Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1994-11-14
1998-10-13
Berch, Mark L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D498047, C07B 6302
Patent
active
058213643
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new diamine salts of clavulanic acid, pharmaceutical compositions thereof, and to the use of these salts in the production of clavulanic acid and salts and esters thereof.
GB patent 1508977 discloses that clavulanic acid, which has the formula (I): ##STR1## and its pharmaceutically acceptable salts and esters are anti-bacterial agents, able to enhance the effectiveness of penicillins and cephalosporins against many .beta.-lactamase-producing bacteria.
U.S. Pat. No. 4,650,795 discloses a group of primary amine salts of clavulanic acid which give stable pharmaceutical compositions.
EP patent 26044 discloses the use of the t-butylamine salt as a useful intermediate in the preparation of clavulanic acid.
The non-prepublished EP patent application 562583 discloses the same use for N,N-diisopropylethylenediammonium di clavulanate and N,N-diethylethylenediammonium di clavulanate, both of the secondary, secondary type.
Surprisingly it has been found that tertiary, tertiary diamine salts of clavulanic acid have improved properties compared to the t-butyl amine salt of clavulanic acid mentioned above. For instance, large crystals of the mono salt of N,N,N',N'-tetramethyl-1,2-diaminoethane clavulanate can easily be precipitated in pure form. The salt is therefore a very useful interediate in the preparation of clavulanic acid.
Accordingly, the present invention provides tertiary, tertiary diamine mono salts of the formula (IIa): ##STR2## and tertiary, tertiary diamine di salts of formula (IIb): ##STR3## where R.sub.1 and R.sub.2 are each a (1-8C)alkyl, (3-8C)cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group, optionally having one or more inert substituents or are interlinked to form a ring of 4-7 ring atoms; R.sub.3 and R.sub.4 are each a (1-8C)alkyl, (3-8C)cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group, optionally having one or more inert substituents or are interlinked to form a ring of 4-7 ring atoms; X is hydrogen or a hydrogen bridge forming group; and m and n are each, independently, 0-5.
An alkyl group may be branched or straight chain.
A C.sub.1 to C.sub.8 alkyl group is preferably a C.sub.1 to C.sub.4 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.butyl or tert.butyl, more preferably it is methyl.
A C.sub.3 to C.sub.8 cycloalkyl group is preferably a C.sub.5 to C.sub.7 cycloalkyl group, for example cyclopentyl, cyclohexyl or cycloheptyl.
Preferably, X is hydrogen, hydroxy or halogen, for instance bromine or chlorine. Most preferably, X is hydrogen or hydroxy.
Preferably n is from 0 to 3 and m is from 0 to 3, more preferably when X is hydrogen or hydroxy. Most preferably n=1, m is 0 and X is hydrogen or n is 1, m is 1 and X is hydroxy.
Suitably inert substituents include halogen, hydroxy, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxyl, C.sub.1 to C.sub.4 acyloxyl and C.sub.1 to C.sub.4 esterified carboxyl.
A halogen atom is, for example, bromine, chlorine or fluorine, preferably, bromine or chlorine.
A C.sub.1 to C.sub.4 alkyl is preferably methyl or ethyl.
A C.sub.1 to C.sub.4 alkoxyl is preferably methoxyl or ethoxyl.
A C.sub.1 to C.sub.4 acyloxyl is preferably C.sub.1 or C.sub.2 acyloxyl.
A C.sub.1 to C.sub.4 esterified carboxyl is preferably C.sub.1 or C.sub.2 esterified carboxyl.
Generally, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have three substituents or fewer, preferably two substituents or fewer. Most preferably R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have one substituent or are unsubstituted.
When R.sub.1 and R.sub.2 or R.sub.3 and R.sub.4 are interlinked to form a ring of 4 to 7 atoms, the ring consists preferably of carbon atoms and is most preferably saturated. Most preferably R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are methyl.
Normally the amine of the formula (III): ##STR4## from which the salts of the formulae (IIa) and (IIb) are derivable is a pharmaceutically acceptable amine.
Preferably, the salts of the formulae (IIa) and (IIb) are derivable from N,N,N',N'-tetramethyl-1,2-diaminoethane, 1,3-bis(dimethylamino)-2-propanol, N,N,N',
REFERENCES:
patent: 5310898 (1994-05-01), Copar
Berch Mark L.
Gist-Brocades N.V.
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