U.S. patent application number 12/610562 was filed with the patent office on 2010-02-25 for heterocyclic compounds as inhibitors of beta-lactamases.
This patent application is currently assigned to Novexel. Invention is credited to Jozsef Aszodi, Claude Fromentin, Maxime Lampilas, David Alan Rowlands.
Application Number | 20100048528 12/610562 |
Document ID | / |
Family ID | 27619669 |
Filed Date | 2010-02-25 |
United States Patent
Application |
20100048528 |
Kind Code |
A1 |
Aszodi; Jozsef ; et
al. |
February 25, 2010 |
HETEROCYCLIC COMPOUNDS AS INHIBITORS OF BETA-LACTAMASES
Abstract
This invention discloses and claims methods for inhibiting
bacterial .beta.-lactamases and treating bacterial infections by
inhibiting bacterial .beta.-lactamases in man or an animal
comprising administering a therapeutically effective amount to said
man or said animal of a compound, or pharmaceutically acceptable
salt thereof, of formula (I) either alone or in combination with a
.beta.-lactamine antibiotic wherein said combination can be
administered separately, together or spaced out over time.
Pharmaceutical compositions comprising a compound of formula (I),
or a combination of a compound of formula (I) and a therapeutically
effective amount of a .beta.-lactamine antibiotic, and a
pharmaceutically acceptable carrier are also disclosed and claimed.
##STR00001##
Inventors: |
Aszodi; Jozsef; (Tucson,
AZ) ; Fromentin; Claude; (Paris, FR) ;
Lampilas; Maxime; (Saint Cloud, FR) ; Rowlands; David
Alan; (Poissy, FR) |
Correspondence
Address: |
HARNESS, DICKEY & PIERCE, P.L.C.
P.O. BOX 828
BLOOMFIELD HILLS
MI
48303
US
|
Assignee: |
Novexel
Romainville
FR
|
Family ID: |
27619669 |
Appl. No.: |
12/610562 |
Filed: |
November 2, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10898754 |
Jul 26, 2004 |
7612087 |
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12610562 |
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PCT/FR2003/000243 |
Jan 27, 2003 |
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10898754 |
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Current U.S.
Class: |
514/195 ;
514/204; 514/205; 514/300 |
Current CPC
Class: |
A61K 31/55 20130101;
A61P 31/04 20180101; A61P 31/00 20180101; A61K 31/439 20130101;
A61K 2300/00 20130101; A61K 31/55 20130101; A61K 2300/00 20130101;
A61K 31/439 20130101 |
Class at
Publication: |
514/195 ;
514/300; 514/204; 514/205 |
International
Class: |
A61K 31/546 20060101
A61K031/546; A61K 31/439 20060101 A61K031/439; A61K 31/431 20060101
A61K031/431 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 28, 2002 |
FR |
02 00951 |
Claims
1-18. (canceled)
19. A pharmaceutical composition comprising (a) a compound, or a
pharmaceutically acceptable salt thereof, of formula (I):
##STR00012## wherein R.sub.1 is hydrogen, COOH, CN, COOR,
CONR.sub.6R.sub.7, (CH.sub.2).sub.n'R.sub.5 or
C(.dbd.NR.sub.6)NHR.sub.7; R is selected from the group consisting
of alkyl containing 1 to 6 carbon atoms optionally substituted by a
pyridyl or carbamoyl radical, --CH.sub.2-alkenyl containing 3 to 9
carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl
containing 7 to 11 carbon atoms, wherein the nucleus of said aryl
or aralkyl is optionally substituted by OH, NH.sub.2, NO.sub.2,
alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6
carbon atoms or by one or more halogen atoms; R.sub.6 and R.sub.7
are identical or different and are independently selected from the
group consisting of hydrogen, alkyl containing 1 to 6 carbon atoms,
aryl containing 6 to 10 carbon atoms and aralkyl containing 7 to 11
carbon atoms optionally substituted by a carbamoyl, ureido or
dimethylamino radical, and alkyl containing 1 to 6 carbon atoms
substituted by a pyridyl radical; n' is 1 or 2; R.sub.5 is selected
from the group consisting of COOH, CN, OH, NH.sub.2,
CO--NR.sub.6R.sub.7, COOR, OR, OCHO, OCOR, OCOOR, OCONHR,
OCONH.sub.2, NHR, NHCOH, NHCOR, NHSO.sub.2R, NH--COORU, NH--CO--NHR
and NHCONH.sub.2 wherein R, R.sub.6 and R.sub.7 are as defined
above; R.sub.2 is hydrogen or (CH.sub.2).sub.n'1R.sub.5 wherein
n'.sub.1 is 0, 1 or 2, and R.sub.5 is as defined above; R.sub.3 is
hydrogen or alkyl containing 1 to 6 carbon atoms; A is a bond
between the two carbons which carry R.sub.1 and R.sub.2,
##STR00013## group wherein R.sub.4 is hydrogen or
(CH.sub.2).sub.n'1R.sub.5 and n'.sub.1 and R.sub.5 are as defined
above, and the dotted line is an optional bond with one of the two
carbons which carry R.sub.1 and R.sub.2; n is 1 or 2; X is a
divalent --C(O)-B- group linked to the nitrogen atom by the carbon
atom wherein B is a divalent --O--(CH.sub.2).sub.n'-- group linked
to the carbonyl by the oxygen atom, a divalent
--NR.sub.8--(CH.sub.2).sub.n'1-- or --NR.sub.8--O-- group linked to
the carbonyl by the nitrogen atom, n'' is 0 or 1, and wherein B is
--NR.sub.8--(CH.sub.2).sub.n''--, R.sub.8 is selected from the
group consisting of hydrogen, OH, R, OR, Y, OY, Y.sub.1, OY.sub.1,
Y.sub.2, OY.sub.2, Y.sub.3, OCH.sub.2CH.sub.2SO.sub.mR,
OSiR.sub.aR.sub.bR.sub.c and SiR.sub.aR.sub.bR.sub.c and wherein B
is --NR.sub.8--O--, R.sub.8 is selected from the group consisting
of hydrogen, R, Y, Y.sub.1, Y.sub.2, Y.sub.3 and
SiR.sub.aR.sub.bR.sub.c, wherein R.sub.a, R.sub.b and R.sub.c is
each independently a linear or branched alkyl containing 1 to 6
carbon atoms or aryl containing 6 to 10 carbon atoms, R is as
defined above and m is 0, 1 or 2; Y is selected from the group
consisting of COH, COR, COOR, CONH.sub.2, CONHR, CONHOH,
CONHSO.sub.2R, CH.sub.2COOH, CH.sub.2COOR, CH.sub.2CONHOH,
CH.sub.2CONHCN, CH.sub.2tetrazole, protected CH.sub.2tetrazole,
CH.sub.2SO.sub.3H, CH.sub.2SO.sub.2R, CH.sub.2PO(OR).sub.2,
CH.sub.2PO(OR)(OH), CH.sub.2PO(R)(OH) and CH.sub.2PO(OH).sub.2;
Y.sub.1 is selected from the group consisting of SO.sub.2R,
SO.sub.2NHCOH, SO.sub.2NHCOR, SO.sub.2NHCOOR, SO.sub.2NHCONHR,
SO.sub.2NHCONH.sub.2 and SO.sub.3H; Y.sub.2 is selected from the
group consisting of PO(OH).sub.2, PO(OR).sub.2, PO(OH)(OR) and
PO(OH)(R); Y.sub.3 is selected from the group consisting of
tetrazole, tetrazole substituted by R, squarate, NH or
NR-tetrazole, NH or NR-tetrazole substituted by R, NHSO.sub.2R and
NRSO.sub.2R wherein R is as defined above; and R.sub.1, R.sub.2 and
R.sub.3 are not simultaneously hydrogen when n is 1, A is
##STR00014## wherein R.sub.4 is hydrogen and X is
--C(O)--O--(CH.sub.2).sub.n'' wherein n'' is 0 or 1, or X is
--CO--NR.sub.8--(CH.sub.2).sub.n'' wherein n'' is 1 and R.sub.8 is
isopropyl, or X is --CO--NR.sub.8--(CH.sub.2).sub.n'' wherein n''
is 0 and R.sub.8 is hydrogen or phenyl; and (b) a therapeutically
effective amount of a .beta.-lactamine antibiotic.
20. A pharmaceutical composition according to claim 19, wherein
said .beta.-lactamine antibiotic comprises an antibiotic selected
from the group consisting of: penams, penems, carbapenems, cephems,
carbacephems, oxacephems, cephamycims, monobactams, and
combinations and pharmaceutically acceptable salts thereof.
21. A pharmaceutical composition according to claim 19, wherein
said .beta.-lactamine antibiotic comprises a cephalosporin
antibiotic selected from the group consisting of: cephalothin,
cephaloridine, cefaclor, cefadroxil, cefamandole, cefazolin,
cephalexin, cephradine, ceftizoxime, cefoxitin, cephacetrile,
cefotiam, cefotaxime, cefsulodin, cefoperazone, ceftizoxime,
cefmenoxime, cefmetazole, cephaloglycin, cefonicid, cefodizime,
cefpirome, ceftazidime, ceftriaxone, cefpiramide, cefbuperazone,
cefozopran, cefepime, cefoselis, cefluprenam, cefuzonam,
cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir, cefpodoxime
axetil, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil,
cefcapene pivoxil, cefditoren pivoxil, cefuroxime, cefuroxime
axetil, loracarbacef, latamoxef, and combinations and
pharmaceutically acceptable salts thereof.
22. A pharmaceutical composition according to claim 21, wherein
said .beta.-lactamine antibiotic comprises ceftazidime.
23. The pharmaceutical composition according to claim 19, wherein n
is 1, R.sub.3 is hydrogen, R.sub.1 is hydrogen, COOR or
CONR.sub.6R.sub.7 wherein R, R.sub.6 and R.sub.7 are as defined in
claim 19, and X is --C(O)-B- wherein B is
--O--(CH.sub.2).sub.n''--or --NR.sub.8--(CH.sub.2).sub.n''--
wherein n'' is 0 and R.sub.8 is as defined in claim 19.
24. The pharmaceutical composition according to claim 19, wherein
R.sub.8 is Y, Y.sub.1 or OY.sub.1.
25. The pharmaceutical composition according to claim 19, wherein
R.sub.2 and R.sub.4 are each hydrogen, and B is
--NR.sub.8--(CH.sub.2).sub.n''-- wherein n'' is 0 and R.sub.8 is
OY.sub.1.
26. The pharmaceutical composition according to claim 25, wherein
R.sub.3 is hydrogen, and R.sub.1 is hydrogen, COOR or
CONR.sub.6R.sub.7.
27. The pharmaceutical composition according to claim 19, wherein
the compound of Formula (I) is selected from the group consisting
of: cis-7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-4-propanoic acid,
trans diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetate, cis diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetate, trans phenylmethyl
3-benzoyl-2-oxo-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate, trans
phenylmethyl
2-oxo-3-(sulphooxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate,
6-[[(4-methylphenyl)sulphonyl]oxy]-1,6-diazabicyclo[3.2.1]octan-7-one,
6-[(methylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octan-7-one,
6-[(4-nitrophenyl)sulphonyl]oxy]-1,6-diazabicyclo[3.2.1]octan-7-one,
trans diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2-carboxylate, trans
(4-nitrophenyl)methyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2-carboxylate,
trans-7-oxo-6-oxa-1-azabicyclo[3.2.1.]octane-2 carboxylic acid,
trans phenylmethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,
trans phenylmethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,
trans phenylmethyl
7-oxo-6-[(phenylsulphonyl)oxy]-1,6-diaza-bicyclo[3.2.1]octane-2-carboxyla-
te, trans phenylmethyl
7-oxo-6-[(2-thienylsulphonyl)oxy]-1,6-diazabicyclo[3-.2.1]octane-2-carbox-
ylat
trans-6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic
acid, trans methyl
6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
trans-7-oxo-N-(phenylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxamide,
trans-7-oxo-N-(2-pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxamide,
trans-7-oxo-N-[2-(3-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1-
] octane-2-carboxamide,
trans-7-oxo-N-[2-(4-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1-
] octane-2-carboxamide,
trans-7-oxo-N-[2-(2-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1-
] octane-2-carboxamide,
trans-N-[3-(aminocarbonyl)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo
[3.-2.1] octane-2-carboxamide,
trans-N-[4-(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo
[3.2.1]octane-2-carboxamide,
trans-N-[3-(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo
[3.2.1]octane-2-carboxamide,
trans-7-oxo-N-[(4-pyridinyl)methyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxamide,
trans-7-oxo-N-(3-pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxamide,
trans-N-(1-amino-1-oxo-3-phenyl-2-propyl)-7-oxo-6-(sulphooxy)-1,6-diazabi-
cyclo[3.2.1]octane-2-carboxamide,
trans-N-(2-amino-2-oxoethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]
octane-2-carboxamide,
trans-N-[3-[(aminocarbonyl)amino]phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabic-
yclo[3.2.1]octane-2-carboxamide,
trans-N-(2-amino-2-oxo-1-phenylethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicycl-
o[3.2.1]octane-2-carboxamide,
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
of 2-amino-2-oxoethyl, trans 2-(4-pyridinyl)ethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1] octane-2-carboxylate,
trans 2-(2-pyridinyl)ethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1] octane-2-carboxylate,
6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one, and
3-methoxy-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one.
28. The pharmaceutical composition of claim 27, wherein said
.beta.-lactamine antibiotic is selected from the group consisting
of: penams, penems, carbapenems, cephems, carbacephems, oxacephems,
cephamycims, monobactams, and combinations and pharmaceutically
acceptable salts thereof.
29. The pharmaceutical composition of claim 27, wherein said
.beta.-lactamine antibiotic is selected from the group consisting
of: amoxicillin, ampicillin, azlocillin, mezlocillin, apalcillin,
hetacillin, bacampicillin, carbenicillin, sulbenicillin,
ticarcillin, piperacillin, azlocillin, mecillinam, pivmecillinam,
methicillin, ciclacillin, talampicillin, aspoxicillin, oxacillin,
cloxacillin, dicloxacillin, flucloxacillin, nafcillin,
pivampicillin, cephalothin, cephaloridine, cefaclor, cefadroxil,
cefamandole, cefazolin, cephalexin, cephradine, ceftizoxime,
cefoxitin, cephacetrile, cefotiam, cefotaxime, cefsulodin,
cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin,
cefonicid, cefodizime, cefpirome, ceftazidime, ceftriaxone,
cefpiramide, cefbuperazone, cefozopran, cefepime, cefoselis,
cefluprenam, cefuzonam, cefpimizole, cefclidin, cefixime,
ceftibuten, cefdinir, cefpodoxime axetil, cefpodoxime proxetil,
cefteram pivoxil, cefetamet pivoxil, cefcapene pivoxil, cefditoren
pivoxil, cefuroxime, cefuroxime axetil, loracarbacef, latamoxef,
imipenem, meropenem, biapenem, panipenem, aztreonam, carumonam, and
combinations and pharmaceutically acceptable salts thereof.
30. The pharmaceutical composition of claim 27, wherein said
.beta.-lactamine antibiotic is selected from the group consisting
of: cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole,
cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin,
cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone,
ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid,
cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide,
cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam,
cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir,
cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil,
cefetamet pivoxil, cefcapene pivoxil, cefditoren pivoxil,
cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, and
combinations and pharmaceutically acceptable salts thereof.
31. The pharmaceutical composition according to claim 19, wherein
said compound of Formula (I) comprises
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide
or a pharmaceutically acceptable salt thereof.
32. The pharmaceutical composition according to claim 19, wherein
said compound of Formula (I) comprises a sodium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide.
33. The pharmaceutical composition of claim 19, wherein said
compound of Formula (I) comprises
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide
or a pharmaceutically acceptable salt thereof and said
.beta.-lactamine antibiotic comprises ceftazidime.
34. The pharmaceutical composition of claim 19, wherein said
compound of Formula (I) comprises a sodium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo-[3.2.1]-octane-2-carboxamide
and said .beta.-lactamine antibiotic comprises ceftazidime.
Description
[0001] This application is a continuation of International
Application No. PCT/FR03/00243 filed Jan. 27, 2003, which claims
the benefit of priority of French Application No. 02 00951, filed
Jan. 28, 2002.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to heterocyclic compounds, endowed
with beta-lactamase inhibitory properties, and therefore are of
interest in combating infectious diseases or in the prevention of
them, in the form of a combination with various antibiotic
compounds of .beta.-lactamine type, in order to reinforce their
effectiveness in combating the pathogenic bacteria which produce
.beta.-lactamases.
[0004] 2. Description of the Art
[0005] It is well known that the enzymatic inactivation of
antibiotics of .beta.-lactamine type, whether compounds of
penicillin or cephalosporin type, in the treatment of bacterial
infections is a obstacle for this type of compound. This
inactivation consists of a degradation process of the
.beta.-lactamines and constitutes one of the mechanisms by which
the bacteria can become resistant to treatments. It is therefore
desirable to act against this enzymatic process by combining an
agent capable of inhibiting the enzyme with the antibacterial agent
of .beta.-lactamine type. When an inhibitor of .beta.-lactamase is
used in combination with an antibiotic of .beta.-lactamine type, it
can thus reinforce its effectiveness against certain
microorganisms.
SUMMARY OF THE INVENTION
[0006] The invention therefore relates to the compounds
corresponding to the formula (I):
##STR00002##
in which: R.sub.1 represents a hydrogen atom, a COOH, CN, COOR,
CONR.sub.6, R.sub.7, (CH.sub.2).sub.n'R.sub.5 or
##STR00003##
radical R is chosen from group constituted by an alkyl radical
containing 1 to 6 carbon atoms, optionally substituted by a pyridyl
or carbamoyl radical, a --CH.sub.2-alkenyl radical containing a
total of 3 to 9 carbon atoms, aryl containing 6 to 10 carbon atoms
or aralkyl containing 7 to 11 carbon atoms, the nucleus of aryl or
aralkyl radical being optionally substituted by an OH, NH.sub.2,
NO.sub.2, alkyl radical containing 1 to 6 carbon atoms, alkoxy
containing 1 to 6 carbon atoms or by one or more halogen atoms,
R.sub.6 and R.sub.7, identical or different, are chosen from the
group constituted by a hydrogen atom, an alkyl radical containing 1
to 6 carbon atoms, aryl containing 6 to 10 carbon atoms and aralkyl
containing 7 to 11 carbon atoms, optionally substituted by a
carbamoyl, ureido or dimethylamino radical, and an alkyl radical
containing 1 to 6 carbon atoms substituted by a pyridyl radical, n'
is equal to 1 or 2 and R.sub.5 is chosen from the group constituted
by a COOH, CN, OH, NH.sub.2, CO--NR.sub.6R.sub.7, COOR, OR, OCHO,
OCOR, OCOOR, OCONHR, OCONH.sub.2, NHR, NHCOH, NHCOR, NHSO.sub.2R,
NH--COOR, NH--CO--NHR or NHCONH.sub.2 radical, R, R.sub.6 and
R.sub.7 being as defined above; R.sub.2 represents a hydrogen atom
or a (CH.sub.2).sub.n'1R.sub.5 group, n'.sub.1 being equal to 0, 1
or 2, and R.sub.5 being as defined above; R.sub.3 represents a
hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms; A
represents a bond between the two carbons which carry R.sub.1 and
R.sub.2 or a
##STR00004##
group, R.sub.4 representing a hydrogen atom or a
(CH.sub.2).sub.n'1R.sub.5 group, n'.sub.1 and R.sub.5 being as
defined above, the dotted line representing an optional additional
bond with one or other of the carbons which carry the substituents
R.sub.1 and R.sub.2, n is equal to 1 or 2, X represents a divalent
--C(O)--B-- group linked to the nitrogen atom by the carbon atom, B
represents a divalent --O--(CH.sub.2).sub.n''-- group linked to the
carbonyl by the oxygen atom, an --NR.sub.8--(CH.sub.2).sub.n'-- or
--NR.sub.8--O-- group linked to the carbonyl by the nitrogen atom,
n'' is equal to 0 or 1 and R.sub.8, in the case of
--NR.sub.8--(CH.sub.2).sub.n''-- is chosen from the group
constituted by a hydrogen, an OH, R, OR, Y, OY, Y.sub.1, OY.sub.1,
Y.sub.2, OY.sub.2, Y.sub.3, OCH.sub.2CH.sub.2SO.sub.mR,
OSiR.sub.aR.sub.bR.sub.c and SiR.sub.aR.sub.bR.sub.c radical, and
in the case of --NR.sub.8--O-- is chosen from the group constituted
by a hydrogen, an R, Y, Y.sub.1, Y.sub.2, Y.sub.3 and
SiR.sub.aR.sub.bR.sub.c radical, R.sub.a, R.sub.b and R.sub.c
representing individually a linear or branched alkyl radical
containing 1 to 6 carbon atoms or an aryl radical containing 6 to
10 carbon atoms, R being as defined previously and m being equal to
0, 1 or 2, Y is chosen from the group constituted by the COH, COR,
COOR, CONH.sub.2, CONHR, CONHOH, CONHSO.sub.2R, CH.sub.2COOH,
CH.sub.2COOR, CH.sub.2CONHOH, CH.sub.2CONHCN, CH.sub.2tetrazole,
protected CH.sub.2tetrazole, CH.sub.2SO.sub.3H, CH.sub.2SO.sub.2R,
CH.sub.2PO(OR).sub.2, CH.sub.2PO(OR)(OH), CH.sub.2PO(R)(OH) and
CH.sub.2PO(OH).sub.2 radicals, Y.sub.1 is chosen from the group
constituted by the SO.sub.2R, SO.sub.2NHCOH, SO.sub.2NHCOR,
SO.sub.2NHCOOR, SO.sub.2NHCONHR SO.sub.2NHCONH.sub.2 and SO.sub.3H
radicals, Y.sub.2 is chosen from the group constituted by the
PO(OH).sub.2, PO(OR).sub.2, PO(OH)(OR) and PO(OH)(R) radicals,
Y.sub.3 is chosen from the group constituted by the following
radicals: tetrazole, tetrazole substituted by the R, squarate, NH
or NR tetrazole, NH or NR tetrazole substituted by the R radical,
NHSO.sub.2R and NRSO.sub.2R, R being as defined above; R.sub.1,
R.sub.2 and R.sub.3 not representing all three at the same time a
hydrogen atom when n is equal to 1 and A represents a
##STR00005##
group in which R4 is a hydrogen atom and [0007] either X represents
the --C(O)--O--(CH.sub.2).sub.n'' group in which n'' is 0 or 1,
[0008] or X represents the --CO--NR.sub.8--(CH.sub.2).sub.n'' group
in which n'' is 1 and R.sub.8 is the isopropyl group, [0009] or X
represents the --CO--NR.sub.8--(CH.sub.2).sub.n'' group in which
n'' is 0 and R.sub.8 is hydrogen or phenyl, as well as the salts of
these compounds with mineral or organic bases or acids, as well as
the internal salts in the form in which they can, if appropriate,
be presented.
[0010] The compounds of formula (I) and their salts are described
and claimed in the International Patent Application No.
PCT/FR01/02418 filed on the 24 Jul. 2001, claiming priority from
the French Application No. .sup.o0010121 filed on the 1 Aug.
2000.
[0011] The compounds of formula (I) are presented in the form of
pure enantiomers or pure diastereoisomers or in the form of a
mixture of enantiomers in particular of racemates, or mixtures of
diastereoisomers. Moreover, the substituents R.sub.1, R.sub.2,
R.sub.4 taken individually on the one hand and X on the other can
be in cis and/or trans position with respect to the ring on which
they are fixed, and the compounds of formula (I) are therefore
presented in the form of cis isomers or trans isomers or
mixtures.
[0012] By alkyl radical containing 1 to 6 carbon atoms, is meant
the methyl, ethyl radical, as well as propyl, butyl, pentyl or
hexyl linear, branched or cyclic.
[0013] By --CH.sub.2-alkenyl radical containing 3 to 9 carbon
atoms, is meant for example the allyl radical, or a butenyl,
pentenyl or hexenyl radical.
[0014] By aryl radical containing 6 to 10 carbon atoms, is meant a
phenyl or naphthyl radical.
[0015] By aralkyl radical containing 7 to 11 carbon atoms, is meant
a benzyl, phenethyl or methylnaphthyl radical.
[0016] By alkyloxy radical containing 1 to 6 carbon atoms, is meant
in particular the methoxy, ethoxy, propoxy, isopropoxy radical, as
well as butoxy, isobutoxy, dry-butoxy or tert-butoxy radical.
[0017] By halogen atom, is meant a fluorine, chlorine, bromine or
iodine atom.
[0018] By squarate radical, is meant the radical of formula:
##STR00006##
[0019] Among the salts with acids of the products of formula (I),
there can be mentioned amongst others, those formed with mineral
acids, such as hydrochloric, hydrobromic, hydroiodic, sulphuric or
phosphoric acids or with organic acids such as formic, acetic,
trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic,
tartaric, citric, oxalic, glyoxylic, aspartic acid,
alkanesulphonics, such methane and ethane sulphonic acids,
arylsulphonics such as benzene and paratoluenesulphonic acids.
[0020] Among the salts with bases of the products of formula (I),
there can be mentioned, amongst others, those formed with mineral
bases such as, for example, sodium, potassium, lithium, calcium,
magnesium or ammonium hydroxide or with organic bases such as, for
example, methylamine, propylamine, trimethylamine, diethylamine,
triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)amino
methane, ethanolamine, pyridine, picoline, dicyclohexylamine,
morpholine, benzylamine, procaine, lysine, arginine, histidine,
N-methylglucamine, or also phosphonium salts, such as
alkyl-phosphoniums, aryl-phosphoniums, alkyl-aryl-phosphoniums, the
alkenyl-aryl-phosphoniums or quaternary ammonium salts such the
salt of tetra-n-butyl-ammonium.
[0021] A subject of the invention is the use of the compounds of
formula (I), as well as their pharmaceutically acceptable salts,
for the preparation of a medicament intended to inhibit the
production of .beta.-lactamases by pathogenic bacteria.
[0022] A subject of the invention is also the use of the compounds
of formula (I), as well as their pharmaceutically acceptable salts,
which inhibit the production of .beta.-lactamases by pathogenic
bacteria, for the preparation of a medicament intended for the
treatment of bacterial infections in man or animals.
[0023] A particular subject of the invention is a use according to
what has gone before, characterized in that the compounds
correspond to formula (I) in which n is equal to 1 and A and
R.sub.2 are as defined above, R.sub.3 represents a hydrogen atom,
R.sub.1 represents a hydrogen atom, a COOR or CONR.sub.6R.sub.7
radical, R.sub.6 and R.sub.7 being as defined above and X
represents a --C(O)--B-- group in which B represents an
--O--(CH.sub.2).sub.n''-- or --NR.sub.8--(CH.sub.2).sub.n''--
group, n'' being equal to O and R.sub.8 having the values as
defined above and, more particularly the values Y, Y.sub.1 and
OY.sub.1, and more particularly, from among these, those
corresponding to formula (I) in which A represents a
##STR00007##
group in which R.sub.4 represents a hydrogen atom, R.sub.2
represents a hydrogen atom and B represents an
NR.sub.8--(CH.sub.2).sub.n''-- group in which n'' is equal to O and
R.sub.8 represents an OY.sub.1 radical.
[0024] A quite particular subject of the invention is a use as
defined above, characterized in that the compounds are chosen from
the list constituted by: [0025]
cis-7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-4-propanoic-acid, [0026]
trans diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetate, [0027] cis
diphenylmethyl 7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetate,
[0028] trans phenylmethyl
3-benzoyl-2-oxo-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate,
[0029] trans phenylmethyl
2-oxo-3-(sulphooxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate,
[0030]
6-[[(4-methylphenyl)sulphonyl]oxy]-1,6-diazabicyclo[3.2.1]octan-7-one,
[0031] 6-[(methylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octan-7-one,
[0032]
6-[(4-nitrophenyl)sulphonyl]oxy]-1,6-diazabicyclo[3.2.1]octan-7-on-
e, [0033] trans diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2-carboxylate, [0034]
trans(4-nitrophenyl)methyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2-carboxylate, [0035]
trans-7-oxo-6-oxa-1-azabicyclo[3.2.1.]octane-2 carboxylic acid,
[0036] trans phenylmethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,
[0037] trans phenylmethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,
[0038] trans phenylmethyl
7-oxo-6-[(phenylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxylat-
e, [0039] trans phenylmethyl
7-oxo-6-[(2-thienylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxy-
late, [0040]
trans-6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic
acid, [0041] trans methyl
6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate, [0042]
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide,
[0043]
trans-7-oxo-N-(phenylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]-
octane-2-carboxamide, [0044]
trans-7-oxo-N-(2-pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oc-
tane-2-carboxamide, [0045]
trans-7-oxo-N-[2-(3-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1-
]octane-2-carboxamide, [0046]
trans-7-oxo-N-[2-(4-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1-
]octane-2-carboxamide, [0047]
trans-7-oxo-N-[2-(2-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1-
]octane-2-carboxamide, [0048]
trans-N-[3-(aminocarbonyl)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.-
2.1]octane-2-carboxamide, [0049]
trans-N-[4-(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.-
2.1]octane-2-carboxamide, [0050]
trans-N-[3-(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.-
2.1]octane-2-carboxamide, [0051]
trans-7-oxo-N-[(4-pyridinyl)methyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]-
octane-2-carboxamide, [0052]
trans-7-oxo-N-(3-pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oc-
tane-2-carboxamide, [0053]
trans-N-(1-amino-1-oxo-3-phenyl-2-propyl)-7-oxo-6-(sulphooxy)-1,6-diazabi-
cyclo[3.2.1]octane-2-carboxamide, [0054]
trans-N-(2-amino-2-oxoethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]o-
ctane-2-carboxamide, [0055]
trans-N-[3-[(aminocarbonyl)amino]phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabic-
yclo[3.2.1]octane-2-carboxamide, [0056]
trans-N-(2-amino-2-oxo-1-phenylethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicycl-
o[3.2.1]octane-2-carboxamide, [0057] trans 2-amino-2-oxoethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,
[0058] trans 2-(4-pyridinyl)ethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,
[0059] trans 2-(2-pyridinyl)ethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate,
[0060] 6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one, [0061]
3-methoxy-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one, as
well as their salts.
[0062] A subject of the invention is also a use as defined above,
characterized in that within a medicament, the compound of formula
(I) is combined with an antibiotic of .beta.-lactamine type chosen
from the group constituted by the penams, the penems, the
carbapenems, the cephems, the carbacephems, the oxacephems, the
cephamycins and the monobactams.
[0063] By .beta.-lactamines, is meant for example the penicillins
such as amoxicillin, ampicillin, azlocillin, mezlocillin,
apalcillin, hetacillin, bacampicillin, carbenicillin,
sulbenicillin, ticarcillin, piperacillin, azlocillin, mecillinam,
pivmecillinam, methicillin, ciclacillin, talampicillin,
aspoxicillin, oxacillin, cloxacillin, dicloxacillin,
flucloxacillin, nafcillin or pivampicillin, the cephalosporins such
as cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole,
cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin,
cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone,
ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid,
cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide,
cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam,
cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir,
cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil,
cefetamet pivoxil, cefcapene pivoxil or cefditoren pivoxil,
cefuroxime, cefuroxime axetil, loracarbacef, latamoxef, the
carbapenems such as imipenem, meropenem, biapenem or panipenem and
the monobactams such as aztreonam and carumonam, as well as their
salts.
[0064] The compounds of formula (I) or their pharmaceutically
acceptable salts, can be administered at the same time as the dose
of an antibiotic of the .beta.-lactamine type, or separately,
preferably after it. This can be carried out in the form of a
mixture of the two active ingredients or in the form of a
pharmaceutical combination of the two separate active
ingredients.
[0065] The dose of the compounds of formula (I) and of their
pharmaceutically acceptable salts can of course vary within wide
limits and must naturally be adapted, in each particular case, to
the individual conditions and to the pathogenic agent, which
produces .beta.-lactamase, to be combated. In general, a daily dose
can range from 0.1 to approximately 10 g as may be convenient.
[0066] Moreover, the ratio of the .beta.-lactamase inhibitor of
formula (I) or of the pharmaceutically acceptable salt of the
latter to the antibiotic of .beta.-lactamine type can also varies
vary within wide limits and must be adapted, in each particular
case, to the individual conditions. In general, a ratio ranging
from approximately 1:20 to approximately 1:1 must be indicated.
[0067] The medicaments as defined above are employed in the form of
pharmaceutical compositions in a mixture with an organic or
mineral, inert pharmaceutical excipient, adapted to the sought
administration method, and a subject of the invention is also said
pharmaceutical compositions.
[0068] These compositions can be solid or liquid and be presented
in the pharmaceutical forms commonly used in human medicine, such
as for example, plain or sugar-coated tablets, gelatin capsules,
granules, suppositories, injectable preparations, ointments,
creams, gels, they are prepared according to the usual methods. The
active ingredient or ingredients can be incorporated with
excipients usually employed in these pharmaceutical compositions,
such as talc, gum arabic, lactose, starch, magnesium stearate,
cocoa butter, aqueous or non-aqueous vehicles, fatty substances of
animal or vegetable origin, paraffin derivatives, glycols, various
wetting, dispersing or emulsifying agents, preservatives.
[0069] These compositions can also be presented in the form of a
lyophilisate intended to be dissolved extemporaneously in an
appropriate vehicle for example apyrogenic sterile water.
[0070] The compounds of formula (I) can be prepared by a process
comprising:
a) a stage during which a carbonylation agent, if appropriate in
the presence of a base, is reacted with a compound of formula
(II):
##STR00008##
in which: R'.sub.1 represents a hydrogen atom or a CN, protected
COOH, COOR', (CH.sub.2)n'R'.sub.5, CONR.sub.6R.sub.7 or
protected
##STR00009##
radical; n', R.sub.6 and R.sub.7 having the above definitions and
R' and R'.sub.5 having the above definitions of R and R.sub.5
respectively, in which the reactive functions which are optionally
present are protected; R'.sub.2 represents a hydrogen atom or a
(CH.sub.2)n'.sub.1R'.sub.5 group, n'.sub.1 and R'.sub.5 being as
defined above; R.sub.3 is as defined previously; A' represents a
bond between the two carbons which carry R'.sub.1 and R'.sub.2 or
a
##STR00010##
group, R'.sub.4 representing a hydrogen atom or a
(CH.sub.2)n'.sub.1R'.sub.5 group, n'.sub.1 and R'.sub.5 being as
defined above, the dotted line representing an optional bond with
one or other of the carbons which carry substituents R'.sub.1 and
R'.sub.2; n is as defined previously; HZ represents a
HO--(CH.sub.2)n''--, HNR'.sub.8--(CH.sub.2).sub.n''-- or
HNR'.sub.8--O-- group, n'' being as defined previously and R'.sub.8
representing a hydrogen atom, a protected OH, R', OR' radical, a Y'
or OY' radical, Y' being chosen from the COH, COR', COOR',
CONH.sub.2, CONHR', protected CONHOH, CONHSO.sub.2R', protected
CH.sub.2COOH, CH.sub.2COOR', protected CH.sub.2CONHOH,
CH.sub.2CONHCN, CH.sub.2tetrazole substituted by R',
CH.sub.2SO.sub.2R', CH.sub.2PO(OR').sub.2, protected
CH.sub.2SO.sub.3, protected CH.sub.2PO(OR')OH, protected
CH.sub.2PO(R')OH, protected CH.sub.2PO(OH).sub.2 groups, a Y'.sub.1
or OY.sub.1 radical, Y'.sub.1 being chosen from the SO.sub.2R',
SO.sub.2NHCOH, SO.sub.2NHCOR', SO.sub.2NHCOOR',
SO.sub.2NHCONH.sub.2, SO.sub.2NHCONHR' and protected SO.sub.3H
groups, a Y'.sub.2 or OY'.sub.2 radical, Y'.sub.2 representing a
protected PO(OH).sub.2, protected PO(OH)(OR'), protected PO(OH)R'
or PO(OR').sub.2 group, or a Y'.sub.3 radical, Y'.sub.3 being
chosen from the protected tetrazole, tetrazole substituted by the
R' radical, protected NH or NR' tetrazole, NH or NR' tetrazole
substituted by the R' radical, NHSO.sub.2R' and NR'SO.sub.2R'
groups, R' being as defined above; with a view to obtaining an
intermediate compound of formula:
##STR00011##
in which: R'.sub.1, R'.sub.2, R.sub.3, A' and n have the same
meanings as above and either X.sub.1 is a hydrogen atom and X.sub.2
represents a -Z-CO--X.sub.3 group, X.sub.3 representing the
remainder of the carbonylation agent, or X.sub.2 is a -ZH group and
X.sub.1 represents a CO--X.sub.3 group, X.sub.3 being as defined
previously; b) a stage during which the intermediate obtained
previously is cyclized, in the presence of a base; and in that: c)
if appropriate, Stage a) is preceded and/or Stage b) is followed by
one or more of the following reactions, in an appropriate order:
[0071] protection of the reaction functions, [0072] deprotection of
the reaction functions, [0073] esterification, [0074]
saponification, [0075] sulphation, [0076] phosphation [0077]
amidification, [0078] acylation, [0079] sulphonylation; [0080]
alkylation; [0081] introduction of a double bond; [0082] formation
of a urea group; [0083] introduction of a tetrazole group; [0084]
reduction of the carboxylic acids; [0085] dehydration of amide to
nitrile; [0086] salification; [0087] ion exchange; [0088]
resolution or separation of diastereoisomers; [0089] oxidation of
sulphide to sulphoxide and/or sulphone.
[0090] As a carbonylation agent, a reagent can be employed such as
phosgene, diphosgene, triphosgene, an aryl chloroformate such as
phenyl or p-nitrophenyl chloroformate, an aralkyl chloroformate
such as benzyl chloroformate, an alkyl or alkenyl chloroformate
such as methyl or allyl chloroformate, an alkyl dicarbonate such as
tert-butyl dicarbonate, carbonyl-diimidazole and their
mixtures.
[0091] The reaction preferably takes place in the presence of a
base or a mixture of bases which neutralize the acid formed. It can
in particular be an amine such as triethylamine,
diisopropylethylamine, pyridine, dimethylaminopyridine. However,
the operation can also be carried out using the starting product of
formula II as base. It is then used in excess. An illustration is
given in the experimental part.
[0092] If appropriate, the product of formula II is employed in the
form of an acid salt, for example a hydrochloride or a
trifluoroacetate.
[0093] As base in Stage b), amines, or also hydrides, alcoholates,
amides or carbonates of alkali or alkaline-earth metals can also be
used.
[0094] The amines can be chosen for example from the above
list.
[0095] As hydride, sodium or potassium hydride can in particular be
used.
[0096] As alkali metal alcoholate, potassium t-butylate is
preferably used.
[0097] As alkali metal amide lithium bis(trimethylsilyl) amide can
in particular be used.
[0098] As a carbonate, sodium or potassium carbonate or bicarbonate
can in particular be used.
[0099] If appropriate, the intermediate of formula III can be
obtained in the form of an acid salt generated during the
carbonylation reaction and in particular a hydrochloride. It is
then employed in the cyclization reaction in this form.
[0100] If appropriate, the cyclization can be carried out without
isolation of the intermediate of formula III.
[0101] The reactions mentioned in Stage c) are generally standard
reactions, which are well-known to a person skilled in the art.
[0102] The reactive functions which it is convenient and
appropriate to protect are carboxylic acid, amine, amide, hydroxy
and hydroxylamine functions.
[0103] The protection of the acid function is in particular carried
out in the form of alkyl esters, allyl, benzyl, benzhydryl or
p-nitrobenzyl esters.
[0104] Deprotection is carried out by saponification, acid
hydrolysis, hydrogenolysis, or also cleavage using soluble
complexes of palladium 0.
[0105] Examples of these protections and deprotections are provided
hereafter in the experimental part.
[0106] Protection of the amines and amides is in particular carried
out in the form of benzylated derivatives, in the form of
carbamates, in particular of allyl, benzyl, phenyl or tertbutyl, or
also in the form of silylated derivatives such as tertbutyl
dimethyl, trimethyl, triphenyl or also diphenyl tertbutyl-silyl
derivatives.
[0107] Deprotection is carried out, according to the nature of the
protective group, by sodium or lithium in liquid ammonia, by
hydrogenolysis or using soluble complexes of palladium 0, by the
action of an acid, or by the action of tetrabutylammonium
fluoride.
[0108] Examples are provided hereafter in the experimental
part.
[0109] The protection of hydroxylamines is carried out in
particular in the form of benzyl or allyl ethers.
[0110] Cleavage of the ethers is carried out by hydrogenolysis or
by using soluble complexes of palladium 0.
[0111] A illustration is provided below in the experimental
part.
[0112] Protection of the alcohols is carried out in a standard
fashion, in the form of ethers, esters or carbonates. The ethers
can be alkyl or alkoxyalkyl ethers, preferably methyl or
methoxyethoxymethyl ethers, aryl or preferably aralkyl ethers, for
example benzyl, or silylated ethers, for example the silylated
derivatives mentioned above. The esters can be any cleavable ester
known to a person skilled in the art and preferably the acetate,
propionate or benzoate or p-nitrobenzoate. The carbonates can be,
for example, methyl, tertbutyl, allyl, benzyl or p-nitrobenzyl
carbonates.
[0113] Deprotection is carried out by means known to a person
skilled in the art, in particular, saponification, hydrogenolysis,
cleavage by soluble complexes of palladium 0, hydrolysis in acid
medium or also, for the silylated derivatives, treatment with
tetrabutylammonium fluoride.
[0114] Examples are provided in the experimental part.
[0115] The sulphation reaction is carried out by the action of
SO.sub.3-amine complexes such as SO.sub.3-pyridine or
SO.sub.3-dimethylformamide, operating in pyridine, the salt formed,
for example the pyridine salt, can then be exchanged for example by
a salt of another amine, of a quaternary ammonium or of an alkali
metal. Examples are provided in the experimental part.
[0116] The phosphation reaction is carried out for example by the
action of a chlorophosphate such as dimethyl, dibenzyl or diphenyl
chlorophosphate.
[0117] The amidification reaction is carried out starting from the
carboxylic acid using an activation agent such as an alkyl
chloroformate or EDCI, by the action of ammonium hydroxide or of an
appropriate amine or their acid salts. Examples are provided
hereafter in the experimental part.
[0118] The acylation and sulphonylation reactions are carried out
on the hydroxyureas by the action respectively of a halide or an
anhydride of an appropriate carboxylic acid or a halide of an
appropriate sulphonic acid. Several examples are provided hereafter
in the experimental part.
[0119] The alkylation reaction is carried out by the action on the
hydroxylated derivatives of an alkyl halide or an alkyl halide
substituted, in particular, by a free or esterified carboxy
radical. Illustrations are provided hereafter in the experimental
part.
[0120] The final optional introduction of a double bond, which is
then preferably situated between the carbon atoms which carry
R.sub.4 and R.sub.1, is carried out by the action of a halogenated
derivative of selenium then oxidation, according to the methods
known to a person skilled in the art. An example is shown hereafter
in the experimental part.
[0121] Formation of a urea group, which relates to the substituent
R.sub.8 is preferably carried out by the action of an appropriate
isocyanate on the free NH. An example is shown hereafter in the
experimental part.
[0122] Introduction of a tetrazole group is carried out by the
action of a halogenated derivative, preferably fluorinated, of the
protected or substituted tetrazole. Deprotection can be carried out
by hydrogenolysis.
[0123] Reduction of the acids to alcohols can be carried out by the
action of a borane or via a mixed anhydride intermediate, by the
action of an alkaline borohydide. The mixed anhydride is prepared
for example using an alkyl chloroformate. An illustration of this
is provided in the experimental part.
[0124] Dehydration of the amide to a nitrile can occur under the
carbonylation and cyclization reaction conditions.
[0125] Oxidation of the sulphide to sulphoxide and/or sulphone can
be carried out by the action of a peracid such as
metachloroperbenzoic or perphthalic acid or any other reagent known
to a person skilled in the art.
[0126] Salification by acids is, if appropriate, carried out by
adding an acid in soluble phase to the compound. Salification by
bases can concern either the compounds comprising an acid function,
in particular carboxy, or those comprising a sulphooxy function or
a phosphoric acid derivative or those comprising a heterocycle with
an acid character. In the first case, the operation is carried out
by adding an appropriate base such as those mentioned previously.
In the second case, the pyridinium salt is obtained directly during
the action of the SO.sub.3-pyridine complex and the other salts are
obtained from this pyridinium salt. In one or other case, the
operation can also be carried out by ion exchange on resin.
Examples of salifications are shown hereafter in the experimental
part.
[0127] Separation of the enantiomers and diastereoisomers can be
carried out according to the techniques known to a person skilled
in the art, in particular chromatography.
[0128] In addition to the processes described previously, the
compounds of formula (I) can of course be obtained by methods which
use at the start a compound of formula (II) in which R'.sub.1, A',
R'.sub.2, R.sub.3 and HZ have the values which lead directly
(without conversion) to those of the compounds that one wishes to
prepare. If appropriate, those of these values which would contain
reaction functions as mentioned above are then protected,
deprotection occurring at the end of the cyclization stage b or at
any other opportune moment in the synthesis. The protections and
deprotections are then carried out as described above.
[0129] Such methods are provided hereafter in the experimental
part.
[0130] The products of formula (II) are known or can be prepared
according to methods known to a person skilled in the art.
References from the literature as well as the preparations are
provided hereafter in the experimental part.
EXAMPLES
[0131] The following examples illustrate the invention, without
however limiting the scope.
[0132] In the examples which follow the following abbreviations
have been used:
[0133] DEAD: diethyl azo-dicarboxylate
[0134] TEA: triethylamine
[0135] DMAP: 4-dimethylamino-pyridine
[0136] EDCI: 1-(3-dimethylamino-propyl)-3-ethylcarbo-diimide
hydrochloride
[0137] THF: tetrahydrofuran
[0138] AIBN: 2.2'-azo-bis-isobutyronitrile
[0139] M: molar molecular mass
[0140] MS: mass spectrometry
[0141] EI: electron impact
[0142] SIMS: secondary ion mass spectrometry
[0143] FAB: fast atom bombardment
Example 1
cis diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-4-propanoate
[0144] 3.16 g (10.6 mmoles) of the hydrochloride of
3-oxo-1-(phenylmethyl)-4-piperidinepropanoic acid (M=297.7 g)
(described in the Japanese Patent Application J54098-772) is mixed
with 100 ml of ethanol and the reaction medium is cooled down to
10.degree. C. 1.84 g of NaBH.sub.4 is added over 15 minutes, under
a stream of nitrogen, whilst maintaining the temperature between 8
and 13.degree. C. The temperature is allowed to rise to ambient
temperature and left in contact for 1 hour 30 minutes. Another 380
mg of NaBH.sub.4 is added and the reaction medium is left overnight
at ambient temperature.
[0145] The solvent is evaporated off under reduced pressure,
followed by taking up in 50 ml of water and adjusting the pH from
10 to 2 using concentrated hydrochloric acid. Evaporation is again
carried out under reduced pressure. The solid residue
(approximately 10.8 g) is washed twice with 100 ml of ethanol then
the solvent is evaporated off under reduced pressure.
[0146] In this way 3.10 g of the hydrochloride of
3-hydroxy-1-(phenylmethyl)-4-piperidinepropanoic acid (M=299.7 g)
is obtained, which corresponds to a yield of 97%.
[0147] 3.10 g (10.3 mmoles) of the compound obtained previously is
diluted in 100 ml of ethanol then 900 mg of 10% Pd/C by
prehydrogenated weight and in 30 ml of ethanol is added to it.
[0148] The reaction medium is left under a hydrogen atmosphere at
normal pressure overnight, then the catalyst is eliminated by
filtration and the ethanol by evaporation under reduced
pressure.
[0149] 1.90 g of the hydrochloride of
trans-3-hydroxy-4-piperidinepropanoic acid (M=209.6 g), is obtained
i.e. a yield of 88%.
[0150] 1.79 g (8.54 mmoles) of the compound obtained previously is
mixed with 20 ml of ethanol and 20 ml of water.
[0151] Then concentrated soda is added until the pH is
approximately 8.5.
[0152] Then, 1 ml of allyl chloroformate and concentrated soda are
added so as to maintain the pH between 8 and 9.
[0153] The reaction mixture is extracted with ethyl acetate then
the aqueous phase is acidified to pH 2 by adding concentrated
hydrochloric acid and reextracting with ethyl acetate. After drying
and evaporating the solvent under reduced pressure, 1.69 g of crude
product is obtained which is taken up in a mixture of
dichloromethane and ethanol, followed by filtering and again
evaporating the solvent under reduced pressure.
[0154] In this way 1.40 g of
trans-3-hydroxy-1-[(2-propenyloxy)carbonyl]-4-piperidinepropanoic
acid (M=257 g) is obtained, i.e. a yield of 60%.
[0155] 3.24 g (12.6 mmoles) of the above hydroxy-acid and 6.4 g of
triphenylphosphine are dissolved in 60 ml of THF at 0.degree. C.
under a nitrogen atmosphere. Then 2.5 ml of DEAD is added and after
15 minutes the reaction mixture is evaporated under reduced
pressure in order to obtain 12 g of crude product. Purification is
carried out by chromatography on silica eluting progressively with
a mixture of dichloromethane and ethyl acetate 9/1, 8/2, 7/3 in
order to separate the cis and trans lactones.
[0156] In this way 2.72 g of cis lactone is obtained in a mixture
with reduced DEAD and phosphine oxide.
[0157] This product is resolubilized in 10 ml of DME and 8 ml of a
1N solution of NaOH is added. After contact for 1 hour, the
reaction mixture is extracted twice with ethyl acetate, then
acidified to pH 2 with 2N HCl, and reextracted with ethyl acetate.
After drying and evaporating the solvent under reduced pressure,
1.07 g of hydroxy-acid is obtained.
[0158] 1.0 g of crude hydroxy-acid is dissolved in a mixture of 5
ml of dichloromethane and 2 ml of methanol, then treated with an
excess of diphenyldiazomethane in dichloromethane, until the
starting product disappears. The solvent is evaporated off under
reduced pressure and the product is purified by chromatography in
order to produce 1.39 g of cis diphenylmethyl
3-hydroxy-1-[(2-propenyloxy)carbonyl]-4-piperidinepropanoate (M=423
g), i.e. an overall yield of 26%.
[0159] Then 1.2 g (2.83 mmoles) of the product obtained previously
is dissolved under a nitrogen atmosphere in 23 ml of
dichloromethane. Then 390 .mu.l of acetic acid then 860 .mu.l of
Bu.sub.3SnH and 70 mg of Pd(PPh.sub.3).sub.4 are added.
[0160] The solvent is evaporated off under reduced pressure in
order to obtain 3.82 g of crude product which is washed with
petroleum ether. 1.27 g of product is obtained which is filtered on
silica with dichloromethane, then with a mixture of dichloromethane
and methanol 95/5 then 90/10. In this way 0.87 g of cis
diphenylmethyl 3-hydroxy-4-piperidinepropanoate (M=339 g) is
obtained, i.e. a yield of 77%.
[0161] 400 mg (1.00 mmole) of the compound obtained previously is
dissolved in 25 ml of dichloromethane, 80 .mu.l of diphosgene
(Cl.sub.3COCOCl), 336 .mu.l of TEA, 144 mg of DMAP are added.
[0162] The reaction medium is left to react at ambient temperature
for 5 hours 30 minutes, then diluted in dichloromethane, followed
by washing with a 10% aqueous solution of tartaric acid, then with
a buffer solution of sodium phosphate at pH 7. The organic phase is
dried over sodium sulphate, then the solvent is evaporated off
under reduced pressure. In this way 380 mg of crude product is
obtained.
[0163] Purification is carried out by chromatography on silica,
eluting with a dichloromethane/ethyl acetate mixture 95/5 with 0.1%
water.
[0164] 184 mg of the title compound is obtained (M=365.43 g), i.e.
a yield of 50%.
[0165] 1H NMR
[0166] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0167] 1.60 to 1.88 (m): NCH.sub.2--CH.sub.2-CH; 2.48 (m):
CH.sub.2--CH.sub.2--CO; 2.78 (d)--2.90 (m)--3.33 to 3.47 (m):
CH.sub.2--N--CH.sub.2; 4.50 (d): CHO--CH.sub.2; 6.89 (s):
CO.sub.2CH(C.sub.6H.sub.5).sub.2; 7.33 (m):
(C.sub.6H.sub.5).sub.2.
[0168] IR (CHCl.sub.3): 1784, 1734, 1600, 1585, 1496 cm.sup.-1
[0169] MS (positive electrospray) m/z: [M].sup.+=365
Example 1a
cis-7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-4-propanoic acid
[0170] 176 mg (0.482 mmoles) of the product obtained previously is
dissolved in 10 ml of acetone. 90 mg of Pd/C at 10% by weight is
added.
[0171] The reaction medium is left to react under a hydrogen
atmosphere at normal pressure for 3 hours. Another 25 mg of
catalyst is added and the reaction is left to continue for 1 hour
15 minutes.
[0172] The catalyst is filtered then the solvent is evaporated off
under reduced pressure in order to obtain 146 mg of product.
[0173] The medium is reacted in 10 ml of acetone with 35 mg of Pd/C
at 10% by weight under a hydrogen atmosphere and the reaction is
left for 1 hour to complete.
[0174] The catalyst is then separated by filtration and the
filtrate is evaporated under reduced pressure. 137 mg of crude
product is obtained which is crystallized from a mixture of ethyl
ether and petroleum ether. In this way 75 mg of the sought product
(M=199 g) is obtained, i.e. a yield of 78%.
[0175] 1H NMR
[0176] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0177] 1.30 to 1.63 (m) and 1.88 (m): NCH.sub.2--CH.sub.2--CH; 2.25
(t): CH.sub.2--CH.sub.2--CO; 3.06 (m) and 3.38 (m):
CH.sub.2--N--CH.sub.2; 4.65 (d): C--CHO--CH.sub.2; 12.08 (s):
mobile H.
[0178] IR (Nujol): 1785, 1717 cm.sup.-1
[0179] MS (FAB) m/z: [M+H].sup.+=200; 159
Example 2
Trans diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetate
[0180] 94 mg (0.259 mmoles) of the compound trans diphenylmethyl
3-hydroxy-4-piperidine-acetate hydrochloride (M=361.87 g)
(described in Eur. J. Med. Chem--Chim. Ther--1982-17(6)531-5) and 7
ml of dichloromethane are mixed under an inert atmosphere.
[0181] The reaction medium is cooled down using an ice bath and 19
.mu.l of diphosgene is injected. Agitation is carried out for 25
minutes, then 72 .mu.l of TEA is injected. Agitation is carried out
at ambient temperature for 30 minutes and the solvent is evaporated
off under reduced pressure, followed by taking up in 7 ml of
toluene.
[0182] 36 .mu.l of TEA then 31 mg of DMAP are added.
[0183] Heating is carried out for 15 minutes at 100.degree. C.,
then the reaction medium is left to return to ambient temperature,
followed by washing twice with 4 ml of 10% tartaric acid in water,
then with 4 ml of water saturated with sodium chloride.
[0184] After drying over magnesium sulphate, filtration is carried
out and the solvent is evaporated off under reduced pressure.
[0185] 78 mg of an oil is obtained which is chromatographed on
silica, eluting with a 95/5 mixture of dichloromethane and ethyl
acetate.
[0186] In this way 35.7 mg of expected compound (M=351.405 g) is
obtained, in the form of white crystals, i.e. a yield of 39%.
Example 2a
trans-7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetic acid
[0187] 38.7 mg (0.110 mmoles) of the product obtained in Example 2
as well as 2 ml of acetone and 38 mg of Pd/C catalyst at 10% by
weight are mixed together under an inert atmosphere.
[0188] The reaction medium is placed under a hydrogen atmosphere at
normal pressure.
[0189] The reaction medium is left to react for 45 minutes, then
the catalyst is eliminated by filtration and the solvent is
evaporated off under reduced pressure.
[0190] In this way 32.6 mg of crude product is obtained.
[0191] Recrystallization is carried out from ethyl ether in order
to obtain 14.2 mg of white crystals of expected compound
(C.sub.8H.sub.10NO.sub.4-- M=185.181 g), i.e. a yield of 69%.
Example 3
cis diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetate
[0192] 1.5 g (5.78 mmoles) of
trans-1-[(1,1-dimethylethoxy)carbonyl]-3-hydroxy-4-piperidineacetic
acid (described in Eur. J. Med. Chem--Chim. Ther--1982-17(6)531-5),
7 ml of dichloromethane, 3.03 g of triphenylphosphine and 22 ml of
tetrahydrofuran are mixed together.
[0193] A solution of 0.91 ml of DEAD in 2.5 ml of tetrahydrofuran
is added. The reaction medium is left to react for 3 hours 20
minutes, then 8.7 ml of 1N soda is added and agitation is carried
out for 1 hour 15 minutes.
[0194] The reaction mixture is extracted twice with ethyl acetate,
then the pH is adjusted to 2 with 2N hydrochloric acid, followed by
extracting three times with ethyl acetate.
[0195] The organic phases are combined and washed with water
saturated in sodium chloride, then dried over magnesium sulphate,
filtered and the solvent is evaporated off under reduced
pressure.
[0196] In this way 1.37 g of white crystals of 1,1-dimethylethyl
(3a.alpha.,7a.alpha.)-hexahydro-2-oxo-furo[2,3-c]pyridine-6(2H)-carboxyla-
te (C.sub.12H.sub.21NO.sub.5-M=259.304 g) is obtained, i.e. a yield
of 91%.
[0197] 1.37 g (5.28 mmoles) of the compound obtained previously and
32 ml of dichloromethane are mixed together under an inert
atmosphere.
[0198] An excess of a solution of diphenyldiazomethane in
dichloromethane is introduced, until the starting product
disappears.
[0199] Then the solvent is evaporated off under reduced pressure
and in this way 2.81 g of crude product is obtained which is
purified by chromatography on silica, using dichloromethane, then a
95/5 mixture of dichloromethane/ethyl acetate as eluent.
[0200] 2.00 g of white crystals of cis diphenylmethyl
1-[(1,1-dimethylethoxy)carbonyl]-3-hydroxy-4-piperidineacetate is
obtained, (M=425.528 g), i.e. a yield of 89%.
[0201] 0.6 g (1.41 mmoles) of the compound obtained previously and
1.93 ml of a solution of hydrogen chloride in methanol at 7.3 mol/l
is introduced,
[0202] Agitation is carried out at ambient temperature and after 15
minutes, 1 ml of dichloromethane is added.
[0203] After another 15 minutes, the reaction medium is evaporated
under reduced pressure.
[0204] Dichloromethane is again added then, evaporation is carried
out. This operation is repeated several times.
[0205] Then the product is crystallized from ethyl ether.
[0206] In this way 0.44 g of the hydrochloride of cis
diphenylmethyl 3-hydroxy-4-piperidineacetate is obtained of
molecular formula, C.sub.20H.sub.23NO.sub.3, HCl (M=361.871 g),
i.e. a yield of 86%.
[0207] This reaction also leads to the formation of variable
quantities of the lactone hydrochloride of
(3a.alpha.,7a.alpha.)-hexahydro-furo[2,3-c]pyridin-2(3H)-one,
(M=177.6 g).
[0208] 0.28 g (0.77 mmoles) of compound C.sub.20H.sub.23NO.sub.3,
HCl obtained previously and 19 ml of dichloromethane are mixed
together under an inert atmosphere.
[0209] 60 .mu.l of diphosgene is added at 0.degree. C. and
agitation is carried out. After 25 minutes 0.32 ml of TEA is
introduced. Then 94 mg of DMAP is added and the reaction medium is
left to return to ambient temperature.
[0210] Agitation is carried out for 4 hours 15 minutes, followed by
washing successively with a 10% aqueous solution of tartaric acid
then with water saturated with sodium chloride, followed by drying
over magnesium sulphate, filtering and the solvent is evaporated
off under reduced pressure.
[0211] In this way 0.265 g of expected compound of molecular
formula C.sub.21H.sub.21NO.sub.4 (M=351.405 g) is obtained, i.e. a
yield of 98%.
[0212] 1H NMR
[0213] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0214] 1.82 (m): NCH.sub.2--CH.sub.2; 2.30 to 2.70 (m):
CO--CH.sub.2--CH; 2.93 (d)--2.99 (dt) and 3.45 (m):
CH.sub.2--N--CH.sub.2; 4.60 (d): CH--CHO--CH.sub.2; 6.87 (s):
CO.sub.2CH(C.sub.6H.sub.5).sub.2; 7.10 to 7.35 (m):
(C.sub.6H.sub.5).sub.2. IR (CHCl.sub.3)=1786, 1734; 1600, 1587,
1496 cm.sup.-1.
[0215] MS (SIMS) m/z: [M+Na].sup.+=374.sup.+.
Example 3a
cis-7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetic acid
[0216] 55 mg (0.156 mmoles) of the product obtained in Example 3, 3
ml of ethyl acetate and 55 mg of Pd/C catalyst at 10% by weight are
mixed together.
[0217] The reaction medium is placed under a hydrogen atmosphere at
normal pressure.
[0218] The reaction medium is left to react for 1 hour 30 minutes,
then the catalyst is filtered out and the solvent is evaporated off
under reduced pressure.
[0219] In this way 38 mg of crude product is obtained which is
crystallized from a mixture of pentane and ethyl ether.
[0220] In this way 16 mg of white crystals of expected compound
(M=185.181 g) is collected, i.e. a yield of 55%.
[0221] 1H NMR
[0222] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0223] 1.63 to 1.86 (m) and 1.91 (m): NCH.sub.2--CH.sub.2; 2.27 to
2.49 (m) and 2.54 (dd): CO--CH.sub.2--CH; 2.98 (d) and 3.54 (d):
CH.sub.2--N--CH.sub.2--CH.sub.2; 3.04 (dt) and 3.41 (dd):
CH.sub.2--N--CH.sub.2--CH.sub.2; 4.71 (d):
[0224] CH--CHO--CH.sub.2
[0225] IR (Nujol): 1784, 1734, 1686 cm.sup.-1.
[0226] MS (SIMS) m/z: [M+H].sup.+=186.sup.+, 167.sup.+.
Example 3b
cis methyl 7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetate
[0227] 78 mg (0.421 mmoles) of the compound obtained in Example 3a
is then dissolved in 1 ml of dichloromethane.
[0228] An excess of diazomethane is added dropwise until a yellow
colouration subsists, then the solvent is evaporated off under
reduced pressure.
[0229] In this way 80 mg of crude product is obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 95/5.
[0230] In this way 8.2 mg of expected compound (M=199.208 g) is
obtained i.e. a yield of 10%.
Example 4
cis-7-oxo-6-oxa-1-azabicyclo[3.2.1]octan-4-acetonitrile
[0231] 67 mg (0.38 mmoles) of the hydrochloride of
(3a.alpha.,7a.alpha.)-hexahydro-furo[2,3-c]pyridin-2(3H)-one,
(M=177.6 g) prepared in Example 3 is dissolved in 1 ml of a
solution of ammonia at 4.17 mol/l in methanol.
[0232] Agitation is carried out for 5 hours, the solvent is
evaporated off under reduced pressure, then another 1 ml of the
solution of ammonia in methanol is added and the reaction is left
to continue for 18 hours.
[0233] The solvent is evaporated off under reduced pressure and in
this way 79 mg of cis-3-hydroxy-4-piperidineacetamide of molecular
formula C7H14O2N2 (M=158 g) is obtained.
[0234] 75 mg of the compound obtained above is mixed under an inert
atmosphere in solution in 9 ml of dichloromethane.
[0235] The reaction medium is cooled down with an ice bath and 30
.mu.l of diphosgene is introduced.
[0236] The reaction medium is maintained at 0-5.degree. C. for 40
minutes, then 0.16 ml of TEA is introduced and after 5 minutes, 46
mg of DMAP is introduced.
[0237] Agitation is carried out for 4 hours at ambient temperature,
followed by washing twice with 2 ml of 10% tartaric acid in water,
then with 2 ml of a saturated aqueous solution of sodium
chloride.
[0238] After drying over MgSO4 and filtering, the solvent is
evaporated off under reduced pressure. In this way 35 mg of crude
product is obtained which is taken up in an ethyl acetate and
dichloromethane mixture 30/70. The impurities are filtered out and
the filtrate is evaporated under reduced pressure.
[0239] In this way 23 mg of expected compound (M=166.18 g) is
obtained in the form of an oil, i.e. a yield of approximately
26%.
[0240] IR (Nujol): 2241, 1777 cm.sup.-1.
[0241] MS (EI) m/z: [M].sup.+=166, 137, 82, 55, 42.
Example 5
3-benzoyl-1,3-diazabicyclo[2.2.1]heptan-2-one
[0242] 1-01 g (5.43 mmoles) of 1,1-dimethylethyl
3-amino-1-pyrrolidinecarboxylate (M=186.25 g) (described in the
Patent Application WO 9801426) and 10 ml of dichloromethane are
mixed under an inert atmosphere, the solution is cooled down to
0.degree. C., then 0.76 ml of TEA. is added dropwise.
[0243] Agitation is carried out for 15 minutes whilst maintaining
the temperature at 0.degree. C., then 0.63 ml of benzoyl chloride
is added.
[0244] The reaction medium is left to return to ambient
temperature, then diluted by adding 10 ml of dichloromethane,
followed by washing with a 10% aqueous solution of tartaric acid,
then with 10 ml of water, drying over magnesium sulphate, filtering
and the dichloromethane is eliminated by evaporation under reduced
pressure.
[0245] In this way 1.30 g of 1,1-dimethylethyl
3-(benzoylamino)-1-pyrrolidinecarboxylate (M=292.36 g) is obtained
in the form of a yellow oil. The corresponding yield is 82%.
[0246] 1.30 g (4.46 mmoles) of this compound is mixed with 10 ml of
methanol.
[0247] The solution is cooled down to 0.degree. C., then 6.12 ml of
a solution of hydrogen chloride at 7.3 moles/l in methanol is
introduced progressively.
[0248] Then the solvent is evaporated off under reduced
pressure.
[0249] In this way 1.01 g of N-(3-pyrrolidinyl)-benzamide
hydrochloride (M=226.707 g) is obtained in the form of oil brown,
i.e. a yield close to 100%.
[0250] 1.01 g (4.46 mmoles) of the compound obtained previously, as
well as 10 ml of dichloromethane are mixed under an inert
atmosphere.
[0251] The reaction medium is cooled down to 0.degree. C., then
1.36 ml of TEA is added dropwise.
[0252] Agitation is carried out for 15 minutes, then 1.44 ml of
diphosgene is added dropwise.
[0253] The reaction medium is maintained at 0.degree. C. for 30
minutes, then left to return to ambient temperature, followed by
diluting with dichloromethane, washing with a 10% aqueous solution
of tartaric acid, then with water, drying over magnesium sulphate,
filtering and concentrating the solvent by evaporating under
reduced pressure in order to obtain 0.615 g of crude product.
[0254] Purification is carried out by chromatography on silica
eluting with a dichloromethane/acetone mixture 90/10.
[0255] In this way 0.320 g of the chloride of
3-(benzoylamino)-1-pyrrolidinecarboxylic acid is recovered which
crystallizes. The corresponding yield is 28%.
[0256] Then 0.585 g (2.31 mmoles) of the preceding compound is
dissolved under an inert atmosphere in 18 ml of
tetrahydrofuran.
[0257] The solution is cooled down to -78.degree. C., then 2.55 ml
of a 1 M solution of lithium bis(trimethyl-silyl)amide in
tetrahydrofuran is added dropwise.
[0258] A yellow solution is obtained which is maintained at
-78.degree. C. for 20 minutes, then agitation is continued for 1
hour whilst allowing the temperature to rise. 350 .mu.l of acetic
acid, then 5 ml of a 10% solution of tartaric acid in water are
added at 0.degree. C., followed by diluting with ethyl acetate then
washing with a 10% solution of tartaric acid then with a solution
of phosphate buffer at pH=7, then with water.
[0259] The organic phase is dried over magnesium sulphate, followed
by filtering and concentrating the solvent by evaporating under
reduced pressure.
[0260] In this way 0.315 g of crude product is obtained in the form
of a yellow solid.
[0261] This crude product is purified by chromatography on silica
eluting with a dichloromethane and ethyl acetate mixture 90/10.
[0262] In this way 0.140 g of expected compound
C.sub.12H.sub.12N.sub.2O.sub.2, (M=216.24 g) is recovered in the
form of a white solid, i.e. a yield of 28%.
[0263] IR (CHCl.sub.3): 1801, 1775, 1675; 1620, 1603, 1582
cm.sup.-1.
[0264] MS (positive electrospray) m/z: [M].sup.+=216, 105, 77.
Example 6
Potassium salt of
trans-6-[(phenylmethoxy)carbonyl]-2-oxo-1,3-diazabicyclo[2.2.1]heptan-3-a-
cetic acid
[0265] 1 g (3.12 mmoles-M=186.25 g) of trans 1-(1,1-dimethylethyl)
and 2-(phenylmethyl)4-amino-1,2-pyrrolidinedicarboxylate (described
in J. Org. Chem. 1991, 56, 3009-3016), 10 ml of tetrahydrofuran,
560 .mu.l of allyl bromoacetate and 660 .mu.l of TEA are mixed
together.
[0266] The reaction medium is left to react under agitation at
ambient temperature for 14 hours, then for 3 hours at 50.degree.
C., followed by diluting with ethyl acetate and washing with a 10%
aqueous solution of tartaric acid, then with a saturated aqueous
solution of sodium chloride.
[0267] The organic phase is dried over magnesium sulphate, filtered
then the solvent is evaporated off under reduced pressure.
[0268] In this way 1.21 g of crude product is obtained which is
purified by chromatography on silica, eluting with a 80/20 mixture
of dichloromethane and ethyl acetate.
[0269] 0.99 mg of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-[[[(2-propenyloxy)carbonyl]methyl]amino]-1,2-pyrrolidin-
e dicarboxylate of molecular formula C.sub.12H.sub.30N.sub.2O.sub.6
(M=418 g) is obtained. 6 ml of a 4 M solution of hydrogen chloride
in ethyl acetate is added under a nitrogen atmosphere and at
0.degree. C. to 0.99 g (2.36 mmoles) of the compound obtained
previously. The reaction medium is left to react at ambient
temperature for 15 minutes.
[0270] The solvent is evaporated off under reduced pressure. A
crude product is obtained which is crystallized from ethyl ether in
order to obtain 0.95 g of the dihydrochloride of trans phenylmethyl
4-[[[(2-propenyloxy)carbonyl]methyl]amino]-2-pyrrolidinecarboxylate,
of molecular formula C.sub.17H.sub.23N.sub.2O.sub.4, 2HCl (M=394
g).
[0271] 0.5 g of this product is dissolved in 20 ml of
dichloromethane and 1.3 ml of 2N soda and 3 ml of water are added.
The reaction medium is left to settle, followed by extracting with
dichloromethane, drying over magnesium sulphate, then filtering and
the solvent is evaporated off under reduced pressure.
[0272] In this way 339 mg of free diamine is obtained. The
corresponding yield is 83%.
[0273] 100 mg (0.314 mmoles) of the diamine obtained previously is
dissolved in 5 ml of acetonitrile at 0.degree. C. and under a
nitrogen atmosphere.
[0274] 21 .mu.l of diphosgene is added. After 15 minutes of
contact, this solution is added, under a nitrogen atmosphere and
over 4 hours, to a mixture containing 38 mg of DMAP, 88 .mu.l of
TEA in 10 ml of acetonitrile heated to 70.degree. C.
[0275] After the addition has ended, the reaction mixture is heated
again for one hour, then cooled down, diluted with ethyl acetate
and washed successively with a 10% aqueous solution of tartaric
acid, then with a saturated aqueous solution of sodium chloride.
After drying over sodium sulphate, filtering and evaporating the
solvents under reduced pressure, 58 mg of crude product is
obtained. This product is purified by chromatography on silica
eluting with a dichloramethane/ethyl acetate mixture 8/2 in order
to produce 19 mg of trans 2-propenyl
6-[(phenylmethoxy)carbonyl]-2-oxo-1,3-diazabicyclo[2.2.1]heptan-3-acetate
of molecular formula C.sub.18H.sub.20N.sub.2O.sub.5 (M=344.57 g),
i.e. a yield of 17%.
[0276] Then 24 mg (0.069 mmoles) of the preceding compound is
dissolved in 250 .mu.l of dichloromethane. 3 mg of
Pd(PPh.sub.3).sub.4 is introduced under a nitrogen atmosphere, then
150 .mu.l of a 0.5 M solution of potassium ethyl-2-hexanoate in
ethyl acetate is added. After a few minutes, a precipitate forms
which is centrifuged and washed twice with 500 .mu.l of ethyl
acetate.
[0277] 24 mg of expected compound C.sub.15H.sub.15KN.sub.2O.sub.5
(M=342 g) is obtained, i.e. a quantitative yield.
[0278] 1H NMR
[0279] In DMSO, at 300 MHz, chemical shifts of the peaks in ppm and
multiplicity:
[0280] 1.83 (ddd) and 2.56: N--CH.sub.2--CHN--CH.sub.2; 2.50 and
2.79 (d): N--CH.sub.2--CHN--CH.sub.2; 3.23 (d) and 3.41 (d):
.dbd.C--N--CH.sub.2--C.dbd.O; 3.62 (ddd): O.dbd.C--CHN--CH.sub.2;
4-0.13 (s): N--CH.sub.2--CHN--CH.sub.2; 5.16 (s):
.dbd.C--O--CH.sub.2--C.sub.6H.sub.5; 7.38 (m):
C.sub.6H.sub.5--CH.sub.2.
[0281] MS (positive electrospray) m/z: [2MK+H].sup.+=723,
[2MK+Na].sup.+=707, [MK+K].sup.+=381, [MK+Na].sup.+=365;
[MK+H].sup.+=343.
Example 7
trans methyl
3-benzoyl-2-oxo-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate
[0282] 0.471 g (1.93 mmole) of trans 1-(1,1-dimethylethyl) and
2-methyl 4-amino-1,2-pyrrolidinedicarboxylate (described in J. Org.
Chem. 1991, 56, 3009-3016) and 3.5 ml of dry dichloromethane to
dissolve it are mixed under a nitrogen atmosphere.
[0283] The solution is cooled down to 0.degree. C., then 269 .mu.l
of TEA is added dropwise.
[0284] Agitation is carried out for 15 minutes whilst maintaining
at 0.degree. C., then 224 .mu.l of benzoyl chloride is added
dropwise.
[0285] The reaction medium is left and the temperature returns to
20.degree. C. over one hour, followed by diluting with 30 ml of
dichloromethane, washing with a 10% aqueous solution of tartaric
acid, then with a saturated solution of sodium bicarbonate, then
with water, drying over magnesium sulphate, filtering,
concentrating by evaporating the dichloromethane under reduced
pressure.
[0286] In this way 0.6 g of a yellow oil is obtained which is
purified by chromatography on silica using a
dichloromethane/methanol mixture 99/1 as eluent.
[0287] In this way 0.499 g of trans 1-(1,1-dimethylethyl) and
2-methyl 4-(benzoylamino)-1,2-pyrrolidine dicarboxylate of
molecular formula C.sub.18H.sub.24N.sub.2O.sub.5 (M=348 g) is
recovered, i.e. a yield of 74%.
[0288] 0.400 g (1.15 mmole) of the compound obtained previously
with 3 ml of ethyl acetate to dissolve the compound are mixed under
a nitrogen atmosphere, then the solution is cooled down to
0.degree. C., 2.89 ml of a solution of 4 mole/l of HCl in ethyl
acetate is added.
[0289] At the end of 15 minutes, agitation is continued at ambient
temperature for 1 hour.
[0290] Then the solvent is eliminated by evaporation under reduced
pressure.
[0291] In this way 0.350 g of the hydrochloride of trans methyl
4-(benzoylamino)-2-pyrrolidinecarboxylate of molecular formula
C.sub.13H.sub.15N.sub.2O.sub.3, HCl (M=284.744 g) is obtained in
the form of a beige solid.
[0292] 0.327 g (1.15 mmole) of the compound obtained previously,
placed under a nitrogen atmosphere, is mixed with 4 ml of
dichloromethane.
[0293] The suspension is cooled down to 0.degree. C., then 352
.mu.l of TEA is added. Agitation is carried out for 15 minutes at
0.degree. C., then 138 .mu.l of diphosgene is added. Agitation is
continued for 5 minutes at 0.degree. C., then the reaction mixture
is left to return to ambient temperature and left to react for 30
minutes, followed by diluting with dichloromethane and washing with
a 10% aqueous solution of tartaric acid, then with water and drying
over magnesium sulphate.
[0294] After filtering, the solvent is eliminated by evaporation
under reduced pressure. In this way 0.360 g of crude product is
obtained which is purified by chromatography on silica eluting with
a dichloromethane/acetone mixture 95/5.
[0295] In this way 93.7 mg of the hydrochloride of trans methyl
4-(benzoylamino)-1-(chlorocarbonyl)-2-pyrrolidine carboxylate
(C.sub.14H.sub.14N.sub.2O.sub.4, HCl (M=310.74 g) is recovered,
i.e. a yield of 26%.
[0296] 93.7 mg (0.301 mmole) of the compound obtained previously,
is mixed under a nitrogen atmosphere, with 3 ml of tetrahydrofuran.
The temperature of the solution is lowered to -78.degree. C., then
332 .mu.l of lithium bis(trimethylsilyl)amide in a 1M solution in
tetrahydrofuran is added dropwise and the reaction medium is
maintained at -78.degree. C. for another 5 minutes.
[0297] Agitation is carried out for 30 minutes at ambient
temperature.
[0298] Then the solution is cooled down to 0.degree. C., and 55
.mu.l of acetic acid is added. 20 ml of ethyl acetate and 3 ml of a
phosphate buffer at pH=7.0 are added. The reaction medium is left
to settle, followed by washing with water, drying over magnesium
sulphate, filtering and concentrating by evaporation. In this way
76 mg of a foam is obtained which is purified by chromatography on
silica eluting with a dichloromethane/acetone mixture 97/3.
[0299] 5 mg of pure expected compound, of molecular formula
(C.sub.14H.sub.14N.sub.2O.sub.4, HCl (M=274.279 g), is recovered
i.e. a yield of 6%.
[0300] IR (CHCl.sub.3): 1805, 1779, 1743, 1669; 1603, 1589, 1486
cm.sup.-1
[0301] MS (EI) m/z: [M].sup.+=274, 215, 169, 105, 77.
Example 7a trans phenylmethyl
3-benzoyl-2-oxo-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate
[0302] The operation is carried out in a similar fashion to that
indicated in Example 7, starting from 0.92 g of trans
1-(1,1-dimethylethyl) and 2-phenylmethyl
4-amino-1,2-pyrrolidinedicarboxylate (described in J. Org. Chem.
1991, 56, 3009-3016) in order to obtain the expected compound with
an overall yield of 5.4% over 4 stages.
Example 8
trans phenylmethyl
2-oxo-3-(phenylsulphonyl)-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate
[0303] 2.97 g (9.26 mmoles) of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-amino-1,2-pyrrolidinedicarboxylate (described in
J. Org. Chem. 1991, 56, 3009-3016) of molecular formula
C.sub.17H.sub.24N.sub.2O.sub.4 (M=320.392 g) is mixed under a
nitrogen atmosphere and 25 ml of dichloromethane is added. The
reaction medium is cooled down to 5.degree. C. and 1.3 ml of TEA is
added. Agitation is carried out for 10 minutes and then 1.63 g of
benzenesulphonyl chloride is added.
[0304] The reaction medium is left under agitation at 5.degree. C.
for 15 minutes, then the temperature of the reaction medium is
allowed to rise to 20.degree. C. for a duration of 45 minutes,
followed by diluting with dichloromethane, washing with a 10%
aqueous solution of tartaric acid, then with phosphate buffer at
pH=7.0, then with a saturated aqueous solution of sodium chloride,
drying over magnesium sulphate and the solvent is evaporated off
under reduced pressure.
[0305] In this way 4.5 g of crude product is obtained which is
chromatographed on silica eluting with a 90/10 mixture of
dichloromethane and ethyl acetate.
[0306] In this way 4.06 g of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-[(phenylsulphonyl)amino]-1,2-pyrrolidinedicarboxylate
of molecular formula C.sub.23H.sub.28N.sub.2O.sub.6S (M=460, 552 g)
is recovered, which corresponds to a yield of 95%.
[0307] 3.83 g (8.31 mmoles) of the sulphonamide obtained previously
is mixed with 10 ml of anhydrous methanol.
[0308] The solution is cooled down to 0.degree. C. and 8.2 ml of a
solution of 10 mol/l of hydrochloric acid in methanol is added at
this temperature.
[0309] Agitation is maintained at 0.degree. C. for 5 minutes, then
the temperature is allowed to rise until at ambient
temperature.
[0310] After 30 minutes, the methanol is evaporated off under
reduced pressure, followed by taking up several times in methanol
then in dichloromethane. Then the hydrochloride is crystallized
from ethyl ether.
[0311] In this way 3.2 g of the hydrochloride of trans phenylmethyl
4-[phenylsulphonyl)amino]-2-pyrrolidinecarboxylate, of molecular
formula C.sub.18H.sub.20N.sub.2O.sub.4S, HCl (M=396.896 g) is
obtained, which corresponds to a yield of 96%.
[0312] 2.78 g (7 mmoles) of the hydrochloride obtained previously
under an inert atmosphere is mixed with 28 ml of
dichloromethane.
[0313] The reaction medium is cooled down to about 0-5.degree. C.,
then 2.15 ml of TEA is added.
[0314] Agitation is continued for 15 minutes at a temperature
comprised between 0 and 5.degree. C., then 0.46 ml of diphosgene is
added.
[0315] The reaction medium is maintained at this temperature for 4
minutes, then a 10% aqueous solution of tartaric acid is added,
followed by diluting with dichloromethane, decanting, washing with
a saturated aqueous solution of sodium chloride, drying over
magnesium sulphate, and concentrating under reduced pressure.
[0316] In this way 3.1 g of a yellow oil is obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 9/1.
[0317] 1.82 g of trans phenylmethyl
1-(chlorocarbonyl)-4-[(phenylsulphonyl)amino]-2-pyrrolidinecarboxylate
of molecular formula C.sub.19H.sub.19ClN.sub.2O.sub.5S (M=422.89 g)
is recovered, which corresponds to a yield of 61%.
[0318] 1.81 g (4.28 mmoles) of the carbamoyl chloride obtained
previously is mixed under an inert atmosphere with 31 ml of
tetrahydrofuran.
[0319] The solution obtained is cooled down to -70.degree. C., then
4.7 ml of a 1M solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran is added at this temperature over 10 minutes.
[0320] Agitation is carried out for 45 minutes at -70.degree. C.,
then the temperature of the reaction medium is allowed to rise to
about 0.degree. C. The reaction medium is maintained at this
temperature for 2 hours 30 minutes.
[0321] Then 295 .mu.l of acetic acid is added, followed by diluting
with dichloromethane, washing with a 10% aqueous solution of
tartaric acid, with a solution of phosphate buffer at pH=7 and with
a saturated aqueous solution of sodium chloride, drying over
magnesium sulphate and concentrating to dryness under reduced
pressure.
[0322] The crude product is purified by chromatography on silica,
eluting with a dichloromethane/ethyl acetate mixture 95/5.
[0323] In this way 244 mg of expected compound of molecular formula
C.sub.19H.sub.18N.sub.2O.sub.5S (M=386.429 g) is obtained, which
corresponds to a yield of 14%.
[0324] 1H NMR
[0325] In CDCl3, at 400 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0326] 2.15 (m): O.dbd.C--CH--CH.sub.2; 2.85 (d) and 3.08 (d):
O.dbd.C--N--CH.sub.2; 3.62 (m): O.dbd.C--CH--N--CH.sub.2; 4.94 (s):
O.sub.2S--N--CH--CH.sub.2; 5.16: CO.sub.2CH.sub.2C.sub.6H.sub.5;
7.34 (m): C.sub.6H.sub.5; 7.57 (m)-7.68 (m) and 8.03 (m):
SO.sub.2C.sub.6H.sub.5.
[0327] IR (CHCl.sub.3): 1780, 1743; 1586, 1499 cm.sup.-1
[0328] MS (positive electrospray) m/z: [2M+Na].sup.+=795;
[0329] [M+Na+CH.sub.3CN].sup.+=450; [M+Na].sup.+=409;
[M+H].sup.+=387.
Example 9
trans phenylmethyl
3-benzoyl-4-methyl-2-oxo-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate
[0330] 18.69 g (58.52 mmoles) of 1-(1,1-dimethyl-ethyl) and
2-(phenylmethyl)4-oxo-1,2 pyrrolidinedicarboxylate (described in
Chem. Pharm. Bull. 43(8)1302-1306 (1995)) of molecular formula
C.sub.17H.sub.21NO.sub.5 (M=319.361 g) and 500 ml of anhydrous
ethyl ether are mixed together under an inert atmosphere.
[0331] A suspension of 10 g of CeCl3 in 50 ml of anhydrous ethyl
ether is added to the solution obtained.
[0332] The suspension is agitated for 30 minutes to 20.degree. C.,
then is cooled down to -60.degree. C.
[0333] Then 20 ml of 3 M solution of MeMgBr in ethyl ether is
added.
[0334] The reaction medium is left to react for 1 hour at
-60.degree. C., then the temperature is allowed to rise to
0.degree. C. over 30 minutes, followed by neutralizing with a 10%
aqueous solution of NH.sub.4Cl, extracting with dichloromethane,
filtering, washing the organic phase with water, drying over
magnesium sulphate, and concentrating to dryness under reduced
pressure.
[0335] In this way 19.33 g of an oil is obtained which is purified
by chromatography on silica eluting with a
dichloromethane/tbutylmethyl-ether mixture 90/10.
[0336] 7.21 g of cis 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-hydroxy-4-methyl-1,2-pyrrolidine dicarboxylate of
molecular formula C.sub.18H.sub.25NO.sub.5 (M=335.404 g) is
obtained, i.e. a yield of 36%, as well as 2.5 g of the alcohol
epimer.
[0337] 3.17 g (9.45 mmoles) of the compound obtained previously and
70 ml of dichloromethane are mixed together under an inert
atmosphere. The reaction medium is cooled down to 5.degree. C. and
2.3 ml of TEA, then 1.28 ml of methane sulphonyl chloride are added
dropwise.
[0338] Agitation is carried out for 45 minutes at 5.degree. C.,
followed by washing with a 10% aqueous solution of tartaric acid,
then with a solution of phosphate buffer at pH 7, then with
water.
[0339] The organic phase is dried over magnesium sulphate and
concentrated to dryness under reduced pressure.
[0340] In this way 3.9 g of an oil is obtained which is purified by
chromatography on silica eluting with a dichloromethane/ethyl
acetate mixture 90/10.
[0341] 2.75 g of cis 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-methyl-4-[(methylsulphonyl)oxy]-1,2-pyrrolidine
dicarboxylate of molecular formula C.sub.19H.sub.27NO.sub.7S
(M=413.494 g) is recovered which corresponds to a yield of 70%.
[0342] A solution of 2.54 g (6.14 mmoles) of the mesylate obtained
previously in 40 ml of dimethylformamide is prepared.
[0343] Then, 519 mg (7.98 mmoles) of NaN.sub.3 is added at
20.degree. C. followed by heating at 50.degree. C. for 2 hours.
After cooling down, the reaction medium is poured into 250 ml of
water and extracted with 250 ml of dichloromethane. The organic
phase is washed with water, dried over magnesium sulphate and
evaporated to dryness under reduced pressure.
[0344] 2.4 g of crude product is obtained which is purified by
chromatography on silica, eluting with a dichloromethane/ethyl
acetate mixture 95/5.
[0345] In this way 1.66 g of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-azido-4-methyl-1,2-pyrrolidine dicarboxylate of
molecular formula C.sub.18H.sub.24N.sub.4O.sub.4 (M=360.42 g) is
recovered (titring approximately 30% by weight), which corresponds
to a yield of approximately 25%.
[0346] 1.85 g of the azide obtained previously (i.e. approximately
1.7 mmole) is dissolved in 18 ml of toluene.
[0347] Then, 1.38 ml of Bu3SnH and 84 mg of AIBN are added at
20.degree. C.
[0348] The reaction medium is taken to 75.degree. C. and maintained
at this temperature for 2 hours.
[0349] The toluene is evaporated off and redissolving is carried
out in ethyl acetate. A saturated aqueous solution of potassium
fluoride is added and agitation is carried out for 30 minutes at
ambient temperature, followed by filtering on clarcel, leaving to
settle and drying the organic phase over magnesium sulphate.
[0350] After evaporation of the solvent under reduced pressure, 3 g
of an oil is obtained which is chromatographed on silica, eluting
with a dichloromethane/methanol mixture 9/1.
[0351] 560 mg of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl)-4-amino-4-methyl-1,2-pyrrolidine dicarboxylate of
molecular formula C.sub.18H.sub.26N.sub.2O.sub.4 (M=334.419 g) is
recovered. The yield is therefore quantitative.
[0352] 578 mg (1.72 mmoles) of the amine obtained previously is
mixed under an inert atmosphere in 30 ml of dichloromethane.
[0353] The reaction medium is cooled down to 5.degree. C. and 290
.mu.l of TEA, then 240 .mu.l of benzoyl chloride are added
dropwise.
[0354] Agitation is continued at 5.degree. C. for 30 minutes,
followed by diluting with dichloromethane, washing with a 10%
aqueous solution of tartaric acid, with a saturated aqueous
solution of sodium carbonate, then with water, drying the organic
phase over magnesium sulphate, and evaporating the solvent under
reduced pressure.
[0355] In this way 950 mg of an oil is obtained which is purified
by chromatography eluting with a dichloromethane/ethyl acetate
mixture 90/10.
[0356] In this way 732 mg of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-(benzoylamino)-4-methyl-1,2-pyrrolidinedicarboxylate
of molecular formula C.sub.25H.sub.30N.sub.2O.sub.5. (M=438.528 g)
is recovered, which corresponds to a yield of 97%.
[0357] 636 mg (1.45 mmoles) of the amide obtained previously is
dissolved in 1.9 ml of ethyl acetate, the reaction medium is cooled
down to about 0-5.degree. C. with an ice bath, then 3.2 ml of a
solution of hydrogen chloride at 4.6 mol/l in ethyl acetate is
added.
[0358] The temperature of the reaction medium is left to rise to
20.degree. C., then after 1 hour, the solvent is evaporated off
under reduced pressure.
[0359] Then the hydrochloride crystallizes from ethyl ether.
[0360] In this way 570 mg of the hydrochloride of trans
phenylmethyl 4-(benzoylamino)-4-methyl-2-pyrrolidine carboxylate of
molecular formula C.sub.20H.sub.22N.sub.2O.sub.3, HCl (M=374.87 g)
is recovered, in the form of a white powder. The yield is therefore
quantitive.
[0361] 100 mg (0.267 mmole) of the hydrochloride obtained
previously is dissolved under an inert atmosphere in 1.5 ml of
dichloromethane.
[0362] The reaction medium is cooled down to about 0-5.degree. C.,
then 90 .mu.l of TEA is added.
[0363] Agitation is carried out for 15 minutes at 5.degree. C.,
then 20 .mu.l of diphosgene is added.
[0364] Agitation is continued for 30 minutes at 5.degree. C.
[0365] Then, the reaction medium is treated with a 10% aqueous
solution of tartaric acid, followed by extracting with
dichloromethane, washing the organic phase with a saturated aqueous
solution of sodium chloride, drying over magnesium sulphate, and
evaporating the solvent under reduced pressure.
[0366] In this way 130 mg of an oil is obtained which is purified
by chromatography on silica eluting with a dichloromethane/ethyl
acetate mixture 9/1.
[0367] Then 72 mg of trans phenylmethyl
4-(benzoylamino)-1-(chlorocarbonyl)-4-methyl-2-pyrrolidine
carboxylate of molecular formula C.sub.21H.sub.21N.sub.2O.sub.4Cl
(M=400.865 g) is recovered, which corresponds to a yield of
67%.
[0368] 373 mg (0.930 mmole) of the compound obtained previously is
dissolved in 9 ml of tetrahydrofuran.
[0369] The solution is then cooled down to -70.degree. C. and 1 ml
of a 1 M solution of lithium bis(trimethylsilyl)amide in the
tetrahydrofuran is added over 5 minutes.
[0370] The reaction medium is left to heat up to 0.degree. C. over
45 minutes, then 69 .mu.l of acetic acid is added, followed by
diluting with dichloromethane, washing with a 10% aqueous solution
of tartaric acid, then with a solution of phosphate buffer at
pH=7.0 and with a saturated aqueous solution of sodium
chloride.
[0371] The organic phase is dried over magnesium sulphate, followed
by concentrating to dryness under reduced pressure, in order to
obtain 330 mg of a crude product which is purified by
chromatography on silica, eluting with a dichloromethane/ethyl
acetate mixture 98/2 containing 0.1% by volume of TEA.
[0372] In this way 123 mg of expected compound of molecular formula
C.sub.21H.sub.20N.sub.2O.sub.4 (M=364.404 g) is recovered, which
corresponds to a yield of 36%.
[0373] 1H NMR
[0374] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0375] 1.76 (s): CH3; 2.11 (dd) and 2.73 (ddd): N--CH--CH.sub.2;
2.93 (dt) and 3.00 (d): N--CH.sub.2; 3.96 (ddd): N--CH--CH.sub.2;
5.21: CO.sub.2CH.sub.2C.sub.6H.sub.5; 7.36 (m):
CH.sub.2C.sub.6H.sub.5; 7.43 (t) and 7.57 (tt) and 7.72 (d):
COC.sub.6H.sub.5.
[0376] IR (CHCl.sub.3): 1776, 1745, 1682; 1601, 1580, 1498
cm.sup.-1
[0377] MS (positive electrospray) m/z: [2M+Na].sup.+=751;
[2M+H].sup.+=729; [M+Na].sup.+=387; [M+H].sup.+=365
Example 10
1-propenyltriphenylphosphonium salt of trans phenylmethyl
2-oxo-3-(sulphooxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate
[0378] 15 g (46.71 mmoles) of cis 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-hydroxy-1,2-pyrrolidinedicarboxylate (commercial
product) of molecular formula C.sub.17H.sub.23NO.sub.5 (M=321.377
g) is dissolved under an inert atmosphere in 225 ml of anhydrous
dichloromethane.
[0379] 5.42 ml of 2,6-lutidine is added to the solution. The
reaction medium is cooled down to -70.degree. C., then, 8.25 ml of
trifluoromethanesulphonic anhydride is introduced over 5
minutes.
[0380] Agitation is carried out for 10 minutes at -70.degree. C.
then 4.43 g of O-allyl-hydroxyl-amine is introduced at -70.degree.
C.
[0381] Then the reaction mixture is left at ambient temperature for
27 hours, followed by diluting with dichloromethane, then washing
with a 10% aqueous solution of tartaric acid, with a saturated
aqueous solution of NaHCO.sub.3, and with water.
[0382] The organic phase is dried over sodium sulphate, and the
solvent is evaporated off under reduced pressure.
[0383] In this way 23 g of a crude oil is obtained which is
purified by chromatography on silica, the eluent being successively
a dichloromethane/ethyl acetate mixture 95/5, 90/10, then
80/20.
[0384] 7.18 g of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-[(2-propenyloxy)amino]-1,2-pyrrolidine
dicarboxylate of molecular formula C.sub.20H.sub.28N.sub.2O.sub.5
(M=376.456 g) is recovered, which corresponds to a yield of
40%.
[0385] 3.25 g (8.63 mmoles) of the compound obtained previously is
dissolved in 3.5 ml of ethyl acetate.
[0386] The reaction medium is cooled down to about 0-5.degree. C.,
then 19 ml of a solution of 4.6 mol/l of hydrogen chloride in ethyl
acetate is added.
[0387] The reaction medium is left to react whilst agitating at
about 0-5.degree. C. for 40 minutes.
[0388] The solvent is evaporated off under reduced pressure,
followed by taking up several times in diethyl ether, whilst
drawing off the liquid supernatant.
[0389] In this way 2.54 g of a hydrochloride is obtained in the
form of a white precipitate, which is dissolved in 55 ml of
dichloromethane under agitation. 7.3 ml of 2N soda is added. After
decanting, the organic phase is dried over sodium sulphate.
[0390] The dichloromethane is evaporated off under reduced
pressure.
[0391] In this way 2.12 g of trans phenylmethyl
4-[(2-propenyloxy)amino]-2-pyrrolidinecarboxylate of molecular
formula C.sub.15H.sub.20N.sub.2O.sub.3 (M=276.337 g) is obtained in
the form of an oil i.e. a yield of 89%.
[0392] 4.14 g (15 mmoles) of the compound obtained previously is
dissolved under an inert atmosphere in 1.5 l of acetonitrile.
[0393] The reaction medium is cooled down to about 0-5.degree. C.
and 1.14 ml of diphosgene is added. Agitation is carried out for 15
minutes whilst maintaining at 0-5.degree. C., then 4.6 ml of TEA,
and 1.83 g of DMAP in 80 ml of acetonitrile are added
successively.
[0394] The temperature is allowed to rise to ambient temperature
and the reaction medium is left to react for 26 hours, then half
the solvent is evaporated off under reduced pressure, followed by
treating with a 10% aqueous solution of tartaric acid, then
extracting with dichloromethane. The organic phase is washed with a
saturated aqueous solution of sodium chloride, dried over magnesium
sulphate and the solvent is evaporated off under reduced
pressure.
[0395] In this way 43 g of crude product is obtained which is
purified by chromatography on silica eluting with a
dichloromethane/ethyl acetate mixture 90/10 containing 0.1% of
TEA.
[0396] 312 mg of trans phenylmethyl
2-oxo-3-(2-propenyloxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate
of molecular formula C.sub.16H.sub.18N.sub.2O.sub.4 (M=302.33 g) is
recovered which corresponds to a yield of 7%.
[0397] 70.2 mg (0.232 mmole) of the compound obtained previously is
dissolved under an inert atmosphere in 2.3 ml of dichloromethane.
Then 26.5 .mu.l of acetic acid and 134 mg of Pd(P(Ph).sub.3).sub.4
are introduced.
[0398] The reaction medium is left to react for 40 minutes at
ambient temperature, then the temperature is lowered to -20.degree.
C. and 2.96 ml of a solution of SO3-pyridine complex at 0.314 mol/l
is added. The reaction medium is left to react for 2 hours and 30
minutes then dichloromethane is added followed by evaporating under
reduced pressure, taking up in 40 ml of dichloromethane and washing
with 5 ml of water. The organic phase is separated and dried over
sodium sulphate, then the solvent is evaporated off under reduced
pressure.
[0399] In this way 280 mg of crude product is obtained which is
purified by chromatography on silica, eluting successively with a
dichloromethane/acetone mixture 80/20 containing 0.1% TEA, then a
dichloromethane/acetone mixture 50/50 containing 0.1% TEA.
[0400] 34.0 mg of expected compound, of molecular formula
C.sub.34H.sub.33N.sub.2O.sub.7SP (M=644.689 g) is recovered in the
form of a yellow oil, i.e. a yield of 23%.
[0401] 1H NMR
[0402] In CDCl3, at 400 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0403] 2.00 (m) and 2.48 (m): CH.sub.2--CH--C.dbd.O; 2.72 (d) and
3.12 (s): CH--CH.sub.2--N, 3.75 (m): CH.sub.2--CH--C.dbd.O.sub.2;
4.71 (s) CH--CH.sub.2--N, 5.18 [AB] CH.sub.2--C.sub.6H.sub.5; 7.35
(m): CH.sub.2--C.sub.6H.sub.5 and 2.29 (m): CH.sub.3--CH.dbd.CH;
6.62 and 7.21 CH.sub.3--CH.dbd.CH; 7.60-7.85
P(C.sub.6H.sub.5).sub.3
[0404] MS (negative and positive electrospray) m/z:
[0405] [Manion].sup.-=341
[0406] [Mcation].sup.+=303
Example 11
1-propenyltriphenylphosphonium salt of trans methyl
2-oxo-3-(sulphooxy)-1,3-diazabicyclo[2.2.1]heptane-6-carboxylate
[0407] The operation is carried out as in Example 10, but starting
from 207 mg of cis 1-(1,1-dimethylethyl) and 2-methyl
4-hydroxy-1,2-pyrrolidinedicarboxylate.
[0408] In this way 12 mg of desired product of formula
C.sub.7H.sub.10N.sub.2O.sub.7S (M=266.231 g) is obtained.
[0409] MS (negative and positive electrospray) m/z:
[0410] [Manion].sup.-=265
[0411] [Mcation].sup.+=303
Example 12a
trans diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-3-carboxylate
[0412] 8 ml of dichloromethane and 347 mg (1 mmole) of the
hydrochloride of cis diphenylmethyl
5-hydroxy-3-piperidinecarboxylate (described in Acta Chem. Scand.
Ser. B 35(4) 289-294) are mixed under an inert atmosphere.
[0413] The reaction medium is cooled down to 0.degree. C., then 346
.mu.l of TEA and 72 .mu.l of diphosgene are added.
[0414] The reaction medium is left to react for 15 minutes whilst
maintaining the temperature at 0.degree. C., then the solvent is
evaporated off under reduced pressure, followed by taking up in 25
ml of dry toluene and filtering to eliminate the hydrochloride from
the TEA.
[0415] 553 .mu.l of TEA is added to the filtrate and heating is
carried out under reflux for 4 hours, followed by diluting with
ethyl acetate, washing with an aqueous solution containing 10%
tartaric acid, then with a saturated aqueous solution of sodium
chloride and drying the organic phase over magnesium sulphate.
[0416] The reaction medium is then evaporated under reduced
pressure and 339 mg of crude product is recovered which is purified
by chromatography on silica, eluting with a toluene/ethyl acetate
mixture 70/30.
[0417] In this way 146 mg of expected compound (M=337.378 g) is
recovered, which corresponds to a yield of 43%.
[0418] 1H NMR
[0419] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0420] 2.15 (ddd) and 2.73 (dq): N--CH.sub.2--CHO--CH.sub.2; 2.92
(tt): O.sub.2C--CH--; 3.00 (d) and 3.45 (d): N--CH.sub.2--CHO; 3.48
(dd) and 4.07 (dd): N--CH.sub.2--CH--CO.sub.2; 4.79 (dt):
N--CH.sub.2--CHO; 6.90 (s): CO.sub.2--CH--(C.sub.6H.sub.5).sub.2;
7.33 (m): (C.sub.6H.sub.5).sub.2.
[0421] IR (CHCl.sub.3): 1792, 1734; 1600, 1585, 1497 cm.sup.-1.
[0422] MS (EI) m/z: [M].sup.+=337, 292, 183, 167.
Example 12b
trans-7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-3-carboxylic acid
[0423] 320 mg of the compound obtained in Example 12a, 17 ml of
acetone and 70 mg of Pd/C catalyst at 20% by weight are mixed
together.
[0424] Agitation is carried out under a hydrogen atmosphere at
normal pressure.
[0425] After 2 hours 30 minutes, another 70 mg of catalyst is added
and the reaction medium is left to react for another 1 hour 30
minutes, followed by filtering.
[0426] The solvent is evaporated off under reduced pressure and in
this way 350 mg of the crude product is obtained which is
crystallized from pentane.
[0427] Filtration is carried out and in this way 158 mg of the
sought product of molecular formula C.sub.7H.sub.9NO.sub.4
(M=171.154 g) is recovered in the form of a grey solid. The
corresponding yield is 89%.
[0428] 1H NMR
[0429] In DMSO, at 300 MHz, chemical shifts of the peaks in ppm and
multiplicity:
[0430] 2.10 (ddd) and 2.43 (dm): N--CH.sub.2--CHO--CH.sub.2; 2.83
(tt): O.sub.2C--CH--; 3.13 (d) and 3.27 (dm): N--CH.sub.2--CHO;
3.40 (dd) and 3.72 (d): N--CH.sub.2--CH--CO.sub.2H; 4.81 (m):
N--CH.sub.2--CHO; 12.54 (broad s): CO.sub.2H.
[0431] IR (nujol): 1782, 1692 cm.sup.-1.
[0432] MS (EI) m/z: [M].sup.+=177, 155, 127, 82, 70.
Example 12c
trans(4-nitrophenyl)methyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-3-carboxylate
[0433] 30 mg (0.175 mmole) of the acid obtained in Example 12b and
0.5 ml of dichloromethane are mixed together under an inert
atmosphere. Then 26.8 mg of 4-nitrobenzyl alcohol, 2.2 mg of DMAP
and 37 mg of EDCI are added.
[0434] The reaction medium is left to react whilst agitating for 2
hours at ambient temperature.
[0435] The organic phase is then diluted with dichloromethane,
washed with a 10% aqueous solution of tartaric acid and with a
solution of phosphate buffer at pH 7.
[0436] After drying the organic phase over sodium sulphate, and
evaporating the solvent under reduced pressure, 57 mg of crude
product is obtained which is purified by chromatography on silica
eluting with a toluene/ethyl acetate mixture 85/15.
[0437] The product is then crystallized from a mixture of ethyl
ether and pentane in order to produce 34 mg of white crystals of
the sought compound (M=306.277 g). The corresponding yield is
63.5%.
[0438] 1H NMR
[0439] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0440] 2.14 (ddd) and 2.84 (dm): N--CH.sub.2--CHO--CHH.sub.2; 2.90
(tt): O.sub.2C--CH--; 3.10 and 3.49 (dm); N--CH.sub.2--CHO; 3.43
(dd) and 4.14 (bd): N--CH.sub.2--CH--CO.sub.2; 5.27 [AB]:
CO.sub.2--CH.sub.2--C.sub.6H.sub.5; 7.56 and 8.24 [AA'BB']:
C--C.sub.6H.sub.5--NO.sub.2.
[0441] IR (CHCl.sub.3): 1799, 1789, 1741; 1609, 1526, 1495
cm.sup.-1.
[0442] MS (EI) m/z: [M].sup.+: 306, 170, 136, 126, 106, 82.
Example 13
6-(phenylmethyl)-1,6-diazabicyclo[3.2.1]octan-7-one
Stage A
[0443] 30.7 ml of TEA is added at about 0-5.degree. C. to a
solution of 20.71 g of 3-amino-pyridine in 200 ml of methylene
chloride. 25.5 ml of benzoyl chloride is then added dropwise over
15 minutes and the reaction medium is left to return to ambient
temperature. Agitation is carried out for 1 hour, followed by
washing with water, then with a saturated solution of sodium
bicarbonate, the organic phase is dried over sodium sulphate and
the solvent is evaporated off under reduced pressure. 42.29 g of
expected crystallized product (M=198.226 g) is obtained.
Stage B
[0444] 4.3 ml of concentrated hydrochloric acid and 500 mg of
rhodium on alumina at 5% by weight are added to a solution of 10 g
of the product obtained in Stage A in 200 ml of methanol. The
reaction medium is place under a hydrogen atmosphere at a pressure
of 60-110 bars for 15 hours.
[0445] The reaction mixture is filtered, rinsed with methanol then
the filtrate is concentrated under reduced pressure. The
hydrochloride of the expected product is obtained in a mixture with
10% of the hydrochloride of the starting product.
[0446] The product is taken up in 250 ml of methylene chloride and
1.1 equivalent of 1N soda is added. After agitation for 15 minutes,
the methylene chloride is decanted, the organic phase is washed
with water, followed by drying and evaporating under reduced
pressure. The residue is chromatographed on silica eluting with a
methylene chloride-methanol-triethylamine mixture 92/8/3.
[0447] 7.4 g of expected crystallized product is obtained, i.e. a
yield of 72%.
Stage C: N-(phenylmethyl)-3-piperidinamine
[0448] 20 g of the product obtained as described in Stage B is
dissolved in 600 ml of 1,2-dimethoxyethane. 14.86 g of lithium
aluminium hydride is added to the solution over 30 minutes,
followed by heating under agitation and under an inert gas at
75-80.degree. C. for 16 hours then cooling down to 0.degree. C. and
11 ml of water is added over 45 minutes, without exceeding
12.degree. C. Agitation is carried out for 10 minutes, followed by
filtering and washing the precipitate with methylene chloride. The
filtrate is concentrated under reduced pressure. 17.8 g of expected
product is obtained in the form of an oil which is distilled under
reduced pressure (boiling temperature: 114-121.degree. C./0.8
mbar). 16 g of expected product is recovered, i.e. a yield of
86%.
Stage D: 6-(phenylmethyl)-1,6-diazabicyclo[3.2.1]octan-7-one
[0449] 1.06 g of product obtained in Stage C is dissolved in 28
cm.sup.3 of toluene, then the reaction medium is cooled down to
0.degree. C. and 337 .mu.l of diphosgene is added under an inert
gas. The temperature is allowed to rise and is maintained at
20.degree. C. for 2 hours. Concentration is carried out under
reduced pressure then the residue is chromatographed on silica
eluting successively with methylene chloride-acetone 95/5 then
80/20 and finally methylene chloride-methanol, triethylamine 92/8/3
and 362 mg of expected product C.sub.13H.sub.16N.sub.2O (M=216.85
g) is obtained i.e. a yield of 30%.
[0450] VPC/Mass spectrum (EI) m/z: [M].sup.+=216, 125, 91.
[0451] IR (CHCl.sub.3): 1718; 1498 cm.sup.-1.
Example 14
6-benzoyl-1,6-diazabicyclo[3.2.1]octan-7-one
Stage A: 3-(benzylamino)-1-piperidinecarboxylic
[0452] 5 g of product obtained in Stage B of Example 13, is
dissolved in 1.25 l of anhydrous toluene under a nitrogen
atmosphere then 3.4 ml of TEA is added and 1.47 ml of diphosgene is
introduced at 0-5.degree. C. over 3 minutes. After 20 minutes at
0-5.degree. C., the reaction medium is left to heat up to
20.degree. C., is maintained under agitation for 75 minutes, then
the solvent is evaporated off under reduced pressure. The residue
is chromatographed on silica eluting with a methylene
chloride-acetone mixture 8/2. 3.44 g of expected product is
obtained (yield of 52.6%).
Stage B
6-benzoyl-1,6-diazabicyclo[3.2.1]octan-7-one
[0453] 48 mg of sodium hydride at 50% in dispersion in oil and 20
ml of THF are introduced under a nitrogen atmosphere. The reaction
medium is cooled down to about 0-5.degree. C., then 266 mg of the
product obtained in Stage A is added in one go.
[0454] The temperature is allowed to rise to ambient temperature,
then 60 .mu.l of acetic acid and 10 ml of phosphate buffer at pH 7
are added.
[0455] Then a little ethyl acetate is added followed by decanting
and reextracting with ethyl acetate. The organic phase is dried
over magnesium sulphate, then the solvents are evaporated off under
reduced pressure.
[0456] The crude product is chromatographed on silica eluting with
dichloromethane containing 2% acetone.
[0457] In this way 143 mg of the sought product
C.sub.13H.sub.12N.sub.2O.sub.2 (M: 228.25 g) is obtained. The
corresponding yield is 62%.
[0458] 1H NMR
[0459] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0460] 1.20-2.15 (m) and 2.42 (m): NCH--CH.sub.2--CH.sub.2--; 2.80
(d) --2.93 (d); 3.11 (m); 3.28 to 3.58 (m): CH.sub.2--N, 4.54 (m):
CH--N, 7.43 (m); 7.55 (m); 7.69 (m): C.sub.6H.sub.5
[0461] IR (CHCl.sub.3): 1758, 1672; 1605, 1586, 1492;
[0462] MS (EI) m/z: [M].sup.+=230, 125, 105, 77
Example 15
7-oxo-1,6-diazabicyclo[3.2.1]octan-6-acetic acid
Stage A
5-[(1,1-dimethylethyl)dimethylsilyl]-1,6-diazabicyclo[3-2-1]octan-7-one]
[0463] 843 mg of lithium is placed under a nitrogen atmosphere and
condensed at -70.degree. C. with 320 ml of ammonia. 7.56 g (34.8
mmoles) of the product obtained in Example 13 in 160 ml of
tetrahydrofuran is added at -70.degree. C. over 10 minutes.
Agitation is carried out for 5 minutes then the ammonia is
distilled under a stream of nitrogen whilst heating slowly to
20.degree. C. 7.9 g of (1,1-dimethylethyl) dimethylsilyl chloride
in 10 cm.sup.3 of tetrahydrofuran is added slowly to the suspension
obtained, at 20.degree. C., then maintained under agitation for 10
minutes. Then 160 cm.sup.3 of ethyl acetate then 60 cm.sup.3 of a
10% aqueous solution of tartaric acid are added, followed by
decanting, reextracting with ethyl acetate washing the organic
phase with water, drying it over sodium sulphate and evaporating
the solvent under reduced pressure. The oil obtained is
chromatographed on silica with 10% water, eluting with methylene
chloride then with a methylene chloride-acetone mixture 8/2 and
3.04 g of expected product is obtained (yield: 36.2%).
[0464] 1H NMR
[0465] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0466] 0.21 (S) and 0.40 (S): SiCH.sub.3; 0.97 (S): SitBu; 1.5 to
1.8 (m) and 2.07 (m): N--CH--CH.sub.2--CH.sub.2; 2.85 (d) and 3.32
(m); --CH--CH.sub.2--N, 2.93 (dt) and 3.32 (m):
--CH.sub.2--CH.sub.2--N, 3.65 (m): CH--N.
[0467] IR (CHCl.sub.3): 1710; 842 cm.sup.-1
[0468] MS (EI) m/z: [M].sup.+: 240, 225, 183, 100, 83, 57.
Stage B
phenylmethyl 7-oxo-1,6-diazabicyclo[3-2-1]octan-6-acetate
[0469] 1.44 g (5.99 mmoles) of the product obtained in Stage A is
dissolved under a nitrogen atmosphere in 14.4 ml of tetrahydrofuran
then 941 .mu.l of phenylmethyl bromoacetate is added and then, 6 ml
of a 1 M solution of tetra-n-butyl ammonium fluoride in
tetrahydrofuran is added dropwise. Agitation is carried out for 10
minutes at 20.degree. C. then the reaction medium is diluted with
15 ml of ethyl acetate and 5 ml of an aqueous solution of phosphate
buffer at pH=7 is added, followed by decanting, reextracting with
ethyl acetate, washing the organic phase with water, drying it over
sodium sulphate and the solvent is evaporated off under reduced
pressure. The oily residue is chromatographed on silica with 10%
water eluting with a methylene chloride-acetone mixture 8/2. 140 mg
of the expected product is obtained. The corresponding yield is
9%.
[0470] IR (CHCl.sub.3): 1746, 1720 cm.sup.-1.
[0471] MS (EI) m/z: [M].sup.+=274, 183, 155, 139, 91, 83.
Stage C: 7-oxo-1,6-diazabicyclo[3.2.1]octane-6-acetic acid
[0472] 137 mg of the product obtained in Stage B is dissolved in
1.5 ml of ethyl acetate, then 14 mg of 10% palladium on carbon is
added to the solution and the reaction medium is placed under a
hydrogen atmosphere. After 15 minutes another 15 mg of palladium on
carbon is added and the reaction medium is maintained under
agitation for 15 minutes. The catalyst is filtered, followed by
rinsing with ethyl acetate, then with acetone and with methanol and
the solvent is evaporated off under reduced pressure. A total of 68
mg of crude product is obtained which is crystallized from ether.
58 mg of the expected product of molecular formula
C.sub.15H.sub.18N.sub.2O.sub.3 (M=274.321 g) is obtained. The
corresponding yield is 63%.
[0473] 1H NMR
[0474] In CDCl3, at 400 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0475] 1.48 (m), 1.63 (m), 1.73 (m) and 1.86 (m):
N--CH--CH.sub.2--CH.sub.2; 2.85 to 3.00 (m), 3.14 (dm) and 3.64
(m): CH.sub.2--N--CH.sub.2 and CH--N, 3.78 and 4.14 [AB]:
CON--CH.sub.2--CO.
[0476] MS (EI) m/z: [M].sup.+=184, 139, 125, 111, 97, 83.
Example 16
7-oxo-N-phenyl-1,6-diazabicyclo[3.2.1]octane-6-carboxamide
[0477] 1 ml of tetrahydrofuran and 99 mg (0.41 mmole) of the
compound obtained in Stage A of Example 15 are mixed under an inert
gas.
[0478] 50 .mu.l of phenyl isocyanate then 450 .mu.l of a 1M
solution of tetrabutylammonium fluoride in THF are added
successively.
[0479] The reaction medium is left to react for 10 minutes, then
diluted with ethyl acetate, followed by washing with water,
decanting and drying the organic phase over magnesium sulphate. The
solvent is evaporated off under reduced pressure. In this way 140
mg of crude product is obtained which is purified by chromatography
on silica eluting with a dichloromethane/ethyl acetate mixture
90/10.
[0480] 21 mg of the title compound, of molecular formula
C.sub.13H.sub.15N.sub.3O (M=245.283 g) is recovered which
corresponds to a yield of 20%.
[0481] 1H NMR
[0482] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0483] 1.78 (m), 2.02 (m) and 2.17 (m): N--CH--CH.sub.2--CH.sub.2;
2.88 (d), 3.13 (dt) and 3.42 (m): CH.sub.2--N--CH.sub.2; 4.49 (m):
CH--N, 7.11 (t); 7.34 (t) and 7.54 (d): C.sub.6H.sub.5; 10.05:
NH.
[0484] IR (CHCl.sub.3): 3302, 3266; 1734; 1700; 1602, 1553, 1501
cm.sup.-1.
[0485] MS (EI) m/z: [M].sup.+: 245, 153, 126, 119, 98, 92.
Example 17a
6-[1-(phenylmethyl)-1H-tetrazol-5-yl]-1,6-diazabicyclo[3.2.1]octan-7-one
[0486] 480 mg (2 mmoles) of the compound obtained in Stage A of
Example 15 is placed under an inert gas.
[0487] Then a solution of 712 mg of
5-fluoro-1-(phenylmethyl)-1H-tetrazole in 1.5 ml of tetrahydrofuran
and then 2 ml of a 1 M solution of tetrabutylammonium fluoride in
THF is added. The reaction medium is left to react for 1 minute,
followed by diluting with ethyl acetate, washing with water,
decanting, drying the organic phase over magnesium sulphate and the
solvent is evaporated off under reduced pressure.
[0488] 1.06 g of an oily product is obtained which is
chromatographed on silica in a dichloromethane/ethyl acetate
mixture 90/10.
[0489] In this way 143 mg of expected compound of molecular formula
C.sub.14H.sub.16N.sub.6O (M=284.324 g) is obtained in the form of
an amorphous white product. The corresponding yield is 25%.
[0490] 1H NMR
[0491] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0492] 1.80 (m), 2.04 (m) and 2.67 (m): N--CH--CH.sub.2--CH.sub.2;
2.83 (d), 2.85 (dm), 3.10 (dd) and 3.44 (dd):
CH.sub.2--N--CH.sub.2; 3.99 (m): CH--N, 5.63 and 5.88 [AB]:
C.sub.6H.sub.5--CH.sub.2; 7.18 (m) and 7.32 (m):
C.sub.6H.sub.5.
Example 17b
6-(1H-tetrazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one
[0493] 120 mg of the product obtained in Example 17a and 2.4 ml of
a methanol/ethyl acetate mixture 90/10 are mixed together then 2.4
ml of THF is added until total dissolution is obtained.
[0494] Then 24 mg of 10% palladium catalyst on carbon is added then
agitation is carried out under a hydrogen atmosphere. After
reaction for 3 hours, the catalyst is filtered, followed by rinsing
with a tetrahydrofuran/methanol mixture, then the solvent is
evaporated off under reduced pressure. Then the product
crystallizes from ethyl ether.
[0495] In this way 72 mg of the title compound of molecular formula
C.sub.7H.sub.10N.sub.6O (M=194.198 g) is obtained in the form of a
white crystallized product. The corresponding yield is 88%.
[0496] 1H NMR
[0497] In DMSO, at 300 MHz, chemical shifts of the peaks in ppm and
multiplicity:
[0498] 1.63 (m), 1.89 (m) and 2.07 (m): N--CH--CH.sub.2--CH.sub.2;
3.14 to 3.20 (m) and 3.43 (m): CH.sub.2--N--CH.sub.2; 4.51 (m):
CH--N.
[0499] IR (Nujol): 1744; 1594 cm.sup.-1.
[0500] MS (EI) m/z: [M].sup.+=194, 165, 124, 111, 98, 83, 68, 56,
41.
Example 18
6-acetyl-1,6-diazabicyclo[3.2.1]octan-7-one
[0501] 140 mg (0.582 mmoles) of the compound obtained in Stage A of
Example 15 is dissolved in 1.4 ml of THF.
[0502] 55 .mu.l of acetic anhydride then 0.58 ml of a 1 M solution
of tetrabutylammonium fluoride in THF are added successively to the
solution obtained, followed by diluting with ethyl acetate, washing
with water, decanting, drying the organic phase over magnesium
sulphate, then the solvent is evaporated off under reduced
pressure.
[0503] In this way 116 mg of a crude oil is obtained which is
chromatographed on silica with a dichloromethane/acetone mixture
80/20.
[0504] In this way 18 mg of expected compound, of molecular formula
C.sub.8H.sub.12N.sub.2O.sub.2 (M=168.196 g) is obtained, which
corresponds to a yield of 18%.
[0505] 1H NMR
[0506] In DMSO, at 300 MHz, chemical shifts of the peaks in ppm and
multiplicity:
[0507] 1.65 to 2.20 (m): N--CH--CH.sub.2--CH.sub.2; 2.54 (s):
CH.sub.3CO--N, 2.83 (d), 3.33 (dm), 3.10 (m) and 3.45 (dd)
CH.sub.2--N--CH.sub.2; 4.55 (m):
[0508] O.dbd.C--N--CH.
[0509] IR (CHCl.sub.3): 1758, 1696 cm.sup.-1.
[0510] MS (EI) m/z: [M].sup.+=168, 140, 126, 98, 43.
Example 19a
6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octan-7-one
[0511] 44.02 g (0.22 mole) of 1,1-dimethylethyl
3-oxo-1-piperidinecarboxylate (C.sub.10H.sub.17NO.sub.3, M=199.251
g) (described in J. Med. Chem. 1986, 29, 224-229) is dissolved in
440 ml of ethanol.
[0512] Then 38.79 g of O-benzyl-hydroxylamine hydrochloride is
added. 54 ml of pyridine is then introduced dropwise, into the
suspension.
[0513] The reaction medium is left to react whilst agitating for 4
hours at approximately 25.degree. C., then the solvent is
evaporated off under reduced pressure, followed by taking up in a
mixture of dichloromethane and ethyl acetate, filtering and rinsing
with dichloromethane, then with a mixture of dichloromethane and
ethyl acetate. The filtrate is then concentrated to dryness under
reduced pressure.
[0514] In this way 69.8 g of a light yellow oil is obtained which
is purified by chromatography on silica. The eluent used is a
cyclohexane/ethyl acetate mixture 80/20.
[0515] 57.21 g of 1,1-dimethylethyl
3-[(phenylmethoxy)imino]-1-piperidinecarboxylate, of molecular
formula C.sub.17H.sub.24N.sub.2O.sub.3 (M=304.39 g) is recovered,
in the form of a very pale yellow oil. The corresponding yield is
85%.
[0516] 24.82 g (0.0815 mmole) of the oxime obtained previously is
dissolved in 163 ml of ethanol cooled down to -10.degree. C. under
nitrogen. Then 25 ml of a borane-pyridine complex is added then,
204 ml of 2N hydrochloric acid is added dropwise over one hour 15
minutes. The solution is agitated for 1 hour 15 minutes at
-5.degree. C., then treated with 100 ml of a saturated solution of
sodium hydrogen carbonate, then with 35 g of sodium carbonate,
which are add by small portions. The pH is then 7-8.
[0517] The reaction medium is extracted with ethyl acetate.
[0518] The organic phases are combined, dried over sodium sulphate
and the solvent is evaporated off under reduced pressure. In this
way 39.0 g of a colourless oily liquid is obtained which is taken
up in 400 ml ethyl acetate.
[0519] The solution is washed with a 0.05 N aqueous solution of
hydrochloric acid, then the phases organic are combined and the
solvent is evaporated off under reduced pressure.
[0520] 35.5 g of a colourless oily liquid is recovered which is
purified by chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 95/5, then with a
dichloromethane/ethyl acetate mixture 80/20.
[0521] In this way 17.89 of 1,1-dimethylethyl
3-[(phenylmethoxy)amino]-1-piperidinecarboxylate of molecular
formula C.sub.17H.sub.26N.sub.2O.sub.3 (M=306.41 g), is recovered
in the form of a colourless oil. The corresponding yield is
72%.
[0522] 6.72 g (21.9 mmoles) of the piperidine obtained previously
is dissolved in 22 ml of ethyl acetate cooled down to -10.degree.
C. 28 ml of a 4.0 mol/l solution of anhydrous hydrochloric acid in
ethyl acetate is added dropwise, over 30 minutes.
[0523] After 1 hour at 0.degree. C., 40 ml of ethyl ether is added,
the dihydrochloride precipitate is filtered and washed with ethyl
ether.
[0524] In this way 3.87 g of a white solid is obtained.
[0525] By crystallizing the filtrate, 1.80 g of the desired product
is also obtained.
[0526] The product obtained is taken up in 60 ml of 1 N soda and
120 ml of ethyl acetate. After decanting, the aqueous phase is
saturated with sodium chloride, then extracted twice with ethyl
acetate. The organic phases are combined and dried over magnesium
sulphate then concentrated to dryness under reduced pressure.
[0527] In this way 3.67 g of N-(phenylmethoxy)-3-piperidinamine, of
molecular formula C.sub.12H.sub.18N.sub.2O (M=206.29 g) is
obtained, which corresponds to a yield of 81%.
[0528] 518 mg (2.5 mmoles) of the compound obtained previously is
dissolved in 5 ml of anhydrous dichloromethane, then 0.5 ml of TEA
is added.
[0529] The whitish suspension obtained is cooled down to
-65.degree. C., then 12.5 ml of a 0.10 mol/l solution of diphosgene
in dichloromethane is added over 15 minutes.
[0530] After reaction for 45 minutes, the colourless solution is
diluted with 15 ml of dichloromethane and treated with 15 ml of
water.
[0531] The medium is left to settle, then the aqueous phase is
extracted with 20 ml of dichloromethane.
[0532] The combined organic phases are dried over magnesium
sulphate, then concentrated to dryness under reduced pressure. In
this way a pale yellow oil is obtained which is purified by
chromatography on silica eluting with an ethyl acetate mixture
90/10, then a dichloromethane/ethyl acetate mixture 80/20.
[0533] In this way 196 mg of expected compound of molecular formula
C.sub.13H.sub.16N.sub.2O.sub.2, (M=232.28 g) is recovered in the
form of a colourless oil. The corresponding yield is 34%.
[0534] 1H NMR
[0535] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0536] 1.59 (m) and 1.93 to 2.18 (m): N--CH--CH.sub.2--CH.sub.2;
2.73 (dt), 2.94 (dt), 3.17 (dt) and 3.40 (dd):
CH.sub.2--N--CH.sub.2; 3.29 (t) N--CH; 4.89 (d): N--O--CH.sub.2--
(C.sub.6H.sub.5); 7.38: C.sub.6H.sub.5.
[0537] IR (CHCl.sub.3): 1747; 1498 cm.sup.-1.
[0538] MS (EI) m/z: [M].sup.+=232, 91.
Example 19b
6-(acetyloxy)-1,6-diazabicyclo[3.2.1]octan-7-one
[0539] 95 mg (0.41 mmole) of the compound obtained in Example 19a
is dissolved in 5 ml of methanol, agitation is carried out with 8
mg of palladium on carbon at 10% by weight, then the suspension is
placed under a hydrogen atmosphere under normal pressure for 1 hour
at 25.degree. C., then the catalyst is filtered.
[0540] After evaporation of the solvent under reduced pressure, 70
mg of white crystals is obtained.
[0541] The crystals are taken up in 2 ml of anhydrous
dichloromethane. The solution is cooled down to -10.degree. C.
under nitrogen. Then 70 .mu.l of pyridine then 40 .mu.l of acetic
anhydride are added and agitation is carried out for 20 minutes.
Concentration is carried out under reduced pressure and 75 mg of
white crystals are obtained which are purified on silica, eluting
with a dichloromethane ethyl acetate mixture 80/20.
[0542] 49 mg of expected compound (M=184.20 g) is recovered in the
form of a white solid. The corresponding yield is 65%.
[0543] 1H NMR
[0544] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0545] 1.60 to 2.2: N--CH--CH.sub.2--CH.sub.2; 2.24 (s): CH.sub.3;
2.95 (d) and 3.54 (dm): N--CH.sub.2--CH; 3.07 (dt) and 3.54 (bdd):
N--CH.sub.2--CH.sub.2; 3.94 (bt): O.dbd.C--N--CH.
[0546] IR (CHCl.sub.3): 1798; 1764 cm.sup.-1.
[0547] MS (EI) m/z: [M].sup.+=184, 142, 125, 43.
Example 19c
6-(benzoyloxy)-1,6-diazabicyclo[3.2.1]octan-7-one
[0548] The operation is carried out in a similar manner to that
which has been described in Example 19b starting from 205 mg of the
compound prepared in Example 19a and 200 mg of benzoic
anhydride.
[0549] In this way 64 mg of expected compound of molecular formula
C.sub.13H.sub.14N.sub.2O.sub.3 (M=246.27 g) is obtained i.e. a
yield 30%.
[0550] 1H NMR
[0551] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0552] 1.64 to 1.95 (m) and 2.10 to 2.35 (m):
CH--CH.sub.2--CH.sub.2; 3.02 (d) and 3.65 (dm): N--CH.sub.2--CH;
3.13 (dt) and 3.55 (bdd): N--CH.sub.2--CH.sub.2; 4.09 (bt):
O.dbd.C--N--CH; 7.49 (m): 7.65 (tt); 8.12 (m): C.sub.6H.sub.5.
[0553] IR (CHCl.sub.3): 1774, 1756; 1602, 1585, 1495 cm.sup.-1.
[0554] MS (EI) m/z: [M].sup.+=246, 105, 77.
Example 19d
6-(1-oxopropoxy)-1,6-diazabicyclo[3.2.1]octane-7-one
[0555] The operation is carried out in a similar manner to that
which has been described in Example 19c, starting from 163 mg of
the compound prepared in Example 19a and 70 .mu.l of propionyl
chloride.
[0556] In this way 17 mg of expected compound of molecular formula
C.sub.9H.sub.14N.sub.2O.sub.3 (M=198.23 g) is obtained, i.e. a
yield of 12%.
[0557] 1H NMR
[0558] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0559] 1.25 (t): O.dbd.C--CH.sub.2--CH.sub.3; 1.65 (m), 1.78 (m)
and 2.10 (m): N--CH--CH.sub.2--CH.sub.2; 2.52 (m)
O.dbd.C--CH.sub.2--CH.sub.3; 2.94 (d) and 3.55 (bd):
N--CH.sub.2--CH; 3.07 (dt) and 3.48 (dd): N--CH.sub.2--CH.sub.2;
3.93 (m): N--CH.sub.2--CH.
[0560] IR (CHCl.sub.3): 1792; 1763 cm.sup.-1.
[0561] MS (EI) m/z: [M].sup.+=198, 170, 142, 125, 97, 57.
Example 19e
6-[[(4-methylphenyl)sulphonyl]oxy]-1,6-diazabicyclo[3.2.1]octan-7-one
[0562] The operation is carried out in a similar manner to that
which has been described in Example 19d, starting from 139 mg of
the compound prepared in Example 19a and 126 mg of tosyl
chloride.
[0563] In this way 77 mg of expected compound of molecular formula
C.sub.13H.sub.16N.sub.2O.sub.4S (M=296.35 g) is obtained i.e. a
yield of 44%.
[0564] 1H NMR
[0565] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0566] 1.55 and 2.99 (m): N--CH--CH.sub.2--CH.sub.2; 2.45 (s):
CH.sub.3; 2.89 (d), 3.00 (dt), 3.29 (dt) and 3.39 (dd):
CH.sub.2--N--CH.sub.2; 4.04 (m): N--CH; 7.35 and 7.91 [AA'BB']
CH.sub.3--C.sub.6H.sub.4--SO.sub.2.
[0567] IR (CHCl.sub.3): 1775; 1599, 1495, 1383; 1193, 1180
cm.sup.-1.
[0568] MS (EI) m/z: [M].sup.+=296, 155, 141, 125, 91.
Example 19f
6-[(methylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octan-7-one
[0569] The operation is carried out in a similar manner to that
which has been described in Example 19e starting from 211 mg of the
compound prepared in Stage 19a and 80 .mu.l of mesyl chloride.
[0570] In this way 50 mg of expected compound of molecular formula
C.sub.17H.sub.12N.sub.2O.sub.4S (M=220.25 g) is obtained i.e. a
yield of 25%.
[0571] 1H NMR
[0572] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0573] 1.56 and 2.38 (m): N--CH--CH.sub.2--CH.sub.2; 3.00 (d), 3.12
(dt) and 3.49 (m): N--(CH.sub.2).sub.2; 3.26 (s): CH.sub.3; 4.12
(m): N--CH.
[0574] IR (CHCl.sub.3): 1775; 1381, 1187 cm.sup.-1.
[0575] MS (EI) m/z: [M].sup.+=220, 141, 125, 97, 79.
Example 19 g
6-[(4-nitrophenyl)sulphonyl]oxy]-1,6-diazabicyclo[3.2.1]octan-7-one
[0576] The operation is carried out in a similar manner to that
which has been described in Example 19f starting from 270 mg of the
compound prepared in Example 19a and 283 mg of
4-nitrobenzenesulphonyl chloride.
[0577] In this way 205.5 mg of expected compound of molecular
formula C.sub.12H.sub.13N.sub.3O.sub.6S (M=327.32 g) is obtained
i.e. a yield of 54%.
[0578] 1H NMR
[0579] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0580] 1.64 (dt), 1.84 (m), 1.99 (m), 2.31 (dm):
NCH--CH.sub.2--CH.sub.2; 2.94 (d), 3.30 (dt), 3.04 (dt), 3.40
(bdd): N(CH.sub.2).sub.2; 4.14: O.dbd.C--N--CH; 8.25 and 8.41
[AA'BB']: NO.sub.2--C.sub.6H.sub.4SO.sub.2.
[0581] IR (CHCl.sub.3): 1776; 1610, 1590, 1538; 1393, 1191
cm.sup.-1.
[0582] MS (EI) m/z: [M].sup.+=327, 186, 141, 125, 111.
Example 20
6-[[(4-methylphenyl)sulphonyl]amino]-1,6-diazabicyclo[3.2.1]octan-7-one
[0583] 5 g (25.1 mmole) of 1,1-dimethylethyl
3-oxo-1-piperidinecarboxylate (described in J. Med. Chem. 1986, 29,
224-229) (C.sub.10H.sub.17NO.sub.3, M=199.251 g) is dissolved in 50
ml of dichloromethane.
[0584] 4.67 of tosylhydrazine is then added to the solution which
is left to react for 2 hours under agitation, then the solvent is
evaporated off under reduced pressure.
[0585] In this way, 9.56 g of 1,1-dimethylethyl
3-[2-[(4-methylphenyl)sulphonyl]hydrazono]-1-piperidinecarboxylate,
of molecular formula C.sub.17H.sub.25N.sub.3O.sub.4S (M=367.47 g)
is obtained with a quantitative yield.
[0586] 4.5 g of the compound obtained previously (12.2 mmoles), 90
ml of a methanol/tetrahydrofuran mixture 50/50, and a few grains of
bromocresol green are mixed together under an inert gas.
[0587] Then 1.62 g of NaBH.sub.3CN is added, followed by cooling
down to about 0-5.degree. C., and a 0.7 mol/l solution of gaseous
hydrogen chloride in methanol is introduced, in such a way so as to
maintain the pH of the medium between 3.8 and 5.4.
[0588] The reaction medium is left to react whilst agitating for 2
hours and 30 minutes.
[0589] 2/3 of the solvents are evaporated under reduced pressure,
then 200 ml of dichloromethane is added followed by washing with a
saturated aqueous solution of sodium bicarbonate.
[0590] The organic phase is dried over sodium sulphate and the
solvent is evaporated off under reduced pressure.
[0591] In this way 4.48 g of 1,1-dimethylethyl
3-[2-[(4-methylphenyl) sulphonyl]hydrazino]-1-piperidinecarboxylate
of molecular formula C.sub.17H.sub.27N.sub.3O.sub.4S (M=369.486 g)
is obtained.
[0592] The corresponding yield is 99%.
[0593] 4.48 g of the compound obtained previously and 9 ml of ethyl
acetate are mixed under an inert gas at 0.degree. C.
[0594] 30 ml of a 4 mol/l solution of gaseous hydrogen chloride in
ethyl acetate is added, agitation is carried out for 15 minutes
followed by filtering and washing the hydrochloride with ethyl
acetate. After drying under reduced pressure, 3.48 g of the
dihydrochloride of 2-(3-piperidinyl)hydrazide of
4-methyl-benzenesulphonic acid, of molecular formula
C.sub.12H.sub.19N.sub.3O.sub.2S, 2HCl (M=342.289 g) is obtained.
The corresponding yield is 84%.
[0595] Then 3.48 g of the compound obtained previously is dissolved
in 5 ml of demineralized water. 10.2 ml of a 2N aqueous solution of
soda is added under vigorous agitation.
[0596] A precipitate forms after 1 to 2 minutes of contact.
Agitation is then carried out for 10 minutes, then the precipitate
is filtered and washed with water, then with ethyl acetate.
[0597] The solid obtained is dried under reduced pressure.
[0598] In this way 2.21 g of 2-(3-piperidinyl)hydrazide of
4-methyl-benzenesulphonic acid, of molecular formula
C.sub.12H.sub.19N.sub.3O.sub.2S (M=269.328 g) is obtained. The
corresponding yield is 81%.
[0599] 500 mg (1.85 mmole) of the amine obtained previously and 20
ml of tetrahydrofuran are mixed under an inert gas.
[0600] 112 .mu.l of diphosgene then 517 .mu.l of TEA and 23 mg of
DMAP are added, at a temperature comprised between 0 and 5.degree.
C., to the suspension obtained.
[0601] The reaction medium is left to react whilst agitating and
whilst allowing the temperature to rise to 20.degree. C., followed
by diluting with ethyl acetate, then washing with a 10% aqueous
solution of tartaric acid, then with demineralized water.
[0602] The organic phase is dried over magnesium sulphate, then the
solvent is evaporated off under reduced pressure.
[0603] 769 mg of a crude product is obtained which is dissolved in
7 ml of dichloromethane and 517 .mu.l of TEA.
[0604] The reaction medium is left to react overnight under
agitation, followed by diluting with dichloromethane, washing with
water, drying over sodium sulphate and the solvent is evaporated
off under reduced pressure.
[0605] The foam obtained (395 mg) is purified by chromatography on
silica with a dichloromethane/ethyl acetate mixture 80/20.
[0606] 44 mg of expected compound, of molecular formula
C.sub.13H.sub.17N.sub.3O.sub.2S (M=295.362 g) is recovered. The
corresponding yield is 8%.
[0607] 1H NMR
[0608] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0609] 1.55 to 1.80 (m) and 2.18 (m): N--CH--CH.sub.2--CH.sub.2;
2.42 (s): CH.sub.3; 2.88 (d) and 2.93 (m); N--CH.sub.2--CH; 3.18 to
3.32 (m): N--CH.sub.2--CH.sub.2; 4.08 (m): N--CH--CH.sub.2; 6.98
(bs): NH.
[0610] IR (CHCl.sub.3): 3264, 1737, 1599, 1490 cm.sup.-1.
[0611] MS (positive electrospray) m/z: [M+Na].sup.+=318,
[M+H].sup.+=296
Example 21
6-[(4-methylphenyl)sulphonyl]-1,6-diazabicyclo[3.2.1]octan-7-one
[0612] 305 mg (1.52 mmole) of 1,1-dimethylethyl
3-amino-1-piperidinecarboxylate (described in J. Med. Chem. 1992,
35, 4334-4343), of molecular formula C.sub.10H.sub.20N.sub.2O.sub.2
(M=200.282 g) is dissolved in 3 ml of anhydrous
dichloromethane.
[0613] Then, 212 .mu.l of TEA is added, followed by cooling down to
5.degree. C. and 278 mg of tosyl chloride is added. Agitation is
carried out whilst allowing the temperature to return to 20.degree.
C. and the reaction medium is left to react for 2 hours, followed
by diluting with dichloromethane and washing firstly with a 10%
aqueous solution of tartaric acid then with a solution of phosphate
buffer at pH=7.
[0614] After separating, the organic phase is dried over magnesium
sulphate, then the solvent is evaporated off under reduced
pressure. In this way an oil is obtained which is purified by
chromatography on silica eluting with a dichloromethane/ethyl
acetate mixture 9/1.
[0615] 440 mg of 1,1-dimethylethyl
3-[[(4-methylphenyl)sulphonyl]amino]-1-piperidinecarboxylate
(described in J. Med. Chem. 1992, 35, 4334-4343) of molecular
formula C.sub.17H.sub.26N.sub.2O.sub.4S (M=354.472 g) is recovered.
The corresponding yield is 82%.
[0616] A mixture of 425 mg of the compound obtained previously and
2.1 ml of a trifluoroacetic acid/dichloromethane mixture 50/50 is
cooled down to 0-5.degree..
[0617] The reaction medium is kept under agitation at 5.degree. C.
for 30 minutes.
[0618] Then the solvent is evaporated off under reduced pressure in
order to obtain 403 mg of
4-methyl-N-(3-piperidinyl)-benzenesulphonamide trifluoroacetate of
molecular formula C.sub.14H.sub.19F.sub.3N.sub.2O.sub.4S (M=368.377
g).
[0619] 228 mg of the compound obtained previously is suspended in 2
ml of methanol, then treated with an excess of DOWEX 21K 20-50 Mesh
resin activated with soda, followed by filtering, rinsing the resin
with methanol, then the filtrate is evaporated under reduced
pressure.
[0620] In this way 123 mg of
4-methyl-N-(3-piperidinyl)-benzenesulphonamide of molecular formula
C.sub.12H.sub.18N.sub.2O.sub.2S (M=254.353 g) is recovered.
[0621] 118 mg of the amine obtained previously is dissolved under
an inert gas in 1.2 ml of dichloromethane.
[0622] Then 98 .mu.l of TEA and then 28 .mu.l of diphosgene are
introduced successively. The reaction medium is left to react
whilst agitating for 30 minutes at 0-5.degree. C., followed by
diluting with dichloromethane, washing the organic phase with a 10%
aqueous solution of tartaric acid, then with water. After drying
over sodium sulphate, filtration and evaporation of the solvent
under reduced pressure, the crude product is purified by
chromatography on silica eluting with a dichloromethane/acetone
mixture 95/5.
[0623] In this way 112 mg of the chloride of
3-[[(4-methylphenyl)sulphonyl]amino]-1-piperidinecarboxylic acid,
of molecular formula C.sub.13H.sub.17ClN.sub.2O.sub.3S (M=316.308
g) is obtained. The corresponding yield is 76%.
[0624] 10 mg of sodium hydride (in suspension at 55-65% in the oil)
and 2 ml of anhydrous tetrahydrofuran are mixed together under an
inert atmosphere.
[0625] Then 71 mg of the product obtained previously is added.
[0626] Agitation is carried out at ambient temperature for 15
minutes, then 12 .mu.l of acetic acid and 2 ml of solution of
phosphate buffer at pH=7 are added.
[0627] Agitation is carried out for another 5 minutes, then 5 ml
ethyl acetate is added, followed by leaving to settle, then
reextracting with ethyl acetate. After separating, the organic
phase is dried over magnesium sulphate, filtered and the solvent is
evaporated off under reduced pressure.
[0628] In this way 65 mg of crude product is obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/acetone mixture 95/5.
[0629] In this way 40 mg of expected compound, of molecular formula
C.sub.13H.sub.16N.sub.2O.sub.3S (M=280.348 g) is recovered. The
corresponding yield is 64%.
[0630] 1H NMR
[0631] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity (presence of two conformers 90/10):
[0632] 1.46 (m), 1.76 (m) and 2.08 (dm): NCH--CH.sub.2--CH.sub.2;
2.44 (s) and 2.45 (s): CH.sub.3; 2.82 (d) and 2.98 (m) and 3.28 to
3.50 (m): --N--(CH.sub.2).sub.2; 4.55 (m) and 4.65 (m): CO--N--CH;
7.33 and 7.78, 7.35 and 8.02 [AA'BB']
CH.sub.3--C.sub.6H.sub.4--SO.sub.2.
[0633] IR (CHCl.sub.3): 1758, 1598, 1995, 1367, 1169 cm.sup.-1.
[0634] MS (EI) m/z: [M].sup.+: 280, 216, 155, 125, 97, 91.
Example 22
6-oxa-1-azabicyclo[3.2.1]oct-3-en-7-one
[0635] 5 ml of dichloromethane and 68 mg of
1,2,3,6-tetrahydro-pyridin-3-ol hydrochloride (M=135.5 g)
(described in Chem. Pharm. Bull. 30(10)3617-3623 (1982)) are mixed
together under an inert gas.
[0636] 33 .mu.l of diphosgene is added and agitation is carried out
for 5 minutes at 0.degree. C. Then 140 .mu.l of TEA and 61 mg of
DMAP are added.
[0637] The reaction medium is left to react at ambient temperature
for 2 hours, followed by diluting with dichloromethane and washing
with a 10% aqueous solution of tartaric acid then with water,
decanting and drying the organic phase over magnesium sulphate. The
solvent is evaporated off under reduced pressure. In this way 5 mg
of crude product is obtained which is purified by chromatography on
silica, eluting with dichloromethane then a dichloromethane/ethyl
acetate mixture 95/5.
[0638] In this way 3 mg of expected compound, of molecular formula
C.sub.6H.sub.7NO.sub.2 (M=125 g) is recovered. The corresponding
yield is 5%.
Example 23
phenylmethyl
trans-3-benzoyl-2-oxo-4-oxa-1,3-diazabicyclo[3.2.1]octane-7-carboxylate
[0639] 5.50 g (13.7 mmoles) of cis 1-(1,1-dimethylethyl) and
2-(phenylmethyl)4-[(methylsulphonyl)oxy]-1,2-pyrrolidine
dicarboxylate (described in J. Org. Chem. 1991, 56, 3009-3016), of
molecular formula C.sub.18H.sub.25NO.sub.7S (M=399.466 g) and 110
ml of dimethylformamide are mixed together under an inert gas then
2.58 g of N-hydroxyphthalimide, then 1.52 g of potassium hydrogen
carbonate is added.
[0640] The reaction medium is heated under agitation at 100.degree.
C. and maintained at this temperature for 4 hours.
[0641] The reaction medium is cooled down to 20.degree. C., 220 ml
of water and ice are added, then extraction is carried out with
isopropyl ether, followed by drying over magnesium sulphate, then
evaporating to dryness under reduced pressure.
[0642] The residue is chromatographed on silica, eluting with a
dichloromethane/ethyl acetate mixture 90/10.
[0643] In this way 3.06 g of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl
4-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-1,2-pyrrolidinedicarboxyl-
ate), of molecular formula C.sub.25H.sub.26N.sub.2O.sub.7
(M=466.494 g) is recovered The corresponding yield is 47%.
[0644] 3.24 g (6.94 mmoles) of the phthalimide obtained previously
is dissolved in 33 ml of dichloromethane.
[0645] 372 .mu.l of hydrazine hydrate is added.
[0646] Agitation is again carried out for 2 hours 30 minutes at
20.degree. C.
[0647] The precipitate formed is filtered, rinsed with
dichloromethane, then the solvent is evaporated off under reduced
pressure.
[0648] 2.91 g of crude product is obtained which is purified by
chromatography on silica, eluting with a dichloromethane/ethyl
acetate mixture 90/10, then 80/20 and 50/50.
[0649] In this way a total of 942 mg of trans 1-(1,1-dimethylethyl)
and 2-(phenylmethyl)4-(aminooxy)-1,2-pyrrolidinedicarboxylate, of
molecular formula C.sub.17H.sub.24N.sub.2O.sub.5 (M=336.39 g) is
recovered. The corresponding yield is 40%.
[0650] 853 mg of the compound obtained previously (2.53 mmoles) and
8.5 ml of anhydrous dichloromethane are mixed together under an
inert gas.
[0651] The reaction medium is cooled down to about 0-5.degree. C.,
then 706 .mu.l of TEA and 588 .mu.l of benzoyl chloride are
added.
[0652] Agitation is carried out for 10 minutes at 0-5.degree. C.,
then the reaction medium is left to heat up to 20.degree. C. and
left again to react for 30 minutes.
[0653] The organic phase is washed with a 10% aqueous solution of
tartaric acid, then with water, followed by decanting and drying
the organic phase over sodium sulphate, the solvent is evaporated
off under reduced pressure.
[0654] In this way 1.38 g of product is obtained, which is mixed
with 25 ml of dichloromethane. The reaction medium is cooled down
to about 10-15.degree. C. and 123 .mu.l of hydrazine hydrate is
added.
[0655] The reaction medium is left to react whilst agitating at
20.degree. C. for two hours and 30 minutes.
[0656] The solvent is evaporated off under reduced pressure.
[0657] In this way 1.13 g of crude product is obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/ethyl acetate mixture 80/20.
[0658] 948 mg of trans 1-(1,1-dimethylethyl) and
2-(phenylmethyl)-4-[(benzoylamino)oxy]-1,2-pyrrolidinedicarboxylate,
of molecular formula C.sub.24H.sub.28N.sub.2O.sub.6 (M=440.50 g) is
recovered.
[0659] The overall yield is therefore 85%.
[0660] 948 mg of the compound obtained previously is dissolved
under agitation in 2 ml ethyl acetate.
[0661] The reaction medium is cooled down to 0-5.degree. C., then
4.7 ml of an approximately 4.6 M solution of gaseous hydrogen
chloride in ethyl acetate is added in one go.
[0662] After 1 hour, the solvent is evaporated off under reduced
pressure and the product is taken up 3 times in ethyl ether.
[0663] The solvent is evaporated off under reduced pressure. In
this way 842 mg of the hydrochloride of trans phenylmethyl
4-[(benzoylamino)oxy]-2-pyrrolidine carboxylate, is obtained in the
form of a white friable foam of formula
C.sub.19H.sub.20N.sub.2O.sub.4, HCl (M=376.84 g).
[0664] The yield is quantitative.
[0665] 47 mg (0.125 mmole) of the hydrochloride obtained previously
is dissolved under an inert gas in 0.5 ml of dichloromethane. 25.2
.mu.l of pyridine is added, then the reaction medium is cooled down
to 0-5.degree. C. and 9.5 .mu.l of diphosgene is added.
[0666] The temperature is allowed to rise to 20.degree. C.,
followed by diluting with dichloromethane, washing the reaction
medium with a 10% aqueous solution of tartaric acid then with
water.
[0667] The organic phase is decanted and dried over sodium
sulphate. Then the solvent is evaporated off under reduced
pressure.
[0668] In this way 43.8 mg of crude product is obtained which is
purified by chromatography on silica eluting with a
dichloromethane/ethyl acetate mixture 90/10.
[0669] 34.9 mg of trans phenylmethyl
4-[(benzoylamino)oxy]-1-(chlorocarbonyl)-2-pyrrolidinecarboxylate,
of molecular formula C.sub.20H.sub.19ClN.sub.2O.sub.5 (M=402.83 g)
is recovered.
[0670] The corresponding yield is 69%.
[0671] 13 mg (0.032 mmole) of the compound obtained previously is
dissolved in 4 ml of toluene.
[0672] 9 .mu.l of TEA and 7.8 mg of DMAP are added.
[0673] The reaction medium is heated to 100.degree. C.
overnight.
[0674] The solvent is evaporated off under reduced pressure then
the residue is purified by chromatography eluting with
dichloromethane.
[0675] In this way 4.3 mg of the expected compound, of molecular
formula C.sub.20H.sub.18N.sub.2O.sub.5 (M=336.37 g) is recovered.
The corresponding yield is 40%.
[0676] 1H NMR
[0677] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0678] 1.97 (ddd) and 2.85 (ddd): N--O--CH--CH.sub.2--CH; 3.80 (dd)
and 4.14 (dd): N--O--CH--CH.sub.2--N; 4.75 (dd): N--CH--CH.sub.2;
4.93 (t): N--O--CH--CH.sub.2; 5.04 and 5.31 [AB]:
O--CH.sub.2--C.sub.6H.sub.5; 7.77: and 7.25 to 7.50 (m)
CH.sub.2--C.sub.6H.sub.5 and OC--C.sub.6H.sub.5.
[0679] IR (CHCl.sub.3): 1735; 1612, 1575, 1496 cm.sup.-1
Example 24
3-benzoyl-1,3-diazabicyclo[2.2.2]octan-2-one
[0680] 2.4 g (10 mmoles) of N-(4-piperidinyl)-benzamide
hydrochloride (described in J. Med. Chem. EN. 17 (1974), 736-739),
of molecular formula C.sub.12H.sub.16N.sub.2O is dissolved under a
nitrogen atmosphere in 30 ml of dichloromethane.
[0681] The reaction medium is cooled down to 0.degree. C., 2.8 ml
of TEA and 0.66 ml of diphosgene are added under agitation.
[0682] After a few minutes, dilution is carried out with
dichloromethane, followed by washing with a 10% aqueous solution of
tartaric acid, then with water, decanting the organic phase, drying
over magnesium sulphate and the solvent is evaporated off under
reduced pressure. Purification is carried out on silica eluting
with a dichloromethane/ethyl acetate mixture 90/10.
[0683] 1.62 g of the chloride of
4-(benzoylamino)-1-piperidinecarboxylic acid, of molecular formula
C.sub.13H.sub.15ClN.sub.2O.sub.5 (M=266.5 g) is obtained. The
corresponding yield is 61%.
[0684] 1.21 g (48 mmoles) of the compound obtained previously is
dissolved under a nitrogen atmosphere in 37 ml of
tetrahydrofuran.
[0685] The solution is cooled down to -78.degree. C., then 5 ml of
a 1M solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran is added dropwise.
[0686] The reaction medium is maintained at -78.degree. C. for 15
minutes, the temperature is allowed to rise to ambient temperature
and the reaction medium is left to react again for one hour.
[0687] The solution is cooled down to 0.degree. C., 720 .mu.l of
acetic acid is added. A precipitate forms, followed by diluting
with ethyl acetate then washing with a 10% aqueous solution of
tartaric acid and with a solution of phosphate buffer at
pH=7.0.
[0688] The organic phase is decanted and dried over magnesium
sulphate, followed by filtering, then the solvent is evaporated off
under reduced pressure. The crude product is purified by
chromatography on silica eluting with a dichloromethane and ethyl
acetate mixture 90/10.
[0689] In this way 0.214 g of expected compound, of formula
C.sub.18H.sub.14N.sub.2O.sub.2 (M=230 g) is obtained crystallized
from ethyl ether.
[0690] The corresponding yield is 20%.
[0691] 1H NMR
[0692] In the DMSO, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0693] 1.71 to 2.02 (m): (CH.sub.2).sub.2--CHN; 3.14 (t):
N--(CH.sub.2).sub.2; 4.84 (m): (CH.sub.2).sub.2--CHN; 7.39 to 7.65
(m): C.sub.6H.sub.5.
[0694] IR (CHCl.sub.3): 1735, 1682; 1618, 1602, 1582; 1488
cm.sup.-1
[0695] MS (positive electrospray) m/z: [2M+Na].sup.+=483;
[M+Na+CH.sub.3CN].sup.+=294; [M+Na].sup.+=253
Example 25
trans diphenylmethyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2-carboxylate
[0696] 15 ml of dichloromethane and 197 mg (0.633 mmole) of trans
diphenylmethyl 5-hydroxy-2-piperidinecarboxylate (described in Rec.
Trav. Chim. (1959), 78, 648-658), of molecular formula
C.sub.19H.sub.21NO.sub.3 are mixed together under an inert
atmosphere.
[0697] The reaction medium is cooled down to 0.degree. C., then 42
.mu.l of diphosgene, 177 .mu.l of TEA then 77 mg of DMAP are added
successively. The reaction medium is left to react for 4 hours at
ambient temperature.
[0698] Then the reaction mixture is washed with a 10% aqueous
solution of tartaric acid, then with a saturated aqueous solution
of sodium chloride.
[0699] The organic phases are combined and dried over magnesium
sulphate, the solvent is evaporated off under reduced pressure and
in this way 195 mg of crude product is obtained which is purified
by chromatography on silica, eluting with dichloromethane
containing 0.1% water.
[0700] An oil is recovered which crystallizes from a pentane/ethyl
ether mixture.
[0701] In this way 108 mg of expected compound is recovered in the
form of white crystals corresponding to the molecular formula
C.sub.20H.sub.19NO.sub.4 (M=337.338 g).
[0702] The corresponding yield is 51%.
[0703] 1H NMR
[0704] In CDCl3, at 400 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0705] 1.86 (m) and 2.03 (m): N--CH--CH.sub.2--CH.sub.2--CO; 2.27
(m): N--CH--CH.sub.2--CH.sub.2--CO; 3.07 (d) and 3.29 (m):
N--CH.sub.2--CHO; 4.31 (dd): N--CH--CH.sub.2; 4.73 (m):
N--CH.sub.2--CHO; 6.93 (s): CO.sub.2--CH--(C.sub.6H.sub.5).sub.2;
7.27 to 7.41 (m): CH(C.sub.6H.sub.5).sub.2;
[0706] IR (CHCl.sub.3): 1788, 1736; 1496 cm.sup.-1;
[0707] MS (SIMS) m/z: [M+Na].sup.+=360, [M+li].sup.+=344;
[M].sup.+=337, 167
Example 26a
trans(4-nitrophenyl)methyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2-carboxylate
[0708] 66 ml of dichloromethane and 1 g (3.56 mmole) of
trans(4-nitrophenyl)methyl 5-hydroxy-2-piperidine carboxylate of
molecular formula C.sub.13H.sub.16N.sub.2O.sub.5 (M=280.282 g) are
mixed together under an inert atmosphere.
[0709] The reaction medium is cooled down to 0.degree. C., and 0.24
ml of diphosgene is added. The reaction medium is left to react
whilst agitating for 10 minutes at 0.degree. C., then left to heat
up to ambient temperature. The solvent is evaporated off under
reduced pressure.
[0710] The residue is dissolved in 66 ml of toluene and 0.99 ml of
TEA is added.
[0711] The flask is immersed in an oil bath at 110.degree. C. and
maintained there for 15 minutes, followed by leaving to return to
ambient temperature, washing with a 10% aqueous solution of
tartaric acid, then with an saturated aqueous solution of sodium
chloride.
[0712] The organic phase is dried over magnesium sulphate then the
solvent is evaporated off under reduced pressure.
[0713] In this way 0.885 g of crude product is obtained which is
purified by chromatography on silica eluting with a toluene/ethyl
acetate mixture 85/15.
[0714] In this way 0.184 g of expected compound, of molecular
formula C.sub.14H.sub.14N.sub.2O.sub.6 (M=306.276 g) is recovered
in the form of a yellow oil.
[0715] The corresponding yield is 17%.
[0716] 1H NMR
[0717] In CDCl3, at 400 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0718] 1.92 (m) and 2.07 (m): N--CH--CH.sub.2--CH.sub.2--CO; 2.22
(m) and 2.30 (m): N--CH--CH.sub.2--CH.sub.2--CO; 3.17 (d) and 3.35
(dm): N--CH.sub.2--CHO; 4.28 (dd): N--CH--CH.sub.2; 4.79 (m):
N--CH.sub.2--CHO; 5.33 [AB]:
CO.sub.2--CH.sub.2--C.sub.6H.sub.4NO.sub.2; 7.56 and 8.25 [AA'BB']:
CH.sub.2--C.sub.6H.sub.4--NO.sub.2
[0719] IR (CHCl.sub.3): 1791, 1745; 1609, 1526, 1495 cm.sup.-1;
[0720] MS (EI) m/z: [M].sup.+=306, 262, 136, 126, 82, 55
Example 26b
trans-7-oxo-6-oxa-1-azabicyclo[3.2.1.]octane-2 carboxylic acid
[0721] 140 mg (0.457 mmole) of the ester obtained in Example 26a, 7
ml of acetone and 28 mg of Pd/C catalyst at 20% by weight are mixed
together.
[0722] The reaction medium is left to react whilst agitating for 25
minutes under a hydrogen atmosphere at normal pressure.
[0723] The catalyst is filtered and then the solvent is evaporated
off under reduced pressure.
[0724] In this way 137 mg of expected compound, of molecular
formula C.sub.7H.sub.9NO.sub.4 (M=171.152 g) is obtained, in the
form of an oil, in mixture with one mole of .beta.-toluidine.
[0725] The corresponding yield is 97%.
[0726] 1H NMR
[0727] In DMSO, at 400 MHz, chemical shifts of the peaks in ppm and
multiplicity:
[0728] 1.84 (m) and 1.95 to 2.05 (m):
N--CH--CH.sub.2--CH.sub.2--CO; 3.13 (d) and 3.24 (dd):
N--CH.sub.2--CHO; 4.02 (dd): N--CH--CH2; 4.81 (dm): N--CH2-CHO.
Example 26c
trans methyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2-carboxylate
[0729] 17.25 mg (0.1 mmole) of the acid obtained in Example 26b is
dissolved in 3 ml of dichloromethane.
[0730] The reaction medium is treated with an excess of
diazomethane in solution in dichloromethane, then the solvent is
evaporated off under reduced pressure.
[0731] In this way 30 mg of crude product is obtained which is
purified by chromatography on silica, eluting with a toluene/ethyl
acetate mixture 90/10.
[0732] 6.7 mg of expected compound (M=485.187 g) is recovered.
[0733] The corresponding yield is 36%.
Example 27
cis(4-nitrophenyl)methyl
7-oxo-6-oxa-1-azabicyclo[3.2.1]octane-2-carboxylate
[0734] 0.802 g (2.034 mmoles) of the trifluoroacetate of
cis(4-nitrophenyl)methyl 5-hydroxy-2-piperidine-carboxylate
(described in Rec. Trav. Chim. (1959), 78, 648-658), of molecular
formula C.sub.13H.sub.16N.sub.2O.sub.5,CF.sub.3CO.sub.2H (M=394.303
g) is introduced under a nitrogen atmosphere, into 40 ml of
dichloromethane and the reaction medium is cooled down to 0.degree.
C. 0.135 ml of diphosgene is added. Agitation is carried out for 15
minutes at 0.degree. C., the temperature is left to rise to ambient
temperature and agitation is continued for 35 minutes.
[0735] The solvent is evaporated off under reduced pressure.
[0736] This product is dissolved in 40 ml of toluene and 1.1 ml of
triethylamine. The reaction mixture is taken to 100.degree. C. for
35 minutes, then left to cool down to ambient temperature, followed
by washing with water then with a solution of phosphate buffer at
pH=7.
[0737] The organic phase is dried over sodium sulphate and the
solvent is evaporated off under reduced pressure.
[0738] In this way 0.56 g of a crude product is obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/acetone mixture 95/5.
[0739] In this way 110 mg of the expected compound, of molecular
formula C.sub.14H.sub.14N.sub.2O.sub.6, (M=306.275 g) is recovered,
in the form of an oil.
[0740] The corresponding yield is 17%.
[0741] 1H NMR
[0742] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0743] 1.80 to 1.94 and 2.10 to 2.45:
N--CH--CH.sub.2--CH.sub.2--CO; 3.07 (d), 3.04 (dm) and 3.86 (dd):
CH--N--CH.sub.2; 4.80 (t): O.dbd.C--O--CH; 5.28 and 5.43 [AB]:
O.dbd.C--O--CH.sub.2--C.sub.6H.sub.5; 7.61 and 8.24
[AA'BB']C.sub.6H.sub.4NO.sub.2
[0744] IR (CHCl.sub.3): 1801, 1794, 1745, 1704; 1609, 1525, 1498
cm.sup.-1.
[0745] MS (EI) m/z: [M].sup.+=306, 262, 136, 126, 83, 55
Example 28a
1-propenyltriphenylphosphonium salt of trans phenylmethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
Stage A
cis phenylmethyl
5-hydroxy-1-(trifluoroacetyl-2-piperidinecarboxylate
[0746] 6.19 g (22.77 mmoles) of the hydrochloride of phenylmethyl
5-hydroxy-2-piperidinecarboxylate, of molecular formula
C.sub.13H.sub.18ClNO.sub.3 (M=271.746 g) (described in Rec. Trav.
Chim. (1959), 78, 648-658) is dissolved under an inert atmosphere
in 80 ml of anhydrous dichloromethane.
[0747] The reaction medium is cooled down to 5.degree. C. and 9.5
ml of TEA is added then, 6.46 ml of trifluoroacetic anhydride is
added dropwise.
[0748] The reaction medium is left to react under agitation at
5.degree. C. for one hour, then diluted with dichloromethane,
followed by washing successively with a 10% solution of tartaric
acid, an aqueous solution of phosphate buffer at pH=7 and an
aqueous solution of sodium chloride.
[0749] The organic phase is decanted and dried over magnesium
sulphate. Then the solvent is evaporated of f under reduced
pressure.
[0750] In this way 10 g of a red oil is obtained which is dissolved
in 100 ml of methanol. The reaction medium is cooled down to about
10.degree. C., and 6.8 g (78 mmoles) of sodium hydrogen carbonate
in solution in 100 ml of water is added slowly, at 20.degree. C.
maximum.
[0751] The reaction medium is left to react under agitation at
20.degree. C. for 30 minutes, then extracted with
dichloromethane.
[0752] The organic phase is decanted, washed with an saturated
aqueous solution of sodium chloride and dried over magnesium
sulphate.
[0753] The solvent is evaporated off under reduced pressure and in
this way 7.6 g of an oil orange oil is collected which is purified
by chromatography on silica, eluting with a dichloromethane/ethyl
acetate mixture 95/5.
[0754] In this way 6 g of expected compound of molecular formula
C.sub.15H.sub.16F.sub.3NO.sub.4 (M=331.294 g) is recovered. The
corresponding yield is 68%.
Stage B trans
phenylmethyl-5-[(2-propenyloxy)amino]-1-(trifluoroacetyl)-2-piperidinecar-
boxylate
[0755] 1.74 g (5.26 mmoles) of the alcohol obtained previously is
introduced into 29 ml of acetonitrile. The reaction medium is
cooled down to -40.degree. C. and 0.61 ml of 2,6-lutidine
(C.sub.5H.sub.3N(CH.sub.3).sub.2) then 0.91 ml of trifluoro
methanesulphonic anhydride is added at this temperature.
[0756] The reaction medium is left to react under agitation for 30
minutes at -40.degree. C. 0.7 ml (10.52 mmoles) of
O-allyl-hydroxylamine is then added, still at -40.degree. C., over
one minute.
[0757] The reaction medium is left to return to 0.degree. C. then
0.61 ml of 2.6 lutidine is added and the medium is left to react
overnight (15 hours), at approximately 5.degree. C., then again for
2 hours at 20.degree. C., followed by diluting with
dichloromethane, washing with an aqueous solution of sodium
hydrogen carbonate, then with a 10% aqueous solution of tartaric
acid and with a saturated aqueous solution of sodium chloride.
[0758] The organic phase is decanted, dried over magnesium sulphate
and the solvent is evaporated off under reduced pressure.
[0759] In this way 2.1 g of a yellow oil is obtained which is
purified by chromatography on silica, eluting with a toluene/ethyl
acetate mixture 90/10.
[0760] 1.23 g of expected compound of molecular formula
C.sub.18H.sub.21F.sub.3N.sub.2O.sub.4 (M=386.374 g) is
recovered.
[0761] The corresponding yield is 61%.
Stage C
trans phenylmethyl
5-[(2-propenyloxy)amino]-2-piperidinecarboxylate
[0762] 1.41 g (3.65 mmoles) of the compound obtained previously is
dissolved under an inert atmosphere in 25 of anhydrous
methanol.
[0763] The reaction medium is cooled down to 0-5.degree. C., then 3
additions of 145 mg of NaBH.sub.4 are carried out spaced 45 minutes
apart.
[0764] The reaction medium is then acidified to pH=2 with a 1N
aqueous solution of hydrochloric acid cooled down to 5.degree. C.
beforehand.
[0765] Extraction is carried out with ethyl acetate.
[0766] The aqueous phase is cooled down to 50.degree. C., 100 ml
ethyl acetate is added, followed by treating with a saturated
solution of sodium carbonate until a pH of 8.5 to 9 is obtained and
extracting the amine with ethyl acetate. The organic phase is
washed with a saturated aqueous solution of sodium chloride, then
dried over of magnesium sulphate and concentrated by evaporation of
the solvent under reduced pressure.
[0767] In this way 0.628 g of expected product of molecular formula
C.sub.16H.sub.22N.sub.2O.sub.3 (M=290.364 g) is obtained.
[0768] The corresponding yield is 59%.
Stage D trans phenylmethyl
7-oxo-6-(2-propenyloxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
[0769] 103 mg (0.35 mmoles) of the amine obtained previously is
dissolved under an inert atmosphere in 35 ml of anhydrous
dichloromethane.
[0770] The solution is cooled down to about 0-5.degree. C., and 0.1
ml of TEA, then 21 .mu.l of diphosgene are added dropwise, at this
temperature.
[0771] The reaction medium is left to react under agitation for 15
minutes at 0-5.degree. C., then the temperature is allowed to rise
to 20.degree. C., and 42 mg of DMAP is added. Agitation is
continued at 20.degree. C. for approximately 5 hours, followed by
diluting with dichloromethane, washing with a 10% aqueous solution
of tartaric acid, then with water.
[0772] The organic phase is dried over magnesium sulphate and
concentrated by evaporation of the solvent under reduced
pressure.
[0773] In this way 70 mg of crude product is obtained which is
purified by chromatography on 5 g of silica, eluting with a
dichloromethane/methanol mixture 98/2.
[0774] 48 mg of expected product of formula
C.sub.17H.sub.20N.sub.2O.sub.4 (M=316.36 g) is recovered.
[0775] The corresponding yield is 43%.
[0776] IR (CHCl.sub.3): 1750; 1642; 1600, 1496 cm.sup.-1.
[0777] MS (positive electrospray) m/z: [M+Na+CH3CN].sup.+=380;
[M+Na].sup.+=339; [M+H].sup.+=317.
Stage E 1-propenyltriphenylphosphonium salt of trans phenylmethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
[0778] 202 mg (0.638 mmoles) of the compound obtained in Stage D is
dissolved under an inert atmosphere in 5.5 ml of anhydrous
dichloromethane.
[0779] 73 .mu.l of acetic acid, 369 mg of
Pd(P(C.sub.6H.sub.5).sub.3).sub.4A are then added at 20.degree. C.
to the solution obtained.
[0780] After agitation for 30 minutes at ambient temperature, the
N-hydroxy-urea formed is treated with 5.5 ml of pyridine and 358 mg
of SO.sub.3-pyridine complex.
[0781] The reaction medium is left to react under agitation for 18
hours at 20.degree. C., followed by concentrating by evaporation of
the solvent under reduced pressure, taking up in 50 ml of
dichloromethane and washing with water. The organic phase is dried
over magnesium sulphate and the dichloromethane is evaporated off
under reduced pressure.
[0782] In this way 650 mg of crude product is obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/acetone mixture 60/40 containing 0.1% by volume of
TEA.
[0783] In this way 280 mg of the phosphonium salt of the expected
compound, of molecular formula C.sub.35H.sub.35N.sub.2O.sub.7PS
(M=646.705 g) is recovered.
[0784] The corresponding yield is 68%.
[0785] 1H NMR
[0786] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0787] 2.05 (m), 2.22 (dm) and 2.33 (m): N--CH--CH.sub.2--CH.sub.2;
2.95 (d) and 3.30 (dt); O.dbd.C--N--CH.sub.2; 4.10 (m) and 4.32
(m): O.dbd.C--N--CH and O.dbd.C--N--CH.sub.2--CH; 5.12 (s):
COO--CH.sub.2--C.sub.6H.sub.5; 7.36: C.sub.6H.sub.5 and 2.30 (m):
CH.sub.3--CH.dbd.CH; 6.65 and 7.20 CH.sub.3--CH.dbd.CH; 7.65-7.85
P(C.sub.6H.sub.5).sub.3.
[0788] IR (CHCl.sub.3): 1746; 1638, 1605, 1587, 1495 cm.sup.-1.
[0789] MS (negative and positive electrospray) m/z:
[Manion].sup.-=355; [Mcation].sup.+=303.
Example 28b
Sodium salt of trans phenylmethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
[0790] 236 mg (0.364 mmoles) of the phosphonium salt obtained in
Stage E of Example 28a is dissolved in 0.8 ml of tetrahydrofuran
and 4 drops of water.
[0791] The solution obtained is passed through a column of DOWEX
50WX8 resin in Na+ form, eluting with water.
[0792] After lyophilization, 127 mg of the expected sodium salt, of
molecular formula C.sub.14H.sub.15N.sub.2O.sub.7SNa (M=378.339 g).
is obtained
[0793] The corresponding yield is 92%.
[0794] 1H NMR
[0795] In DMSO, at 300 MHz, chemical shifts of the peaks in ppm and
multiplicity:
[0796] 1.65 to 2.02: N--CH--CH.sub.2--CH.sub.2; 2.91 (d) and 3.04
(dt): O.dbd.C--N--CH.sub.2; 4.00 to 4.05: O.dbd.C--N--CH and
O.dbd.C--N--CH.sub.2--CH; 5.20 [AB]: COO--CH.sub.2--C.sub.6H.sub.5;
7.39 (m): C.sub.6H.sub.5.
[0797] IR (Nujol): 1744; 1495 cm.sup.-1.
[0798] MS (negative electrospray)_m/z; [M].sup.-=355.
Example 28c
trans phenylmethyl
7-oxo-6-[(phenylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxylat-
e
[0799] 48 mg (0.152 mmoles) of the derivative obtained in Stage D
of Example 28a is dissolved in 1.2 ml of dichloromethane.
[0800] 26 .mu.l of acetic acid then 88 mg of Pd (PPh.sub.3).sub.4
are added to it at 20.degree. C., and the reaction medium is left
to react for 2 hours at 200 under agitation, followed by diluting
by the addition of toluene and the solvents are evaporated off
under reduced pressure.
[0801] 1.5 ml of dichloromethane, 25 .mu.l of pyridine and 24 .mu.l
of benzenesulphonyl chloride are added to the crude product
obtained.
[0802] The reaction medium is left to react at 20.degree. C. under
agitation for 1 hour then 12.5 .mu.l of pyridine and 10 .mu.l of
benzenesulphonyl chloride are added.
[0803] Agitation is carried out for 15 minutes at 20.degree. C.,
followed by diluting with dichloromethane, washing successively
with a 10% aqueous solution of tartaric acid, a solution of
phosphate buffer at pH=7 and with a saturated aqueous solution of
sodium chloride.
[0804] The aqueous phase is dried over magnesium sulphate, and the
solvent is evaporated off under reduced pressure. 180 mg of a
yellow oil is obtained which is purified by chromatography on
silica, eluting with a dichloromethane/methyl and t-butyl ether
mixture 95/5.
[0805] In this way 20 mg of expected compound, of molecular formula
C.sub.20H.sub.20N.sub.2O.sub.6S (M=416.456 g) is recovered. The
corresponding yield is 31%.
[0806] 1H NMR
[0807] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0808] 1.83 (m) and 2.00 to 2.25 (m): N--CH--CH.sub.2--CH.sub.2;
3.02 (d) and 3.16 (dm): O.dbd.C--N--CH.sub.2; 4.04 (m) and 4.11
(dd): O.dbd.C--N--CH and O.dbd.C--N--CH.sub.2--CH; 5.21 (s):
COO--CH.sub.2--C.sub.6H.sub.5; 7.34 (m): C.sub.6H.sub.5; 7.56 (m),
7.70 (m) and 8.03 (m): O.sub.2S--C.sub.6H.sub.5.
[0809] IR (CHCl.sub.3): 1780, 1738; 1600, 1585, 1498; 1386, 1193
cm.sup.-1.
[0810] MS (positive electrospray) m/z: [2M+Na].sup.+=855;
[M+Na+CH.sub.3CH].sup.+=480; [M+Na].sup.+=439; [MH].sup.+=417.
Example 28d
trans pheylmethyl
7-oxo-6-[(2-thienylsulphonyl)oxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxy-
late
[0811] Starting from 100 mg (0.316 mmoles) of the compound obtained
in Stage D of Example 28a, the operation is carried out in a
similar manner to that which has just been described, except that
instead of using benzenesulphonyl chloride, 2 thienyl sulphonyl
chloride is used.
[0812] In this way 8 mg of expected compound, of molecular formula
C.sub.18H.sub.18N.sub.2O.sub.6S.sub.2 (M=422.481 g) is recovered.
The corresponding yield is 30%.
[0813] 1H NMR
[0814] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0815] 1.84 (m) and 2.10 to 2.25: N--CH--CH.sub.2--CH.sub.2; 3.02
(d) and 3.24 (dt): O.dbd.C--N--CH.sub.2; 4.06 (m):
O.dbd.C--N--CH.sub.2--CH; 4.14 (dd): O.dbd.C--N--CH; 5.22 (s):
COO--CH.sub.2--C.sub.6H.sub.5; 7.17 (dd):
SO.sub.3--C--S--CH.dbd.CH; 7.35 (bs): C.sub.6H.sub.5; 7.80 (dd):
SO.sub.3--C.dbd.CH; 7.87 (m): SO.sub.3--C--S--CH.
[0816] IR (CHCl.sub.3): 1780, 1739; 1600, 1503, 1495 cm.sup.-1.
[0817] MS (positive electrospray) m/z: [M+Na+CH.sub.3CN].sup.+=867;
[2M+Na].sup.+=445; 339, 298, 91.
Example 28e
trans phenylmethyl
6-(2-hydroxy-2-oxoethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxyla-
te
Stage A trans phenylmethyl
7-oxo-6-[2-oxo-2-(2-propenyloxy)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-c-
arboxylate
[0818] 48 mg (0.15 mmoles) of the compound obtained in Stage D of
Example 28a is dissolved under an inert atmosphere in 1.5 ml of
anhydrous dichloromethane.
[0819] 18 .mu.l of acetic acid then 88 mg of
Pd(P(C.sub.6H.sub.5).sub.3).sub.4 are added at 20.degree. C. and
the reaction medium is left under agitation for 1 hour at
20.degree. C., followed by filtering on silica, eluting with a
dichloromethane/t-butyl and methyl ether of mixture 7/3.
[0820] The solvent is evaporated off under reduced pressure and 70
mg of hydroxy urea is obtained which is taken up in 2 ml of
dichloromethane, then 85 .mu.l of TEA and 64 .mu.l of allyl
bromoacetate are added.
[0821] Agitation is carried out to 20.degree. C. for 3 hours and 30
minutes, followed by washing successively with a 10% aqueous
solution of tartaric acid, with an aqueous solution of phosphate
buffer at pH=7 and with water.
[0822] The organic phase is dried and the solvent is evaporated off
under reduced pressure.
[0823] In this way 60 mg of crude product is obtained which is
chromatographed on silica eluting with a dichloromethane/t-butyl
and methyl ether mixture 90/10 containing 0.1% TEA.
[0824] 22 mg of molecular formula C.sub.19H.sub.22N.sub.2O.sub.6,
(M=374.396 g) is recovered. The corresponding yield is 39%.
Stage B
trans phenylmethyl
6-(2-hydroxy-2-oxoethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxyla-
te
[0825] 22 mg (0.0587 mmoles) of the compound obtained previously is
dissolved under an inert atmosphere in 1 ml of anhydrous
dichloromethane.
[0826] 10 .mu.l of acetic acid and 34 mg of
Pd(P(C.sub.6H.sub.5).sub.3).sub.4 are added at 20.degree. C. and
the reaction medium is left to react under agitation at 20.degree.
C. for 30 minutes.
[0827] The reaction medium is concentrated and taken up in toluene
in order to eliminate the acetic acid.
[0828] In this way 49 mg of crude product is obtained to which 2 ml
of phosphate buffer of pH 7 is added, then it is washed twice with
1 ml of dichloromethane.
[0829] The solvent is evaporated off and 46 mg of crude product is
obtained which is purified by chromatography on silica, eluting
firstly with a dichloromethane/t-butyl and methyl ether mixture
90/10 then with a dichloromethane/ethanol mixture 60/40.
[0830] In this way 4.5 mg of expected compound, of molecular
formula C.sub.37H.sub.37N.sub.2O.sub.6P (M=636.691 g) is obtained.
The corresponding yield is 12%.
Example 29a
trans(4-nitrophenyl)methyl
6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
Stage A
cis 1-(1,1-dimethylethyl) and
2-[(4-nitrophenyl)methyl]5-(methylsulphonyl)oxy-1,2-piperidinedicarboxyla-
te
[0831] 11.25 g (29.5 mmoles) of cis 1-(1,1-dimethylethyl) and
2-[(4-nitrophenyl)methyl]5-hydroxy-1,2-piperidinedicarboxylate
(described in Rec. Trav. Chim. (1959), 78, 648-658), of molecular
formula C.sub.18H.sub.24N.sub.2O.sub.7 (M=380.398 g) is dissolved
under an inert atmosphere in 112 ml of dichloromethane.
[0832] The reaction medium is cooled down to 0-5.degree. C., then 5
ml of TEA then 2.44 ml of methanesulphonyl chloride are introduced
successively.
[0833] The temperature is allowed to return to 20.degree. C. under
agitation and the medium is left to react for 1 hour, followed by
diluting with dichloromethane, washing twice with water, drying
over sodium sulphate, and the solvent is evaporated off under
reduced pressure.
[0834] In this way 16 g of a crude oil is obtained which is
purified by chromatography on silica, eluting with dichloromethane
containing 2% ethyl acetate.
[0835] 9.14 g of expected product of molecular formula
C.sub.19H.sub.26N.sub.2O.sub.9S (M=458.491 g) is recovered. The
corresponding yield is 67%.
Stage B trans 1-(1,1-dimethylethyl) and
2-[(4-nitrophenyl)methyl]5-azido-1,2-piperidinedicarboxylate
[0836] 11.1 g (24.2 mmoles) of the mesylate obtained previously is
dissolved under an inert atmosphere in 111 ml of
dimethylformamide.
[0837] Then 1.73 g of sodium nitride NaN.sub.3 is added.
[0838] The reaction medium is heated under agitation at 80.degree.
C. and is maintained at this temperature for 18 hours, then left to
return to 20.degree. C. The dimethylformamide is evaporated off
under reduced pressure until a small volume is obtained, then
dilution is carried out with ethyl acetate, followed by washing
with a 2N solution of soda, then with water, drying over magnesium
sulphate, then the solvents are evaporated off under reduced
pressure.
[0839] The crude oil obtained is purified by chromatography on
silica eluting with dichloromethane containing 2% ethyl
acetate.
[0840] In this way 7.34 g of expected compound, of molecular
formula C.sub.18H.sub.23N.sub.5O.sub.6 (M=405:413 g) is obtained in
the form of a yellow oil which crystallizes.
[0841] The corresponding yield is 75%.
Stage C
trans 1-(1,1-dimethyl-ethyl) and
2-[(4-nitrophenyl)methyl]5-amino-1,2-piperidinedicarboxylate
[0842] 7.34 g (18.1 mmoles) of the azide obtained previously is
introduced into 150 ml of tetrahydrofuran and 30 ml of water.
[0843] 7.2 g of triphenylphosphine is added, then the reaction
medium is left to react overnight under agitation at 20.degree.
C.
[0844] Then the solvent is evaporated off under reduced pressure
and two entrainments are carried out with ethyl acetate.
[0845] In this way a dry extract is obtained which is purified by
chromatography on silica, eluting with dichloromethane containing
5% methanol.
[0846] 5.62 g of expected compound, of molecular formula
C.sub.18H.sub.25N.sub.3O.sub.6 (M=379.416 g) is recovered. The
corresponding yield is 82%.
Stage D
trans 1-(1,1-dimethylethyl) and
2-[(4-nitrophenyl)methyl]5-(benzoylamino)-1,2-piperidinedicarboxylate
[0847] 700 mg (1.84 mmole) of the amine obtained previously is
dissolved in 8 ml of dichloromethane.
[0848] The reaction medium is cooled down to 0.degree. C., then 257
.mu.l of TEA then 214 .mu.l of benzoyl chloride are introduced.
[0849] The temperature is allowed to return to 20.degree. C.
[0850] After reaction for 40 minutes, dilution is carried out with
dichloromethane, followed by washing with a saturated solution of
sodium hydrogen carbonate, then with water, drying over sodium
sulphate and the solvent is evaporated off under reduced
pressure.
[0851] In this way 867 mg of expected compound, of molecular
formula C.sub.25H.sub.29N.sub.3O.sub.7 (M=483.525 g) is obtained.
The corresponding yield is 97%.
Stage E
hydrochloride of trans(4-nitrophenyl)methyl
5-(benzoylamino)-2-piperidine carboxylate
[0852] 861 mg (8 mmole) of the amide obtained previously, 9 ml of
methanol, and 2.3 ml of a solution of gaseous hydrogen chloride at
8 mol/l in methanol are mixed together.
[0853] The temperature is allowed to return to 20.degree. C. and
the reaction medium is left to react for 3 hours. Then 1.15 ml of a
solution of hydrogen chloride in methanol is added.
[0854] Agitation is carried out for 20 minutes at 20.degree. C.,
then the solvent is evaporated off under reduced pressure.
[0855] Then two entrainments are carried out with dichloromethane,
then two entrainments with ethyl ether.
[0856] The product crystallizes from ethyl ether.
[0857] In this way 715 mg of expected compound of molecular formula
C.sub.20H.sub.22ClN.sub.3O.sub.5 (M=419.967 g) is obtained.
[0858] The corresponding yield is 96%.
Stage F
trans(4-nitrophenyl)methyl
5-(benzoylamino)-1-(chlorocarbonyl)-2-piperidine carboxylate
[0859] 1.08 g (2.58 mmole) of the hydrochloride obtained as
previously and 11 ml of dichloromethane are mixed together.
[0860] The suspension obtained is cooled down to about 0-5.degree.
C. and 791 .mu.l of TEA is added, then 161 .mu.l of diphosgene is
added to the solution obtained.
[0861] Agitation is carried out for 5 minutes at 0-5.degree. C.,
then the reaction medium is left to return to 20.degree. C., and
left under agitation for another 30 minutes, followed by diluting
with dichloromethane, washing with a 10% aqueous solution of
tartaric acid, then with water, drying over sodium sulphate and the
solvent is evaporated off under reduced pressure.
[0862] The crude product is purified by chromatography on silica
eluting with dichloromethane containing 5% acetone.
[0863] 969 mg of expected compound of molecular formula
C.sub.21H.sub.20ClN.sub.3O.sub.6 (M=445.862 g) is recovered.
[0864] The corresponding yield is 84%.
Stage G
trans(4-nitro-phenyl)methyl
6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
[0865] 928 mg (2.08 mmoles) of the compound obtained previously and
27 ml of tetrahydrofuran are mixed together under an inert gas.
[0866] The solution obtained is cooled down to -78.degree. C. under
agitation, then 2.1 ml of a 1M solution of lithium
bis(trimethylsilyl)amide in tetrahydrofuran is introduced.
[0867] The reaction medium is left under agitation for 10 minutes
at -78.degree. C. then 130 .mu.l of acetic acid is added and
agitation is carried out whilst allowing the temperature to rise to
15.degree. C., followed by diluting with ethyl acetate then washing
successively with a 10% aqueous solution of tartaric acid, with a
solution of phosphate buffer at pH=7 and with water, drying over
magnesium sulphate and the solvent is evaporated off under reduced
pressure.
[0868] In this way 1.6 g of a dry extract is obtained which is
purified by chromatography on silica eluting with a
dichloromethane/acetone mixture 98/2.
[0869] The product is then crystallized from ethyl ether in order
to produce 204 mg of expected compound, of molecular formula
C.sub.21H.sub.19N.sub.3O.sub.6 (M=409.441 g).
[0870] The corresponding yield is 24%.
[0871] 1H NMR
[0872] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0873] 1.98 (m), 2.22 (m) and 2.40 (m): N--CH--CH.sub.2--CH.sub.2;
3.08 (d) and 3.42 (dt): O.dbd.C--N--CH.sub.2; 4.23 (dd):
O.dbd.C--N--CH; 4.53 (m): O.dbd.C--N--CH.sub.2--CH; 5.34 [AB]:
COO--CH.sub.2--C.sub.6H.sub.5; 7.69 (m): 8.25 (m): 7.44 (m) and
7.56 (m): C.sub.6H.sub.5 and C.sub.6H.sub.4NO.sub.2.
[0874] IR (CHCl.sub.3): 1763, 1744, 1676; 1609, 1603, 1583, 1526,
1492 cm.sup.-1.
[0875] MS (EI) m/z: [M].sup.+=409, 304, 273, 201, 105, 77.
Example 29b
trans-6-benzoyl-7-oxo-1,6-iazabicyclo[3.2.1]octane-2-carboxylic
acid
[0876] 89 mg of the ester obtained in Example 29a, 4 ml of acetone
and 6 mg of 10% Pd/C catalyst are mixed together.
[0877] The reaction medium is left to react under agitation, at
20.degree. C. and under a hydrogen atmosphere for 2 hours 45
minutes, then the catalyst is filtered and the filtrate evaporated
under reduced pressure.
[0878] In this way 88 mg of a resin is obtained which is
crystallized from 0.5 ml of ethyl ether.
[0879] In this way 54 mg of expected compound, of molecular formula
C.sub.14H.sub.14N.sub.2O.sub.4 (M=274.278 g) is obtained. The
corresponding yield is 91%.
[0880] 1H NMR
[0881] In CDCl3, at 250 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0882] 1.96 (m), 2.10 (m) and 2.37 (m): N--CH--CH.sub.2--CH.sub.2;
3.13 (d) and 3.41 (dm): O.dbd.C--N--CH.sub.2; 4.10 (bd):
O.dbd.C--N--CH; 4.52 (m): O.dbd.C--N--CH.sub.2--CH; 7.44 (m): 7.56
(tt) and 7.69 (dd) C.sub.6H.sub.5.
[0883] MS (EI) m/z: M.sup.+=274, 229, 169, 105, 77.
Example 29c
trans methyl
6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
[0884] 2 ml of a solution of diazomethane at 12.7 g/l in
dichloromethane is added under agitation to 28 mg (0.102 mmole) the
acid obtained in Example 29b.
[0885] The solvent is evaporated off under reduced pressure and the
residue is purified by chromatography on silica eluting with a
dichloromethane/ethyl acetate mixture 98/2.
[0886] 18.4 mg of expected compound, of molecular formula
C.sub.15H.sub.16N.sub.2O.sub.4 (M=288.305 g) is recovered. The
corresponding yield is 63%.
[0887] 1H NMR
[0888] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0889] 1.90 to 2.42: N--CH--CH.sub.2--CH.sub.2; 3.12 (d) and 3.44
(dt): O.dbd.C--N--CH.sub.2; 3.83 (s): CH.sub.3; 4.17 (bd):
O.dbd.C--N--CH; 4.54 (m): O.dbd.C--N--CH.sub.2--CH; 7.44 (t), 7.56
(t) and 7.69 (d): C.sub.6H.sub.5.
[0890] MS (EI) m/z: [M].sup.+=288, 229, 183, 155, 105, 77.
Example 29d
trans-6-benzoyl-7-oxo-N-(phenylmethyl)-1,6-diazabicyclo[3.2.1]octane-2-car-
boxamide
[0891] 30 mg (0.109 mmole) of
trans-6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic
acid obtained in Example 29b, 0.5 ml of dichloromethane, 23 mg of
EDCI and 13 .mu.l of benzylamine are mixed together.
[0892] The reaction medium is left to react for 30 minutes under
agitation followed by diluting with dichloromethane, washing with a
10% aqueous solution of tartaric acid, decanting and drying the
organic phase over sodium sulphate.
[0893] The solvent is evaporated off under reduced pressure in
order to obtain a crude product which is purified by chromatography
on silica eluting with a dichloromethane/acetone mixture 98/2.
[0894] In this way 19.5 mg of expected compound, of molecular
formula C.sub.21H.sub.21N.sub.3O.sub.3 (M=363.419 g) is obtained.
The corresponding yield is 49%.
[0895] 1H NMR
[0896] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0897] 1.97 (m), 2.34 (m) and 2.59 (m): N--CH--CH.sub.2--CH.sub.2;
2.90 (d), 3.33 (m), 3.99 (bd) and 4.50 (m): O.dbd.C--N--CH,
O.dbd.C--N--CH.sub.2--CH, O.dbd.C--N--CH.sub.2,
CO--NH--CH.sub.2--C.sub.6H.sub.5; 6.94 (bt): NH; 7.24 to 7.58 (m)
and 7.68 (m): C.sub.6H.sub.5--CO and C.sub.6H.sub.5--CH.sub.2.
[0898] IR (CHCl.sub.3): 3411, 1763, 1680; 1603, 1583, 1519, 1498
cm.sup.-1.
Example 29e
6-benzoyl-N--[methyl(phenylmethyl)]-7-oxo-1,6-diazabicyclo[3.2.1]octane-2--
carboxamide
[0899] The operation is carried out in a similar manner to Example
29d starting from 50 mg (0.182 mmole) of the acid obtained in
Example 29b and 45 .mu.l of N-methyl-benzylamine.
[0900] In this way 12 mg of expected compound, of molecular formula
C.sub.22H.sub.23N.sub.3O.sub.3 (M=377.45 g) is recovered. The
corresponding yield is 17%.
[0901] MS (EI) m/z: [M].sup.+=377, 272, 105.
Example 29f
6-benzoyl-2-(hydroxymethyl)-1,6-diazabicyclo[3.2.1]octan-7-one
[0902] 100 mg (364 mmole) of
trans-6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic
acid obtained in Example 29b is dissolved, under an inert
atmosphere, in 3 ml of tetrahydrofuran.
[0903] The reaction medium is cooled down to -10.degree. C. and 40
.mu.l of methylmorpholine, then 38 .mu.l of ethyl chloroformate are
added.
[0904] The reaction medium is left to react for 15 minutes at
-10.degree. C., then the temperature is allowed to rise to
0.degree. C. and 27 mg of NaBH.sub.4, then, dropwise, 1.5 ml of
methanol are added.
[0905] The reaction medium is left under agitation at 0.degree. C.
for 2 hours then left to return to ambient temperature.
[0906] 3 ml of water is added, the reaction medium is left under
agitation for 15 minutes, then a few drops of ammonium chloride are
added. Extraction is carried out with ethyl acetate, followed by
drying over magnesium sulphate, filtering and the solvent is
evaporated off under reduced pressure.
[0907] In this way 85 mg of a crude product is obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/methanol mixture 98/2.
[0908] In this way 25 mg of expected compound, of molecular formula
C.sub.14H.sub.16N.sub.2O.sub.3 (M=260.3 g) is recovered. The
corresponding yield is 26%.
[0909] 1H NMR
[0910] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0911] 1.61 (m, 1H), 2.00 (m, 2H) 2.30 (m, 1H):
CH--CH.sub.2--CH.sub.2--CH; 2.19: 3.23 (d) and 3.26 (dt):
N--CH.sub.2; 3.60 (m): N--CH--CH.sub.2--OH; 3.70 (m) and 3.77 (dd):
CH--CH.sub.2--O; 4.56 (m): N--CH--CH.sub.2--N.
[0912] MS (SIMS) m/z: [M+Na].sup.+=283, [M+H].sup.+=261,
[M].sup.+=260, 229, 105.
Example 30
trans(4-nitrophenyl)methyl
6-acetyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
[0913] 1 g (2.63 mmoles) of the product prepared in Stage C of
Example 29 is dissolved in 12 ml of dichloromethane. 250 .mu.l of
acetic anhydride is added, the reaction medium is left to react for
10 minutes under agitation, then diluted with dichloromethane and
washed with a saturated aqueous solution of sodium hydrogen
carbonate.
[0914] The organic phase is dried over sodium sulphate, followed by
evaporating to dryness under reduced pressure in order to obtain
1.2 g of trans 1-(1,1-dimethylethyl) and
2-[(4-nitrophenyl)methyl]5-(acetylamino)-1,2-piperidinedicarboxylate,
of molecular formula C.sub.20H.sub.27N.sub.3O.sub.7 (M=421.453
g).
[0915] This product is used without purification in stages similar
to Stages E to G of Example 29 and in this way 14 mg of expected
compound, of molecular formula C.sub.16H.sub.17N.sub.3O.sub.6
(M=347.330 g) is collected. The corresponding yield is 17%.
[0916] 1H NMR
[0917] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0918] 1.87 (m), 2.00 to 2.30 (m): N--CH--CH.sub.2--CH.sub.2; 2.54
(s): N--CO--CH.sub.3; 2.95 (d) and 3.21 (m): O.dbd.C--N--CH.sub.2;
4.26 (bd): O.dbd.C--N--CH; 4.55 (m): O.dbd.C--N--CH.sub.2--CH; 5.34
[AB]: CO.sub.2--CH.sub.2--C.sub.6H.sub.4; 7.57 and 8.25 [AA'BB']:
C.sub.6H.sub.4--NO.sub.2.
[0919] MS (EI) m/z: [M].sup.+=347, 304, 211, 169, 125, 43.
Example 31
trans(4-nitrophenyl)methyl and 2-propenyl
7-oxo-1,6-diazabicyclo[3.2.1]octane-2,6-dicarboxylate
[0920] 1.24 g (3.278 mmoles) of the product prepared in Stage C of
Example 29a is dissolved, under a nitrogen atmosphere, in 8 ml of
dichloromethane.
[0921] The solution is cooled down to 0.degree. C., then 0.45 ml of
TEA then 0.35 ml of allyl chloroformate are added dropwise.
[0922] The reaction medium is maintained at 0.degree. C. for 15
minutes, then is left to react under agitation for 1 hour at
ambient temperature, followed by diluting with 20 ml of
dichloromethane, washing with an aqueous solution of sodium
bicarbonate, and twice with water, drying over magnesium sulphate,
and the solvent is evaporated off under reduced pressure.
[0923] In this way 1.5 g of trans 1-(1,1-dimethylethyl) and
2-[(4-nitrophenyl)methyl]5-[[(2-propenyloxy)carbonyl]amino]-1,2-piperidin-
edicarboxylate of molecular formula C.sub.22H.sub.28N.sub.3O.sub.8,
(M=462.486 g) is obtained.
[0924] The corresponding yield is 99%.
[0925] This product is used in stages similar to Stages E to G of
Example 29a and in this way 30.6 mg of expected compound, of
molecular formula C.sub.18H.sub.19N.sub.3O.sub.7, (M=389.368 g) is
obtained in the form of a white solid. The corresponding yield is
40%.
[0926] 1H NMR
[0927] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0928] 1.91 (m), 2.00 to 2.29 (m): N--CH--CH.sub.2--CH.sub.2; 2.98
(d) and 3.25 (bd): O.dbd.C--N--CH.sub.2; 4.27 (t) O.dbd.C--N--CH;
4.37 (bs): O.dbd.C--N--CH.sub.2--CH; 4.77 (bd):
COO--CH.sub.2--CH.dbd.; 5.33 (s): COO--CH.sub.2--C.sub.6H.sub.4;
5.29 to 5.46: CH.sub.2.dbd.CH; 5.98 (m): CH.sub.2.dbd.CH; 7.96 and
8.29 [AA'BB']: C.sub.6H.sub.4--NO.sub.2.
[0929] IR (CHCl.sub.3): 1801, 1775, 1738, 1724; 1649; 1608, 1595,
1526 cm.sup.-1.
[0930] MS (positive electrospray) m/z: [2M+Na].sup.+=801,
[M+Na+CH.sub.3CN].sup.+=453, [M+Na].sup.+=412
Example 31a
trans phenylmethyl
6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate
[0931] 200 mg of trans phenylmethyl
5-(benzoylamino)-1-(chlorocarbonyl)-2-piperidinecarboxylate, of
molecular formula C.sub.21H.sub.21ClN.sub.2O.sub.4 (M=400.87 g),
prepared in a similar manner to Stages A to F of Example 29a and 6
ml of anhydrous tetrahydrofuran are mixed together under an inert
atmosphere and the reaction medium is cooled down to -78.degree.
C.
[0932] 0.55 ml of a 1M solution of lithium bis
(trimethylsilyl)amide in tetrahydrofuran is added dropwise.
[0933] The reaction medium is left to react under agitation at
-78.degree. C. for 10 minutes then 25 .mu.l of acetic acid is
added.
[0934] The temperature is allowed to rise to ambient temperature,
then the reaction medium is poured into 10 ml of a 10% aqueous
solution of tartaric acid, followed by extracting with ethyl
acetate, washing with an aqueous solution of phosphate buffer at
pH=7, then with water, drying over magnesium sulphate and bringing
to dryness by evaporation of the solvent under reduced
pressure.
[0935] In this way 158 mg of a crude product is obtained which is
purified by chromatography on silica, eluting with a
dichloromethane/acetone mixture 98/2.
[0936] In this way 70 mg of expected compound, of molecular formula
C.sub.21H.sub.20N.sub.2O.sub.4 (M=364.40 g) is recovered. The
corresponding yield is 39%.
[0937] 1H NMR
[0938] In CDCl3, at 400 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[0939] 2.15 (m) and 2.25 (m):
NCH--CH.sub.2--CH.sub.2--CH--CO.sub.2; 1.94 (m) and 2.36 (m):
NCH--CH.sub.2--CH.sub.2--CH--CO.sub.2; 4.20 (d) N--CH--CO.sub.2;
4.50 (q): NCH--CH.sub.2--CH.sub.2--CH--CO.sub.2; 3.08 (d) and 3.40
(dt): N--CH.sub.2; 5.25 [AB]: CO.sub.2--CH.sub.2--C.sub.6H.sub.5;
7.38 (bs): CH.sub.2--C.sub.6H.sub.5; 7.43 (bt) and 7.55 (bt) and
7.69 (bd) C.sub.6H.sub.5--CO.
[0940] IR (CHCl.sub.3): 1764, 1744, 1675; 1602, 1584, 1498
cm.sup.1.
[0941] MS (SIMS) m/z: [M+Na].sup.+=387, [M+H].sup.+=365, 259, 257,
229, 105, 91.
Example 31b
phenylmethyl
6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-ene-2-carboxylate
[0942] 46 mg (0.126 mmoles) of the product obtained in Example 31a
and 0.5 ml of anhydrous tetrahydrofuran are mixed together, under a
nitrogen atmosphere.
[0943] The reaction medium is cooled down to -70.degree. C. and
0.31 ml of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran
is added.
[0944] The reaction medium is left to react for 2 hours at
-70.degree. C., then the temperature is allowed to rise to
-15.degree. C. and 0.41 ml of a solution of C.sub.6H.sub.5--SeCl at
0.7 mol/l in THF is added at this temperature.
[0945] The reaction medium is left under agitation at -15.degree.
C. for 15 minutes, then left to return to ambient temperature over
15 minutes and poured into a mixture of water and ice containing a
few drops of a saturated aqueous solution of sodium
bicarbonate.
[0946] Extraction is carried out with ethyl acetate, followed by
washing with water, drying and the solvent is evaporated off under
reduced pressure.
[0947] The residue is purified by chromatography on silica eluting
with a dichloromethane/acetone mixture 98/2 and in this way 15 mg
of phenylmethyl
6-benzoyl-7-oxo-2-(phenylselenyl)-1,6-diazabicyclo[3.2.1]octane-2-carboxy-
late, of molecular formula C.sub.27H.sub.24N.sub.2O.sub.4Se
(M=519.46 g) is collected. The corresponding yield is 23%.
[0948] 15 mg (0.029 mmole) of the compound obtained previously and
0.3 ml of dichloromethane are mixed together.
[0949] The reaction medium is cooled down to 0.degree. C. and 15 mg
of meta-chloroperbenzoic acid in solution in 0.15 ml of
dichloromethane is added.
[0950] The reaction medium is left under agitation at 0.degree. C.
for 15 minutes, then left to return to ambient temperature,
followed by pouring into approximately 20 ml of water, extracting
with dichloromethane and washing the organic phase with an aqueous
solution of phosphate buffer at pH=7, drying over magnesium
sulphate, filtering and the solvent is evaporated off under reduced
pressure.
[0951] In this way 15 mg of crude product is obtained which is
purified on silica eluting with a dichloromethane/acetone mixture
98/2.
[0952] In this way 5 mg of expected compound, of molecular formula
C.sub.21H.sub.18N.sub.2O.sub.4 (M=362.39 g) is recovered. The
corresponding yield is 48%.
[0953] 1H NMR
[0954] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity: 2.66 (td) and 2.99 (tdd): N--CH--CH.sub.2; 3.03
(d) and 3.77 (ddd): N--CH.sub.2; 4.76 (tt): N--CH; 5.23 [AB]:
CO2-CH.sub.2--C.sub.6H.sub.5; 7.02 (dt): N--C.dbd.CH; 7.30 to 7.38
(m): CH.sub.2--C.sub.6H.sub.5; 7.42 (tm), 7.54 (tm) and 7.62 (dm);
C.sub.6H.sub.5--CO;
Example 31c
6-benzoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-ene-2-carboxylic
acid
[0955] 20 mg (0.055 mmole) of the product obtained in Example 31b
is mixed, 0.4 ml of acetone and 4 mg of 10% Pd/C catalyst are
added.
[0956] The reaction medium is placed under a hydrogen atmosphere
and left to react for 3 hours under vigorous agitation.
[0957] Filtration is carried out and the catalyst is washed with
acetone then with methanol. The filtrate is evaporated under
reduced pressure.
[0958] In this way 14 mg of expected compound, of molecular formula
C.sub.14H.sub.12N.sub.2O.sub.4 (M=272.4 g) is obtained. The
corresponding yield is 93%.
[0959] MS (EI) m/z: [M].sup.+: 272, 105.
Example 32a
trans 2-propenyl
7-oxo-6-(2-phenylmethoxy)-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylate
Stage A
cis 2-propenyl
5-hydroxy-1-[(trifluoroacetyl)-2-piperidinecarboxylate
[0960] 17 g (0.059 mole) of cis 1-(1,1-dimethylethyl) and
2-(2-propenyl)5-hydroxy-1,2-piperidinedicarboxylate (described in
Rec. Trav. Chim. (1959), 78, 648-658), of molecular formula
C.sub.14H.sub.23NO.sub.5 (M=285-3431 g) is dissolved in 17 ml ethyl
acetate.
[0961] A solution of 51 ml of hydrogen chloride in ethyl acetate at
150 g/l is added at 0.degree. C.
[0962] The reaction medium is left to return to ambient temperature
and left to react under agitation for 1 hour 30 minutes.
[0963] The ethyl acetate is evaporated under reduced pressure,
followed by taking up in ethyl ether, which is in turn eliminated
under reduced pressure.
[0964] In this way 12 g of a pale yellow solid is obtained which is
mixed with 200 ml of tetrahydrofuran. The reaction medium is cooled
down to 0.degree. C., then 37.6 ml of TEA is added.
[0965] The temperature is maintained at 0.degree. C., then 16.8 ml
of trifluoroacetic anhydride is added slowly.
[0966] The temperature is allowed to rise to 20.degree. C. and the
reaction medium is left to react for another 20 minutes under
agitation.
[0967] Then 20 ml of water is added.
[0968] The solution obtained is agitated for 1 hour at ambient
temperature and poured into 300 ml of water, followed by extracting
with ethyl acetate, washing with water, drying over sodium
sulphate, and the solvent is evaporated off under reduced
pressure.
[0969] 15.7 g of crude product is obtained which is purified by
chromatography on silica eluting with a dichloromethane/ethyl
acetate mixture 90/10.
[0970] In this way 12.3 g of expected compound, of molecular
formula C.sub.11H.sub.14F.sub.3NO.sub.4 (M=281.23 g), is obtained
in the form of a yellow oil. The corresponding yield is 73%.
Stage B
trans 2-propenyl
5-[(phenylmethoxy)amino]-1-(trifluoroacetyl)2-piperidinecarboxylate
[0971] 10.9 g (38.7 mmoles) of the compound obtained in Stage A and
150 ml of acetonitrile are mixed together.
[0972] The pale yellow solution obtained is cooled down to
-30.degree. C., then, 4.94 ml of 2,6-lutidine and 6.7 ml of
trifluoromethanesulphonic anhydride are added. Agitation is carried
out for 15 minutes, then, still at -30.degree. C., 9.57 g of
O-benzylhydroxylamine is added.
[0973] At end of the addition, the temperature is left to rise to
0.degree. C. and the reaction medium is left to react for 1 hour at
this temperature. Then 4.9 ml of 2,6-lutidine is added and the
reaction medium is left in contact for 3 days at 0.degree. C.,
followed by pouring into 500 ml of water, extracting with ethyl
acetate, washing successively with water, with an aqueous solution
of phosphate buffer at pH=7.0, with a saturated aqueous solution of
sodium chloride, then again with water.
[0974] After drying over sulphate sodium, the solvent is evaporated
off under reduced pressure.
[0975] In this way 23 g of crude product is obtained which is
dissolved in 150 ml of dichloromethane, followed by washing with a
10% aqueous solution of tartaric acid, drying over sodium sulphate
and the solvent is evaporated off under reduced pressure.
[0976] In this way 16.1 g of a yellow oil is recovered which is
purified by chromatography on silica.
[0977] 12.1 g of expected compound, of molecular formula
C.sub.18H.sub.21F.sub.3N.sub.2O.sub.4 (M=386.37 g) is recovered in
crystallized form. The corresponding yield is 72%.
Stage C
trans 2-propenyl 5-[(phenylmethoxy)amino]-2-piperidine
carboxylate
[0978] 80 ml of methanol is cooled down to -10.degree. C., then
4.15 g (37.8 mmoles) of NaBH.sub.4 is added.
[0979] A solution of 10.6 g (27.4 mmoles) of the compound obtained
previously in 80 ml of methanol is added slowly, under agitation,
over 30 minutes, to this mixture whilst maintaining the temperature
at -10.degree. C.
[0980] Then the temperature is allowed to rise to 0.degree. C.,
then this temperature is maintained for 3 hours.
[0981] The reaction mixture is poured into 450 ml of ice and water
and 150 ml ethyl acetate, followed by decanting, washing with
water, drying the organic phase over sodium sulphate and then the
solvent is evaporated off under reduced pressure.
[0982] In this way 8.2 g of a yellow oil is obtained which is
dissolved in 80 ml of tetrahydrofuran, a solution of 2.43 g of
oxalic acid in 25 ml of THF is added. The oxalate which
crystallizes is filtered and washed with a little THF then dried
under reduced pressure and dissolved in a saturated solution of
sodium bicarbonate. Extraction is carried out with ethyl acetate,
followed by washing the organic phase with water, drying over
sodium sulphate and the solvent is evaporated off under reduced
pressure.
[0983] In this way 4.39 g of expected compound, of molecular
formula C.sub.16H.sub.22N.sub.2O.sub.3 (M=290.36 g), is obtained in
the form of an oil which crystallizes when the temperature is below
20.degree. C. The corresponding yield is 55%.
Stage D
trans 2-propenyl
7-oxo-6-(2-phenylmethoxy)-1,6-diaza-bicyclo[3.2.1]-octane-2-carboxylate
[0984] 3.2 g (11 mmoles) of the oil obtained previously is
dissolved under a nitrogen atmosphere in 500 ml of
acetonitrile.
[0985] The solution obtained is cooled down to 0.degree. C. using
an ice bath and 3.37 ml of TEA, then 0.796 ml of diphosgene, and
1.48 g of DMAP are added.
[0986] The temperature is allowed to rise to 20.degree. C. and the
reaction medium is left to react for 2 hours under agitation.
[0987] Then the reaction mixture is poured into 200 ml of a 0.1 N
aqueous solution of hydrochloric acid, 400 ml of water is added,
followed by extracting with dichloromethane, washing with water and
drying over sodium sulphate.
[0988] Then the solvent is evaporated off under reduced pressure so
as to obtain 3.1 g of expected compound, of molecular formula
C.sub.17H.sub.20N.sub.2O.sub.4 (M=316.36 g), in the form of
crystals. The corresponding yield is 89%.
[0989] 1H NMR
[0990] 1.66 (m) and 2.00 to 2.16 (m)
O.dbd.C--CH--CH.sub.2--CH.sub.2; 2.94 (d) and 3.07 (dt)
N--CH.sub.2; 3.31 (m) N--CH.sub.2--CH; 4.14 (dd) O.dbd.C--CH, 4.68
(dt) CH.sub.2--CH.dbd.CH.sub.2; 4.90 and 5.06 [AB]
CH.sub.2--C.sub.6H.sub.5; 5.26 (dq) and 5.34 (dq)
CH.sub.2--CH.dbd.CH.sub.2; 5.92 (m) CH.sub.2--CH.dbd.CH.sub.2; 7.37
to 7.42 (m) C.sub.6H.sub.5.
[0991] IR (CHCl.sub.3): 1748; 1646; 1496 cm.sup.-1.
[0992] MS (positive electrospray) m/z: [2M+Na].sup.+=655,
[M+Na+CH.sub.3CN].sup.+=380, [M+Na].sup.+=339, [M+H].sup.+=317,
289, 91.
Example 32b
trans-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylic
acid and its cyclohexylamine salt
[0993] 2.21 g (6.98 mmoles) of the compound obtained in Example 32a
is dissolved under a nitrogen atmosphere in 44 ml of
dichloromethane.
[0994] A 0.5M solution of sodium ethyl-hexanoate in ethyl acetate
is added.
[0995] Then 242 mg of tetrakistriphenylphosphine palladium is added
in one go, then the reaction medium is maintained under agitation
for 1 hour, followed by diluting with 22 ml ethyl acetate, pouring
into 75 ml of a saturated solution of NaH.sub.2PO.sub.4, extracting
with ethyl acetate and drying the organic phase over sodium
sulphate. The solvent is evaporated off under reduced pressure in
order to obtain 3.5 g of a yellow residue which is dissolved in a
mixture of 11 ml of ethyl acetate and 0.8 ml of
cyclohexylamine.
[0996] The crystallized cyclohexylamine salt is separated by
filtration and washed with ethyl ether, then the solvent is
evaporated off under reduced pressure. In this way a total 2.51 g
of crystallized salt is obtained which is dissolved in 25 ml of a
saturated aqueous solution of NaH.sub.2PO.sub.4. After extraction
with ethyl acetate, the organic phases are combined and dried over
sodium sulphate, then the solvent is evaporated off under reduced
pressure.
[0997] In this way 1.82 g of expected compound of molecular formula
C.sub.14H.sub.16N.sub.2O.sub.4 (M=276.29 g), is recovered in
crystallized form. The corresponding yield is 94%.
[0998] 1H NMR
[0999] In CDCl3, at 300 MHz, chemical shifts of the peaks in ppm
and multiplicity:
[1000] 1.68 (m) and of 2.20 to 2.22 (m):
CH--CH.sub.2--CH.sub.2--CH; 2.89 (d) and 3.11 (ddd): N--CH.sub.2;
3.34 (dd) N--CH.sub.2--CH, 4.13 (bd): N--CH--C.dbd.O; 4.90 and 5.05
[AB]: CH.sub.2--O; 7.32 to 7.43: C.sub.6H.sub.5.
[1001] MS (SIMS) m/z: [M+Na].sup.+=299, [M+H].sup.+=277.91.
Example 33a
pyridinium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
Stage A
trans-7-oxo-6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
[1002] 1.1 g (4 mmole) of the compound obtained in Example 32b is
dissolved in 30 ml of dichloromethane.
[1003] 0.67 ml of TEA is added to this solution.
[1004] The solution is cooled down to 5.degree. C. and 0.57 ml of
isobutyl chloroformate is added quite quickly.
[1005] The reaction medium is maintained under agitation for 20
minutes at 5.degree. C., then 3 ml of concentrated ammonia is added
slowly, under vigorous agitation.
[1006] Agitation is maintained for one hour at ambient temperature,
the reaction medium is diluted with 30 ml of water, followed by
extracting with dichloromethane, washing with water, drying over
sodium sulphate and concentrating under reduced pressure.
[1007] In this way 1.1 g of expected product of molecular formula
C.sub.14H.sub.17N.sub.3O.sub.3 (M=275.31 g) is obtained. The yield
is quantitative.
Stage B
trans-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
[1008] 1.1 g of the compound obtained in Stage A, 30 ml of methanol
and 300 mg of 10% Pd/C are mixed together.
[1009] The reaction medium is placed under a hydrogen atmosphere
then the mixture is agitated vigorously for 45 minutes.
[1010] The catalyst is then filtered, followed by washing with
methanol then with a dichloromethane/methanol mixture.
[1011] The filtrate is evaporated under reduced pressure.
[1012] In this way 800 mg of expected product of molecular formula
C.sub.7H.sub.11N.sub.3O.sub.3 (M=185.18 g) is obtained in the form
of a colourless foam.
Stage C
Pyridinium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
[1013] 800 mg of the compound obtained previously and 20 ml of
anhydrous pyridine are mixed together under a nitrogen
atmosphere.
[1014] Then 1.91 g of SO.sub.3-pyridine complex is added.
[1015] The mixture is agitated for 20 hours at ambient
temperature.
[1016] The reaction medium is then filtered and the solvent
evaporated off under reduced pressure.
[1017] In this way the expected product of molecular formula
C.sub.12H.sub.16N.sub.4O.sub.6S, C.sub.5H.sub.5N (M=344.35 g) is
obtained in the form of a yellow product.
Example 33b
Tetrabutylammonium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
[1018] The product obtained previously is introduced into 40 ml of
a concentrated aqueous solution of NaH.sub.2PO.sub.4 so as to
obtain a pH of 4.
[1019] Extraction is carried out with ethyl acetate then 1.01 g of
tetrabutyl ammonium hydrogen sulphate is added to the aqueous
phase
[1020] Agitation is carried out for 10 minutes at ambient
temperature, followed by extracting with 4 times 300 ml ethyl
acetate, drying the organic-phase over sodium sulphate and
concentrating under reduced pressure.
[1021] In this way 1.530 g of a colourless foam is obtained which
is purified by chromatography on silica, eluting with an
acetone/dichloromethane/TEA solvent 50/48/2.
[1022] In this way 1.02 g of expected product of molecular formula
C.sub.23H.sub.46N.sub.4O.sub.6S (M=506.71 g), is recovered in the
form of a colourless foam. The corresponding overall yield is
50%.
Example 33c
Sodium salt of
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide
[1023] The product obtained in Example 33b is dissolved in 7 ml of
an acetone/water mixture 1/1 then deposited on a column of 180 g of
DOWEX 50WX8 resin in Na.sup.+ form and eluted with water. After
evaporation of the water under reduced pressure, the product
crystallizes.
[1024] In this way 542 mg of expected compound, of formula
C.sub.7H.sub.10N.sub.3NaO.sub.6S (M=287.23 g) is obtained. The
corresponding yield is 94%.
[1025] 1H NMR
[1026] In DMSO, at 300 MHz, chemical shifts of the peaks in ppm and
multiplicity:
[1027] 1.55 to 2.10 (3H): CH--CH.sub.2--CH.sub.2--CH; 2.91 (d) and
3.02 (bd): N--CH.sub.2; 3.38 (bs): N--CH.sub.2--CH; 3.68 (d):
N--CH--C.dbd.O; 7.23 and 7.44: NH.sub.2.
[1028] MS (negative electrospray) m/z: [M].sup.-=264
Examples 34 to 47
[1029] The following carboxamides were prepared following an
operating method similar to that which is used in Example 33
starting from 110 mg of the acid obtained in Example 32b.
[1030] The only difference is that in Stage 1, the reagent used,
i.e. the ammonia solution, is replaced by a solution of the
corresponding amine.
[1031] Thus, only the R1 group as defined for formula I varies.
Example 34
[1032] Starting from 49 .mu.l of benzylamine, 64 mg of the sodium
salt of
trans-7-oxo-N-(phenylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane--
2-carboxamide is obtained i.e. an overall yield of 38%.
[1033] MS (positive electrospray) m/z: [M+Na].sup.+=400,
[M+H].sup.+=378
Example 35
[1034] Starting from 43 .mu.l of 2-pyridinemethanamine, 37 mg the
sodium salt of
trans-7-oxo-N-(2-pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[-
3.2.1]octane-2-carboxamide is obtained i.e. an overall yield of
14%.
[1035] MS (positive electrospray) m/z: [M+H].sup.+=379
Example 36
[1036] Starting from 51.3 mg of 3-pyridineethanamine, 42 mg of the
sodium salt of
trans-7-oxo-N-[2-(3-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyc-
lo[3.2.1]octane-2-carboxamide is obtained i.e. an overall yield of
20%.
[1037] MS (positive electrospray) m/z: [M+H].sup.+=393
Example 37
[1038] Starting from of 51.3 mg of 4-pyridineethanamine, 40 mg of
the sodium salt of
trans-7-oxo-N-[2-(4-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1-
]octane-2-carboxamide is obtained i.e. a yield of 20%.
[1039] MS (positive electrospray) m/z: [M+Na].sup.+=415,
[M+H].sup.+=393
Example 38
[1040] Starting from 50.2 mg of 2-pyridineethanamine, 45 mg of the
sodium salt of
trans-7-oxo-N-[2-(2-pyridinyl)ethyl]-6-(sulphooxy)-1,6-diazabicyc-
lo[3.2.1]octane-2-carboxamide is obtained i.e. a yield of 23%.
[1041] MS (positive electrospray) m/z: [M+H].sup.+=393
Example 39
[1042] Starting from 58.3 mg of 3-amino-benzamide, 43 mg of the
sodium salt of
trans-N-[3-(aminocarbonyl)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabi-
cyclo[3.2.1]octane-2-carboxamide is obtained i.e. a yield of
22%.
[1043] MS (negative electrospray) m/z: [M].sup.-=383
Example 40
[1044] Starting from 58.3 mg of 4-dimethylamino-benzenamine, 65.3
mg of the sodium salt of
trans-N-[4-(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.-
2.1]octane-2-carboxamide is obtained i.e. a yield of 40%.
[1045] MS (negative electrospray) m/z: [M].sup.-=383
Example 41
[1046] Starting from 58.3 mg of 3-dimethylamino-benzenamine, 91 mg
of the sodium salt of
trans-N-[3-(dimethylamino)phenyl]-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.-
2.1]octane-2-carboxamide is obtained i.e. a yield of 54%.
[1047] MS (negative electrospray) m/z: [M].sup.-=383
Example 42
[1048] Starting from 43 .mu.l of 4-pyridinemethanamine, 24.6 mg of
the sodium salt of
trans-7-oxo-N-[(4-pyridinyl)methyl]-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]-
octane-2-carboxamide is obtained i.e. a yield of 15%.
[1049] MS (negative electrospray) m/z: [M].sup.-=355
Example 43
[1050] Starting from 44 .mu.l of 3-pyridinemethanamine, 44.7 mg of
the sodium salt of
trans-7-oxo-N-(3-pyridinylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oc-
tane-2-carboxamide is obtained i.e. a yield of 26%.
[1051] MS (negative electrospray) m/z: [M].sup.-=355
Example 44
[1052] Starting from 84 mg (+-)-alpha-amino-benzenepropanamide, 55
mg of the sodium salt of
trans-N-(1-amino-1-oxo-3-phenyl-2-propyl)-7-oxo-6-(sulphooxy)-1,6-diazabi-
cyclo[3.2.1]octane-2-carboxamide is obtained i.e. a yield of
27%.
[1053] MS (negative electrospray) m/z: [M].sup.-=411, 321
Example 45
[1054] Starting from 46 mg of hydrochloride of 2-amino-acetamide
and 61 .mu.l of TEA, 25 mg of the sodium salt of
trans-N-(2-amino-2-oxoethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]o-
ctane-2-carboxamide is obtained i.e. a yield of 13%.
[1055] MS (negative electrospray) m/z: [M].sup.-=321, 249
Example 46
[1056] Starting from 64 mg of (3-aminophenyl)-urea, 43 mg of the
sodium salt of
trans-N-[3-[(aminocarbonyl)amino]phenyl]-7-oxo-6-(sulphooxy)-1,6--
diazabicyclo[3.2.1]octane-2-carboxamide is obtained i.e. a yield of
24%.
[1057] MS (negative electrospray) m/z: [M].sup.-=398, 153, 111
Example 47
[1058] Starting from 63 mg of (+-)-alpha-amino-benzeneacetamide, 64
mg of the sodium salt of
trans-N-(2-amino-2-oxo-1-phenylethyl)-7-oxo-6-(sulphooxy)-1,6-diazabicycl-
o[3.2.1]octane-2-carboxamide is obtained i.e. a yield of 38%
[1059] MS (negative electrospray) m/z: [M].sup.-=397
Examples 48 to 51
[1060] The following compounds were prepared from 110 mg of the
compound obtained in Stage E of Example 32, which is esterified
each time with the appropriate alcohol in order to obtain the final
product.
[1061] Then, the operation is carried out in a similar manner to
that described in Stages B to E of Example 33.
Example 48
[1062] Starting from 31.5 mg of 2-hydroxy-acetamide, 54 mg of the
sodium salt of trans 2-amino-2-oxoethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate is
obtained i.e. a yield of 32%.
[1063] MS (negative electrospray) m/z: [M].sup.-=322
Example 49
[1064] Starting from 51.7 mg of 4-pyridineethanol, 20 mg of the
sodium salt of trans 2-(4-pyridinyl)ethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate is
obtained i.e. a yield of 8.5%.
[1065] MS (negative electrospray) m/z: [M].sup.-=370
Example 50
[1066] Starting from 47.3 mg of 2-pyridineethanol, 47 mg of the
sodium salt of trans 2-(2-pyridinyl)ethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate is
obtained i.e. a yield of 23.4%.
[1067] MS (negative electrospray) m/z: [M].sup.-=370
Example 51
[1068] Starting from 57.7 mg of 3-pyridineethanol, 50 mg of the
sodium salt of trans 2-(3-pyridinyl)ethyl
7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxylate is
obtained i.e. a yield of 26%.
[1069] MS (negative electrospray) m/z: [M].sup.-=370
Example 52
Sodium salt of
3-methoxy-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one
Stage A
[1070] 10 g (50 mmoles) of 1,1-dimethylethyl
3,5-dioxo-1-piperidinecarboxylate is dissolved in 10 ml of
methanol, then 6 g (54 mmoles) of O-allylhydroxylamineamine
hydrochloride is added.
[1071] The reaction medium is left under agitation for 3 hours,
then the solvent is evaporated off under reduced pressure.
[1072] The residue is taken up in water, followed by extracting
with dichloromethane, washing the organic phase with water, then
drying it over sodium sulphate.
[1073] After filtration and evaporation of the solvent under
reduced pressure, 10.6 g of 1,1-dimethylethyl
5-methoxy-3-[(2-propenyloxy)imino]-3,6-dihydro-1(2H)-pyridinecarboxylate
of molecular formula C.sub.14H.sub.22N.sub.2O.sub.4 (M=282.342 g)
is obtained. The corresponding yield is 75%.
Stage B
[1074] 10.6 g (37.6 mmoles) of the product obtained in Stage A and
212 ml of methanol are placed in a flask.
[1075] The solution is cooled down to -5.degree. C., 37.8 g sodium
cyanoborohydide, then 58.2 ml of boron fluoride etherate are added,
followed by diluting with dichloromethane, pouring onto a mixture
of water and 2N soda, extracting with dichloromethane, washing the
organic phase with water, drying over sodium sulphate, filtering
and the solvent is evaporated off under reduced pressure. The
product obtained is purified by chromatography on silica eluting
with an AcOEt/dichloromethane mixture 10/90.
[1076] In this way 5.5 g of 1,1-dimethylethyl
5-methoxy-3-[(2-propenyloxy)amino]-3,6-dihydro-1(2H)-pyridinecarboxylate
of molecular formula C.sub.14H.sub.24N.sub.2O.sub.2 (M=284.36 g) is
obtained. The corresponding yield is 51%.
Stage C
[1077] 5.5 g (19.3 mmoles) of the product obtained in Stage B, 27.5
ml of dichloromethane and 4.2 ml of anisole are introduced into a
flask.
[1078] Then 27.5 ml of trifluoroacetic acid is added.
[1079] The TFA and dichloromethane are eliminated under reduced
pressure.
[1080] The residue is taken up in water and extraction is carried
out 3 times with AcOEt. The aqueous phase is rendered basic by the
addition of ammonium hydroxide, then extracted with AcOEt.
[1081] The organic phases are washed with water, followed by drying
over sodium sulphate, filtering, then the solvent is evaporated off
under reduced pressure.
[1082] In this way 2.45 g of
5-methoxy-N-(2-propenyloxy)-1,2,3,6-tetrahydro-3-pyridinamine of
molecular formula C.sub.9H.sub.16N.sub.2O.sub.2 (M=184.24 g) is
obtained. The corresponding yield is 69%.
Stage D
[1083] 2.45 g (0.0133 mmole) of the product obtained in Stage C is
dissolved under an inert atmosphere in 826 ml of acetonitrile and
the solution is cooled down to 0.degree. C. 0.778 ml of diphosgene
is added.
[1084] The temperature is allowed to rise to ambient temperature,
then 5.56 ml of TEA is added.
[1085] Agitation is carried out overnight at ambient temperature,
then the solvent is evaporated off under reduced pressure.
[1086] The residue is taken up in water, followed by extracting
with AcOEt, washing the organic phase with water, drying over
sodium sulphate, filtering, then the solvent is evaporated off
under reduced pressure.
[1087] The residue is purified by chromatography on silica eluting
with an AcOEt/dichloromethane mixture 1/9.
[1088] In this way 1.13 g of
3-methoxy-6-(2-propenyloxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one
of molecular formula C.sub.10H.sub.14N.sub.2O.sub.3 (M=210.23 g) is
recovered.
[1089] The corresponding yield is 40.3%.
Stage E
[1090] In a flask placed under an inert atmosphere, 105 mg (0.5
mmole) of the product obtained in Stage D is dissolved in 1.1 ml of
dichloromethane, 57 .mu.l of acetic acid, then 317 mg of
Pd[P(C.sub.6H.sub.5).sub.3].sub.4 are added.
[1091] After reaction for 1 hour, 1.1 ml of pyridine, then 238 mg
of SO.sub.3-pyridine complex are added.
[1092] The reaction medium is left under agitation overnight, then
the solvent is evaporated off under reduced pressure.
[1093] The residue is taken up in water, followed by extracting
with dichloromethane, washing with water, drying the organic phase
over sodium sulphate, filtering and the solvent is evaporated off
under reduced pressure.
[1094] The residue is purified by chromatography on silica, eluting
with a trichloromethane/acetonitrile mixture 50/50.
[1095] In this way 148 mg of the 1-propenyltriphenylphosphonium
salt of
3-methoxy-6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one of
molecular formula C.sub.28H.sub.29N.sub.2O.sub.6PS is
recovered.
[1096] The corresponding yield is 53%.
Stage F
[1097] 148 mg of the product obtained in Stage E is dissolved in
water containing 10% THF.
[1098] The solution obtained is passed through a column of DOWEX
50WX8 resin in Na.sup.+ form, eluting with water containing 10%
THF.
[1099] The product collected is lyophilized in order to obtain 51
mg of the expected sodium salt, of molecular formula
C.sub.7H.sub.9N.sub.2O.sub.6SNa (M=272.21 g).
[1100] The corresponding yield is 70%.
[1101] 1H NMR
[1102] 3.04 (d) and 3.25 (dd): C.dbd.CH--CH--CH.sub.2--N, 3.41 (d)
and 3.71 (dd): N--CH.sub.2--C.dbd.CH; 3.47 (s): CH.sub.3--O; 4.20
(dd): C.dbd.CH--CH--CH.sub.2--N, 5.19 (bd):
C.dbd.CH--CH--CH.sub.2--N
[1103] MS (negative electrospray) m/z: [M].sup.-=249, [M
--CH.sub.3].sup.-=235
Example 53
Sodium salt of
6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one
Stage A
[1104] 1.03 g (5.2 mmoles) of 1,1-dimethylethyl
3,6-dihydro-3-oxo-1(2H)-pyridinecarboxylate of molecular formula
C.sub.10H.sub.15NO.sub.3 is dissolved in 15 ml of ethanol. 572 mg
(5.2 mmoles) of O-allylhydroxylamineamine, then 1.3 ml of pyridine
are added.
[1105] The reaction medium is left under agitation for 15 minutes,
then 100 ml of dichloromethane is added, followed by washing with a
10% aqueous solution of tartaric acid, drying the organic phase
over magnesium sulphate, filtering and the solvent is evaporated
off under reduced pressure.
[1106] In this way 1.36 g of 1,1-dimethylethyl
3,6-dihydro-3-[(2-propenyloxy)imino]-1(2H)-pyridinecarboxylate of
molecular formula C.sub.13H.sub.20N.sub.2O.sub.3 (M=252.32 g) is
obtained.
[1107] The corresponding yield is quantitative.
Stage B
[1108] The operation is carried out as indicated in Stage A of
Example 52 starting from 1.38 g of the product obtained in Stage A,
15.1 g of sodium cyanoborohydide and 8.3 ml of boron trifluoride
etherate.
[1109] In this way 0.99 g of a mixture of 2/3 of 1,1-dimethylethyl
3-[(2-propenyloxy)amino]-1-piperidinecarboxylate and 1/3 of
1,1-dimethylethyl
3,6-dihydro-3-[(2-propenyloxy)amino]-1(2H)-pyridine carboxylate of
molecular formula C.sub.13H.sub.22N.sub.2O.sub.3 (M=254.33 g) is
recovered after purification.
[1110] The corresponding yield is 71%.
Stage C
[1111] 1.07 g (4.26 mmoles) of a mixture obtained in Stage B is
dissolved in 2 ml of AcOEt. The reaction medium is cooled down to
0.degree. C., then 5.8 ml of a 7.3 M solution of hydrogen chloride
in AcOEt is added and the medium is left to react for 2 hours 30
minutes at 0.degree. C.
[1112] The solvent is evaporated off under reduced pressure,
followed by taking up in ether, filtering the precipitate and
drying under reduced pressure.
[1113] In this way 560 mg of
N-(2-propenyloxy)-1,2,3,6-tetrahydro-3-pyridinamine dihydrochloride
of molecular formula C.sub.8H.sub.16Cl.sub.2N.sub.2O (M=227.14 g)
is obtained.
[1114] The corresponding yield is 57%.
Stage D
[1115] 560 mg (2.46 mmoles) of the product obtained in Stage C is
dissolved in 6 ml of dichloromethane, then 2.5 ml of 2N soda is
added.
[1116] After decanting, the aqueous phase is extracted with
AcOEt.
[1117] The organic phases are combined, followed by drying over
magnesium sulphate and filtering, then the solvent is evaporated
off under reduced pressure.
[1118] In this way 278 mg of
N-(2-propenyloxy)-1,2,3,6-tetrahydro-3-pyridinamine of molecular
formula C.sub.8H.sub.14N.sub.2O (M=154.21 g) is obtained.
[1119] The corresponding yield is 73%.
Stage E
[1120] 270 mg (1.75 mmoles) of the product obtained in Stage D is
dissolved under an argon atmosphere in 45 ml of acetonitrile, 760
.mu.l of TEA and 105 .mu.l of diphosgene are added.
[1121] The reaction medium is left to react for 15 minutes at
0.degree. C., then left to return to ambient temperature and left
to react for another 2 hours.
[1122] Then 213 mg of DMAP is added and the medium is left to react
overnight.
[1123] AcOEt is added, followed by washing with a 10% aqueous
solution of tartaric acid and with water.
[1124] The organic phase is dried over magnesium sulphate, filtered
and the solvent is evaporated off under reduced pressure.
[1125] The crude product obtained is purified on silica, eluting
with a dichloromethane/acetone mixture 95/5 containing 0.1%
TEA.
[1126] In this way 36 mg of
6-(2-propenyloxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one of
molecular formula C.sub.9H.sub.12N.sub.2O.sub.2 (M=180.21 g) is
recovered.
[1127] The corresponding yield is 11%.
Stage F
[1128] The operation is carried out in a similar manner to that
described in Stage E of Example 52 starting from 51 mg (0.27 mmole)
of the product obtained in Stage E, 33 .mu.l of acetic acid, 165 mg
of Pd[P(C.sub.6H.sub.5).sub.3].sub.4 and 132 mg of
SO.sub.3-pyridine complex.
[1129] In this way 29.6 mg of the 1-propenyltriphenylphosphonium
salt of 6-(sulphooxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one is
recovered.
[1130] This salt is passed through a column of DOWEX 50WX8 resin in
Na.sup.+ form, followed by eluting with water containing 10%
THF.
[1131] The product collected is lyophilized in order to obtain 13
mg of the expected sodium salt, of molecular formula
C.sub.6H.sub.7N.sub.2O.sub.5SNa (M=242.19 g).
[1132] The corresponding yield is 20%.
[1133] MS (negative electrospray) m/z: [M].sup.-=219
Example 54
Sodium salt of 6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octan-7-one
[1134] The operation is carried out as indicated in Stage A of
Example 53 starting from 12 g (0.061 mole) of 1,1-dimethylethyl
3,6-dihydro-3-oxo-1(2H)-pyridinecarboxylate of molecular formula
C.sub.10H.sub.15NO.sub.3, 9.7 g of O-benzylhydroxylamine
hydrochloride and 15 ml of pyridine.
[1135] In this way 19.4 g of 1,1-dimethylethyl
3,6-dihydro-3-[(phenylmethoxy)imino]-1(2H)-pyridinecarboxylate of
molecular formula C.sub.17H.sub.22N.sub.2O.sub.3 (M=302.38 g) is
obtained.
[1136] The corresponding yield is quantitative.
Stage B
[1137] The operation is carried out as indicated in Stage B of
Example 53 starting from 14.9 g (0.0496 mole) of the product
obtained in Stage A, 12 g of sodium cyanoborohydide and 30 ml of
boron trifluoride etherate. In this way 8.2 g of a mixture of 2/3
of 1,1-dimethylethyl
3,6-dihydro-3-[(phenylmethoxy)amino]-1(2H)-pyridinecarboxylate and
1/3 of 1,1-dimethylethyl
3-[(phenylmethoxy)amino]-1-piperidinecarboxylate of molecular
formula C.sub.17H.sub.24N.sub.2O.sub.3 (M=304.39 g) is obtained
after purification.
[1138] The corresponding yield is 55%.
Stage C
[1139] The operation is carried out as indicated in Stage C of
Example 53 starting from 9.3 g (0.0306 mole) of a mixture obtained
in Stage B and 106 ml of a solution of hydrogen chloride in AcOEt
at 7 mol/l.
[1140] In this way 8.39 g of a mixture of 2/3 of
N-(phenylmethoxy)-1,2,3,6-tetrahydro-3-pyridinamine dihydrochloride
and 1/3 of N-(phenylmethoxy)-3-piperidinamine dihydrochloride of
molecular formula C.sub.12H.sub.18Cl.sub.2N.sub.2O (M=277.20 g) is
obtained.
[1141] The corresponding yield is 98%.
Stage D
[1142] The operation is carried out as indicated in Stage D of
Example 53 starting from 8.30 g (0.0299 mole) of the mixture
obtained in Stage C and 30 ml of 2N soda.
[1143] In this way 5.95 g of mixture of 2/3 of
N-(phenylmethoxy)-1,2,3,6-tetrahydro-3-pyridinamine and 1/3 of
N-(phenylmethoxy)-3-piperidinamine of molecular formula
C.sub.12H.sub.16N.sub.2O (M=204.27 g) is obtained.
[1144] The corresponding yield is 98%.
Stage E
[1145] The operation is carried out as indicated in Stage E of
Example 53 starting from 5.02 g (0.0246 mole) of a mixture obtained
in Stage D, 2.43 ml of diphosgene, 7.4 ml of TEA and 3 g of
DMAP.
[1146] In a flask equipped of a magnetic stirrer, 5.020 g (0.0246
mole) of the product obtained in Stage D and 1.2 ml of
1,2-dichloroethane are introduced at 0.degree. C. and under
argon.
[1147] 2.43 g of diphosgene is added.
[1148] In this way 2.4 g of
6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]oct-3-in-7-one of
molecular formula C.sub.13H.sub.14N.sub.2O.sub.2 (M=230.27 g) is
recovered after purification. The corresponding yield is 42%.
[1149] 512 mg of
6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octan-7-one of molecular
formula C.sub.13H.sub.16N.sub.2O.sub.2 (M=232.27 g) is also
recovered.
[1150] The corresponding yield is 9%.
Stage F
[1151] 0.128 g (0.551 mmole) of
6-(phenylmethoxy)-1,6-diazabicyclo[3.2.1]octan-7-one obtained in
Stage E is dissolved in 1 ml of methanol.
[1152] 0.035 g of Pd/C catalyst is added and the reaction medium is
placed under a hydrogen atmosphere at normal pressure. At the end
of the reaction, the reaction medium is filtered, rinsed with
methanol and the solvent is evaporated off under reduced
pressure.
[1153] In this way 76 mg of
6-hydroxy-1,6-diazabicyclo[3.2.1]octan-7-one of molecular formula
C.sub.6H.sub.10N.sub.2O.sub.2 (M=142.16 g) is obtained.
[1154] The corresponding yield is quantitative.
Stage G
[1155] In a flask placed under an inert atmosphere, 75 mg (0.528
mmole) of the product obtained in Stage F is introduced into 2 ml
of pyridine.
[1156] 235 mg of SO.sub.3-pyridine complex is added and the
reaction medium is left to react for 2 hours.
[1157] Then a few drops of water are added and the solvent is
evaporated off under reduced pressure.
[1158] In this way 361 mg of crude product is obtained which is
purified by chromatography on silica eluting with a
dichloromethane/ethanol mixture 6/4 containing 0.1% by weight of
TEA.
[1159] In this way 32 mg of the purified triethylammonium salt of
6-(sulphooxy)-1,6-diazabicyclo[3.2.1]octan-7-one, of molecular
formula C.sub.11H.sub.15N.sub.3O.sub.5S (M=301.32 g) is
recovered.
[1160] The corresponding yield is 17%.
Stage H
[1161] 31 mg of the product obtained in Stage G is dissolved in 0.5
ml of water containing 10% THF.
[1162] The solution obtained is passed through a column of DOWEX
50WX8 resin in Na.sup.+ form, eluting with water containing 10%
THF.
[1163] The product collected is lyophilized in order to obtain 20
mg of the expected sodium salt, of molecular formula
C.sub.9H.sub.9N.sub.2O.sub.5SNa (M=221 g).
[1164] The corresponding yield is 77%.
[1165] MS (negative electrospray) m/z: [M-H].sup.-=221
Pharmacological Study of the Products of the Invention
[1166] I/The compounds of formula (I) and their pharmaceutically
acceptable salts show marked inhibitory activities against the
.beta.-lactamases of various bacterial strains and these useful
therapeutic properties can be determined in vitro on isolated
.beta.-lactamases:
A. Preparation of the .beta.-Lactamases Tem-1 and P99
[1167] The .beta.-lactamases are isolated from bacterial strains
which are resistant to penicillins and cephalosporins (Tem1 and P99
are produced by E. coli 250HT21 and E. Cloacae 293HT6
respectively).
[1168] The bacteria are cultured at 37.degree. C. in heart-brain
culture at 37 g/l (DIFCO). They are harvested at the end of the
exponential phase, cooled down and centrifuged. The bacterial
pellets are taken up in sodium phosphate buffer 50 mM, pH 7.0 and
centrifuged again. The bacteria are taken up in two volumes of the
same buffer and lyzed using a French-Press maintained at 4.degree.
C. After centrifugation for 1 hour at 100,000 g, at 4.degree. C.,
the supernatants containing the soluble fraction of the bacterial
extracts are recovered and frozen at -80.degree. C.
B. Determination of the .beta.-Lactamases Activity
[1169] The method uses Nitrocefin (OXOID), cephalosporin chromogene
as substrate, of which the product hydrolyzed by the B-lactamases
is red and absorbs at 485 nm. Beta-lactamase activity is determined
kinetically by measurement of the absorbance variation at 485 nm
resulting from the hydrolysis of the substrate using a plate
spectrophotometer (Spectra Max More Molecular Devices). The
experiments are carried out at 37.degree. C. The quantity of enzyme
was normalized and the measurements are carried out at initial
speed.
C. Determination of Compound Inhibitory Activity on Lactamases
[1170] Two measurements were carried out, without preincubation and
with preincubation of the enzyme and inhibitor (5 nm), in order to
test the irreversibility of the reaction. The products are tested
at 6 or 8 concentrations in duplicate. The reaction mixture
contains 100 .mu.M of Nitrocefin and 50 mM sodium phosphate buffer
pH7.0.
D. Calculations of the IC50
[1171] The hydrolysis speeds are measured with and without
inhibitor. The concentration of inhibitor which inhibits by 50% the
hydrolysis reaction of Nitrocefin by the enzyme (CI50) is
determined. The data is processed using GraFit software (Erathycus
Software).
TABLE-US-00001 EXAMPLE n.sup.o IC.sub.50 nM/TEM1 IC.sub.50 nM/P99
1a 700 (>10 000) 2 462 -- 2a 6730 -- 3 590 9800 3a 4400 -- 3b
2010 -- 4 2710 -- 5 1010 -- 7 650 250 7a 55 17 8 1400 62 9 8500 630
10 0.26 1.50 14 6400 -- 19.sup.e 11 -- 19f 110 -- 19g 29 -- 22 5100
-- 25 28 600 26a 115 1850 26b 4900 26c 1100 7000 28b 9.5 12 28c 29
1100 28d 1.3 390 28.sup.e 52 -- 29b 460 4200 29c 450 -- 29d 9500
2000 29.sup.e 4200 6300 29f 5200 -- 30 3500 -- 31 5700 -- 33 17 330
34 27 32 35 53 56 36 23 110 37 29 160 38 35 77 39 31 50 40 51 96 41
14 120 42 25 70 43 31 76 44 59 100 45 12 60 46 26 70 47 18 43 48 15
120 49 8.2 98 50 18 150 52 11 4600 53 15 5900 54 3100 --
[1172] II/Inhibition of the .beta.-lactamases shown above
potentiates the antibiotic activity of .beta.-lactamine type
antibiotics, thus leading to a synergic effect, as the following
results also show, which express the minimal inhibitory
concentration in vitro (MIC in .mu.g/ml), vis-a-vis a certain
number of pathogenic microorganisms, of combinations of cefotaxime
and piperacillin with compounds of formula (I) at a concentration
of 5 mg/l.
[1173] The operation is carried out as follows, using the so-called
micro-dilution in liquid medium method.
[1174] A series of concentrations of the .beta.-lactamine is
prepared in the presence of a constant concentration (5 mg/l) of
the product to be studied, each is then seeded with various
bacterial strains.
[1175] After incubation for 24 hours in a heating chamber at
37.degree. C., the growth inhibition is evaluated by the absence of
any bacterial development, which allows the minimal inhibitory
concentrations (MIC) for each strain to be determined, expressed in
milligrams/l.
[1176] The following results were obtained:
TABLE-US-00002 Trial Cefo- Wt. Ex. N.sup.o Strain Phenotype taxime
Ex. 35 33 1 011GO66 S. aureus PeniR 1.2 1.2 2.5 2 250HT21 E. coli
Tem1 <=0.04 <=0.04 <=0.04 3 250HT22 E. coli Tem2 <=0.04
<=0.04 <=0.04 4 250CF1 E. coli Tem3 >40 0.15 <=0.04 5
250SJ1 E. coli Tem7 0.08 <=0.04 <=0.04 6 250HT26 E. coli SHV1
0.6 <=0.04 <=0.04 7 250BE1 E. coli SHV4 40 0.08 <=0.04 8
250HT23 E. coli Class D 0.08 <=0.04 <=0.04 9 293HT6 E.
cloacae Class C >40 0.6 <=0.04 10 301HT6 Serratia Serratia
0.3 <=0.04 0.08 11 391HT7 P. aeruginosa PSE 40 20 20 12 391HT8
P. aeruginosa PSE 40 20 20 Trial N.sup.o Ex. 34 Ex. 36 Ex. 37 Ex.
38 Ex. 39 Ex. 40 Ex. 41 1 1.2 1.2 1.2 1.2 2.5 2.5 2.5 2 <=0.04
<=0.04 <=0.04 <=0.04 <=0.04 <=0.04 <=0.04 3
<=0.04 <=0.04 <=0.04 <=0.04 <=0.04 <=0.04
<=0.04 4 0.15 0.3 0.3 0.3 0.08 0.6 2.5 5 <=0.04 <=0.04
0.08 <=0.04 <=0.04 0.15 0.6 6 <=0.04 <=0.04 <=0.04
<=0.04 <=0.04 <=0.04 <=0.04 7 0.08 0.3 0.6 0.3 0.08 1.2
>40 8 <=0.04 <=0.04 <=0.04 <=0.04 <=0.04
<=0.04 0.08 9 0.6 20 >40 20 1.2 >40 >40 10 <=0.04
0.08 0.08 0.08 <=0.04 0.08 0.08 11 20 40 20 40 20 >40 >40
12 20 40 20 40 20 >40 >40 Trial N.sup.o Ex. 42 Ex. 43 Ex. 44
Ex. 48 Ex. 49 1 2.5 2.5 2.5 2.5 2.5 2 <=0.04 <=0.04 <=0.04
<=0.04 <=0.04 3 <=0.04 <=0.04 0.15 <=0.04 <=0.04
4 <=0.04 0.08 0.3 <=0.04 0.08 5 <=0.04 <=0.04 0.08
<=0.04 <=0.04 6 <=0.04 <=0.04 0.08 <=0.04 <=0.04
7 <=0.04 <=0.04 0.6 0.08 <=0.04 8 <=0.04 <=0.04
<=0.04 <=0.04 <=0.04 9 0.3 0.08 >40 0.15 Nd 10
<=0.04 <=0.04 10 <=0.04 Nd 11 20 20 >40 40 Nd 12 20 20
>40 >40 nd Trial Wt. N.sup.o Strain Phenotype Piperacillin
Ex. 35 Ex. 33 Ex. 34 1 011GO66 peniR 10 1.2 1.2 0.6 2 250HT21 Tem1
>40 2.5 0.3 5 3 250HT22 Tem2 >40 20 0.6 >40 4 250CF1 Tem3
>40 10 1.2 >40 5 250SJ1 Tem7 >40 5 0.6 >40 6 250HT26
SHV1 >40 5 1.2 20 7 250BE1 SHV4 >40 20 1.2 >40 8 250HT23
Class D >40 10 2.5 40 9 293HT6 Class >40 5 0.6 10 10 301HT6
Serratia 5 1.2 0.6 1.2 11 391HT7 PSE >40 >40 >40 >40 12
391HT8 PSE >40 >40 10 >40 Trial N.sup.o Ex. 36 Ex. 37 Ex.
38 Ex. 39 Ex. 40 Ex. 41 Ex. 42 1 1.2 0.6 0.6 1.2 0.6 1.2 1.2 2 5
2.5 5 2.5 10 40 1.2 3 40 >40 >40 20 >40 >40 2.5 4 40 40
20 40 >40 >40 2.5 5 20 >40 >40 >40 >40 >40 2.5
6 20 20 40 40 >40 >40 5 7 >40 >40 >40 20 >40
>40 5 8 20 40 >40 10 20 40 5 9 20 40 40 20 >40 >40 1.2
10 1.2 2.5 1.2 0.6 1.2 1.2 0.6 11 >40 >40 >40 >40
>40 >40 >40 12 >40 >40 >40 >40 >40 >40
>40 Trial Ex. Ex. Ex. Ex. N.sup.o Ex. 43 Ex. 44 Ex. 45 Ex. 46 47
48 49 50 1 1.2 2.5 1.2 0.6 0.6 1.2 1.2 1.2 2 1.2 5 1.2 5 2.5 0.6
1.2 2.5 3 1.2 >40 2.5 >40 20 2.5 2.5 40 4 2.5 40 2.5 2.5 5
1.2 1.2 5 5 5 >40 2.5 >40 40 1.2 5 40 6 5 >40 2.5 >40
2.5 1.2 20 40 7 10 >40 5 40 5 2.5 20 40 8 2.5 40 10 10 10 5 10
40 9 2.5 >40 1.2 >40 >40 2.5 10 >40 10 0.6 >40 0.6
1.2 1.2 0.6 nd 0.6 11 >40 >40 >40 >40 >40 >40 nd
>40 12 >40 >40 >40 >40 >40 >40 nd >40
Example of a Pharmaceutical Composition:
[1177] 1/A pharmaceutical composition (lyophilisates) for injection
was prepared containing
TABLE-US-00003 on the one hand: compound of Example 35 500 mg on
the other hand: Cefotaxime 1 g Sterile aqueous excipient s.q.f. 5
cm.sup.3
[1178] The two active ingredients can, if desired, be introduced
separately into two distinct ampoules or flasks.
[1179] 2/A pharmaceutical composition (lyophilisates) for injection
was prepared containing
TABLE-US-00004 on the one hand: compound of Example 33 250 mg on
the other hand: Cefpirone 1 g Excipient sterile aqueous s.q.f. 5
cm.sup.3
[1180] The two active ingredients can, if desired, be introduced
separately into two distinct ampoules or flasks.
* * * * *