped :~ F~
1~514~0 of solvent and leached with petroleum ether and the syrupy residue dissolved by stirring with 10 ml 2-pentanon. The solution was kept at ~5C overnight whereupon the crude product crystallized and was collected by filtration.
i The,crude product was dissolved in methylene chloride (12 ml) and washed with cold saturated brine (2xlS ml). After drying the organic phase over sodium sulphate, the solvent was removed under reduced pressure and the resulting residue slurried with dry acetone (S ml) affording the analytically pure crystalline product, m.p. 147-149C (decomposition). [~]D = +163.5 (c=l;
96 % ethanol). lR (KBr): 1795 cm~l (~)-lactam car~onyl); 1760 cm~l (ester ' 10 carbonyl); 1675 cm~l (-CH=NH-). '' ¦ A proton NMR spectrum of the product showed only one signal for ,~ the C-3 proton indicating the presence of only one stereoisomer. This was confirmed by a carbon-13 NMR spectrum in CDC13 since only one signal was seen for the 2~.-methyl carbon at 29.44 ppm (from TMS) whereas a mixture of the two , stereoisomers gave signals for this carbon at 29.51 and 30.50 ppm.
,, Found: C 50.21; H 6.62; C1 7.55; N 8.89; S 6.56; Calc. for ' C20~32C1N3C69~ CSC.25; ~ 6,75; ol 7.42; N 5.79; S 6.71.
t 1 ~
' 'j F :`
~ C -/7-( ~
, !, ~ ` ` `
1(~514;~0 MMR (D20): -CH2CH3 3 H t at 1.27 ppm (J=7.O HZ) -OCHO-C(2)(CH3)217 H m at 1.4-2.1 ppm ~H2'CH2 - c~
N 4 H m at 3.4-3.9 ppm ,CH2 _OCH2CH3 2 H q at 4.25 ppm (J=7.0 Hz) C(3)H 1 H s at 4.65 ppm C(5)H 1 H d at 5.56 ppm 1J=4.0 Hz) .
C(6)H 1 H d at 5.64 ppm (J=4.0 Hz) -OCH- 1 H q at 6.79 ppm (J=5.5 Hz) i: +
N-CH=N- 1 H s, at 8.05 ppm ~ H broad .~
,~ -1 ~ :
f ~
F
'~'!,``~ G - J~~
,. ~
~ . ~
..
Claims (25)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
and pharmaceutically acceptable salts thereof, wherein R1 and R2 which are the same or different, are alkyl groups containing from 1 to 10 carbon atoms, or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring system, R3 is selected from the group consisting of and in which R4 is selected from the group consisting of alkyl groups containing from 1 to 8 carbon atoms and phenyl and R5 is selected from the group consist-ing of hydrogen, methyl and ethyl, with the proviso that when R1 and R2 to-gether with the adjacent nitrogen atom form a hexahydro-1H-azepine ring, R3 is and R5 is methyl R4 is not ethyl, which process comprises (a) reacting a reactive derivative of a compound of the formula III
III
wherein R1 and R2 have the meanings specified above and R6 is oxygen or sul-phur, with a compound or a salt of a compound of formula IV
IV
wherein R3 has the meaning specified above, or (b) reacting a reactive deriva-tive of a compound of formula VI
VI
with a compound of formula VII
VII
wherein R1, R2 and R3 have the meanings specified above, or (c) reacting a compound or a salt of a compound of formula II
II
with a compound of formula wherein R1, R2 and R3 have the meanings specified above to obtain the compound of formula I or a salt thereof and, if required, converting the compound of formula I into a pharmaceutically acceptable salt.
and pharmaceutically acceptable salts thereof, wherein R1 and R2 which are the same or different, are alkyl groups containing from 1 to 10 carbon atoms, or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring system, R3 is selected from the group consisting of and in which R4 is selected from the group consisting of alkyl groups containing from 1 to 8 carbon atoms and phenyl and R5 is selected from the group consist-ing of hydrogen, methyl and ethyl, with the proviso that when R1 and R2 to-gether with the adjacent nitrogen atom form a hexahydro-1H-azepine ring, R3 is and R5 is methyl R4 is not ethyl, which process comprises (a) reacting a reactive derivative of a compound of the formula III
III
wherein R1 and R2 have the meanings specified above and R6 is oxygen or sul-phur, with a compound or a salt of a compound of formula IV
IV
wherein R3 has the meaning specified above, or (b) reacting a reactive deriva-tive of a compound of formula VI
VI
with a compound of formula VII
VII
wherein R1, R2 and R3 have the meanings specified above, or (c) reacting a compound or a salt of a compound of formula II
II
with a compound of formula wherein R1, R2 and R3 have the meanings specified above to obtain the compound of formula I or a salt thereof and, if required, converting the compound of formula I into a pharmaceutically acceptable salt.
2. A process according to claim 1(a) wherein the reactive deriva-tive of the compound of formula III is an acid amide halogenide, a dialkyl sulphate complex of an acid amide or an acid amide acetal.
3. A process according to claim 1(a) wherein the reactive deriva-tive of the compound of formula III is a compound of formula V
wherein R1 and R2 are as specified in claim 1 and R7 is an alkyl group.
wherein R1 and R2 are as specified in claim 1 and R7 is an alkyl group.
4. A process according to claim 1(b) wherein the reactive deriva-tive of the compound of formula VI is the product of reaction between the compound of formula IV and a dihalogendimethyl ether in the presence of a tertiary organic base.
5. A process according to claim 1 wherein R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring containing from 3 to 7 carbon atoms and R3 is of the formula wherein R4 is an alkyl group containing from 1 to 8 carbon atoms and R5 is hydrogen, methyl or ethyl.
6. A process according to claim 5 wherein the heterocyclic ring contains 6 or 7 carbon atoms.
7. A process according to claim 1 wherein a compound of the formula I with one or more asymmetrical centers is resolved in its optical antipodes.
8. A compound conforming to the structural formula or a pharmaceutically acceptable salt thereof, in which formula R1 and R2 which are the same or different, are either alkyl groups containing from 1 to 10 carbon atoms, or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic ring system; R3 is selected from the group consisting of and in which radicals R4 is selected from the group consisting of alkyl groups containing from 1 to 8 carbon atoms, and phenyl, R5 is selected from the group consisting of hydrogen, methyl and ethyl, with the proviso that when R1 and R2 together with the adjacent nitrogen atom form a hexahydro-1H-azepine ring R3 is R5 and R5 is methyl, R4 is not ethyl whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
9. A compound according to claim 8, which contains one or more asymmetrical centers, in the form of a pure stereoisomer whenever prepared by the process of claim 7 or by an obvious chemical equivalent thereof.
10. A process according to claim 1 in which R1 and R2 together form a hexamethylene group and R3 is 1-acetoxyethyl.
11. A process according to claim 1 in which 1'-acetoxyethyl 6-(hexahydro-1H-azepin-1-yl)methyleneamino penicillanate is prepared by reacting 1'-acetoxy-ethyl 6-aminopenicillanate with 1-hexamethyleneimino-carboxaldehyde-dimethyl-acetate.
12. 1'-Acetoxyethyl 6-(hexahydro-1H-azepin-1-yl)methyleneamino penicillanate whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
13. A process according to claim 1 in which R1 and R2 together form a hexamethylene group and R3 is ethoxycarbonyloxymethyl.
14. A process according to claim 1 in which ethoxycarbonyloxy methyl-6-(hexahydro-1H-azepin-1-yl)-methyleneamino penicillanate is prepared by reacting ethoxycarbonyloxymethyl-6-amino-penicillanate with 1-hexamethy-leneaminacarboxaldehyde-dimethylacetal.
15. A process according to claim 1 in which ethoxycarbonyloxymethyl 6-(hexahydro-1H-azepin-1-yl)-methyleneaminopenicilllanate is prepared by reacting ethoxycarbonyloxymethyl-6-amino-penicillanate with hexahydro-1H-azepin-1-yl-chloroformiminium chloride.
16. A process according to claim 15 in which the ethoxycarbonyloxy-methyl-6-amino penicillanate is prepared by reacting ethoxycarbonyloxymethyl-6-phenylacetamide penicillanate with phosphorus penta chloride in the presence of quinoline, followed by addition of methanol, to remove the phenylacetyl side chain in the 6-position.
17. Ethoxycarbonyloxymethyl 6-(hexahydro-1H(azepin-1-yl)-methylene-amino-penicillanate whenever prepared by the process of claim 14, 15 or 16 or by an obvious chemical equivalent thereof.
18. A process according to claim 1 in which R1 and R2 together form a pentamethylene group and R3 is 1-ethoxycarbonyloxyethyl.
19. A process according to claim 1 in which 1'-ethoxycarbonyloxy-ethyl 6-(piperidyl-1-)-methyleneaminopenicillanate is prepared by reacting 1'-ethoxycarbonyloxyethyl-6-amino penicillanate with N-piperidylchloroformi-minium chloride.
20. A process according to claim 19 in which the ethoxycarbonyloxy-methyl-6-amino penicillanate is prepared by reacting ethoxycarbonyloxymethyl-6-phenylacetamido-penicillanate with phosphorus penta chloride in the presence of quinoline, followed by addition of methanol, to remove the phenylacetyl side chain in the 6-position.
21. 1'-Ethoxycarbonyloxyethyl 6-(piperidyl-1-)-methyleneamino-penicillanate whenever prepared by the process of claim 19 or 20 or by an obvious chemical equivalent thereof.
22. A process according to claim 1 in which R1 and R2 together forms pentamethylene groups and R3 is 1-acetoxyethyl.
23. A process according to claim 1 in which 1'-acetoxyethyl-6-(piperidyl-1)-methyleneaminopenicillanate is prepared by reacting 1'-acetoxyethyl-6-amino penicillanate with N-piperidylchloroformiminiumchloride.
24. A process according to claim 23 in which the ethoxycarbonyloxy-methyl-6-amino penicillanate is prepared by reacting ethoxycarbonyloxymethyl-6-phenylacetamide penicillanate with phosphorus penta, chloride in the presence of quinoline, followed by addition of methanol, to remove the phenylacetyl side chain in the 6-position.
25. l'-Acetoxyethyl 6-(piperidyl-1)-methyleneaminopenicillanate when-ever prepared by the process of claim 23 or 24 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1168972A GB1427139A (en) | 1972-03-13 | 1972-03-13 | Penicillins |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1051420A true CA1051420A (en) | 1979-03-27 |
Family
ID=9990894
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA165,831A Expired CA1051420A (en) | 1972-03-13 | 1973-03-12 | ESTERS OF .alpha.-SUBSTITUTED AMIDINOPENICILLANIC ACIDS |
Country Status (10)
Country | Link |
---|---|
JP (3) | JPS5526147B2 (en) |
AT (1) | AT331391B (en) |
CA (1) | CA1051420A (en) |
CH (2) | CH582708A5 (en) |
DE (1) | DE2311131C3 (en) |
DK (1) | DK145699C (en) |
FR (1) | FR2181811B1 (en) |
GB (1) | GB1427139A (en) |
NL (1) | NL176943C (en) |
SE (2) | SE416811B (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1427139A (en) * | 1972-03-13 | 1976-03-10 | Astra Laekemedel Ab | Penicillins |
SU566843A1 (en) * | 1975-01-06 | 1977-07-30 | Ордена Трудового Красного Знамени Институт Органической Синтеза Ан Латвийской Сср | Method of preparing derivatives of 6- -amidino penicillanic acid |
GB1529448A (en) * | 1975-10-29 | 1978-10-18 | Leo Pharm Prod Ltd | 6-amidinopenicillanic acid derivatives |
GB1579931A (en) * | 1976-04-15 | 1980-11-26 | Leo Pharm Prod Ltd | Bis-penicillanoyl-oxy-alkanes |
US4345071A (en) | 1976-06-29 | 1982-08-17 | Leo Pharmaceutical Products, Ltd. A/S | Derivatives of penicillanic acid |
GB1585165A (en) * | 1976-06-29 | 1981-02-25 | Leo Pharm Prod Ltd | Derivatives of 6-amidino penicillanic acid |
LU77362A1 (en) * | 1977-05-17 | 1979-01-19 | ||
IL54859A (en) * | 1977-06-21 | 1982-01-31 | Rech Applications Therap | Derivatives of amidinopenicillanic acid,their production and pharmaceutical compositions containing them |
JPS57156495A (en) * | 1981-03-23 | 1982-09-27 | Kyoto Yakuhin Kogyo Kk | Cephalosporin derivative and remedy for microbism used in oral administration |
JPS5865474U (en) * | 1981-10-28 | 1983-05-04 | 松下電器産業株式会社 | electric valve |
IT1190897B (en) * | 1982-06-29 | 1988-02-24 | Opos Biochimica Srl | PROCEDURE FOR THE PREPARATION OF THE 1-ETHOXYCARBONYLOXYETHYL ACID ACID 6- (D (-) - ALPHA AMINOALPHA-PHENYLACETAMIDE) -PENICILLANIC |
US4606865A (en) * | 1982-09-20 | 1986-08-19 | Astra Lakemedel Aktiebolag | Methods for the preparation of α-bromodiethylcarbonate |
JPH0495170U (en) * | 1990-12-27 | 1992-08-18 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1003479A (en) * | 1963-05-30 | 1965-09-02 | Wyeth John & Brother Ltd | Acetoxymethyl benzylpenicillinate |
DE1795423C3 (en) * | 1967-09-29 | 1974-02-28 | Loevens Kemiske Fabrik Produktionsaktieselskab, Ballerup (Daenemark) | Pivaloyloxymethyl alpha-aminobenzyl penicillinate |
BE758782A (en) * | 1969-11-11 | 1971-05-10 | Leo Pharm Prod Ltd | NEW DERIVATIVES OF 6-AMIDINO PENICILLANIC ACID, THEIR PREPARATION PROCESS AND THEIR APPLICATIONS AS ANTIBIOTICS |
JPS4828904A (en) * | 1971-08-19 | 1973-04-17 | ||
GB1427139A (en) * | 1972-03-13 | 1976-03-10 | Astra Laekemedel Ab | Penicillins |
-
1972
- 1972-03-13 GB GB1168972A patent/GB1427139A/en not_active Expired
- 1972-03-15 SE SE7203298A patent/SE416811B/en unknown
- 1972-03-15 DK DK119772A patent/DK145699C/en active
-
1973
- 1973-03-07 DE DE2311131A patent/DE2311131C3/en not_active Expired
- 1973-03-12 JP JP2890473A patent/JPS5526147B2/ja not_active Expired
- 1973-03-12 NL NLAANVRAGE7303434,A patent/NL176943C/en not_active IP Right Cessation
- 1973-03-12 CA CA165,831A patent/CA1051420A/en not_active Expired
- 1973-03-12 AT AT213973A patent/AT331391B/en not_active IP Right Cessation
- 1973-03-12 FR FR7308757A patent/FR2181811B1/fr not_active Expired
- 1973-03-13 CH CH461576A patent/CH582708A5/xx not_active IP Right Cessation
- 1973-03-13 CH CH366873A patent/CH582707A5/xx not_active IP Right Cessation
-
1977
- 1977-12-29 JP JP15850177A patent/JPS53101394A/en active Pending
-
1978
- 1978-05-24 SE SE7805910A patent/SE7805910L/en unknown
-
1980
- 1980-02-01 JP JP1194780A patent/JPS55105688A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
GB1427139A (en) | 1976-03-10 |
FR2181811A1 (en) | 1973-12-07 |
DE2311131A1 (en) | 1973-10-18 |
ATA213973A (en) | 1975-11-15 |
DK145699C (en) | 1983-07-25 |
AU5321273A (en) | 1974-09-12 |
JPS55105688A (en) | 1980-08-13 |
NL176943B (en) | 1985-02-01 |
NL7303434A (en) | 1973-09-17 |
JPS53101394A (en) | 1978-09-04 |
FR2181811B1 (en) | 1976-07-02 |
AT331391B (en) | 1976-08-25 |
CH582708A5 (en) | 1976-12-15 |
JPS5526147B2 (en) | 1980-07-11 |
CH582707A5 (en) | 1976-12-15 |
JPS49287A (en) | 1974-01-05 |
DK145699B (en) | 1983-01-31 |
SE7805910L (en) | 1978-05-24 |
SE416811B (en) | 1981-02-09 |
NL176943C (en) | 1985-07-01 |
DE2311131C3 (en) | 1982-06-09 |
DE2311131B2 (en) | 1979-02-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3697507A (en) | Esters of {60 -aminobenzylpenicillin | |
US4579854A (en) | Bronchodilating 8-hydroxy-5-{(1R)-1-hydroxy-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)-amino]ethyl} carbostyril | |
CA1051420A (en) | ESTERS OF .alpha.-SUBSTITUTED AMIDINOPENICILLANIC ACIDS | |
US4342772A (en) | β-Lactam compounds, antibacterial compositions thereof and method of use | |
US3939270A (en) | Pharmaceutical preparations containing α-aminopenicillins | |
US5112834A (en) | Imidazole protectorant for the stomach and intestine | |
EP0354583A1 (en) | DC-88A derivatives | |
CA1104126A (en) | Method for producing derivatives of penicillanic acid | |
EP0039086B1 (en) | Novel ampicillin esters and production thereof | |
US4089963A (en) | Esters of amidinopenicillanic acids, pharmaceutical preparations and method for treating infectious diseases | |
US4246262A (en) | Derivatives of amidinopenicillanic acid | |
US3850956A (en) | Fused imidazolidine derivatives | |
US3655658A (en) | 7(alpha-amino-alpha-phenylacetamido)-cephalosporanate esters | |
CA1055929A (en) | ESTERS OF .alpha.-SUBSTITUTED AMIDINOPENICILLANIC ACIDS | |
US4181659A (en) | Bis-penicillanoyloxy-alkanes | |
PL90581B1 (en) | 6-(methyleneamino)-penicillanic acid derivs[FR2073338A1] | |
CA1144540A (en) | 6-AMIDINOPENICILLANIC ACID DERIVATIVES INCLUDING THE RADICAL OF A .beta.-LACTAMASE INHIBITOR AND PROCESS FOR PREPARING THE SAME | |
US3719668A (en) | Semi-synthetic penicillin esters | |
US3864331A (en) | Acyloxymethyl esters of {60 -aminopenicillins | |
US3951957A (en) | Chloromethyl ester of penicillins | |
US3819643A (en) | Esters of 6-amino penicillanic acid | |
US3847913A (en) | Cephalosporanic acid esters | |
KR810000857B1 (en) | Method for producing bis-penicillanoyloxy-alkanes | |
FI66858B (en) | PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC ANALYZED SULFOXIMIDERS AND SALTERS | |
KR850000474B1 (en) | Process for preparing 6beta-(2-(2'-methylphenoxycarbonyl)-2-thien-3'-yl acetamido)-penicillanic acid |