Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-30
2004-11-30
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C540S228000, C540S230000, C540S222000, C540S301000
Reexamination Certificate
active
06825344
ABSTRACT:
This invention relates to a process for the preparation of cephalosporin compounds and intermediates for the synthesis of such compounds.
WO 92/01696 discloses compounds of formula (I):
wherein R
1
is hydrogen, methoxy or formamido; R
2
is an acyl group, in particular that of an antibacterially active cephalosporin; CO
2
R
3
is a carboxy group or a carboxylate anion, or R
3
is a readily removable carboxy protecting group (such as a pharmaceutically acceptable in vivo hydrolysable ester group); R
4
represents hydrogen or up to four substituents selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkylamino, CO
2
R, CONR
2
, SO
2
NR
2
(where R is hydrogen or C
1-6
alkyl), aryl and heterocyclyl, which may be the same or different and wherein any R
4
alkyl substituent is optionally substituted by any other R
4
substituent; X is S, SO, SO
2
, O or CH
2
; and m is 1 or 2; and salts thereof. Compounds of formula (I) have antibacterial activity.
WO 92/01696 discloses various methods of synthesis of compounds of formula (I). It is an object of the present invention to provide alternative process enabling more convenient methods of synthesis of compounds of formula (I). Other objects and advantages of the present invention will be apparent from the following description.
According to the present invention a process for the preparation of a compound of formula (II) is provided
which process includes the step of cyclising a compound of formula (II):
wherein in formulae (II) and (III) R
1
, R
2
, R
3
, R
4
, X and m are as defined in formula (I) above and the dotted line indicates that the compounds (II) and (III) may be a 2-cephem or a 3-cephem system, and where in formula (III) the substituent(s) R
4
when other than hydrogen may replace any of the hydrogen atoms bonded to carbon atoms in the side chain.
In compounds (II) the bonding carbon atom of the cyclic ether moiety which links the ring to the cephalosporin nucleus is asymmetric. The present invention includes either stereoisomer, as well as mixtures of both isomers.
In compounds of formula (II) wherein R
1
is formamido, the formamido group can exist in conformations wherein the hydrogen atoms of the —NH—CHO moiety are cis- or trans-; of these the cis conformation normally predominates.
Preferred compounds within formula (II) are pharmaceutically acceptable, i&e are compounds of formula (IIA) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof:
wherein R
1
, R
2
, R
4
, m and X are as defined with respect to formula (II) and the group CO
2
R
5
is CO
2
R
3
where CO
2
R
3
is a carboxy group or a carboxylate anion.
Those compounds of the formula (II) wherein R
3
is a readily removable carboxy protecting group other than a pharmaceutically acceptable in vivo hydrolysable ester or which are in non-pharmaceutically acceptable salt form are primarily useful as intermediates in the preparation of compounds of the formula (IIa) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof.
Suitable readily removable carboxy protecting groups for the group R
3
include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters. The derivative is preferably one which may readily be cleaved in vivo.
It will be appreciated that also included within the scope of the invention are processes for the preparation of salts and carboxy-protected derivatives, including in vivo hydrolysable esters, of any carboxy groups that may be present as optional substituents in compounds of formula (II) or (IIa). Also included within the scope of the invention are processes for the preparation of acid addition salts of any amino group or substituted amino group that may be present as optional substituents in compounds of formula (II) or (IIa).
Suitable ester-forming carboxyl-protecting groups R
3
are those which may be removed under conventional conditions. Such groups include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus-containing group, an oxime radical of formula —N═CHR
7
where R
7
is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined below.
When used herein the term ‘aryl’ includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C
1-6
) alkyl, phenyl, (C
1-6
) alkoxy, hydroxy(C
1-6
)alkyl, mercapto(C
1-6
)alkyl, halo(C
1-6
)alkyl, hydroxy, amino, nitro, carboxy, (C
1-6
) alkylcarbonyloxy, alkoxycarbonyl, formyl, or (C
1-6
)alkylcarbonyl groups.
The terms ‘heterocyclyl’ and ‘heterocyclic’ as used herein include aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups selected from halogen, (C
1-6
)alkyl, (C
1-6
)alkoxy, halo(C
1-6
)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C
1-6
)alkoxycarbonyl, (C
1-6
)alkoxycarbonyl(C
1-6
)alkyl, aryl, and oxo groups. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. The term ‘heteroaryl’ refers to heteroaromatic heterocyclic rings. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
The term ‘heteroaryl’ as used herein means a heteroaromatic heterocyclic ring or ring system, suitably having 5 or 6 ring atoms in each ring.
When used herein the terms ‘alkyl’ alkenyl, alkynyl and ‘alkoxy’ include straight and branched chain groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl and butyl. A particular alkyl group is methyl.
When used herein the term ‘halogen’ refers to fluorine, chlorine, bromine and iodine.
A carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R
3
group, for example, acid- and base-catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected.
Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v):
wherein R
a
is hydrogen, (C
1-6
) alkyl, (C
3-7
) cycloalkyl, methyl, or phenyl, R
b
is (C
1-6
)alkyl, (C
1-6
)alkoxy, phenyl, benzyl, (C
3-7
) cycloalkyl, (C
3-7
) cycloalkyloxy, (C
1-6
) alkyl (C
3-7
)cycloalkyl, 1-amino (C
1-6
)alkyl, or 1-(C
1-6
)alkyl) amino (C
1-6
) alkyl; or R
a
and R
b
together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; R
c
represents (C
1-6
)alkylene optionally substituted with a methyl or ethyl group and R
d
and R
e
independently represent (C
1-6
)alkyl; R
f
represents (C
1-6
)alkyl; R
g
represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C
1-6
)alkyl, or (C
1-6
)alkoxy; Q is oxygen or NH; R
h
is hydrogen or (C
1-6
)alkyl; R
i
is hydrogen, (C
1-6
)alkyl optionally substituted by halogen, (C
2-6
)alkenyl, (C
1-6
)alkoxycarbonyl, aryl or heteroaryl; or R
h
and R
i
together form (C
1-6
)alkylene; R
j
represents hydrogen, (C
1-6
)alkyl or (C
1-6
)alkoxycarbonyl; and R
k
represents (C
1-8
)alkyl, (C
1-8
)alkoxy, (C
1-6
)alkoxy(C
1-6
)alkoxy or aryl.
Examples of suitable in v
Best Desmond John
Burton George
Gasson Brian Charles
Osborne Neal Frederick
Walker Graham
Berch Mark L.
Ling Lorraine B.
Liu Lance Y.
Munchhof Martha G.
Pfizer Inc.
LandOfFree
Process for the preparation of cephalosporin compounds and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of cephalosporin compounds and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of cephalosporin compounds and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3312882