U.S. patent application number 12/211509 was filed with the patent office on 2009-01-15 for novel heterocyclic compounds, their preparation and their use as medicaments, in particular as antibacterials and beta-lactamase inhibitors.
This patent application is currently assigned to Novexel. Invention is credited to Michel Klich, Maxime Lampilas, Branislav Musicki, David Allen Rowlands.
Application Number | 20090018329 12/211509 |
Document ID | / |
Family ID | 32830321 |
Filed Date | 2009-01-15 |
United States Patent
Application |
20090018329 |
Kind Code |
A1 |
Lampilas; Maxime ; et
al. |
January 15, 2009 |
NOVEL HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND THEIR USE AS
MEDICAMENTS, IN PARTICULAR AS ANTIBACTERIALS AND BETA-LACTAMASE
INHIBITORS
Abstract
The invention relates to novel heterocyclic compounds of general
formula (I), and their salts with a base or an acid: ##STR00001##
The invention also relates to a method for preparing these
compounds, and to their use as medicaments, in particular as
antibacterials and .beta.-lactamase inhibitors.
Inventors: |
Lampilas; Maxime; (St.
Cloud, FR) ; Musicki; Branislav; (Paris, FR) ;
Klich; Michel; (Villemomble, FR) ; Rowlands; David
Allen; (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: |
32830321 |
Appl. No.: |
12/211509 |
Filed: |
September 16, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10727911 |
Dec 4, 2003 |
7439253 |
|
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12211509 |
|
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60484323 |
Jul 2, 2003 |
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Current U.S.
Class: |
540/568 |
Current CPC
Class: |
C07D 471/08 20130101;
A61P 31/00 20180101 |
Class at
Publication: |
540/568 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 6, 2002 |
FR |
02 15428 |
Claims
1. A compound of general formula (III) or one of its salts
comprising: ##STR00016## wherein R'.sub.1 selected from the group
consisting of H, CN, protected COOH, COOR.sub.9,
(CH.sub.2).sub.n'R'.sub.5, CONR.sub.6R.sub.7, and ##STR00017##
wherein R.sub.9 is selected from the group consisting of alkyl
containing from 1 to 6 carbon atoms, optionally substituted with
one or more halogen atoms or with a pyridyl; --CH.sub.2-alkenyl
containing in total from 3 to 9 carbon atoms; aryl containing from
6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon
atoms, the aryl or aralkyl being optionally substituted with a
substituent selected from the group consisting of NO.sub.2,
protected OH, protected NH.sub.2, alkyl containing from 1 to 6
carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or
more halogen atoms, n' is equal to 1 or 2, R'.sub.5 is selected
from the group consisting of protected OH, CN, protected NH.sub.2,
CO--NR.sub.6R.sub.7, protected COOH, COOR.sub.9, and OR.sub.9,
R.sub.9 being as defined above, R.sub.6 and R.sub.7 are
individually selected from the group consisting of hydrogen, an
alkyl radical containing from 1 to 6 carbon atoms, an alkoxy
radical containing from 1 to 6 carbon atoms, an aryl radical
containing from 6 to 10 carbon atoms, an aralkyl radical containing
from 7 to 11 carbon atoms and an alkyl radical containing from 1 to
6 carbon atoms which is substituted with a pyridyl radical;
R'.sub.2 is selected from the group consisting of hydrogen,
halogen, R.sub.9, S(O).sub.mR.sub.9, OR.sub.9, NHCOH, NHCOR.sub.9,
NHCOOR.sub.9 and NHSO.sub.2R.sub.9, R.sub.9 being as defined above
and m being 0, 1 or 2, R'.sub.4 represents a hydrogen atom or
(CH.sub.2).sub.n'.sub.1R'.sub.5, n'.sub.1 being 0, 1 or 2 and
R'.sub.5 being as defined above; wherein R.sub.3 and R'.sub.4 or
R'.sub.1 and R.sub.3 together with the carbon atoms to which they
are attached, form a phenyl or an aromatic heterocycle containing
from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur,
and substituted with one or more groups selected from the group
consisting of --(CH.sub.2).sub.b-phenyl and
--(CH.sub.2).sub.b-aromatic heterocycle, where b is an integer from
0 to 6 and each of said phenyl and heterocycle are optionally
substituted with one or more substituents selected from halogen,
alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1
to 6 carbon atoms and CF.sub.3; X.sub.1 is hydrogen and X.sub.2
is-Z-CO--X.sub.3 or X.sub.2 is -ZH and X.sub.1 is CO--X.sub.3,
where X.sub.3 represents the residue of the carbonylating agent, ZH
is selected from the group consisting of
HNR'.sub.8--(CH.sub.2).sub.n''--, where n'' is 0 or 1 and R'.sub.8
is selected from the group consisting of hydrogen, R.sub.9,
protected OH, OR.sub.9, Y'.sub.1, OY', Y'.sub.1, OY'.sub.1,
Y'.sub.2, OY'.sub.2, Y'.sub.3,
O--CH.sub.2--CH.sub.2--S(O).sub.m--R'', SiRaRbRc and OSiRaRbRc,
each of Ra, Rb and Rc individually being a linear or branched alkyl
containing from 1 to 6 carbon atoms or an aryl containing from 6 to
10 carbon atoms, R.sub.9 and m being as defined above, Y' is
selected from the group consisting of COH, COR.sub.9, COOR.sub.9,
CONH.sub.2, CONHR.sub.9, CONHSO.sub.2R.sub.9, CH.sub.2COOR.sub.9,
protected CH.sub.2tetrazole, CH.sub.2SO.sub.2R.sub.9,
CH.sub.2PO(OR.sub.9).sub.2, protected CONHOH, protected
CH.sub.2COOH, protected CH.sub.2CONHOH, protected CH.sub.2SO.sub.3,
protected CH.sub.2PO(OR)(OH), protected CH.sub.2PO(R)(OH) and
protected CH.sub.2PO(OH).sub.2, Y'.sub.1 is selected from the group
consisting of SO.sub.2R.sub.9, SO.sub.2NHCOH, SO.sub.2NHCOR.sub.9,
SO.sub.2NHCOOR.sub.9, SO.sub.2NHCONH.sub.2, SO.sub.2NHCONHR.sub.9
and protected SO.sub.3H, Y'.sub.2 is selected from the group
consisting of PO(OR.sub.9).sub.2, protected PO(OH).sub.2, protected
PO(OH)(OR) and protected PO(OH)(R), Y'.sub.3 is selected from the
group consisting of protected tetrazole, tetrazole substituted with
R.sub.9, protected squarate, protected NHtetrazole, protected
NR.sub.9tetrazole, protected NH, NR.sub.9tetrazole substituted with
R.sub.9, NHSO.sub.2R.sub.9 and NSO.sub.2R.sub.9, R is selected from
the group consisting of an alkyl radical containing from 1 to 6
carbon atoms, optionally substituted with one or more halogen atoms
or with a pyridyl radical; a --CH.sub.2-alkenyl radical containing
in total from 3 to 9 carbon atoms; a (poly)alkoxyalkyl group
containing 1 to 4 oxygen atoms and 3 to 10 carbon atoms; an aryl
radical containing from 6 to 10 carbon atoms or an aralkyl radical
containing from 7 to 11 carbon atoms, the aryl or aralkyl radical
being optionally substituted with a radical selected from the group
consisting of OH, NH.sub.2, NO.sub.2, alkyl containing from 1 to 6
carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or
more halogen atoms; R'' being selected from alkyl radicals
containing from 1 to 6 carbon atoms substituted with one or more
radicals selected from hydroxy, protected hydroxy, oxo, halogen and
cyano radicals; and n is 1.
2. A compound of claim 1 wherein said salt is a hydrochloride or
trifluoroacetate.
3. A compound of claim 1 having said general formula (III) or one
of its salts with an acid: ##STR00018## wherein R'.sub.1 is
CONR.sub.6R.sub.7 in which R.sub.6 or R.sub.7 is an alkoxy radical
containing from 1 to 6 carbon atoms and R'.sub.2, R.sub.3,
R'.sub.4, X.sub.1, X.sub.2, n, and all other values are as defined
in claim 1.
4. A compound of claim 3 wherein said salt is a hydrochloride or
trifluoroacetate.
5. A compound of general formula (II) or one of its salts with an
acid comprising: ##STR00019## wherein R'.sub.1 selected from the
group consisting of H, CN, protected COOH, COOR.sub.9,
(CH.sub.2).sub.n'R'.sub.5, CONR.sub.6R.sub.7, and ##STR00020##
wherein R.sub.9 is selected from the group consisting of alkyl
containing from 1 to 6 carbon atoms, optionally substituted with
one or more halogen atoms or with a pyridyl; --CH.sub.2-alkenyl
containing in total from 3 to 9 carbon atoms; aryl containing from
6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon
atoms, the aryl or aralkyl being optionally substituted with a
substituent selected from the group consisting of NO.sub.2,
protected OH, protected NH.sub.2, alkyl containing from 1 to 6
carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or
more halogen atoms, n' is equal to 1 or 2, R'.sub.5 is selected
from the group consisting of protected OH, CN, protected NH.sub.2,
CO--NR.sub.6R.sub.7, protected COOH, COOR.sub.9, and OR.sub.9,
R.sub.9 being as defined above, R.sub.6 and R.sub.7 are
individually selected from the group consisting of hydrogen, an
alkyl radical containing from 1 to 6 carbon atoms, an alkoxy
radical containing from 1 to 6 carbon atoms, an aryl radical
containing from 6 to 10 carbon atoms, an aralkyl radical containing
from 7 to 11 carbon atoms and an alkyl radical containing from 1 to
6 carbon atoms which is substituted with a pyridyl radical;
R'.sub.2 is selected from the group consisting of hydrogen,
halogen, R.sub.9, S(O).sub.mR.sub.9, OR.sub.9, NHCOH, NHCOR.sub.9,
NHCOOR.sub.9 and NHSO.sub.2R.sub.9, R.sub.9 being as defined above
and m being 0, 1 or 2, R'.sub.4 represents a hydrogen atom or
(CH.sub.2).sub.n'.sub.1R'.sub.5, n'.sub.1 being 0, 1 or 2 and
R'.sub.5 being as defined above; wherein R.sub.3 and R'.sub.4 or
R'.sub.1 and R.sub.3 together with the carbon atoms to which they
are attached, form a phenyl or an aromatic heterocycle containing
from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur,
and substituted with one or more groups selected from the group
consisting of --(CH.sub.2).sub.b-phenyl and
--(CH.sub.2).sub.b-aromatic heterocycle, where b is an integer from
0 to 6 and each of said phenyl and heterocycle are optionally
substituted with one or more substituents selected from halogen,
alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1
to 6 carbon atoms and CF.sub.3; ZH is selected from the group
consisting of HNR'.sub.8--(CH.sub.2).sub.n''--, where n'' is 0 or 1
and R'.sub.8 is selected from the group consisting of hydrogen,
R.sub.9, protected OH, OR.sub.9, Y', OY', Y'.sub.1, OY'.sub.1,
Y'.sub.2, OY'.sub.2, Y'.sub.3,
O--CH.sub.2--CH.sub.2--S(O).sub.m--R'', SiRaRbRc and OSiRaRbRc,
each of Ra, Rb and Rc individually being a linear or branched alkyl
containing from 1 to 6 carbon atoms or an aryl containing from 6 to
10 carbon atoms, R.sub.9 and m being as defined above, Y' is
selected from the group consisting of COH, COR.sub.9, COOR.sub.9,
CONH.sub.2, CONHR.sub.9, CONHSO.sub.2R.sub.9, CH.sub.2COOR.sub.9,
protected CH.sub.2tetrazole, CH.sub.2SO.sub.2R.sub.9,
CH.sub.2PO(OR.sub.9).sub.2, protected CONHOH, protected
CH.sub.2COOH, protected CH.sub.2CONHOH, protected CH.sub.2SO.sub.3,
protected CH.sub.2PO(OR)(OH), protected CH.sub.2PO(R)(OH) and
protected CH.sub.2PO(OH).sub.2, Y'.sub.1 is selected from the group
consisting of SO.sub.2R.sub.9, SO.sub.2NHCOH, SO.sub.2NHCOR.sub.9,
SO.sub.2NHCOOR.sub.9, SO.sub.2NHCONH.sub.2, SO.sub.2NHCONHR.sub.9
and protected SO.sub.3H, Y'.sub.2 is selected from the group
consisting of PO(OR.sub.9).sub.2, protected PO(OH).sub.2, protected
PO(OH)(OR) and protected PO(OH)(R), Y'.sub.3 is selected from the
group consisting of protected tetrazole, tetrazole substituted with
R.sub.9, protected squarate, protected NHtetrazole, protected
NR.sub.9tetrazole, protected NH, NR.sub.9tetrazole substituted with
R.sub.9, NHSO.sub.2R.sub.9 and NSO.sub.2R.sub.9, R is selected from
the group consisting of an alkyl radical containing from 1 to 6
carbon atoms, optionally substituted with one or more halogen atoms
or with a pyridyl radical; a --CH.sub.2-alkenyl radical containing
in total from 3 to 9 carbon atoms; a (poly)alkoxyalkyl group
containing 1 to 4 oxygen atoms and 3 to 10 carbon atoms; an aryl
radical containing from 6 to 10 carbon atoms or an aralkyl radical
containing from 7 to 11 carbon atoms, the aryl or aralkyl radical
being optionally substituted with a radical selected from the group
consisting of OH, NH.sub.2, NO.sub.2, alkyl containing from 1 to 6
carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or
more halogen atoms; R'' being selected from alkyl radicals
containing from 1 to 6 carbon atoms substituted with one or more
radicals selected from hydroxy, protected hydroxy, oxo, halogen and
cyano radicals; and n is 1.
6. A compound of claim 5 wherein said salt is a hydrochloride or
trifluoroacetate.
7. A compound of claim 5 wherein R'.sub.1 is CONR.sub.6R.sub.7 in
which R.sub.6 or R.sub.7 is an alkoxy radical containing from 1 to
6 carbon atoms, wherein all the other values are as defined in
claim 5.
8. A compound of claim 7 wherein said salt is a hydrochloride or
trifluoroacetate.
9. A compound selected from the compounds having general formulas
(IV), (V), or (VI) or one of their salts: ##STR00021## wherein
R'.sub.1 selected from the group consisting of H, CN, protected
COOH, COOR.sub.9, (CH.sub.2).sub.n'R'.sub.5, CONR.sub.6R.sub.7, and
##STR00022## wherein R9 is selected from the group consisting of
alkyl containing from 1 to 6 carbon atoms, optionally substituted
with one or more halogen atoms or with a pyridyl;
--CH.sub.2-alkenyl containing in total from 3 to 9 carbon atoms;
aryl containing from 6 to 10 carbon atoms or aralkyl containing
from 7 to 11 carbon atoms, the aryl or aralkyl being optionally
substituted with a substituent selected from the group consisting
of NO.sub.2, protected OH, protected NH.sub.2, alkyl containing
from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon
atoms and one or more halogen atoms, n' is equal to 1 or 2,
R'.sub.5 is selected from the group consisting of protected OH, CN,
protected NH.sub.2, CO--NR.sub.6R.sub.7, protected COOH,
COOR.sub.9, and OR.sub.9, R.sub.9 being as defined above, R.sub.6
and R.sub.7 are individually selected from the group consisting of
hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, an
alkoxy radical containing from 1 to 6 carbon atoms, an aryl radical
containing from 6 to 10 carbon atoms, an aralkyl radical containing
from 7 to 11 carbon atoms and an alkyl radical containing from 1 to
6 carbon atoms which is substituted with a pyridyl radical;
R'.sub.2 is selected from the group consisting of hydrogen,
halogen, R.sub.9, S(O).sub.mR.sub.9, OR.sub.9, NHCOH, NHCOR.sub.9,
NHCOOR.sub.9 and NHSO.sub.2R.sub.9, R.sub.9 being as defined above
and m being 0, 1 or 2, R'.sub.4 represents a hydrogen atom or
(CH.sub.2).sub.n'.sub.1R'.sub.5, n'.sub.1 being 0, 1 or 2 and
R'.sub.5 being as defined above; wherein R.sub.3 and R'.sub.4 or
R'.sub.1 and R.sub.3 together with the carbon atoms to which they
are attached, form a phenyl or an aromatic heterocycle containing
from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur,
and substituted with one or more groups selected from the group
consisting of --(CH.sub.2).sub.b-phenyl and
--(CH.sub.2).sub.b-aromatic heterocycle, where b is an integer from
0 to 6 and each of said phenyl and heterocycle are optionally
substituted with one or more substituents selected from halogen,
alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1
to 6 carbon atoms and CF.sub.3; A represents hydrogen or a group
protecting the nitrogen; R.sub.11 represents a leaving group; and n
is 1.
10. A compound of claim 9 wherein said salt is a hydrochloride or
trifluoroacetate.
11. A compound selected from the compounds having general formulas
(VII), (VIII) and (VIII') or one of its salts comprising:
##STR00023## wherein R'.sub.1 selected from the group consisting of
H, CN, protected COOH, COOR.sub.9, (CH.sub.2).sub.n'R'.sub.5,
CONR.sub.6R.sub.7, and ##STR00024## wherein R.sub.9 is selected
from the group consisting of alkyl containing from 1 to 6 carbon
atoms, optionally substituted with one or more halogen atoms or
with a pyridyl; --CH.sub.2-alkenyl containing in total from 3 to 9
carbon atoms; aryl containing from 6 to 10 carbon atoms or aralkyl
containing from 7 to 11 carbon atoms, the aryl or aralkyl being
optionally substituted with a substituent selected from the group
consisting of NO.sub.2, protected OH, protected NH.sub.2, alkyl
containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6
carbon atoms and one or more halogen atoms, n' is equal to 1 or 2,
R'.sub.5 is selected from the group consisting of protected OH, CN,
protected NH.sub.2, CO--NR.sub.6R.sub.7, protected COOH,
COOR.sub.9, and OR.sub.9, R.sub.9 being as defined above, R.sub.6
and R.sub.7 are individually selected from the group consisting of
hydrogen, an alkyl radical containing from 1 to 6 carbon atoms, an
alkoxy radical containing from 1 to 6 carbon atoms, an aryl radical
containing from 6 to 10 carbon atoms, an aralkyl radical containing
from 7 to 11 carbon atoms and an alkyl radical containing from 1 to
6 carbon atoms which is substituted with a pyridyl radical;
R'.sub.2 is selected from the group consisting of hydrogen,
halogen, R.sub.9, S(O).sub.mR.sub.9, OR.sub.9, NHCOH, NHCOR.sub.9,
NHCOOR.sub.9 and NHSO.sub.2R.sub.9, R.sub.9 being as defined above
and m being 0, 1 or 2, R'.sub.4 represents a hydrogen atom or
(CH.sub.2).sub.n'.sub.1R'.sub.5, n'.sub.1 being 0, 1 or 2 and
R'.sub.5 being as defined above; wherein R.sub.3 and R'.sub.4 or
R'.sub.1 and R.sub.3 together with the carbon atoms to which they
are attached, form a phenyl or an aromatic heterocycle containing
from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur,
and substituted with one or more groups selected from the group
consisting of --(CH.sub.2).sub.b-phenyl and
--(CH.sub.2).sub.b-aromatic heterocycle, where b is an integer from
0 to 6 and each of said phenyl and heterocycle are optionally
substituted with one or more substituents selected from halogen,
alkyl containing from 1 to 6 carbon atoms, alkoxy containing from 1
to 6 carbon atoms and CF.sub.3; R'.sub.8 is selected from the group
consisting of hydrogen, R.sub.9, protected OH, OR.sub.9, Y'.sub.1,
OY'.sub.1, Y'.sub.1, OY'.sub.1, Y'.sub.2, OY'.sub.2, Y'.sub.3,
O--CH.sub.2--CH.sub.2--S(O).sub.m--R'', SiRaRbRc and OSiRaRbRc,
each of Ra, Rb and Rc individually being a linear or branched alkyl
containing from 1 to 6 carbon atoms or an aryl containing from 6 to
10 carbon atoms, R.sub.9 and m being as defined above; Y' is
selected from the group consisting of COH, COR.sub.9, COOR.sub.9,
CONH.sub.2, CONHR.sub.9, CONHSO.sub.2R.sub.9, CH.sub.2COOR.sub.9,
protected CH.sub.2tetrazole, CH.sub.2SO.sub.2R.sub.9,
CH.sub.2PO(OR.sub.9).sub.2, protected CONHOH, protected
CH.sub.2COOH, protected CH.sub.2CONHOH, protected CH.sub.2SO.sub.3,
protected CH.sub.2PO(OR)(OH), protected CH.sub.2PO(R)(OH) and
protected CH.sub.2PO(OH).sub.2, Y'.sub.1 is selected from the group
consisting of SO.sub.2R.sub.9, SO.sub.2NHCOH, SO.sub.2NHCOR.sub.9,
SO.sub.2NHCOOR.sub.9, SO.sub.2NHCONH.sub.2, SO.sub.2NHCONHR.sub.9
and protected SO.sub.3H, Y'.sub.2 is selected from the group
consisting of PO(OR.sub.9).sub.2, protected PO(OH).sub.2, protected
PO(OH)(OR) and protected PO(OH)(R), Y'.sub.3 is selected from the
group consisting of protected tetrazole, tetrazole substituted with
R.sub.9, protected squarate, protected NHtetrazole, protected
NR.sub.9tetrazole, protected NH, NR.sub.9tetrazole substituted with
R.sub.9, NHSO.sub.2R.sub.9 and NSO.sub.2R.sub.9, R is selected from
the group consisting of an alkyl radical containing from 1 to 6
carbon atoms, optionally substituted with one or more halogen atoms
or with a pyridyl radical; a --CH.sub.2-alkenyl radical containing
in total from 3 to 9 carbon atoms; a (poly)alkoxyalkyl group
containing 1 to 4 oxygen atoms and 3 to 10 carbon atoms; an aryl
radical containing from 6 to 10 carbon atoms or an aralkyl radical
containing from 7 to 11 carbon atoms, the aryl or aralkyl radical
being optionally substituted with a radical selected from the group
consisting of OH, NH.sub.2, NO.sub.2, alkyl containing from 1 to 6
carbon atoms, alkoxy containing from 1 to 6 carbon atoms and one or
more halogen atoms; R'' being selected from alkyl radicals
containing from 1 to 6 carbon atoms substituted with one or more
radicals selected from hydroxy, protected hydroxy, oxo, halogen and
cyano radicals; A represents hydrogen or a group protecting the
nitrogen; and n is 1.
12. A compound of claim 11 wherein said salt is a hydrochloride or
trifluoroacetate.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/727,911 filed on Dec. 4, 2003; which claims the benefit
of U.S. Provisional Application No. 60/484,323, filed on Jul. 2,
2003; as well as the benefit of French Patent Application No. 02
15428 filed on Dec. 6, 2002. The entire disclosures of each of the
above applications are incorporated herein by reference.
BACKGROUND
[0002] The invention relates to novel heterocyclic compounds, their
preparation and their use as medicaments, in particular as
antibacterials.
[0003] The preparation of a bicyclic derivative having the
empirical formula C.sub.10H.sub.18N.sub.2O is described in
particular in the journal J. Org. Chem., Vol. 37, No. 5, 1972,
pages 697 to 699.
[0004] The preparation of bicyclic derivatives having the empirical
formulae C.sub.6H.sub.9NO.sub.2 and C.sub.7H.sub.11NO.sub.2 is
described in particular in the journal J. Org. Chem., Vol. 45, No.
26, 1980, pages 5325-5326.
[0005] The preparation of bicyclic derivatives having the empirical
formulae C.sub.10H.sub.18N.sub.2O and C.sub.7H.sub.12N.sub.2O is
described in particular in the review Chemical Reviews, 1983, vol.
83, No. 5, pages 549 to 555.
[0006] The preparation of a compound having the empirical formula
C.sub.12H.sub.12N.sub.2O is described in particular in the journal
Angew. Chem. Int. Ed. 2000, 39, No. 3, pages 625 to 628.
[0007] No particular use of these compounds in the therapeutic
field was described in these documents.
[0008] Moreover, patent application WO 2002 10172-A describes
azabicyclic compounds used in the therapeutic, in particular
antibacterial, field.
SUMMARY
[0009] The subject of the invention is the compounds corresponding
to the following formula (I):
##STR00002##
[0010] In which: [0011] a) either R.sub.1 represents a hydrogen
atom, a radical COOH, COOR, CN, (CH.sub.2).sub.n'R.sub.5,
CONR.sub.6R.sub.7 or
##STR00003##
[0012] R is chosen from the group consisting of an alkyl radical
containing from 1 to 6 carbon atoms, optionally substituted with
one or more halogen atoms or with a pyridyl radical, a
--CH.sub.2-alkenyl radical containing in total from 3 to 9 carbon
atoms, a (poly)alkoxyalkyl group containing 1 to 4 oxygen atoms and
3 to 10 carbon atoms, an aryl radical containing from 6 to 10
carbon atoms or an aralkyl radical containing from 7 to 11 carbon
atoms, the nucleus of the aryl or aralkyl radical being optionally
substituted with a radical OH, NH.sub.2, NO.sub.2, alkyl containing
from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon
atoms or with one or more halogen atoms,
[0013] R.sub.5 is chosen from the group consisting of a COOH, CN,
OH, NH.sub.2, CO--NR.sub.6R.sub.7, COOR or OR radical, R being as
defined above,
[0014] R.sub.6 and R.sub.7 are individually chosen from the group
consisting of a hydrogen atom, an alkyl radical containing from 1
to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon
atoms, an aryl radical containing from 6 to 10 carbon atoms and an
aralkyl radical containing from 7 to 11 carbon atoms and an alkyl
radical containing from 1 to 6 carbon atoms which is substituted
with a pyridyl radical, n' is equal to 1 or 2,
[0015] R.sub.3 and R.sub.4 form together a phenyl or a 5- or
6-membered heterocycle with an aromatic character containing from 1
to 4 heteroatoms chosen from nitrogen, oxygen and sulfur, which is
substituted with one or more groups R', R' being chosen from the
group consisting of the radicals
--(O).sub.a--(CH.sub.2).sub.b--(O).sub.a--CONR.sub.6R.sub.7,
--(O).sub.a--(CH.sub.2).sub.b--OSO.sub.3H,
--(O).sub.a--(CH.sub.2).sub.b--SO.sub.3H, --(O).sub.a--SO.sub.2R,
--(O).sub.a--SO.sub.2--CHal.sub.3,
--(O).sub.a--(CH.sub.2).sub.b--NR.sub.6R.sub.7, --(O).sub.a--
(CH.sub.2).sub.b--NH--COOR, --(CH.sub.2).sub.b--COOH,
--(CH.sub.2).sub.b--COOR, --OR'', OH, --(CH.sub.2).sub.b-- phenyl
and --(CH.sub.2).sub.b-- 5- or 6-membered heterocycle with an
aromatic character containing from 1 to 4 heteroatoms chosen from
nitrogen, oxygen and sulfur, the phenyl and the heterocycle being
optionally substituted with one or more halogens, alkyl containing
from 1 to 6 carbon atoms, alkoxy containing from 1 to 6 carbon
atoms or CF.sub.3, R, R.sub.6 and R.sub.7 being as defined above,
R'' being chosen from the group consisting of alkyl radicals
containing from 1 to 6 carbon atoms substituted with one or more
hydroxy, protected hydroxy, oxo, halogen or cyano radicals, a being
equal to 0 or 1 and b being an integer from 0 to 6, it being
understood that, when R' is OH, R.sub.1 represents the radical
CONR.sub.6R.sub.7 in which R.sub.6 or R.sub.7 is an alkoxy
containing from 1 to 6 carbon atoms, [0016] b) or R.sub.4
represents a hydrogen atom or a group (CH.sub.2).sub.n'1R.sub.5,
n'.sub.1 being equal to 0, 1 or 2 and R.sub.5 being as defined
above,
[0017] and R.sub.1 and R.sub.3 form together a substituted phenyl
or heterocycle, as defined above,
[0018] in both cases a) and b)
[0019] R.sub.2 is chosen from the group consisting of a hydrogen
atom, a halogen atom and the radicals R, S(O).sub.mR, OR, NHCOR,
NHCOOR and NHSO.sub.2R, R being as defined above and m being equal
to 0, 1 or 2,
[0020] X represents a divalent group --C(O)--B-- linked to the
nitrogen atom by the carbon atom,
[0021] B represents a divalent group --O--(CH.sub.2).sub.n''--
linked to the carbonyl by the oxygen atom, a group
--NR.sub.8--(CH.sub.2).sub.n''-- or --NR.sub.8--O-linked to the
carbonyl by the nitrogen atom, n'' is equal to 0 or 1 and R.sub.8
is chosen from the group consisting of a hydrogen atom, a radical
OH, R, OR, Y, OY, Y.sub.1, OY.sub.1, Y.sub.2, OY.sub.2, Y.sub.3,
O--CH.sub.2--CH.sub.2--S(O)m-R, SiRaRbRc and OSiRaRbRc, Ra, Rb and
Rc individually representing a linear or branched alkyl radical
containing from 1 to 6 carbon atoms or an aryl radical containing
from 6 to 10 carbon atoms, and R and m being as defined above,
[0022] Y is chosen from the group consisting of the radicals COH,
COR, COOR, CONH.sub.2, CONHR, CONHOH, CONHSO.sub.2R, CH.sub.2COOH,
CH.sub.2COOR, CHF--COOH, CHF--COOR, CF.sub.2--COOH, CF.sub.2--COOR,
CN, CH.sub.2CN, 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,
[0023] Y.sub.1 is chosen from the group consisting of the radicals
SO.sub.2R, SO.sub.2NHCOH, SO.sub.2NHCOR, SO.sub.2NHCOOR,
SO.sub.2NHCONHR, SO.sub.2NHCONH.sub.2 and SO.sub.3H,
[0024] Y.sub.2 is chosen from the group consisting of the radicals
PO(OH).sub.2, PO(OR).sub.2, PO(OH)(OR) and PO(OH)(R),
[0025] Y.sub.3 is chosen from the group consisting of the radicals
tetrazole, tetrazole substituted with the radical R, squarate, NH
or NR tetrazole, NH or NR tetrazole substituted with the radical R,
NHSO.sub.2R and NRSO.sub.2R, CH.sub.2 tetrazole and CH.sub.2
tetrazole substituted with the radical R, R being as defined above,
n is equal to 1 or 2.
[0026] The subject of the invention is also the salts of these
compounds which may be obtained with inorganic or organic bases or
acids.
DETAILED DESCRIPTION
[0027] It is clear that the compounds according to the invention
are structurally distinguishable from the prior art compounds
mentioned above.
[0028] The asymmetric carbon atoms contained in the compounds of
formula (I) may independently of each other present the R, S or RS
configuration and the subject of the invention is therefore also
the compounds of formula (I) which exist in the form of pure
enantiomers or pure diastereoisomers or in the form of a mixture of
enantiomers, in particular racemates, or of mixtures of
diastereoisomers.
[0029] It is apparent from the preceding text that the substituents
R.sub.1, R.sub.2 or R.sub.4 taken individually on the one hand and
X on the other hand may be at the cis and/or trans position in
relation to the ring to which they are attached and that the
subject of the invention is therefore the compounds of formula (I)
which exist in the form of cis isomers or of trans isomers or of
mixtures.
[0030] Moreover, it is understood that the invention does not
extend to compounds of formula (I) in which R' represents a group
--(O).sub.a--(CH.sub.2).sub.b--OSO.sub.3H or
--(O).sub.a--(CH.sub.2).sub.b--(O).sub.a--CONR.sub.6R.sub.7 in
which a is equal to 1 and b is equal to 0.
[0031] The expression alkyl radical containing from 1 to 6 carbon
atoms is understood to mean the methyl, ethyl, propyl or isopropyl
radical, and the butyl, pentyl or hexyl radical, which may be
linear or branched.
[0032] The expression --CH.sub.2-alkenyl radical containing from 3
to 9 carbon atoms is understood to mean for example the allyl
radical, or a butenyl, pentenyl or hexenyl radical.
[0033] The expression aryl radical containing from 6 to 10 carbon
atoms is understood to mean a phenyl or naphthyl radical.
[0034] The expression aralkyl radical containing from 7 to 11
carbon atoms is understood to mean a benzyl, phenethyl or
methylnaphthyl radical.
[0035] The expression alkoxy radical containing from 1 to 6 carbon
atoms is understood to mean in particular the methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy
radical.
[0036] The expression protected hydroxy radicals is understood to
mean radicals protected with any groups known to persons skilled in
the art, but more particularly, for dihydroxy compounds, with
groups of the 1,3-dioxolanyl type.
[0037] The expression halo radical or halogen atom is understood to
mean fluorine, chlorine, bromine or iodine.
[0038] In the substitutions with one or more atoms or radicals
mentioned above, the term several may mean 2, 3, 4 or 5.
[0039] The expression squarate radical is understood to mean the
radical of formula:
##STR00004##
[0040] The expression heterocycle with an aromatic character is
understood to mean in particular those chosen from the list which
follows, the two bonds symbolizing the joining with the
nitrogen-containing ring (R.sub.3R.sub.4 or R.sub.1R.sub.3):
##STR00005##
With X.dbd.NH, NR', S, O
##STR00006##
[0041] R' being as defined above.
[0042] Among the acid salts of the products of formula (I), there
may be mentioned, inter alia, those formed with inorganic acids
such as hydrochloric, hydrobromic, hydriodic, sulfuric or
phosphoric acids, or with organic acids such as formic, acetic,
trifluoroacetic, propionic, benzoic, maleic, fumaric, succinic,
tartaric, citric, oxalic, glyoxylic or aspartic acids,
alkanesulfonic acids such as methane- and ethanesulfonic acids,
arylsulfonic acids such as benzene- and para-toluenesulfonic
acids.
[0043] Among the base salts of the products of formula (I), there
may be mentioned, inter alia, those formed with inorganic 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)aminomethane, ethanolamine, pyridine, picoline,
dicyclohexylamine, morpholine, benzylamine, procaine, lysine,
arginine, histidine, N-methylglucamine, or else phosphonium salts
such as alkylphosphonium, arylphosphoniums, alkylarylphosphonium,
alkenylarylphosphonium, or quaternary ammonium salts such as
tetra-n-butylammonium salt.
[0044] Among the compounds of formula (I), the subject of the
invention is in particular those in which n is equal to 1 and those
in which R.sub.2 is a hydrogen atom.
[0045] Among these, those preferred are the compounds of formula
(I) in which R.sub.3 and R.sub.4 form together a substituted phenyl
or heterocycle as defined above. Among the latter, there may be
mentioned in particular the compounds of formula (I) in which
R.sub.3 and R.sub.4 form together a phenyl or a heterocycle chosen
from the group consisting of substituted thienyl and pyrazolyl.
[0046] Among the compounds of formula (I), the subject of the
invention is in particular those in which R.sub.1 is chosen from
the group consisting of the hydrogen atom and the groups
COOCH.sub.3, COOC.sub.2H.sub.5, CONH.sub.2, CONHCH.sub.3 and
CONHOCH.sub.3.
[0047] Among the compounds of formula (I), the subject of the
invention is furthermore in particular those in which X represents
a divalent group --CO--B-- in which B represents a group
--NR.sub.8--(CH.sub.2).sub.n''-- as defined above, in which n'' is
equal to 0.
[0048] Among the latter, there may be mentioned in particular those
in which R.sub.8 is a group OY in which Y is chosen from the groups
CH.sub.2COOH, CH.sub.2COOR, CHF--COOH, CHF--COOR, CF.sub.2--COOH,
CF.sub.2--COOR, CN, CH.sub.2CN, 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 or OY.sub.1, in which
Y.sub.1 is chosen from the groups SO.sub.2R, SO.sub.2NHCOR,
SO.sub.2NHCOOR, SO.sub.2NHCONHR and SO.sub.3H, R being as defined
above.
[0049] Among the compounds of formula (I), the subject of the
invention is furthermore in particular those in which R' is chosen
from the group consisting of --O--CH.sub.2--CHOH--CH.sub.2OH,
--CH.sub.2--CH.sub.2--NH.sub.2, --CH.sub.2--COOC.sub.2H.sub.5,
--CH.sub.2--CH.sub.2-phenyl, --CH.sub.2-phenyl, --O--CO--NHphenyl,
--O--CO--NHC.sub.2H.sub.5, --O--SO.sub.2--CF.sub.3,
--O--(CH.sub.2).sub.2--O--SO.sub.3H,
--O--(CH.sub.2).sub.2--O--CH.sub.3, --CH.sub.2--COOH,
--O--CH.sub.2-(2,2-dimethyl-1,3-dioxolan-4-yl), --CO--NH.sub.2,
--CO--NHphenyl, --CH.sub.2-(p-OCH.sub.3 phenyl) and phenyl
optionally substituted with CH.sub.3, C.sub.2H.sub.5, F and
CF.sub.3.
[0050] Among the compounds of formula (I), the subject of the
invention is most particularly the compounds whose names are as
follows:
[0051] the triethylammonium salt of
5,6-dihydro-6-oxo-N.sup.2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e-
][1,3]diazepine-2,8(8H)-dicarboxamide,
[0052] the sodium salt of
4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]di-
azepine-1-carboxamide,
[0053] the sodium salt of
1,4,5,8-tetrahydro-1-[(4-methoxyphenyl)methyl]-5-(sulfoxy)-6H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepin-6one,
[0054] the sodium salt of
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,
[0055] the sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-2-[2-(trifluoromethyl)phenyl]--
4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,
[0056] the sodium salt of
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,
[0057] the sodium salt of
trans-8-(2,3-dihydroxypropoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-m-
ethano-4H-2,4-benzodiazepine-5-carboxamide,
[0058] the sodium salt of ethyl
trans-3-(4-fluorophenyl)-4,6,7,8-tetrahydro-6-oxo-7-(sulfoxy)-5,8-methano-
-5H-thieno[2,3-e][1,3]diazepine-4-carboxylate,
[0059] the sodium salt of
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide,
[0060] the sodium salt of
1,4,5,8-tetrahydro-1-phenyl-5-(sulfoxy)-6H-4,7-methanopyrazolo[3,4-e][1,3-
]diazepin-6-one,
[0061] the sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5-(sulfoxy)-1H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide,
[0062] the triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-(phenylmethyl)-5-(sulfoxy)-4H-4,7-methan-
opyrazolo[3,4-e][1,3]diazepine-8-carboxylate,
[0063] the triethylammonium salt of methyl
trans-4,5,6,8-tetrahydro-6-oxo-1-(2-phenylethyl)-5-(sulfoxy)-1H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate,
[0064] the triethylammonium salt of ethyl
trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-1H-4,7-met-
hanopyrazolo[3,4-e][1,3]diazepine-1-acetate,
[0065] the triethylammonium salt of ethyl
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-4H-4,7-methanopyr-
azolo[3,4-e][1,3]diazepine-2(8H)-acetate,
[0066] the di(triethylammonium) salt of
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-sulfoxy-4H-4,7-methanopyraz-
olo[3,4-e][1,3]diazepine-2(8H)acetic acid,
[0067] the pyridinium salt of methyl
trans-1-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate,
[0068] the pyridinium salt of methyl
trans-2-(aminocarbonyl)-2,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4H-4,7-metha-
nopyrazolo[3,4-e]diazepine-8-carboxylate,
[0069] the sodium salt of methyl
trans-2-(4-fluorophenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate,
[0070] the sodium salt of methyl
trans-2(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-7-
H-thieno[2,3-e][1,3]diazepine-8-carboxylate,
[0071] the sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-9-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,
[0072] the sodium salt of
trans-1,2,3,5-tetrahydro-N-methoxy-8-[(2-methoxyethoxy)methoxy]-3-oxo-2-(-
sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide,
[0073] the sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-8-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,
[0074] the sodium salt of ethyl
trans-8-[[(ethylamino)carbonyl]oxy]-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)--
1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,
[0075] the sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[[trifluoromethyl)sulfonyl]o-
xy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,
[0076] the disodium salt of
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[2-(sulfoxy)ethoxy]-1,4-meth-
ano-4H-2,4-benzodiazepine-5-carboxamide,
[0077] the sodium salt of
trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-3-ox-
o-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide,
[0078] the triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-(2-phenylethyl)-5-(sulfoxy)-4H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepine-8-carboxylate.
[0079] Another subject of the invention is a method allowing the
preparation of the compounds of formula (I). This method is
characterized in that it comprises: a step during which a reaction
is brought about between a carbonylating agent, where appropriate
in the presence of a base, and a compound of formula (II):
##STR00007##
in which: [0080] a) either R'.sub.1 represents a hydrogen atom, a
radical CN, protected COOH, COOR.sub.9, (CH.sub.2).sub.n'R'.sub.5,
CONR.sub.6R.sub.7,
##STR00008##
[0081] R.sub.9 is chosen from the group consisting of an alkyl
radical containing from 1 to 6 carbon atoms, optionally substituted
with one or more halogen atoms or with a pyridyl radical, a
--CH.sub.2-alkenyl radical containing in total from 3 to 9 carbon
atoms, an aryl radical containing from 6 to 10 carbon atoms or an
aralkyl radical containing from 7 to 11 carbon atoms, the nucleus
of the aryl or aralkyl radical being optionally substituted with a
radical NO.sub.2, protected OH, protected NH.sub.2, alkyl
containing from 1 to 6 carbon atoms, alkoxy containing from 1 to 6
carbon atoms or with one or more halogen atoms,
[0082] R'.sub.5 is chosen from the group consisting of a radical
protected OH, CN, protected NH.sub.2, CO--NR.sub.6R.sub.7,
protected COOH, COOR.sub.9, OR.sub.9, R.sub.9 being as defined
above,
[0083] n', R.sub.6 and R.sub.7 are as defined above,
[0084] R.sub.3 and R'.sub.4 form together a phenyl or a 5- or
6-membered heterocycle with an aromatic character containing from 1
to 4 heteroatoms chosen from nitrogen, oxygen and sulfur, and
optionally substituted with one or more groups R.sub.10, R.sub.10
being chosen from the group consisting of a hydrogen atom and the
alkyl radicals containing from 1 to 6 carbon atoms substituted with
one or more hydroxy, oxo, halogen or cyano radicals, or with a
radical alkenyl containing from 2 to 6 carbon atoms, halo,
protected OH, --OR, OR'', R'' being as defined above,
--(CH.sub.2).sub.b-phenyl or --(CH.sub.2).sub.b-heterocycle with an
aromatic character, which is optionally substituted, as defined
above; [0085] b) or R'.sub.4 represents a hydrogen atom or a group
(CH.sub.2).sub.n'1R'.sub.5, n'.sub.1 being equal to 0, 1 or 2 and
R'.sub.5 being as defined above,
[0086] and R'.sub.1 and R.sub.3 form together an optionally
substituted phenyl or heterocycle as defined above for R.sub.3 and
R'.sub.4,
[0087] in both cases a) and b)
[0088] R'.sub.2 is chosen from the group consisting of a hydrogen
atom, a halogen atom and the radicals R.sub.9, S(O).sub.mR.sub.9,
OR.sub.9, NHCOH, NHCOR.sub.9, NHCOOR.sub.9 and NHSO.sub.2R.sub.9, m
and R.sub.9 being as defined above,
[0089] ZH represents a group HO--(CH.sub.2).sub.n'',
HNR'.sub.8--(CH.sub.2).sub.n-- or HNR'.sub.8--O, n'' is as defined
above and R'.sub.8 represents a hydrogen atom, a radical R.sub.9,
protected OH, OR.sub.9, Y', OY', Y'.sub.1, OY'.sub.1, Y'.sub.2,
OY'.sub.2, Y'.sub.3, O--CH.sub.2--CH.sub.2--S(O).sub.m--R'',
SiRaRbRc and OSiRaRbRc, Ra, Rb and Rc individually representing a
linear or branched alkyl radical containing from 1 to 6 carbon
atoms or an aryl radical containing from 6 to 10 carbon atoms and
R9 and m being as defined above,
[0090] Y' is chosen from the group consisting of the radicals COH,
COR.sub.9, COOR.sub.9, CONH.sub.2, CONHR.sub.9,
CONHSO.sub.2R.sub.9, CH.sub.2COOR.sub.9, protected
CH.sub.2tetrazole, CH.sub.2SO.sub.2R.sub.9,
CH.sub.2PO(OR.sub.9).sub.2, protected CONHOH, protected
CH.sub.2COOH, protected CH.sub.2CONHOH, protected CH.sub.2SO.sub.3,
protected CH.sub.2PO(OR)(OH), protected CH.sub.2PO(R)(OH) and
protected CH.sub.2PO(OH).sub.2,
[0091] Y'.sub.1 is chosen from the group consisting of the radicals
SO.sub.2R.sub.9, SO.sub.2NHCOH, SO.sub.2NHCOR.sub.9,
SO.sub.2NHCOOR.sub.9, SO.sub.2NHCONH.sub.2, SO.sub.2NHCONHR.sub.9
and protected SO.sub.3H, Y'.sub.2 is chosen from the group
consisting of the radicals PO(OR.sub.9).sub.2, protected
PO(OH).sub.2, protected PO(OH)(OR) and protected PO(OH)(R),
[0092] Y'.sub.3 is chosen from the group consisting of the radicals
protected tetrazole, tetrazole substituted with the radical
R.sub.9, protected squarate, protected NH tetrazole, protected
NR.sub.9 tetrazole, protected NH, NR.sub.9 tetrazole substituted
with the radical R.sub.9, NHSO.sub.2R.sub.9 and NSO.sub.2R.sub.9,
R.sub.9 being as defined above, and n is as defined above;
[0093] in order to obtain an intermediate compound of formula:
##STR00009##
in which: R'.sub.1, R'.sub.2, R.sub.3, R'.sub.4 and n have the same
meanings as above and either X.sub.1 is a hydrogen atom and X.sub.2
represents a group -Z-CO--X.sub.3, X.sub.3 representing the residue
of the carbonylating agent, or X.sub.2 is a group -ZH and X.sub.1
represents a group CO--X.sub.3, X.sub.3 being as defined above;
[0094] b) a step in which the intermediate obtained above is
cyclized, in the presence of a base; and in that:
[0095] c) where appropriate, step a) is preceded and/or step b) is
followed by one or more of the following reactions, in an
appropriate order:
[0096] protection of the reactive functional groups;
[0097] deprotection of the reactive functional groups;
[0098] esterification;
[0099] saponification;
[0100] sulfation;
[0101] phosphatization;
[0102] amidation;
[0103] acylation;
[0104] sulfonylation;
[0105] alkylation;
[0106] formation of a urea group;
[0107] reduction of carboxylic acids;
[0108] reduction of ketones and aldehydes to alcohols;
[0109] salification;
[0110] ion exchange;
[0111] resolution or separation of diastereoisomers;
[0112] oxidation of sulfide to sulfoxide and/or sulfone;
[0113] oxidation of aldehyde to acid;
[0114] oxidation of alcohol to ketone;
[0115] halogenation or dehalogenation;
[0116] carbamoylation;
[0117] carboxylation;
[0118] introduction of an azido group;
[0119] reduction of an azido to amine;
[0120] reactions of coupling of aromatic or heteroaromatic halides
or triflates or of heterocyclic nitrogens with aryl- or
heteroarylboronic acids;
[0121] reactions of coupling of aromatic or heteroaromatic halides
or triflates with stannyl-containing reagents;
[0122] hydrogenation of double bonds;
[0123] dihydroxylation of double bonds;
[0124] cyanidation.
[0125] As carbonylating agent, it is possible to use a reagent such
as phosgene, diphosgene, triphosgene, an aryl chloroformate such as
phenyl or p-nitrophenyl chloroformate, an aralkyl chloroformate
such as benzyl chloroformate, alkyl or alkenyl chloroformate such
as methyl or allyl chloroformate, an alkyl dicarbonate such as
tert-butyl dicarbonate, carbonyldiimidazole and mixtures
thereof.
[0126] The reaction preferably occurs in the presence of a base or
of a mixture of bases which neutralizes the acid formed. It may be
in particular an amine such as triethylamine,
diisopropylethylamine, pyridine, dimethylaminopyridine. However, it
is also possible to carry out the procedure using the starting
material of formula II as base. An excess thereof is used in this
case.
[0127] Where appropriate the product of formula II is used in the
form of an acid salt, for example a hydrochloride or a
trifluoroacetate.
[0128] As a base in step b), it is also possible to use amines, or
else hydrides, alcoholates, amides or carbonates of alkali or
alkaline-earth metals.
[0129] The amines may be chosen for example from the list
above.
[0130] As hydride, it is possible to use in particular sodium or
potassium hydride.
[0131] As alkali metal alcoholate, potassium t-butoxide is
preferably used.
[0132] As alkali metal amide, it is possible to use in particular
lithium bis(trimethylsilyl)amide.
[0133] As carbonate, it is possible to use in particular sodium or
potassium carbonate or bicarbonate.
[0134] Where appropriate, the intermediate of formula III may be
obtained in the form of an acid salt generated during the
carbonylation reaction, and in particular a hydrochloride. It is
then used in the cyclization reaction in this form.
[0135] Where appropriate, the cyclization may be performed without
isolating the intermediate of formula III.
[0136] The reactions mentioned in step c) are in general
conventional reactions which are well known to persons skilled in
the art.
[0137] The reactive functional groups which should, where
appropriate, be protected are carboxylic acid, amine, amide and
hydroxy functional groups.
[0138] The protection of the acid functional group is carried out
in particular in the form of alkyl esters, allyl, benzyl,
benzhydryl or p-nitrobenzyl esters.
[0139] The deprotection is carried out by saponification, acid
hydrolysis, hydrogenolysis, or else cleavage with the aid of
soluble complexes of Palladium 0.
[0140] The protection of the amines, of the heterocyclic nitrogens
and of the amides is carried out in particular, depending on the
case, in the form of benzyl-containing or trityl-containing
derivatives, in the form of carbamates, in particular of allyl,
benzyl, phenyl or tert-butyl, or else in the form of
silyl-containing derivatives such as tert-butyl dimethyl,
trimethyl, triphenyl or else diphenyl tert-butyl-silyl derivatives,
or phenylsulfonylalkyl or cyanoalkyl derivatives.
[0141] The deprotection is carried out, depending on the nature of
the protecting group, with sodium or lithium, in liquid ammonia, by
hydrogenolysis or with the aid of soluble complexes of Palladium 0,
by the action of an acid, or by the action of tetrabutylammonium
fluoride or of strong bases such as sodium hydride or potassium
t-butoxide.
[0142] The protection of the hydroxylamines is carried out in
particular in the form of benzyl or allyl ethers.
[0143] The cleavage of the ethers is carried out by hydrogenolysis
or with the aid of soluble complexes of Palladium 0.
[0144] The protection of alcohols and of the phenols is carried out
conventionally, in the form of ethers, esters or carbonates. The
ethers may be alkyl or alkoxyalkyl ethers, preferably methyl or
methoxyethoxymethyl ethers, aryl or preferably aralkyl, for example
benzyl, ethers, or silyl-containing ethers, for example the
silyl-containing derivatives mentioned above. The esters may be any
cleavable ester known to persons skilled in the art, preferably
acetate, propionate or benzoate or p-nitrobenzoate. The carbonates
may be for example methyl, tert-butyl, allyl, benzyl or
p-nitrobenzyl carbonates.
[0145] The deprotection is carried out by means known to persons
skilled in the art, in particular saponification, hydrogenolysis,
cleavage with soluble complexes of Palladium 0, hydrolysis in acid
medium or else, for the silyl-containing derivatives, treatment
with tetrabutylammonium fluoride.
[0146] Examples of protections and deprotections of the reactive
functional groups are provided in the experimental part.
[0147] The sulfation reaction is carried out by the action of
SO.sub.3-amine complexes such as SO.sub.3-pyridine or
SO.sub.3-dimethylformamide, the procedure being carried out in
pyridine, it being possible for the salt formed, for example the
pyridine salt, to then be exchanged for example with a salt of
another amine, a quaternary ammonium or an alkali metal. Examples
are provided in the experimental part.
[0148] The phosphatization reaction is carried out for example by
the action of chlorophosphate such as dimethyl, dibenzyl or
diphenyl chlorophosphate.
[0149] The amidation reaction is carried out starting with the
carboxylic acid, with the aid of an activating agent such as an
alkyl chloroformate, EDCI or BOP, by the action of aqueous ammonia
or an appropriate amine or alkoxyamine or their acid salts.
Examples are provided below in the experimental part.
[0150] The acylation and sulfonylation reactions are carried out in
alcohols, amines or heterocyclic nitrogens, by the action,
depending on the cases, of an appropriate carboxylic acid or
sulfonic acid halide or anhydride, where appropriate in the
presence of a base. Several examples are provided below in the
experimental part.
[0151] The alkylation reaction, which, in the context, is
understood in the broad sense and relates to the introduction of
variously substituted alkyl groups as defined above, in particular
the definition of R', is carried out by the action, on the
hydroxylated derivatives, the enolates of esters or ketones, the
amines or the heterocyclic nitrogens, depending on the cases, of an
alkyl sulfate or an alkyl or substituted alkyl halide.
Illustrations are provided below in the experimental part.
[0152] The reduction of acids to alcohols may be carried out by the
action of a borane or via an intermediate mixed anhydride, by the
action of an alkali metal borohydride. The mixed anhydride is
prepared for example with the aid of an alkyl chloroformate. The
reduction of a ketone or aldehyde to an alcohol is preferably
carried out by the action of sodium borohydride. Illustrations are
provided in the experimental part.
[0153] The dehydration of an amide to a nitrile may take place
under carbonylation and cyclization reaction conditions.
[0154] The oxidation of sulfides to sulfoxide and/or sulfone may be
carried out by the action of a peracid such as
meta-chloroperbenzoic or perphthalic acid or any other reagent
known to persons skilled in the art.
[0155] Salification with acids is, where appropriate, carried out
by addition of an acid, in a soluble phase, to the compound.
Salification with bases may involve compounds containing an acid
functional group and in particular compounds containing a carboxyl
functional group, those containing a sulfoxy functional group or a
functional group derived from phosphoric acid or those containing a
heterocycle with an acidic character.
[0156] In the case of a carboxyl functional group, the procedure is
carried out by adding an appropriate base such as those mentioned
above. In the case of a sulfoxy functional group or a functional
group derived from phosphoric acid, the pyridinium salt is directly
obtained during the action of the SO.sub.3-pyridine complex and the
other salts are obtained from this pyridinium salt. In either case,
it is also possible to carry out the procedure by ion exchange on a
resin. Examples of salifications with acids or with bases, and
including a heterocycle with an acidic character, are presented
below in the experimental part.
[0157] The oxidation of an aldehyde to an acid may be carried out
by the action of potassium permanganate or sodium chlorite.
[0158] The oxidation of an alcohol to a ketone may be carried out
by the action of pyridinium chlorochromate.
[0159] The expression halogenation is understood to mean the
introduction of a halogenated substituent from a hydroxy or direct
halogenation of an aromatic or heteroaromatic ring. Depending on
the case, the reaction may for example be carried out by the action
of iodine or in the presence of triphenylphosphine, by the action
of bromine in acetic acid or else of iodine in the presence of
C.sub.6H.sub.5I(OCOCF.sub.3).sub.2, or else by the reaction of an
electrophilic halogenated reagent such as N-fluorosulfonylimide in
the presence of a strong base. Such reagents are known to persons
skilled in the art and examples are presented below in the
experimental part.
[0160] The dehalogenation may be carried out by hydrogenolysis.
[0161] The carbamoylation reaction may be carried out by using a
chloroformate or diphosgene and then an amine or, where
appropriate, ammonia, or else using an appropriate isocyanate.
[0162] The carboxylation reaction may be carried out by the action
of an alkyllithium and then of carbon dioxide gas or of a
chloroformate.
[0163] The introduction of an azido group may be carried out for
example by the action of sodium azide on a mesylate or iodo type
intermediate.
[0164] The reduction of an azide group may be carried out by the
action of trialkyl- or triarylphosphine.
[0165] The reaction of couplings of aromatic halides with tin
derivatives is carried out by a so-called Stille method. An
illustration is given in the experimental part.
[0166] The hydrogenation of double bonds, which may be
carbon-carbon or carbon-nitrogen bonds, are carried out by methods
known to persons skilled in the art.
[0167] The dihydroxylation of a carbon-carbon double bond is
carried out in particular by the action of osmium tetroxide.
[0168] The cleavage of the diols is preferably carried out with
sodium periodate.
[0169] The introduction of a cyano is carried out by nucleophilic
substitution with the aid of an alkali metal cyanide.
[0170] Illustrations of these reactions are presented below in the
experimental part.
[0171] The separation of the enantiomers and diastereoisomers may
be carried out according to techniques known to persons skilled in
the art, in particular chromatography.
[0172] In addition to using the methods described above, compounds
of formula (I) may of course be obtained by methods which start
with a compound of formula (II) in which R'.sub.1, R'.sub.2,
R.sub.3, R'.sub.4 and ZH have the values which lead directly
(without conversion) to those of the compounds which it is desired
to prepare. Where appropriate, those of these values which might
contain reactive functional groups as mentioned above are then
protected, the deprotection taking place after the cyclization step
b or at any other appropriate time during the synthesis. The
protections and deprotections are then carried out as described
above.
[0173] Such methods are provided below in the experimental
part.
[0174] The subject of the invention is also a method according to
the preceding text, according to which the compound of formula (II)
in which ZH represents a group HO--(CH.sub.2).sub.n''-- or
HNR'.sub.8--(CH.sub.2).sub.n''-- in which n'' is equal to 0, or a
group HNR'.sub.8--O-- is obtained by a method characterized in that
a compound of formula (IV):
##STR00010##
in which R'.sub.1, R'.sub.2 and n are as defined above, R.sub.3 and
R'.sub.4 have the values defined above or else values which are
precursors of the values defined above and A represents a hydrogen
atom or a group protecting the nitrogen, is treated with a reducing
agent, in order to obtain a compound of formula (V):
##STR00011##
in which A, R'.sub.1, R'.sub.2, R.sub.3, R'.sub.4 and n retain
their above mentioned meaning, in which, where appropriate, the OH
group is replaced with a leaving group, in order to obtain a
compound of formula (VI):
##STR00012##
in which A, R'.sub.1, R.sub.3, R'.sub.4 and n retain their
abovementioned meaning and R.sub.11 represents a leaving group,
which is then treated with a compound of formula Z.sub.1H.sub.2 in
which Z.sub.1 represents a divalent group --NR'.sub.8-- or
--ONR'.sub.8--, R'.sub.8 retaining the above-mentioned meaning, in
order to obtain a compound of formula (VIII) or (VIII'):
##STR00013##
in which A, R'.sub.1, R'.sub.2, R.sub.3, R'.sub.4, n'' and R'.sub.8
are as defined above, and then, where appropriate, with an
appropriate agent for deprotecting the nitrogen atom, and in that,
where appropriate, the intermediate of formula (IV), (V), (VIII) or
(VIII') is subjected to one or more of the reactions described in
step c) of the method described above, in an appropriate order.
[0175] The subject of the invention is also a method according to
the preceding text, according to which the compound of formula (II)
in which ZH represents a group NHR'.sub.8--(CH.sub.2).sub.n''-- in
which n'' is equal to 0 is obtained by a method characterized in
that a compound of formula (IV) as defined above is treated with a
compound of formula H.sub.2NR'.sub.8, in order to obtain a compound
of formula (VII):
##STR00014##
in which A, R'.sub.1, R'.sub.2, n and R'.sub.8 are as defined above
and R.sub.3 and R.sub.4 have the values defined above or else
values which are precursors of the values defined above, which is
reacted with a reducing agent in order to obtain a compound of
formula (VIII):
##STR00015##
in which A, R'.sub.1, R'.sub.2, R.sub.3, R'.sub.4, n'' and R'.sub.8
are as defined above, which is treated, where appropriate, with an
appropriate agent for deprotecting the nitrogen atom, and in that,
where appropriate, the intermediate of formula (VII) or (VIII) is
subjected to one or more of the reactions described in step c) of
the method described above, in an appropriate order.
[0176] The compounds of formula (II) in which ZH represents a group
HO--(CH.sub.2).sub.n'' in which n'' is equal to 1 may be obtained
according to the methods described for example by S. Shiotani et
al. Chem. Pharm. Bull. 15(1)88-93 (1967) (compound "IV" p. 89) or
else by N. Itoh. Chem. Pharm. Bull 16 (3)-455-470 (1968) (compound
"XVIII" p. 461) using an appropriate starting compound. The
compounds of formula (II) in which ZH represents a group
NHR''.sub.8--(CH.sub.2).sub.n'' in which n'' is equal to 1 may be
obtained from the above compounds by a method which is identical to
that described above for the preparation of the compounds in which
n''=0.
[0177] The group protecting the nitrogen is in particular one of
those which are mentioned above.
[0178] The reducing agent is in particular an alkali metal
borohydride.
[0179] The leaving group is in particular a phosphate or a
sulfonate, for example a mesylate or a tosylate, obtained by the
action of a corresponding sulfonyl chloride in the presence of a
base, or a halogen, more particularly a chlorine, a bromine or an
iodine, obtained for example by the action of thionyl chloride or
of P(C.sub.6H.sub.5).sub.3CBr.sub.4 or PBr.sub.3 or, in the case of
an iodine atom, by the action of an alkali metal iodide on a
sulfonate.
[0180] The deprotecting agent is in particular one of those
mentioned above.
[0181] The reducing agent which is reacted on the compound of
formula (VII) is in particular a sodium cyano- or
acetoxyborohydride.
[0182] For practical reasons or for reasons linked to the nature of
the reactions involved, it may be necessary or desirable to carry
out on the intermediates of formula (IV), (V) or (VII) one or more
of the reactions described in step c) of the method defined above.
It is understood that these reactions are carried out under the
conditions which are defined above.
[0183] The products of general formula (I) possess a very good
antibiotic activity on Gram(+) bacteria such as staphylococci or
streptococci. Their efficacy on Gram(-) bacteria, in particular on
enterobacteria, is particularly notable.
[0184] These properties make said products and their
pharmaceutically acceptable acid and base salts suitable for use as
medicaments in the treatment of conditions caused by sensitive
microbes and in particular in that of staphylococcia, such as
staphylococcal septicemia, facial or cutaneous malignant
staphylococcia, pyoderma, septic or suppurant wounds, anthrax,
phlegmons, erysipelas, post-influenzal or acute primitive
staphylococcia, broncho-pneumonia, or pulmonary suppurations.
[0185] These products may also be used as medicaments in the
treatment of colibacillosis and related infections, proteus,
klebsiella and salmonella infections and in other conditions caused
by Gram(-) bacteria.
[0186] The compounds of general formula (I) are moreover endowed
with beta-lactamase inhibiting properties, and are therefore of
interest in controlling infectious diseases or in their prevention,
in the form of a combination with various .beta.-lactam type
antibiotic compounds, in order to enhance their efficacy in
controlling .beta.-lactamase producing pathogenic bacteria.
[0187] It is well known that the enzymatic inactivation of
.beta.-lactam type antibiotics, whether penicillin or cephalosporin
type compounds, in the treatment of bacterial infections is an
obstacle for this type of compounds. This inactivation consists in
a process of degradation of the .beta.-lactams and constitutes one
of the mechanisms for which bacteria can become resistant to
treatments. It is therefore desirable to be able to counter this
enzymatic process by combining with the .beta.-lactam type
antibacterial agent an agent capable of inhibiting the enzyme. When
a .beta.-lactamase inhibitor is used in combination with a
.beta.-lactam type antibiotic, it can therefore enhance its
efficacy against certain microorganisms.
[0188] The subject of the present invention is therefore also, as
medicaments and in particular as medicaments intended for the
treatment of bacterial infections in humans or animals, and as
medicaments intended for inhibiting the production of
.beta.-lactamases by pathogenic bacteria, the compounds of formula
(I) as defined above and their salts with pharmaceutically
acceptable acids and bases.
[0189] The subject of the invention is more particularly, as
medicaments, the products of formula (I) as described above in
which n is equal to 1 and those in which R.sub.2 is a hydrogen
atom.
[0190] The subject of the invention is most particularly, as
medicaments, the products of formula (I) in which R.sub.3 and
R.sub.4 form together a substituted phenyl or heterocycle as
defined above, and in particular a phenyl or a heterocycle chosen
from the group consisting of substituted thienyl and pyrazolyl.
[0191] Among the latter, there may be mentioned in particular those
in which R.sub.1 is chosen from the group consisting of the
hydrogen atom and the groups COOCH.sub.3, COOC.sub.2H.sub.5,
CONH.sub.2, CONHCH.sub.3 and CONHOCH.sub.3.
[0192] Among the compounds of formula (I), the subject of the
invention is in particular, as medicaments, the products of formula
(I) in which X represents a divalent group --CO--B in which B
represents a group --NR.sub.8--(CH.sub.2).sub.n'-- as defined
above, in which n'' is equal to 0.
[0193] Among the latter, there may be mentioned in particular those
in which R.sub.8 is a group OY in which Y is chosen from the groups
CH.sub.2COOH, CH.sub.2COOR, CHF--COOH, CHF--COOR, CF.sub.2--COOH,
CF.sub.2--COOR, CH.sub.2CONHOH, CH.sub.2CONHCN, CH.sub.2 tetrazole,
protected CH.sub.2 tetrazole, 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 or OY.sub.1, in which Y.sub.1 is chosen from
the groups SO.sub.2R, SO.sub.2NHCOR, SO.sub.2NHCOOR,
SO.sub.2NHCONHR and SO.sub.3H, R being as defined above, and those
in which R' is chosen from the group consisting of
--O--CH.sub.2--CHOH--CH.sub.2OH, --CH.sub.2--CH.sub.2NH.sub.2,
--CO--NH.sub.2, --CO--NHphenyl, --CH.sub.2-- (pOCH.sub.3-phenyl)
and phenyl optionally substituted with CH.sub.3, C.sub.2H.sub.5, F
and CF.sub.3.
[0194] Among the compounds of formula (I), the subject of the
invention is most particularly, as medicaments, the compounds whose
names are as follows:
[0195] the triethylammonium salt of
5,6-dihydro-6-oxo-N.sup.2-phenyl-5(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e]-
[1,3]diazepine-2,8(8H)-dicarboxamide,
[0196] the sodium salt of
4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]di-
azepine-1-carboxamide,
[0197] the sodium salt of
1,4,5,8-tetrahydro-1-[(4-methoxyphenyl)methyl]-5-(sulfoxy)-6H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepin-6-one,
[0198] the sodium salt of
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,
[0199] the sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-2-[2-(trifluoromethyl)phenyl]--
4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,
[0200] the sodium salt of
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxamide,
[0201] the sodium salt of
trans-8-(2,3-dihydroxypropoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-m-
ethano-4H-2,4-benzodiazepine-5-carboxamide,
[0202] the sodium salt of ethyl
trans-3-(4-fluorophenyl)-4,6,7,8-tetrahydro-6-oxo-7-(sulfoxy)-5,8-methano-
-5H-thieno[2,3-e][1,3]diazepine-4-carboxylate,
[0203] the sodium salt of
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide,
[0204] the sodium salt of
1,4,5,8-tetrahydro-1-phenyl-5-(sulfoxy)-6H-4,7-methanopyrazolo[3,4-e][1,3-
]diazepin-6-one,
[0205] the sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5(sulfoxy)-1H-4,7-methanopyrazolo-
[3,4-e][1,3]diazepine-8-carboxamide,
[0206] the triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-(phenylmethyl)-5-(sulfoxy)-4H-4,7-methan-
opyrazolo[3,4-e][1,3]diazepine-8-carboxylate,
[0207] the triethylammonium salt of methyl
trans-4,5,6,8-tetrahydro-6-oxo-1-(2-phenylethyl)-5-(sulfoxy)-1H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate,
[0208] the triethylammonium salt of ethyl
trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-1H-4,7-met-
hanopyrazolo[3,4-e][1,3]diazepine-1-acetate,
[0209] the triethylammonium salt of ethyl
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-4H-4,7-methanopyr-
azolo[3,4-e][1,3]diazepine-2(8H)-acetate,
[0210] the di(triethylammonium) salt of
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-sulfoxy-4H-4,7-methanopyraz-
olo[3,4-e][1,3]diazepine-2(8H)acetic acid,
[0211] the pyridinium salt of methyl
trans-1-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate,
[0212] the pyridinium salt of methyl
trans-2-(aminocarbonyl)-2,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4H-4,7-metha-
nopyrazolo[3,4-e][diazepine-8-carboxylate,
[0213] the sodium salt of methyl
trans-2-(4-fluorophenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate,
[0214] the sodium salt of methyl
trans-2(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-7-
H-thieno[2,3-e][1,3]diazepine-8-carboxylate,
[0215] the sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-9-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,
[0216] the sodium salt of
trans-1,2,3,5-tetrahydro-N-methoxy-8-[(2-methoxyethoxy)methoxy]-3-oxo-2-(-
sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide,
[0217] the sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-8-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,
[0218] the sodium salt of ethyl
trans-8-[[(ethylamino)carbonyl]oxy]-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)--
1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,
[0219] the sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[[trifluoromethyl)sulfonyl]o-
xy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate,
[0220] the disodium salt of
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[2-(sulfoxy)ethoxy]-1,4-meth-
ano-4H-2,4-benzodiazepine-5-carboxamide,
[0221] the sodium salt of
trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-3-ox-
o-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide,
[0222] the triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-(2-phenylethyl)-5-(sulfoxy)-4H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate.
[0223] The .beta.-lactam type antibiotic with which it is possible
to combine the compound of formula (I) may be chosen from the group
consisting of penams, penems, carbapenems, cephems, carbacephems,
oxacephems, cephamycins and monobactams.
[0224] The expression .beta.-lactams is understood to mean for
example penicillins such as amoxicillin, ampicillin, aziocillin,
meziocillin, apalcillin, hetacillin, bacampicillin, carbenicillin,
sulbenicillin, ticarcillin, piperacillin, aziocillin, mecillinam,
pivmecillinam, methicillin, ciclacillin, talampicillin,
aspoxicillin, oxacillin, cloxacillin, dicloxacillin,
flucloxacillin, nafcillin or pivampicillin, cephalosporins such as
cephalothin, cephaloridin, cefaclor, cefadroxil, cefamandole,
cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin,
cephacetril, cefotiam, cefotaxime, cefsulodin, cefoperazone,
ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid,
cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide,
cefbuperazone, cefozopran, cefepim, 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, carbapenems
such as imipenem, meropenem, biapenem or panipenem and monobactams
such as aztreonam and carumonam, and their salts.
[0225] The compounds of formula (I) or their pharmaceutically
acceptable salts may be administered at the same time as the dose
of .beta.-lactam type antibiotics or separately, preferably after
the latter. This may 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.
[0226] The dosage of the compounds of the formula (I) and of their
pharmaceutically acceptable salts may of course vary within wide
limits and should naturally be adjusted, in each particular case,
to the individual conditions and to the pathogenic agent to be
controlled. In general, for a use in the treatment of bacterial
infections, the daily dose may be between 0.250 g and 10 g per day,
by the oral route in humans, with the product described in Example
24 or 45 or else between 0.25 g and 10 g per day by the
intramuscular or intravenous route. For a use as a .beta.-lactamase
inhibitor, a daily dose in humans which may range from 0.1 to about
10 g may be suitable.
[0227] Moreover, the ratio of the .beta.-lactamase inhibitor of
formula (I) or of the pharmaceutically acceptable salt thereof to
the .beta.-lactam type antibiotic may also vary within wide limits
and should be adjusted, in each particular case, to the individual
conditions. In general, a ratio ranging from about 1:20 to about
1:1 should be recommended.
[0228] The antibiotic or .beta.-lactamase inhibitor medicaments as
defined above are used in the form of pharmaceutical compositions
in the form of a mixture with an inert, organic or inorganic
pharmaceutical excipient suitable for the desired mode of
administration, and the subject of the invention is also the
pharmaceutical compositions containing, as active ingredient, at
least one of the compounds of the invention defined above and the
compositions containing, as active ingredient, at least one of the
compounds of the invention as defined above and at least one
.beta.-lactam type medicament.
[0229] These compositions may be administered orally, rectally,
parenterally, in particular intramuscularly, or locally as a
topical application to the skin and the mucous membranes.
[0230] The compositions according to the invention may be solid or
liquid and may be provided in the dosage forms commonly used in
human medicine, such as for example simple or sugar-coated tablets,
gelatine capsules, granules, suppositories, preparations for
injection, ointments, creams, gels; they are prepared according to
the customary methods. The active ingredient(s) may be incorporated
into excipients normally used in these pharmaceutical compositions,
such as talc, gum arabic, lactose, starch, magnesium stearate,
cocoa butter, aqueous or nonaqueous vehicles, fatty substances of
animal or plant origin, paraffin derivatives, glycols, various
wetting, dispersing or emulsifying agents, preservatives.
[0231] These compositions may be provided in particular in the form
of a lyophilisate indended to be dissolved immediately before use
in an appropriate vehicle, for example apyrogenic sterile
water.
[0232] The dose administered is variable depending on the condition
to be treated, the subject in question, the route of administration
and the product considered. It may be for example between 0.250 g
and 10 g per day, orally in humans, with the product described in
Example 1 or alternatively between 0.25 g and 10 g per day
intramuscularly or intravenously.
[0233] The products of formula (I) may also be used as
disinfectants for surgical instruments.
[0234] The subject of the invention is finally, as novel industrial
products and in particular as intermediate products necessary for
the preparation of the products of formula (I):
[0235] the products of formula (III) as defined above in which
R.sub.3 and R'.sub.4 or R'.sub.1 and R.sub.3 form together a phenyl
or a heterocycle with an aromatic character, which is substituted
with a radical
[0236] --(CH.sub.2).sub.b-phenyl or --(CH.sub.2).sub.b-heterocycle
with an aromatic character, which is optionally substituted, as
defined above, and their salts with acids and in particular their
hydrochlorides and trifluoroacetates;
[0237] the products of formula (III) as defined above, in which
R'.sub.1 represents a radical CONR.sub.6R.sub.7 in which R.sub.6 or
R.sub.7 represents an alkoxy radical containing from 1 to 6 carbon
atoms, all the other values being as defined in formula III, and
their salts with acids and in particular their hydrochlorides and
trifluoroacetates;
[0238] the products of formula (II) as defined above, in which
R.sub.3 and R'.sub.14 or R'.sub.1 and R.sub.3 form together form
together a phenyl or a heterocycle with an aromatic character,
which is substituted with a radical --(CH.sub.2).sub.3-phenyl or
--(CH.sub.2).sub.b-heterocycle with an aromatic character, which is
optionally substituted, as defined above, and their salts with
acids and in particular their hydrochlorides and
trifluoroacetates;
[0239] the products of formula (II) as defined above, in which
R'.sub.1 represents a radical CONR.sub.6R.sub.7 in which R.sub.6 or
R.sub.7 represents an alkoxy radical containing from 1 to 6 carbon
atoms, all the other values being as defined in formula III, and
their salts with acids and in particular their hydrochlorides and
trifluoroacetates;
[0240] the products of formulae (IV), (V), (VI), (VII), (VIII) and
(VIII') as defined above, in which R.sub.3 and R'.sub.4 or R'.sub.1
and R.sub.3 represents a radical --(CH.sub.2).sub.3-phenyl or
--(CH.sub.2).sub.b-heterocycle with an aromatic character, which is
optionally substituted, as defined above, and their salts with an
acid and optionally their hydrochlorides and trifluoroacetates;
[0241] the products of formulae (IV), (V), (VI), (VII), (VIII) and
(VIII') as defined above, in which R'.sub.1 represents a radical
CONR.sub.6R.sub.7 in which R.sub.6 or R.sub.7 represents an alkoxy
radical containing from 1 to 6 carbon atoms, all the other values
being as defined in formulae (IV), (V), (VI), (VII), (VIII) and
(VIII'), and their salts with an acid and in particular their
chlorohydrides and trifluoroacetates.
[0242] The products of formula (IV) can be prepared for example
according to methods provided below in the experimental part.
[0243] The following examples illustrate the invention without
however limiting the scope thereof.
EXAMPLES
[0244] In the preceding description and in the examples which
follow, the following abbreviations have been used: [0245] DEAD:
diethyl azodicarboxylate [0246] TEA: triethylamine [0247] DMAP:
4-dimethylaminopyridine [0248] EDCl:
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0249]
THF: tetrahydrofuran [0250] AcOEt: ethyl acetate [0251] DMF:
N,N-dimethylformamide [0252] AIBN: 2,2'-azobisisobutyronitrile
[0253] M: molecular molar mass [0254] MS: mass spectrometry [0255]
EI: electron impact [0256] SIMS: secondary ion mass spectrometry
[0257] FAB: fast atom bombardment [0258] BOP:
benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate
[0259] HOBt: 1-hydroxybenzotriazole hydrate [0260] DBU:
diazabicycloundecene [0261] (BOC).sub.2O: t-butyl dicarbonate
[0262] NaBH.sub.3CN: sodium cyanoborohydride [0263] DMSO: dimethyl
sulfoxide [0264] DIEA: diisopropylethyldiamine [0265] MEMCI:
2-methoxyethoxymethyl chloride [0266] TMSCN: trimethylsilyl cyanide
[0267] BOC--ON:
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile
Example 1
Methyl
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyra-
zolo[3,4-e][1,3]diazepine-8-carboxylate
[0268] Stage A1
Preparation of [2-(phenylthio)ethyl]hydrazine
[0269] Step 1
[0270] 100 g of 2-bromoethylphenyl sulfide dissolved in 1 l of
ethanol are introduced into a round-bottomed flask placed under a
nitrogen atmosphere, and 184.2 g of hydrazine hydrate are added.
The medium is heated at 100.degree. C. overnight. Once the reaction
is complete, the solvent is then distilled off under reduced
pressure at 80.degree. C.-90.degree. C. 65 g of potassium carbonate
and 1 l of methylene chloride are then added to the medium. The
medium is stirred for 15 minutes, the organic phase is then
extracted with 2.times.500 ml of water, the organic phase is then
dried over magnesium sulfate, filtered and evaporated under reduced
pressure. The residue is next taken up in 750 ml of an
ethanol/water mixture to which 12 ml of concentrated sulfuric acid
are added dropwise. The product crystallizes and the precipitate is
filtered and then rinsed with an ethanol/water, 80/20, solution and
then with ether. The product is then dried under reduced
pressure.
[0271] 81.84 g of [2-(phenylthio)ethyl]hydrazine hemisulfate salt
having the empirical formula C.sub.8H.sub.12N.sub.2S+1/2 of
H.sub.2SO.sub.4 are obtained. (M=217.3 g). The yield obtained is
81%.
[0272] Step 2
[0273] 79.7 g of the product obtained in the preceding step 1 are
dissolved in 1.9 l of dichloromethane. 400 ml of 1 N sodium
hydroxide are then added, and the medium is vigorously stirred. The
organic phase is next extracted with dichloromethane, the organic
phase is then dried over MgSO.sub.4 and evaporated off under
reduced pressure. [2-(Phenylthio)ethyl]hydrazine having the
empirical formula C.sub.8H.sub.12N.sub.2S is obtained with a
quantitative yield (M=168.26 g). The yield obtained is 89%.
[0274] Stage A2
[0275] 56.0 g (of 1,1-dimethylethyl
3,5-dioxo-1-piperidinecarboxylate having the empirical formula
C.sub.10H.sub.15NO.sub.4 (prepared by a method similar to that
described in Heterocycles, 22, 2769-2773, (1984), replacing methyl
chloroformate with (BOC).sub.2O, are prepared as a suspension. 55.5
ml of N,N-dimethylformamide dimethyl acetal at 95% are added at
room temperature. The medium is stirred for half an hour at
80.degree. C. and then for 3 hours at 50.degree. C. The solvent is
evaporated off under reduced pressure. 79 g of 1,1-dimethylethyl
4-[(dimethylamino)methylene]-3,5-dioxo-1-piperidinecarboxylate
having the empirical formula C.sub.13H.sub.20N.sub.2O.sub.4 are
thus obtained. The corresponding yield is 99%.
[0276] Stage B
[0277] 79 g of the product obtained in stage A2 are dissolved in 1
liter of absolute methanol, and then 54.5 g of
[2-(phenylthio)ethyl]hydrazine are added. The medium is stirred for
3 hours 30 minutes at room temperature. The solvent is evaporated
off under reduced pressure and the medium is purified by
chromatography on silica eluting with a dichloromethane/AcOEt 1/1
mixture.
[0278] The compound 1,1-dimethylethyl
1,4,5,7-tetrahydro-4-oxo-1-[2-(phenylthio)ethyl]-6H-pyrazolo[3,4-c]pyridi-
ne-6-carboxylate having the empirical formula
C.sub.19H.sub.23N.sub.3O.sub.3S is obtained (M=373.48 g). The
corresponding yield obtained is 57.6%.
[0279] Stage C
[0280] 74.5 g of the ketone obtained in the preceding stage B are
dissolved in 372.5 ml of methanol, in a round-bottomed flask placed
under a nitrogen atmosphere, the medium is then cooled with an ice
bath and 7.58 g of sodium borohydride are introduced in small
fractions over 20 minutes.
[0281] The medium is allowed to return to room temperature over two
hours, and then dichloromethane and an aqueous tartaric acid
solution at 10% are successively added. The medium is vigorously
stirred and then separated by decantation and reextracted with
dichloromethane. The organic phases are combined and they are dried
over magnesium sulfate, filtered and the solvent of the filtrate is
separated off under reduced pressure. The residue is taken up in
dichloromethane, filtered and the solvent is again evaporated off
under reduced pressure.
[0282] 72.5 g of the compound 1,1-dimethylethyl
1,4,5,7-tetrahydro-4-hydroxy-1-[2-(phenylthio)ethyl]-6H-pyrazolo[3,4-c]py-
ridine-6-carboxylate having an empirical formula
C.sub.19H.sub.25N.sub.3O.sub.3S are obtained (M=375.49 g). The
corresponding yield is 97%.
[0283] Stage D
[0284] 75 g of the product obtained in the preceding stage C are
dissolved in 1 l of dichloromethane at 0.degree. C. 118 g of
methachloroperbenzoic acid at 70% are added, and the medium is then
stirred for 1 h 30 min at room temperature. 1.5 l of
dichloromethane and 1.6 l of 0.5 N sodium thiosulfate are added to
the reaction medium. After extraction of the organic phase, it is
rewashed with 1 l of sodium thiosulfate and then with 1.5 l of
NaHCO.sub.3 and finally with 1.5 l of water. The aqueous phases are
then again reextracted with dichloromethane and then the various
organic phases are combined, dried over magnesium sulfate,
filtered, and the solvent is then evaporated off under reduced
pressure.
[0285] The crude product is recrystallized from isopropyl ether to
give 81 g of the compound 1,1-dimethylethyl
1,4,5,7-tetrahydro-4-hydroxy-1-[2-[1-propenylsulfonyl]ethyl]-6H-pyrazolo[-
3,4-c]pyridine-6-carboxylate having the empirical formula
C.sub.19H.sub.25N.sub.3O.sub.5S (M=407.49 g). The corresponding
yield is 99%.
[0286] Stage E
[0287] 57.2 g of the product obtained in the preceding stage D are
dissolved in 572 ml of anhydrous THF in a round-bottomed flask
placed under an inert atmosphere and at a temperature of
-30.degree. C. 337 ml of a 1 M potassium tert-butoxide solution in
THF are then added. The medium is stirred for 1 hour and then 20 ml
of acetic acid are added to the reaction medium. An aqueous
bicarbonate solution of NaHCO.sub.3 and NaCl is then added, and the
organic phase is then extracted several times with ethyl acetate.
The organic phases are dried over magnesium sulfate, filtered and
the solvent evaporated under reduced pressure. 57.4 g of crude
product are recovered, which product is then purified on silica,
eluting with a dichloromethane/acetone, 4/6, mixture.
[0288] 38.6 g of 1,1-dimethylethyl
1,4,5,7-tetrahydro-4-hydroxy-6H-pyrazolo[3,4-c]pyridine-6-carboxylate
having the empirical formula C.sub.11H.sub.17N.sub.3O.sub.3 are
obtained after evaporation of the solvent (M=239.28 g). The
corresponding yield is 84%.
[0289] Stage F
[0290] 35 g of the product obtained in the preceding stage E are
dissolved in 890 ml of dichloromethane, in a round-bottomed flask
placed under a nitrogen atmosphere. 49.77 g of (Ph).sub.3CCl are
added and the solution is then cooled to -30.degree. C. with a dry
ice/acetone mixture. 24.7 ml of triethylamine are then added, and
the reaction medium is stirred, while allowing the temperature to
return to room temperature over 4 h 30 min. After evaporation of
the solvent under reduced pressure, the residue is then poured into
1.6 l of ethyl acetate and the medium is washed with 1.8 l of
water. The organic phase is then dried over magnesium sulfate,
filtered, and the solvent evaporated off under reduced pressure.
The residue is taken up in ethyl ether and the precipitate obtained
is washed in pentane. After drying, 62.5 g of 1,1-dimethylethyl
2,4,5,7-tetrahydro-4-hydroxy-2-(triphenylmethyl)-6H-pyrazolo[3,4-c]pyridi-
ne-6-carboxylate having the empirical formula
C.sub.30H.sub.31N.sub.3O.sub.3 are obtained (M=481.60 g). The yield
is 99%.
[0291] Stage G
[0292] 26.6 g of the alcohol obtained in the preceding stage F are
dissolved in 230 ml of THF, in a round-bottomed flask placed under
a nitrogen atmosphere, the medium is then cooled to -78.degree. C.
and 81 ml of tert-butyllithium are introduced as a 1.7 M solution
in pentane. The reaction is allowed to proceed for 15 minutes at
-78.degree. C., and carbon dioxide gas is introduced in excess over
10 minutes, and then the temperature is allowed to return to room
temperature.
[0293] The reaction mixture is hydrolyzed by adding 100 ml of water
and 300 ml of ethyl acetate and then acidified to pH=4 by addition
of formic acid. The aqueous phase is extracted several times with
ethyl acetate and then the organic phase is dried over MgSO.sub.4,
filtered and the solvent evaporated under reduced pressure to give
29.8 g of crude product. The latter is dissolved in 300 ml of ether
and then extracted with 3.times.200 ml of a saturated NaHCO.sub.3
solution. The aqueous phase is acidified to pH=4 by addition of
formic acid and then extracted with ethyl acetate. After drying
over MgSO.sub.4, filtration and evaporation under reduced pressure,
14.8 g of acid having the empirical formula
C.sub.31H.sub.31N.sub.3O.sub.5 (M=525.61 g) are obtained.
[0294] The 14.8 g of the compound obtained are then esterified in
the presence of 3.7 g of K.sub.2CO.sub.3 and 4.9 ml of dimethyl
sulfate. The medium is stirred for 1 hour at room temperature and
then 7.4 ml of triethylamine are added. After 40 minutes, 300 ml of
ethyl acetate and 200 ml of water are added. After stirring, the
medium is separated by decantation and the aqueous phase then
reextracted with ethyl acetate. The organic phases are washed with
a solution of water saturated with NaCl. The organic phases are
then dried over magnesium sulfate and the solvent is evaporated
under reduced pressure.
[0295] 11.23 g of 6-(1,1-dimethylethyl) and 7-methyl
2,4,5,7-tetrahydro-4-hydroxy-2-(triphenylmethyl)-6H-pyrazolo[3,4-c]pyridi-
ne-6,7-dicarboxylate having the empirical formula
C.sub.32H.sub.33N.sub.3O.sub.5 are obtained (M=739.64 g). The
corresponding yield over the two steps is 42%.
[0296] Stage H
[0297] 1 g of the product obtained in the preceding stage G is
solubilized in 50 ml of dichloromethane in a round-bottomed flask
under an argon atmosphere. 2.8 g of triethylamine are added
followed by 4.8 g of dilute (CH.sub.3SO.sub.2).sub.2O in 1 ml of
dichloromethane. The medium is stirred for one hour at -70.degree.
C. and then 0.68 g of O-benzylhydroxylamine is added. The medium is
again stirred for 10 minutes at -78.degree. C., for 1 h 20 min at
-50.degree. C. and finally at 0.degree. C. overnight. The medium is
left for a further one hour at 20.degree. C., and then
dichloromethane is added and the organic phase is washed with a
tartaric acid solution and then an aqueous NaCl solution and
finally pure water. The organic phase is dried over MgSO.sub.4,
filtered and the solvent is evaporated off under reduced pressure.
11.9 g of product are obtained, which product is purified on
silica, eluting with a petroleum ether/ethyl acetate, 8/2,
mixture.
[0298] 8.9 g of 6-(1,1-dimethylethyl) and 7-methyl
2,4,5,7-tetrahydro-4-[(phenylmethoxy)amino]-2-(triphenylmethyl)-6H-pyrazo-
lo[3,4-c]pyridine-6,7-dicarboxylate having the empirical formula
C.sub.39H.sub.40N.sub.4O.sub.5 are obtained (M=644.78 g). The
corresponding yield is 75%.
[0299] Stage I
[0300] 10 g of the product obtained in the preceding stage H are
dissolved in 70 ml of ethyl acetate, in a round-bottomed flask kept
at 0.degree. C. 35 ml of a saturated hydrochloric acid solution in
ethyl acetate are added and then the medium is stirred for 3 hours.
After evaporation of the solvent, crude methyl
4,5,6,7-tetrahydro-4[(phenylmethoxy)amino]-2H-pyrazolo[3,4-c]pyridine-7-c-
arboxylate dihydrochloride is obtained.
[0301] Stage J
[0302] The crude product obtained in stage I is taken up in water.
The aqueous phase is then washed with ethyl acetate. The aqueous
phase is next brought to pH=10 with a solution of aqueous ammonia
at 20% and then extracted three times with ethyl acetate. After
drying over magnesium sulfate, filtration, and evaporation of the
solvent under reduced pressure, 4.21 g of methyl
4,5,6,7-tetrahydro-4-[(phenylmethoxy)amino]-2H-pyrazolo[3,4-c]pyridine-7--
carboxylate having the empirical formula
C.sub.15H.sub.18N.sub.4O.sub.3 are obtained (M=302.34 g). The
corresponding yield in both steps I and J is 89.7%.
[0303] Stage K
[0304] 9.24 g of the product obtained in the preceding stage I, 3
liters of acetonitrile and 12.3 ml of TEA are introduced into a
round-bottomed flask placed under an argon atmosphere and cooled by
an ice bath. The medium is stirred for 2 minutes and 1.85 ml of
diphosgene are then introduced. The solution is stirred at
20.degree. C. for 1 hour. The medium is diluted with AcOEt and the
medium is washed with a tartaric acid solution at 10% and then with
water. The organic phase is dried over magnesium sulfate and the
solvent is evaporated off under reduced pressure.
[0305] The crude product is dissolved in 500 ml of dichloromethane
with 0.5 ml of DBU. After 10 minutes of contact, the reaction
mixture is washed with a tartaric acid solution at 10% and with
water. After evaporation of the solvent under reduced pressure.
[0306] 9.6 g of methyl
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3-
,4-e][1,3]diazepine-8-carboxylate having the empirical formula
C.sub.16H.sub.16N.sub.4O.sub.4 are obtained (M=328.33 g). The
corresponding yield is 95%.
[0307] Stage L
[0308] 0.2 g of the product obtained in the preceding stage K is
dissolved in 2 ml of DMF in a round-bottomed flask kept at
0.degree. C. under a nitrogen atmosphere, and 0.115 g of benzyl
bromide is added followed by 0.032 g of NaH. The medium is stirred
for 10 minutes at 0.degree. C. and then the temperature is allowed
to return to room temperature. After one hour, the reaction is
stopped. The reaction medium is poured into an aqueous NaCl
solution and the medium is extracted twice with ethyl acetate. The
organic phase is then dried over magnesium sulfate, filtered and
the solvent is evaporated off under reduced pressure. 231 mg of
product are obtained, which product is purified on a silica column,
eluting with a methylene chloride/ethyl acetate/triaethylamine
95/0.5/0.1% mixture. After evaporation of the solvent, 70 mg of the
compound methyl
trans-2,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-(phenylmethyl)-4H-4,7--
methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.23H.sub.22N.sub.4O.sub.4 are obtained
(M=418.46 g). The corresponding yield is 27%.
[0309] Stage M
[0310] 65 mg of the product obtained in the preceding stage are
dissolved in 1 ml of MeOH and then 29 mg of 10% palladium on carbon
are added and the medium is placed under a hydrogen atmosphere,
with vigorous stirring. When the starting material has been
consumed, the catalyst is filtered off and the solvent is
evaporated off under reduced pressure.
[0311] 47 mg of the compound methyl
trans-2,5,6,8-tetrahydro-5-hydroxy-6-oxo-2-(phenylmethyl)-4H-4,7-methanop-
yrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.16H.sub.16N.sub.4O.sub.4 are obtained (M=328.33
g).
[0312] Stage N
[0313] 0.047 g of the product obtained in the preceding stage M is
dissolved in 1 ml of pyridine containing a few crystals of a 4
.ANG. molecular sieve. 0.068 g of the pyridine SO.sub.3 complex is
then added. The medium is stirred overnight at room temperature.
The sieve is then filtered off and rinsed with water and then with
methylene chloride. After evaporation of the solvents coevaporated
with toluene, 114 mg of crude product are obtained which are
purified on silica, eluting with a methylene
chloride/ethanol/triethylamine 90/10/0.1% mixture. 41 mg of the
compound of triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-(phenylmethyl)-5-(sulfoxy)-4H-4,7-methan-
opyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.22H.sub.31N.sub.5O.sub.7S are obtained (M=509.58).
The yield obtained over the two stages M and N is 52%.
[0314] Proton NMR:
[0315] DMSO-d.sub.6 at 300 MHz (chemical shift and multiplicity):
1.12 (broad s): (CH.sub.3CH.sub.2).sub.3N; 3.05 (l):
(CH.sub.3CH.sub.2).sub.3N; 3.45 (m): N--CH.sub.2--CH; 4.75 (m):
-)N--CH.sub.2--CH; 3.73 (s): CH.sub.3OOC--CH; 4.98 (s):
CH.sub.3OOC--CH; 5.28 (broad s): N--CH.sub.2-.phi.; 7.22 to 7.39
(m) aromatic H; 7.87 (s): N--CH.
[0316] LC/MS (negative electrospray): general conditions
[0317] Kromasil C18 column 4.6.times.250 mm, 5.mu. oven at
30.degree. C.
[0318] Flow rate=1 ml/min V.sub.inj=15 .mu.l
[0319] Detection .lamda.=200-400 mm
[0320] MS/ESP +/-mode CV=50V
[0321] Eluent: A=H.sub.2O (0.1% HCO.sub.2H)
[0322] B=CH.sub.3CN
TABLE-US-00001 Gradient: Time A % B % 0.00 80.0 20.0 15.00 50.0
50.0 25.00 20.0 80.0 40.00 80.0 20.0 50.00 80.0 20.0
[0323] LC/MS (negative electrospray) m/z: TR=9.70 min
M.sup.-=407.
Example 2
Triethylammonium salt of methyl
trans-4,5,6,8-tetrahydro-6-oxo-1-(phenylethyl)-5-(sulfoxy)-1H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepine-8-carboxylate
[0324] Stage A
[0325] 0.1 g of the product obtained in stage K of Example 1 is
dissolved in 0.8 ml of DMF, in a round-bottomed flask placed under
a nitrogen atmosphere at 0.degree. C. 0.062 g of
2-bromophenylethane is added followed by 0.015 g of NaH. The medium
is stirred for 15 minutes at 0.degree. C. and the reaction medium
is allowed to return to room temperature. The medium is stirred for
6 hours, a saturated aqueous NaCl solution is then added and the
aqueous phase is extracted several times with ethyl acetate. After
drying the organic phase over magnesium sulfate, the solvent is
filtered and evaporated off under reduced pressure. The crude
product obtained is filtered on silica, eluting with a methylene
chloride/acetone/triethylamine, 98/2/0.1%, mixture. After
evaporating the solvent, 28.8 mg are obtained, that is a yield of
21.5% of the compound isomer A, methyl
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1-(phenylethyl)-1H-4,7-m-
ethanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate, having the
empirical formula C.sub.24H.sub.24N.sub.4O.sub.4 (432.46 g), and 37
mg are obtained, that is a yield of 28% of isomer B, methyl
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-(2-phenylethyl)-1H-4,7-
-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.24H.sub.24N.sub.4O.sub.4 (M=432.48 g).
[0326] Stage B
[0327] 0.028 g of the isomer A obtained in the preceding stage A is
dissolved in 1 ml of methanol, in a round-bottomed flask placed
under a nitrogen atmosphere, and 0.0168 g of 10% palladium on
carbon is then added. The medium is placed under a hydrogen
atmosphere. After 2 hours, the reaction is stopped and the reaction
medium is filtered and the solvent is evaporated under reduced
pressure. 13.8 mg of methyl
trans-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-1-(phenylethyl)-1H-4,7-methanopy-
razolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.17H.sub.18N.sub.4O.sub.4 are obtained (M=342.36 g).
The corresponding yield is 62%.
[0328] Stage C
[0329] 0.0130 g of the product obtained in the preceding stage B is
dissolved in 1 ml of pyridine, in a round-bottomed flask, and 0.018
g of pyridine-SO.sub.3 complex is added. The medium is stirred
overnight at room temperature and then the reaction mixture is
filtered and rinsed with a methylene chloride/water mixture. After
evaporation, 19 mg of crude product are obtained which are purified
by chromatography on silica, eluting with a methylene
chloride/ethanol/triethylamine, 95/15/0.1%, mixture. 6.6 mg of the
triethylammonium salt of methyl
trans-4,5,6,8-tetrahydro-6-oxo-1-(phenylethyl)-5-(sulfoxy)-1H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.23H.sub.33N.sub.5O.sub.7S are obtained (M=523.61 g).
The corresponding yield is 20%.
[0330] LC/MS (negative electrospray) m/z: TR=13.02 min
[MH].sup.-=421 and [2M+Na-2H].sup.-=865.
Example 3
Triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-(2-phenylethyl)-5-(sulfoxy)-4H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate
[0331] Stage A
[0332] The procedure is carried out as in Stage M of Example 1 with
0.037 g of the isomer B obtained in Stage A of Example 2, 0.022 g
of palladium on carbon, and 0.5 ml of methanol. 28 mg of the
compound methyl
trans-2,5,6,8-tetrahydro-5-hydroxy-6-oxo-2-(2-phenylethyl)-4H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.17H.sub.18N.sub.4O.sub.4 are obtained (342.36 g). The
corresponding yield is 96%.
[0333] Stage B
[0334] The procedure is carried out as in Example 1 in Stage M with
0.028 g of the product obtained in the preceding stage A, 0.039 g
of the pyridine-SO.sub.3 complex and 1 ml of pyridine. 20 mg of the
triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-(2-phenylethyl)-5-(sulfoxy)-4H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.23H.sub.33N.sub.5O.sub.7S are obtained (M=523.61 g).
The corresponding yield is 47%.
[0335] LC/MS (negative electrospray), m/z: TR=11.87 min
[2M.sup.-+Na-2H].sup.-=865.sup.- and [M].sup.-=421.sup.-.
Example 4
Triethylammonium salt of ethyl
trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-1H-4,7-met-
hanopyrazolo[3,4-e][1,3]diazepine-1-acetate
[0336] Stage A
[0337] 0.2 g of the product obtained in Stage K of Example 1 is
dissolved in 2 ml of acetonitrile, in a round-bottomed flask. 0.150
.mu.l of ethyl bromoacetate and 240 .mu.l of DIEA are added. The
medium is heated at 50.degree. C. for 24 hours and then the
reaction medium is extracted with ethyl acetate, the organic phase
is washed with an aqueous tartaric acid solution at 10% and then
with an aqueous NaCl solution. The organic phase is dried over
magnesium sulfate, filtered off and the solvent is evaporated off
under reduced pressure. 266 mg of the crude product are obtained
which are purified by chromatography on silica, eluting with a
methylene chloride/acetone/triethylamine, 95/0.5/0.1%, mixture. 37
mg of the isomer A, ethyl
trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(phenylmethoxy)-1H-4-
,7-methanopyrazolo[3,4-e][1,3]diazepine-1-acetate having the
empirical formula C.sub.20H.sub.22N.sub.4O.sub.6 are obtained
(M=414.42 g). The corresponding yield is 11.8%.
[0338] 88 mg of the isomer B, ethyl
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(phenylmethoxy)-4H-4,7-meth-
anopyrazolo[3,4-e][1,3]diazepine-2(8H)-acetate having the empirical
formula C.sub.20H.sub.22N.sub.4O.sub.6 are also obtained (412.42
g). The corresponding yield is 28%.
[0339] Stage B
[0340] The procedure is carried out as in Stage M of Example 1 with
0.020 g of the isomer A obtained in the preceding stage, 0.01 g of
palladium on carbon and 0.5 ml of methanol. 24.2 mg of the compound
ethyl
trans-4,5,6,8-tetrahydro-5-hydroxy-8-(methoxycarbonyl)-6-oxo-1H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-1-acetate having the empirical
formula C.sub.13H.sub.16N.sub.4O.sub.6 are obtained (324.30 g). The
corresponding yield is 83%.
[0341] Stage C
[0342] The procedure is carried out as in Stage N of Example 1 with
0.024 g of the product obtained in the preceding stage, 0.035 g of
the pyridine-SO.sub.3 complex and 1 ml of pyridine. 28.8 mg of the
compound of triethylammonium salt of ethyl
trans-4,5,6,8-tetrahydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-1H-4,7-met-
hanopyrazolo[3,4-e][1,3]diazepine-1-acetate having the empirical
formula C.sub.19H.sub.31N.sub.5O.sub.9S are obtained (505.55). The
corresponding yield is 77%.
[0343] LC/MS (negative electrospray), m/z:
[0344] TR=6.06 min [M]-=403.
[0345] proton NMR:
[0346] CDCl.sub.3 at 300 MHz and 60.degree. C. (chemical shift and
multiplicity): 1.28 (t) CH.sub.3--CH.sub.2--O--CO; 4.20 (q):
CH.sub.3--CH.sub.2--O--CO; 5.06 and 4.96 (AB): O--CO--CH.sub.2--N;
3.84 (s): CH.sub.3--O--CO; 5.32 (s): CH.sub.3--O--CO--CH--N, 3.45
(d) and 3.82 (dd): N--CH.sub.2--CH--N, 5.00 (d):
N--CH.sub.2--CH--N; 7.62 (s): N.dbd.CH--C, 1.28 (t):
CH.sub.3--CH.sub.2--N; 3.15 (q): CH.sub.3--CH.sub.2--N.
Example 5
Triethylammonium salt of ethyl
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-4H-4,7-methanopyr-
azolo[3,4-e][1,3]diazepine-2(8H)-acetate
[0347] Stage A
[0348] The procedure is carried out as in Stage M of Example 1 with
0.067 g of the isomer B obtained in Stage A of Example 4, 0.038 g
of palladium on carbon and 0.4 ml of methanol. 62 mg of the
compound ethyl
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(phenylmethoxy)-4H-4,7-meth-
anopyrazolo[3,4-e][1,3]diazepine-2(8H)-acetate having the empirical
formula C.sub.13H.sub.16N.sub.4O.sub.6 are obtained (324.30 g). The
corresponding yield is 90%.
[0349] Stage B
[0350] The procedure is carried out as in Stage M of Example 1 with
0.062 g of the product obtained in the preceding stage, 0.091 g of
the pyridine-SO.sub.2 complex and 2 ml of pyridine. 79 mg of the
compound of triethylammonium salt of ethyl
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(sulfoxy)-4H-4,7-methanopyr-
azolo[3,4-e][1,3]diazepine-2(8H)acetate having the empirical
formula C.sub.19H.sub.31N5O.sub.9S are obtained (M=505.55 g). The
corresponding yield is 82%.
[0351] LC/MS (negative electrospray), m/z:
[0352] TR=5.64 min M.sup.-=403.
[0353] proton NMR: CDCl.sub.3 (chemical shift and multiplicity):
1.28 (t): CH.sub.3--CH.sub.2OCO; 4.22 (q): CH.sub.3--CH.sub.2--OCO;
4.90 and 4.80 (AB): CH.sub.3--CH.sub.2--OCO--CH.sub.2--N, 3.85 (s):
CH.sub.3O--CO; 5.26 (s): CH.sub.3--O--CO--CH--N; 3.63 (d) and 3.82
(dd): N--CH.sub.2--CH--N, 4.99 (broad d): N--CH.sub.2--CH--C.dbd.;
7.53 (s): C.dbd.CH--N.
Example 6
Triethylammonium salt of methyl
2,5,6,8-tetrahydro-6-oxo-2-[(phenylamino)carbonyl]-5-(sulfoxy)-4H-4,7-met-
hanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate
[0354] Stage A
[0355] 0.3 g of the compound obtained in Stage K of Example 1 is
dissolved in 5 ml of CH.sub.2Cl.sub.2, in a round-bottomed flask.
0.109 g of phenyl isocyanate is added. The reaction medium is then
stirred for 1 hour. After evaporation, a crude product is obtained
which is purified by chromatography on silica, eluting with a
methylene chloride/ethyl acetate/triethylamine, 99/1/0.1%, mixture.
176 mg of the isomer A of methyl
trans-4,5,6,8-tetrahydro-6-oxo-1-[(phenylamino)carbonyl]-5-(phenyl-
methoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate,
and 63.5 mg of the isomer B of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-[(phenylamino)carbonyl]-5-(phenylmethoxy-
)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having
the empirical formula C.sub.23H.sub.21N.sub.5O.sub.5 [lacuna]
(M=447.45 g). The corresponding yields of isomers A and B are 36%
and 14%.
[0356] Stage B
[0357] The procedure is carried out as in Stage M of Example 1,
with 0.054 g of the isomer B obtained in the preceding stage, 0.008
g of palladium on carbon, 5 ml of methanol, 1 ml of THF. 44 mg of
the compound methyl
trans-2,5,6,8-tetrahydro-5-hydroxy-6-oxo-2-[(phenylamino)carbonyl]-4H-4,7-
-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.16H.sub.15N.sub.5O.sub.5 are obtained
(357.33 g). The corresponding yield is quantitative.
[0358] Stage C
[0359] The procedure is carried out as in Stage M of Example 1 with
40 mg of the product obtained in the preceding stage, 62 mg of the
pyridine-SO.sub.3 complex and 3 ml of pyridine. 21 mg of the
compound of triethylammonium salt of methyl
2,5,6,8-tetrahydro-6-oxo-2-[(phenylamino)carbonyl]-5-(sulfoxy)-4H-4,7-met-
hanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.22H.sub.31N.sub.6O.sub.8S are obtained
(M=532.59 g). The corresponding yield is 35%.
[0360] LC/MS (negative electrospray), m/z: MH.sup.-=436.
[0361] proton NMR in DMSO-d.sub.6 at 300 MHz, chemical shift and
multiplicity: 3.80: CH.sub.3--O--CO; 5.17 (s):
CH.sub.3--O--CO--CH--N; 3.48 (d) and 3.59 (dd): N--CH.sub.2--CH--N,
4.91 (d): N--CH.sub.2--CH--C.dbd.; 8.41 (s): C.dbd.CH--N, 7.71 (d),
7.36 (t), 7.14 (t) for aromatic H, 10.40 (s): NH.
Example 7
Triethylammonium salt of
5,6-dihydro-6-oxo-N.sup.2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e-
][1,3]diazepine-2,8(8H)-dicarboxamide
[0362] Stage A
[0363] 0.445 g of the product of the isomer B obtained in Stage A
of Example 8 is dissolved in 10 ml of dioxane, in a round-bottomed
flask. 10 ml of water are then added, followed by 0.995 ml of
normal sodium hydroxide. An aqueous NaH.sub.2PO.sub.4 solution is
added to the reaction medium. The medium is extracted twice with
ethyl acetate. The organic phase is dried over magnesium sulfate,
filtered and the solvent is evaporated under reduced pressure. 460
mg of the compound
trans-2,5,6,8-tetrahydro-6-oxo-2-[(phenylamino)carbonyl]-5-(phenylmethoxy-
)-4H-4,7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylic acid
having the empirical formula C.sub.22H.sub.19N.sub.5O.sub.5 are
obtained (M=433.43 g). The yield is quantitative.
[0364] Stage B
[0365] 0.16 g of the product obtained in the preceding stage is
dissolved in 5 ml of DMF, in a round-bottomed flask placed under a
nitrogen atmosphere. 0.239 g of BOP, 0.073 g of HOBt, 0.039 g of
NH.sub.4Cl and 0.139 ml of DIEA are successively added. After
stirring for 2 h 30 min, ethyl acetate is added and the organic
phase is washed with water. The organic phase is then successively
washed with a tartaric acid solution at 10%, an NaHCO.sub.3
solution, a buffer solution of pH 7, and an aqueous NaCl solution.
The organic phase is dried over magnesium sulfate and then filtered
and the solvent is separated off under reduced pressure. 160 mg of
crude product are obtained, which product is taken up in ether to
give 100 mg of the compound
trans-5,6-dihydro-6-oxo-N.sup.2-phenyl-5-(phenylmethoxy)-4H-4,7-methanopy-
razolo[3,4-e][1,3]diazepine-2,8(8H)-dicarboxamide having the
empirical formula C.sub.22H.sub.20N.sub.6O.sub.4 (M=432.44 g). The
corresponding yield is 64%.
[0366] Stage C
[0367] The procedure is carried out as in Stage M of Example 1 with
0.09 g of the product obtained in the preceding Stage B, 0.018 g of
palladium on carbon, 2 ml of THF, 2 ml of methanol and 1 ml of
ethyl acetate. 74 mg of the compound
trans-5,6-dihydro-6-oxo-N.sub.2-phenyl-5-(phenylmethoxy)-4H-4,7-methanopy-
razolo[3,4-e][1,3]diazepine-2,8(8H)-dicarboxamide having the
empirical formula C.sub.15H.sub.14N.sub.6O.sub.4 are obtained
(M=342.32 g). The yield is quantitative.
[0368] Stage D
[0369] The procedure is carried out as in Stage M of Example 1 with
0.079 g of the product obtained in the preceding stage, 0.110 g of
the pyridine-SO.sub.3 complex and 2 ml of pyridine. 26 mg of the
compound of triethylammonium salt of
5,6-dihydro-6-oxo-N2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e][1,3-
]diazepine-2,8(8H)-dicarboxamide having the empirical formula
C.sub.20H.sub.19N.sub.7O.sub.7S are obtained (M=501.48 g). The
corresponding yield is 25%.
[0370] LC/MS (negative electrospray), m/z: M.sup.-=421.
Example 8
Triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-(phenylsulfonyl)-5-(sulfoxy)-4H-4,7-meth-
anopyrazolo[3,4-e][1,3]diazepine-8-carboxylate
[0371] Stage A
[0372] 0.30 g of the product obtained in Stage K of Example 1 is
dissolved in 5 ml of dichloromethane, in a round-bottomed flask
placed under an argon atmosphere. 0.19 ml of TEA and 0.242 g of
phenylsulfonyl chloride are added. After one hour, the reaction
medium is washed with an aqueous NaH.sub.2PO.sub.4 solution and the
organic phase is separated and then dried over magnesium sulfate
and filtered. The solvent is evaporated off under reduced pressure
to give 850 mg of crude product. The product is purified by
chromatography on silica eluting with a CH2Cl2/AcoEt/TEA 95/5/0.1
mixture. 128 mg of the compound methyl
trans-2,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-(phenylsulfonyl)-4H-4,-
7-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.22H.sub.20N.sub.4O.sub.6S are obtained
(M=468.49 g). The corresponding yield is 29%.
[0373] Stage B
[0374] The procedure is carried out as in Stage M of Example 1 with
0.125 g of the product obtained in the preceding stage, 0.156 g of
palladium on carbon, 3 ml of THF and 3 ml of methanol. 98 mg of the
compound methyl
trans-2,5,6,8-tetrahydro-5-hydroxy-6-oxo-2-(phenylsulfonyl)-4H-4,7-methan-
opyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.15H.sub.14N.sub.4O.sub.6S are obtained (M=378.37 g).
The corresponding yield is quantitative.
[0375] Stage C
[0376] The procedure is carried out as in Stage M of Example 1 with
0.079 g of the product obtained in the preceding stage, 0.10 g of
the pyridine-SO.sub.3 complex and 3 ml of pyridine. 3.6 mg of the
compound of triethylammonium salt of methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-(phenylsulfonyl)-5-(sulfoxy)-4H-4,7-meth-
anopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.20H.sub.19N.sub.5O.sub.9S.sub.2 are obtained
(M=547.53 g). The corresponding yield is 3.5%.
[0377] LC/MS (negative electrospray), m/z: M.sup.-=457.
Example 9
Di(triethylammonium) salt of
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-sulfoxy-4H-4,7-methanopyraz-
olo[3,4-e][1,3]diazepine-2(8H)-acetic acid
[0378] Stage A
[0379] 2.0 g of the product obtained in Stage K of Example 1 are
dissolved in 20 ml of dry acetonitrile in a round-bottomed flask.
3.1 ml of DIEA are added followed by 1.9 ml of allyl bromoacetate.
The medium is stirred overnight at 50.degree. C. and then ethyl
acetate is added. The reaction medium is washed with a tartaric
acid solution at 10% and then with an aqueous NaCl solution. The
organic phase is dried over magnesium sulfate, filtered and the
solvent is evaporated under reduced pressure. The crude product
obtained is purified by chromatography on silica, eluting with a
heptane/ethyl acetate/triethylamine, 1/1/0.1%, mixture. 1.48 g of
the compound 2-propenyl
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(phenylmethoxy)-4H-4,7-meth-
anopyrazolo[3,4-e][1,3]diazepine-2(8H)acetate having the empirical
formula C.sub.21H.sub.22N.sub.4O.sub.6 are obtained (M=426.43 g).
The corresponding yield is 57%.
[0380] Stage B
[0381] 0.084 g of the product obtained in the preceding stage is
dissolved in 1 ml of dichloromethane, in a round-bottomed flask. 2
mg of Pd(PPh.sub.3).sub.4 and 0.043 g of PhSiH.sub.3 are obtained.
After stirring for one hour, 3.5 mg of Pd(PPh.sub.3).sub.4 are
again stirred in 1 ml of methylene chloride. The reaction mixture
is next evaporated off and then taken up in a THF/water mixture.
Ethyl acetate and NaH.sub.2PO.sub.4 are added, and the organic
phase is then extracted; the latter is washed with water and then
dried over magnesium sulfate, filtered and the solvent is
evaporated off under reduced pressure. 90.8 mg of the compound
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-(phenylmethoxy)-4H-4,7-meth-
anopyrazolo[3,4-e][1,3]diazepine-2(8H)-acetic acid having the
empirical formula C.sub.18H.sub.18N.sub.4O.sub.6 are obtained
(M=386.37 g). The crude product is used as it is in the next
stage.
[0382] Stage C
[0383] The procedure is carried out as in Stage M of Example 1 with
0.090 g of the crude product obtained in the preceding stage, 0.036
g of palladium on carbon and 3 ml of ethanol. 77 mg of the compound
trans-5,6-dihydro-5-hydroxy-8-(methoxycarbonyl)-6-oxo-4H-4,7-methanopyraz-
olo[3,4-e][1,3]diazepine-2(8H)-acetic acid having the empirical
formula C.sub.11H.sub.12N.sub.4O.sub.6 are obtained (M=296.24 g).
The yield is quantitative.
[0384] Stage D
[0385] The procedure is carried out as in Stage M of Example 1 with
0.070 g of the product obtained in the preceding stage, 0.113 g of
the pyridine-SO.sub.3 complex and 1 ml of pyridine. The crude
product is purified on XAD4 resin, eluting with a water/acetone
100/0, 95/5, 50/50 gradient. 14 mg of the compound of
di(pyridinium) salt of
trans-5,6-dihydro-8-(methoxycarbonyl)-6-oxo-5-sulfoxy-4H-4,7-methanopyraz-
olo[3,4-e][1,3]diazepine-2(8H)acetic acid having the empirical
formula C.sub.17H.sub.27N.sub.50.sub.9S, C.sub.6H.sub.16N are
obtained (M=477.50 g). The corresponding yield is 13%.
[0386] LC/MS (negative electrospray), m/z: TR=3.12 min
M.sup.-=375.
Example 10
Pyridinium salt of methyl
trans-1-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate
[0387] Stage A
[0388] 0.188 g of the product obtained in Stage K of Example 1 is
dissolved in 30 ml of dichloromethane, in a round-bottomed flask
placed under an argon atmosphere at 0.degree. C. 70 .mu.l of
diphosgene are added and then after 1 h 15 min 0.49 ml of a
concentrated aqueous ammonia solution is added. After one hour,
methylene chloride is added to the reaction medium and the organic
phase is washed with an aqueous NaH.sub.2PO.sub.4 solution and then
with an aqueous NaCl solution. The organic phases are dried over
magnesium sulfate, filtered and the solvent is evaporated under
reduced pressure. The crude product obtained is purified by
chromatography on silica, eluting with a methylene chloride/ethyl
acetate/triethylamine, 8/2/0.1%, mixture, and then next eluting
with a dichloromethane/ethyl acetate/triethylamine, 7/3/0.1%,
mixture. After evaporation of the fractions, 32 mg of the isomer A
of compound methyl
trans-1-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-
-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate are obtained
with a yield of 15%, and 79 mg of the isomer B of the compound
methyl
trans-2-(aminocarbonyl)-2,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4H-4,7-
-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate with a yield of
37%. The empirical formulae of the isomers are
C.sub.17H.sub.17N.sub.5O.sub.5 (M=371.36 g).
[0389] Stage B
[0390] The procedure is carried out as in Stage M of Example 1 with
30 mg of the isomer A obtained in the preceding stage, 9 mg of
palladium on carbon, 2 ml of methanol and 0.5 ml of water. 22 mg of
the compound methyl
trans-1-(aminocarbonyl)-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-1H-4,7--
methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.10H.sub.11N.sub.5O.sub.5 are obtained
(M=281.23 g). The yield is quantitative.
[0391] Stage C
[0392] The procedure is carried out as in Stage M of Example 1 with
0.022 g of the product obtained in the preceding stage, 0.037 g of
the pyridine-SO.sub.3 complex and 2 ml of pyridine. The crude
product is purified on XAD4 resin with a water/acetone gradient. 13
mg of the compound of pyridinium salt of methyl
trans-1-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.15H.sub.16N.sub.6O.sub.8S are obtained (M=440.39 g).
The yield is 64%.
[0393] LC/MS (negative electrospray): TR=4.20 min MH.sup.-=360.
Example 11
Pyridinium salt of methyl
trans-2-(aminocarbonyl)-2,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate
[0394] Stage A
[0395] The procedure is carried out as in Stage M of Example 1 with
0.079 g of the isomer B obtained in Stage A of Example 10, 0.010 g
of palladium on carbon, 4 ml of methanol and 0.5 ml of water. 54 mg
of compound methyl
trans-2-(aminocarbonyl)-2,5,6,8-tetrahydro-5-hydroxy-6-oxo-4H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.10H.sub.11N.sub.5O.sub.5 are obtained (M=281.23 g).
The corresponding yield is 98%.
[0396] Stage B
[0397] The procedure is carried out as in Stage M of Example 1 with
0.059 g of the product obtained in the preceding stage, 0.1 g of
the pyridine-SO.sub.3 complex and 3 ml of pyridine. The crude
product is purified on XAD4 resin with a water/acetone gradient. 40
mg of the compound of pyridinium salt of methyl
trans-2-(aminocarbonyl)-2,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.16H.sub.15N.sub.6O.sub.8S are obtained (M=440.39 g).
The corresponding yield is 45%.
[0398] LC/MS (negative electrospray): TR=3.63 min MH.sup.-=360.
Example 12
Sodium salt of 1,1-dimethylethyl
2-(4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3-
]diazepin-1-yl)ethyl]carbamate
[0399] Stage A
[0400] 50 g of BOC--NH--NH.sub.2 are dissolved in 250 ml of
anhydrous DMF, in a round-bottomed flask placed under an inert
atmosphere. The medium is cooled to -10.degree. C., 16.5 g of
sodium hydride at 50% in oil are then added in small fractions.
[0401] Propylene bromide is then added and the medium is kept
stirred overnight at room temperature. Water and a 1 M sodium
hydrogen phosphate solution are then slowly added, followed by 200
ml of an AcOEt/heptane 2/1 mixture, and then the medium is
extracted and the organic phase is dried over magnesium
sulfate.
[0402] The medium is filtered and the solvent is next evaporated
off under reduced pressure. The crude product obtained is purified
on silica, eluting with a dichloromethane/AcOEt 95/5 mixture.
[0403] 24 g of pure 1,1-dimethylethyl
2-(2-propenyl)-hydrazinecarboxylate are thus recovered. The
corresponding yield is 76%.
[0404] Stage B
[0405] 24 g of the product obtained in Stage A are dissolved in 80
ml of AcOEt.
[0406] The medium is cooled to 0.degree. C., 332 ml of a 5.5 N
hydrochloric acid solution in AcOEt are then added. The medium is
stirred for 1 hour 30 minutes at room temperature, and then
filtered and washed with ether.
[0407] 15 g of (2-propenyl)hydrazine having the empirical formula
C.sub.3H.sub.8N.sub.2.2HCl are thus obtained in the form of white
crystals. The corresponding yield is 84%.
[0408] Stage C
[0409] 11 g of the product having the empirical formula
C.sub.14H.sub.21N.sub.3O.sub.4 obtained in Stage A2 of Example 1
are dissolved in 130 ml of ethanol.
[0410] 6.51 g of the product obtained in Stage B and 11.33 g of
potassium carbonate are added.
[0411] The suspension is stirred for 45 minutes, and then the
ethanol is evaporated off under reduced pressure. The residue is
solubilized in AcOEt, and then the organic phase is washed with
water, it is then dried over magnesium sulfate, filtered and the
solvent is evaporated off under reduced pressure.
[0412] 10.8 g of 1,1-dimethylethyl
3,5-dioxo-4-[[2-(2-propenyl)hydrazino]methylene]-1-piperidinecarboxylate
having the empirical formula C.sub.14H.sub.21N.sub.3O.sub.3 are
thus obtained (M=295.34 g). The corresponding yield is 80%.
[0413] Stage D
[0414] 10.8 g of the product obtained in Stage C are dissolved in
120 ml of toluene.
[0415] 1 g of p-toluenesulfonic acid monohydrate is added and the
medium is heated under reflux for one hour.
[0416] The medium is allowed to cool, it is poured into AcOEt, the
organic phase is washed with water and it is dried over magnesium
sulfate. The solvent is evaporated off under reduced pressure.
[0417] 8.5 g of crude product are thus obtained, which product is
purified by chromatography on silica, eluting with a heptane/AcOEt
2/1 mixture.
[0418] 7.5 g of 1,1-dimethylethyl
4,7-dihydro-4-oxo-1-(2-propenyl)-1H-pyrazolo[3,4-c]pyridine-6(5H)-carboxy-
late having the empirical formula C.sub.14H.sub.19N.sub.3O.sub.3
are thus recovered (M=277.33 g). The corresponding yield is
74%.
[0419] Stage E
[0420] 7.5 g of the product obtained in Stage D are introduced into
a round-bottomed flask. 4.74 g of O-benzylhydroxylamine are next
added, followed by 150 ml of pyridine. The medium is stirred for 1
hour at 20.degree. C. The solvent is next evaporated off under
reduced pressure and then the medium is diluted with
dichloromethane, washed with an aqueous tartaric acid solution at
10%, then with demineralized water. The organic phase is then dried
over sodium sulfate and the solvent is evaporated off under reduced
pressure. The crude product obtained is then chromatographed on
silica, eluting with a dichloromethane/AcOEt 95/5 mixture to give
9.72 g of 1,1-dimethylethyl
4,7-dihydro-4-[(phenylmethoxy)imino]-1-(2-propenyl)-1H-pyrazolo[3,4-c]pyr-
idine-6(5H)-carboxylate having the empirical formula
C.sub.21H.sub.26N.sub.4O.sub.3 (M=382.47 g). The corresponding
yield is 90%.
[0421] Stage F
[0422] 9.2 g of the product obtained in Stage E are introduced into
750 ml of methanol. The medium is cooled to around 0-5.degree. C.,
and 24.2 g of NaBH.sub.3CN and 36.51 ml of boron trifluoride
etherate are then added. The medium is stirred for 30 minutes,
while it is kept at 0-5.degree. C., the temperature is then allowed
to return to 20.degree. C. and the medium is stirred at this
temperature for 30 minutes. The reaction medium is next poured into
water saturated with sodium hydrogen carbonate. The medium is
stirred for 45 minutes, and then separated by decantation, the
organic phase is washed with demineralized water and it is dried
over sodium sulfate. The solvent is then evaporated off under
reduced pressure to give the crude product which is purified by
chromatography on silica, eluting with dichloromethane containing
2% acetone.
[0423] 5.3 g of 1,1-dimethylethyl
4,7-dihydro-4-[(phenylmethoxy)amino]-1-(2-propenyl)-1H-pyrazolo[3,4-c]pyr-
idine-6(5H)-carboxylate having the empirical formula
C.sub.21H.sub.28N.sub.4O.sub.3 are thus obtained (M=384.48 g). The
corresponding yield is 60%.
[0424] Stage G
[0425] The procedure is carried out as indicated in Stage I of
Example 1 with 5.25 g of the product obtained in Stage F and a 5.5
N hydrogen chloride solution. The procedure is carried out as
indicated in Stage J of Example 1 on the product obtained.
[0426] 3.95 g of
N-(phenylmethoxy)-1-(2-propenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyr-
idin-4-amine having the empirical formula C.sub.16H.sub.20N.sub.4O
are thus obtained (M=284.36 g). The corresponding yield is 90%.
[0427] Stage H
[0428] The procedure is carried out as indicated in Stage K of
Example 1 with 3.8 g of the product obtained in Stage G, 4.2 ml of
TEA and 0.8 ml of diphosgene.
[0429] 2.5 g of
5-(phenylmethoxy)-1-(2-propenyl)-4,5,7,8-tetrahydro-4,7-methanopyrazolo[3-
,4-e][1,3]diazepin-6(1H)one having the empirical formula
C.sub.17H.sub.18N.sub.4O.sub.2 are thus obtained (M=310.36 g). The
corresponding yield is 68%.
[0430] Stage I
[0431] 6 g (19.33 mmol) of the product obtained in the preceding
Stage H are dissolved in 180 ml of THF, 180 ml of tert-butanol and
60 ml of water. 3.92 g (29 mmol) of N-methylmorpholine N-oxide are
introduced therein, followed by 2.98 ml (0.579 mmol) of osmium
tetroxide. The medium is stirred for 54 hours at room temperature.
After evaporation of the THF, the medium is taken up in a 1 M
aqueous NaH.sub.2PO.sub.4 solution. The medium is extracted with an
ethyl acetate/heptane at 20% mixture and then with
dichloromethane/methylene chloride and THF. After drying the
organic phase over MgSO.sub.4 and then evaporating the solvents
under reduced pressure, 6.16 g of
1-(2,3-dihydroxypropyl)-1,4,5,8-tetrahydro-5-(phenylmethoxy)-6H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.17H.sub.20N.sub.4O.sub.4 are obtained (M=344.37 g). The
corresponding yield obtained is 93%.
[0432] Stage J
[0433] 6.13 g (17.8 mmol) of the product obtained in the preceding
stage I are dissolved in 140 ml of THF. 45 ml of methanol are then
added, followed by 45 ml of water. The solution obtained is cooled
to 0.degree. C. 6.08 g of sodium metaperiodate are then added. The
medium is stirred for 2 hours, while the temperature is allowed to
rise to 20.degree. C. After 2 hours, 1.52 g of sodium metaperiodate
are added and the medium is again stirred for 40 minutes. Once the
reaction is complete, 260 ml of a 1 M aqueous NaH.sub.2PO.sub.4
solution are added, and then the solution is saturated with solid
NaCl and extracted with THF and with an ethyl acetate/heptane at
30% mixture. The organic phase is washed with a saturated aqueous
NaH.sub.2PO.sub.4 solution and then dried over MgSO.sub.4. After
evaporation of the solvent under reduced pressure, 9.98 g of
4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,-
4-e][1,3]diazepine-1-acetaldehyde having the empirical formula
C.sub.16H.sub.16N.sub.4O.sub.4 are obtained (M=342.39 g). The yield
obtained is quantitative.
[0434] Stage K
[0435] 5.6 g of the product obtained in the preceding Stage J are
dissolved in 100 ml of ethanol and then 2.71 g of NaBH.sub.4 are
added, at 0.degree. C. in portions. The medium is stirred for 2
hours at 0.degree. C. and then the ethanol is evaporated off, ice,
methylene chloride and, little by little, a 1 M aqueous
NaH.sub.2PO.sub.4 solution are added. The gaseous emission is high.
The aqueous phase is then extracted with methylene chloride and the
organic phase is washed with a thiosulfate solution in order to
remove the NaIO.sub.4 residues. After drying the organic phase over
MgSO.sub.4, the solvents are evaporated off under reduced
pressure.
[0436] A solid residue is obtained which is crystallized from an
ethyl ether and isopropanol mixture. After filtration, 3.45 g of
1,4,5,8-tetrahydro-1-(2-hydroxyethyl)-5-(phenylmethoxy)-6H-4,7-methanopyr-
azolo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.16H.sub.18N.sub.4O.sub.3 are obtained (M=314.35 g. The
corresponding yield is 62%.
[0437] Stage L
[0438] 1.35 g (4.29 mmol) of the product obtained in the preceding
Stage K are dissolved in 50 ml of THF. 0.69 ml of pyridine are then
added at room temperature, followed by 1.46 g of
triphenylphosphine. 1.42 g of iodine are added in portions and
then, after 2 hours, 200 mg of iodine, 220 mg of triphenylphosphine
and 0.13 ml of pyridine are added. An NaH.sub.2PO.sub.4 solution is
poured into the medium and then extracted with an ethyl
acetate/heptane mixture, and the organic phase is washed with a
saturated aqueous NaCl solution. After evaporation of the solvents
under reduced pressure of the organic phase, 1.6 g of crude product
are obtained, which product is purified by liquid chromatography,
eluting with a dichloromethane/acetonitrile at 10% mixture. 1.60 g
of the product
1,4,5,8-tetrahydro-1-(2-iodoethyl)-5-(phenylmethoxy)-6H-4,7-methanopyrazo-
lo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.17H.sub.171N.sub.4O.sub.2 are obtained (M=424.24 g). The
yield obtained is 88%.
[0439] Stage M
[0440] 408 g of the product obtained in the preceding stage L are
dissolved in 4 ml of DMF. The solution is stirred at room
temperature in the presence of 128 mg of sodium azide. The medium
is stirred for 5 hours and then the solution is treated with an
aqueous NaH2PO.sub.4 solution and the medium is extracted with an
ethyl acetate/heptane 1/1 mixture. The organic phase is washed with
a saturated aqueous NaCl solution, and then the solvents are
evaporated off under reduced pressure. 328 mg of the compound
1-(2-azidoethyl)-1,4,5,8-tetrahydro-5-(phenylmethoxy)-6H-4,7-methanopyraz-
olo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.16H.sub.17N.sub.7O.sub.2 are obtained (M=339.36 g). The
corresponding yield is quantitative.
[0441] Stage N
[0442] 323 mg of the product obtained in the preceding stage are
dissolved in 10 ml of anhydrous THF. The solution is cooled to
0.degree. C. and then 300 mg of triphenylphosphine are added in
portions. The reaction medium is stirred at room temperature for 16
hours. Once the reaction is complete, 345 .mu.l of demineralized
water are added and the medium is stirred for several hours. After
treatment, the compound
1-(2-aminoethyl)-1,4,5,8-tetrahydro-5-(phenylmethoxy)-6H-4,7-methanopyraz-
olo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.16H.sub.19N.sub.5O.sub.2 is obtained (M=313.36 g).
[0443] Stage O
[0444] The compound obtained in the preceding stage is dissolved in
5 ml of anhydrous THF. 280 .mu.l of triethylamine are added
followed by 182 mg of Boc anhydride in solution in 0.5 ml of THF.
The reaction is stirred for 2 hours and then the reaction medium is
washed with NaH.sub.2PO.sub.4, and it is extracted with a mixture
of ethyl acetate containing 20% of heptane. The organic phase is
dried over magnesium sulfate, filtered and the solvent is then
evaporated off under reduced pressure. The oily residue obtained is
taken up in ether and triturated with pentane. After filtration of
the precipitated P.phi..sub.3O, the filtrate is evaporated off and
then purified by chromatography on silica, eluting with a toluene
isopropyl alcohol at 18 to 15% mixture. After evaporation, 362 mg
of the compound 1,1-dimethylethyl
[2-[4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,4-
-e][1,3]diazepin-1-yl]ethyl]carbamate having the empirical formula
C.sub.21H.sub.27N.sub.5O.sub.4 are obtained (M=413.48 g). The
corresponding yield is 81%.
[0445] Stage P
[0446] The procedure is carried out as in Stage M of Example 1 with
339 mg of the product obtained in the preceding stage, 750 mg of
palladium on carbon in 17 ml of ethanol/acetic acid mixture (1 drop
of acetic acid per 1 ml of ethanol). 281 mg of compound
1,1-dimethylethyl
[2-(4,5,6,8-tetrahydro-5-hydroxy-6-oxo-1H-4,7-methanopyrazolo[3,4-e][1,3]-
diazepin-1-yl)ethyl]carbamate having the empirical formula
C.sub.14H.sub.28N.sub.5O.sub.4 are obtained (M=323.35 g). The yield
obtained is quantitative.
[0447] Stage Q
[0448] The procedure is carried out as in Stage M of Example 1 with
the crude product obtained in the preceding stage, 400 mg of the
pyridine-SO.sub.3 complex and 6 ml of pyridine. The pyridinium
salts of the expected product are obtained.
[0449] Stage R
[0450] The pyridinium salt obtained in the preceding stage is taken
up in an aqueous solution containing 10% of THF. The solution is
passed over 90 g of Dowex resin activated beforehand with sodium
hydroxide. The fractions are then lyophilized and 60 mg of crude
product are obtained, which product is purified from acetone. After
evaporation, the residue is redissolved in 1 ml of demineralized
water and then attached. 255 mg of compound of sodium salt of
1,1-dimethylethyl
2-(4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3-
]diazepin-1-yl)ethyl]carbamate having the empirical formula
C.sub.14H.sub.20N.sub.50.sub.7S Na are obtained (M=425.20 g). The
yield obtained is 73%.
[0451] proton NMR, DMSO-d.sub.6, 300 MHz (chemical shift and
multiplicity) 1.38 (s): 0-C--(CH.sub.3).sub.3; 3.07 (d) and 3.49
(dd): N--CH.sub.2--CH; 4.67 (d): N--CH.sub.2--CH; 3.94 (m):
N--CH.sub.2--CH.sub.2--NH; 3.20 (m): N--CH.sub.2--CH.sub.2--NH;
6.95 (tl): N--CH.sub.2--CH.sub.2--NH; 4.26 and 4.33:
N--CH.sub.2--C.dbd.; 7.39 (s): N.dbd.CH.
[0452] LC/MS (negative electrospray), m/z: M.sup.-=402.1,
(2M+Na.sup.+).sup.-=827.2.
Example 13
Sodium salt of
1-(2-aminoethyl)-1,4,5,8-tetrahydro-5-(sulfoxy)-6H-4,7-methanopyrazolo[3,-
4-e][1,3]diazepin-6-one
[0453] Stage A
[0454] 140 mg of the product obtained in Stage R of Example 12 are
dissolved in 2 ml of trifluoroacetic acid. The trifluoroacetic acid
solution is cooled beforehand to 0.degree. C. The medium is stirred
for 10 minutes at 0.degree. C. and then the trifluoroacetic acid is
evaporated off. The residue is treated more than once by adding
toluene and the latter is evaporated off in order to remove the
residual trifluoroacetic acid. The residue is washed with an
H.sub.2O/THF at 10% mixture and then dried under vacuum. 90 mg of
the compound of sodium salt of
1-(2-aminoethyl)-1,4,5,8-tetrahydro-5-(sulfoxy)-6H-4,7-methanopyrazolo-
[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.9H.sub.12N.sub.5O.sub.5S Na are obtained (M=325.28 g).
[0455] proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity. 3.09 (d) and 3.52 (dd): N--CH.sub.2--CH; 4.72 (d):
N--CH.sub.2--CH; 4.38 (broad s): N--CH.sub.2--C.dbd.; 3.22 (broad
t), 4.13 (m): N--CH.sub.2--CH.sub.2--NH.sub.2; 7.86 (broad s):
N--CH.sub.2--CH.sub.2--NH.sub.2; 7.51 (s): N.dbd.CH.
[0456] LC/MS (negative electrospray), m/z: M.sup.-=302.1 g,
(2M.sup.-+H.sup.+).sup.-=605.0 g and
(2M.sup.-+Na.sup.+).sup.-=627.1 g.
Example 14
Sodium salt of
1-[2-[(aminocarbonyl)oxy]ethyl]-1,4,5,8-tetrahydro-5-(sulfoxy)-6H-4,7-met-
hanopyrazolo[3,4-e][1,3]diazepin-6-one
[0457] Stage A
[0458] 0.172 g of the compound obtained in Stage K of Example 12 is
dissolved in dichloromethane. 122 mg of DMAP and 202 mg of
p-NO.sub.2 PhO--COCl are added at 0.degree. C. The medium is
stirred for one hour at 0.degree. C. under an argon atmosphere and
then evaporated to dryness and the residue is solubilized in DMF.
Gaseous NH.sub.3 is bubbled through for 20 seconds and the medium
is stirred for 5 minutes. The yellow suspension obtained is poured
into ethyl acetate and washed several times with an aqueous
NaHCO.sub.3 solution at 10%. The organic phase is evaporated off
and the residue is reextracted with THF. After evaporation of the
THF, the residue is taken up in ethyl acetate and 80 mg of white
crystals of the compound 1-[2-[(aminocarbonyl)
oxy]ethyl]-1,4,5,8-tetrahydro-5-(phenylmethoxy)-6H-4,7-methanopyrazolo[3,-
4-e][1,3]diazepin-6-one having the empirical formula
C.sub.17H.sub.19N.sub.9O.sub.4 are obtained (M=357.37 g). The
corresponding yield is 81%.
[0459] Stage B
[0460] The procedure is carried out as in Stage M of Example 1 with
0.070 g of the product obtained in the preceding stage and 1.5 ml
of acetic acid. 52 mg of the product
1-[2-[(aminocarbonyl)oxy]ethyl]-1,4,5,8-tetrahydro-5-hydroxy-6H-4,7-metha-
nopyrazolo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.10H.sub.13N.sub.5O.sub.4 are obtained (M=267.25 g). The yield
is quantitative.
[0461] Stage C
[0462] The procedure is carried out as in Stage M of Example 1 with
0.052 g of the product obtained in the preceding stage, 0.070 g of
the pyridine-SO.sub.3 complex and 2 ml of pyridine. The pyridinium
salt of the expected compound is obtained; the latter is then
treated as in Stage R of Example 12 on Dowex resin and 62 mg are
obtained in the form of yellow crystals of the compound of sodium
salt of
1-[2-[(aminocarbonyl)oxy]ethyl]-1,4,5,8-tetrahydro-5-(sulfoxy)-6H-4,7-met-
hanopyrazolo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.10H.sub.12N.sub.5O.sub.7S Na (M=346.30+22.99 g). The yield
obtained is 78%.
[0463] LC/MS (negative electrospray), m/z: M.sup.-346.1
[0464] proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 3.11 (d) and 3.49 (dd): N--CH.sub.2--CH; 4.68 (d):
N--CH.sub.2--CH; 4.12 (m): N--CH.sub.2--CH.sub.2--O; 6.54 (broad
s): NH.sub.2 and 7.39 (s): N.dbd.CH.
Example 15
Sodium salt of
4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]di-
azepine-1-acetamide
[0465] Stage A
[0466] 0.54 g of the product obtained in Stage J of Example 12 is
dissolved in acetonitrile. A solution of 30 mg of NaH.sub.2PO.sub.4
in 0.3 ml of water is added. A 0.189 ml solution of an
H.sub.2O.sub.2 solution at 30% is then added, and finally a
solution of 0.22 g of NaO.sub.2Cl in 2 ml of water is added
dropwise over 30 minutes. The medium is kept stirred at room
temperature for 4 hours. An aqueous NaHCO.sub.3 solution is then
added and the medium is extracted several times with ethyl acetate.
The aqueous phase is treated with aqueous NaHSO.sub.4 and then
extracted with an ethyl acetate-THF mixture. The organic phase is
dried over magnesium sulfate, filtered and, after evaporation of
the solvent, 0.290 mg is obtained in the form of white crystals of
the compound
4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,4-e][-
1,3]diazepine-1-acetic acid having the empirical formula
C.sub.16H.sub.16N.sub.4O.sub.4 (M=328.33 g). The corresponding
yield is 52%.
[0467] Stage B
[0468] 0.29 g of the compound obtained in the preceding stage is
dissolved in 32 ml of DMF. 0.59 g of BOP is added followed by 0.188
g of HOBT. The medium is stirred for 5 minutes and then 0.099 g of
NH.sub.4Cl is added followed by 0.64 ml of diisopropylethylamine.
The medium is stirred for two hours at room temperature and then
the reaction medium is poured into 0.1 N hydrochloric acid and the
medium is extracted with THF. The organic phase is washed with an
NHCO.sub.3 solution and then the organic phase is dried over
magnesium sulfate and the solvent is evaporated off under reduced
pressure. A crude product is obtained which is taken up in
methanol. 0.066 g is obtained in the form of white crystals of
compound
4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,4-e][-
1,3]diazepine-1-acetamide, having the empirical formula
C.sub.16H.sub.17N.sub.5O.sub.3 (M=327.35 g). The corresponding
yield is 23%.
[0469] Stage C
[0470] The procedure is carried out as in Stage M of Example 1 with
56 mg of the product obtained in the preceding stage, 1 ml of
acetic acid and 20 mg of palladium on carbon. 48 mg are obtained in
the form of white crystals of the compound
4,5,6,8-tetrahydro-5-hydroxy-6-oxo-1H-4,7-methanopyrazolo[3,4-e][1,3]diaz-
epine-1-acetamide having the empirical formula
C.sub.9H.sub.11N.sub.5O.sub.3 (M=237.22 g). The corresponding yield
is quantitative.
[0471] Stage D
[0472] The procedure is carried out as in Stage M of Example 1 with
0.048 g of the compound obtained in the preceding stage, 1.5 ml of
pyridine and 0.1 g of the pyridine-SO.sub.3 complex. 33 mg of the
expected pyridine salt are obtained.
[0473] Stage E
[0474] The procedure is carried out as in Stage R of Example 12 and
the sodium salt of the expected compound of sodium salt of
4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]di-
azepine-1-acetamide having the empirical formula
C.sub.9H.sub.10N.sub.5O.sub.6SNa is obtained (M=316.27 g+23 g).
[0475] LC/MS (negative electrospray) M.sup.-=316.
[0476] proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 3.07 (d), 3.49 (dd): N--CH.sub.2--CH; 4.68 (d):
N--CH.sub.2--CH; 4.23 and 4.37: N--CH.sub.2--C.dbd.; 4.59 and 4.67:
CH.sub.2--CO--NH.sub.2; 7.36 (s): N.dbd.CH.
Example 16
Disodium salt of
1,4,5,8-tetrahydro-5-(sulfoxy)-1-[2-(sulfoxy)ethyl]-6H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepin-6-one
[0477] Stage A
[0478] 0.080 g of the product obtained in Stage K of Example 12 is
solubilized in 1 ml of ethanol and 0.5 ml of THF. 20 mg of 10%
palladium on carbon are added and the medium is placed under
hydrogen. After stirring for 4 hours at room temperature the
catalyst is filtered off and the solution is evaporated to dryness.
0.059 g of a resin is obtained which is used as it is in the next
step.
[0479] Stage B
[0480] 0.059 mg of the resin obtained in the preceding stage is
solubilized to 2 ml of pyridine in the presence of 0.250 g of
pyridine-SO.sub.3 complex. After stirring overnight at room
temperature, the solution is evaporated to dryness and the residue
is filtered on Dowex resin prepared beforehand with sodium
hydroxide, the elution is carried out with a water-THF, 90/10,
mixture. After evaporation to dryness of the fraction, the residue
is taken up in methanol and then in ether. 0.70 g is obtained in
the form of yellow crystals of the disodium salt of
1,4,5,8-tetrahydro-5-(sulfoxy)-1-[2-(sulfoxy)ethyl]-6H-4,7-methan-
opyrazolo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.9H.sub.10N.sub.4O.sub.9S.sub.2 2NA (M=382.33+46 g). The yield
obtained is 65%.
[0481] proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 3.02 (d), 3.47 (dd): N--CH.sub.2--CH; 4.67 (d):
N--CH.sub.2--CH; 3.95 (m), 4.13 (m): N--CH.sub.2--CH.sub.2--O; 4.32
and 4.41: N--CH.sub.2--C.dbd.; 7.32 (s): N.dbd.CH.
[0482] LC/MS (negative electrospray) (M.sup.2-+Na).sup.-=405.0 g.
(M.sup.2-+H).sup.-=383.1 g.
Example 17
Sodium salt of
4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]di-
azepine-1-carboxamide
[0483] Stage A
[0484] 1.6 g of the product obtained in Stage L of Example 12 are
dissolved in 16 ml of anhydrous DMF. 260 mg of potassium cyanide
are added and the medium is stirred at room temperature for 20
hours. The reaction medium is washed with water and then extracted
with an ethyl acetate/heptane at 20% mixture. The organic phase is
dried over magnesium sulfate and then, after evaporation of the
solvents under reduced pressure, a crude residue is obtained which
is purified by chromatography on silica, eluting with first of all
dichloromethane and then a dichloromethane/methanol at 10% mixture.
After evaporation of the fractions containing the expected product,
1.20 g of
4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazolo[3,4-e][-
1,3]diazepine-1-propanenitrile having the empirical formula
C.sub.17H.sub.17N.sub.5O.sub.2 are obtained (M=323.36 g). The
corresponding yield is 98%.
[0485] Stage B
[0486] 2.15 g of the product obtained in the preceding stage are
dissolved in 20 ml of anhydrous DMF. The solution is cooled to
0.degree. C. and then 290 mg of NaH at 50% in oil are added. The
medium is stirred for 3 h 30 min at 0.degree. C. The solution is
treated with NaH.sub.2PO.sub.4 and extracted with an ethyl
acetate/heptane at 20% mixture. The organic phases are dried over
magnesium sulfate, filtered and the solvent is evaporated off under
reduced pressure. 1.19 g of compound
1,4,5,8-tetrahydro-5-(phenylmethoxy)-6H-4,7-methanopyrazolo[3,4-e][1,3]di-
azepin-6-one having the empirical formula
C.sub.14H.sub.14N.sub.4O.sub.2 are obtained (M=270.29 g). The
corresponding yield is 42%.
[0487] Stage C
[0488] A solution cooled to 0.degree. C. of 451 mg of the product
obtained in the preceding stage is prepared in 45 ml of anhydrous
methylene chloride. 700 .mu.l of triethylamine are added to this
solution followed by 201 .mu.l of diphosgene, still at 0.degree. C.
The medium is stirred for 2.5 hours at 0.degree. C. and then
ammonia is bubbled through for 20 minutes at 0.degree. C. The
reaction medium is treated with NaH.sub.2PO.sub.4 and then the
medium is evaporated to dryness. The residue is triturated in
isopropyl ether and pentane and is then isolated by filtration. The
solid residue is purified by chromatography on silica, eluting with
a methylene chloride/methanol, 90/10, mixture. 200 mg of the
compound
4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-1H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-1-carboxamide having the empirical formula
C.sub.15H.sub.15N.sub.5O.sub.3 are obtained (M=313.32 g). The
corresponding yield is 38%.
[0489] Stage D
[0490] The procedure is carried out as in Stage M of Example 1,
with 190 mg of the product obtained in the preceding stage, 475 mg
of palladium on carbon and 10 ml of ethanol in the presence of 1%
acetic acid. 150 mg of compound
4,5,6,8-tetrahydro-5-hydroxy-6-oxo-1H-4,7-methanopyrazolo[3,4-e]-
[1,3]diazepine-1-carboxamide are obtained. The corresponding yield
is quantitative.
[0491] Stage E
[0492] The procedure is carried out as in Stage M of Example 1 with
150 mg of the product obtained in the preceding stage, 427 mg of
the pyridine-SO.sub.3 complex and 3 ml of pyridine. 130 mg of the
expected pyridinium salt are obtained.
[0493] Stage F
[0494] The procedure is carried out as in Stage R of Example 12
starting with 130 mg of the pyridinium salt obtained in the
preceding stage in the presence of Dowex resin. 130 mg of the
compound of sodium salt of
4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]di-
azepine-1-carboxamide having the empirical formula
C.sub.8H.sub.8N.sub.5O.sub.6S,Na are obtained (M=325.24 g).
[0495] LC/MS (negative electrospray): m/z
[0496] MH.sup.-=302; MH.sup.---CONH.sub.2=259
[0497] proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 3.22 (d), 3.48 (dd), 3.25 (d) and 3.56 (dd):
N--CH.sub.2--CH; 4.73 (d) and 4.79 (d): N--CH.sub.2--CH; 4.22 and
4.36 (AB), 4.45 and 4.54 (AB): N--CH.sub.2.dbd.C; 7.76 (broad s),
7.84 (broad s), 7.90 (broad s), 7.94 (broad s): .dbd.OCNH.sub.2;
7.69 (s), 8.16 (s): N.dbd.CH--.
Example 18
Sodium salt of
1,4,5,8-tetrahydro-1-[(4-methoxyphenyl)methyl]-5-(sulfoxy)-6H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepin-6-one
[0498] Stage A
[0499] The procedure is carried out as in Stage C of Example 12
with 7.8 g of the product obtained in Stage A of Example 1, 6.03 g
of the product obtained in Stage A1 of Example 1, 2.93 g of
NaHCO.sub.3 and 100 ml of ethanol. 8.74 g are obtained in the form
of a beige powder of the compound 1,1-dimethyl
4-[[2-[(4-methoxyphenyl)methyl]hydrazino]methylene]-3,5-dioxo-1-piperidin-
ecarboxylate having the empirical formula
C.sub.19H.sub.25N.sub.3O.sub.5 (M=375.43 g).
[0500] Stage B
[0501] The procedure is carried out as in Stage D of Example 12
with 8.74 g of the product obtained in the preceding stage, 800 mg
of para-toluenesulfonic acid and 250 ml of toluene. 5.30 g of the
compound 1,1-dimethylethyl
1,4,5,7-tetrahydro-1-[(4-methoxyphenyl)methyl]-4-oxo-6H-pyrazolo[3,4-c]py-
ridine-6-carboxylate having the empirical formula
C.sub.19H.sub.23N.sub.3O.sub.4 are obtained (M=357.41 g). The
corresponding yield is 63%.
[0502] Stage C
[0503] The procedure is carried out as in Stage E of Example 12
with 5.3 g of the product obtained in the preceding stage, 1.79 g
of O-benzylhydroxylamine hydrochloride and 5 ml of pyridine. 6.26 g
of compound 1,1-dimethylethyl
1,4,5,7-tetrahydro-1-[(4-methoxyphenyl)methyl]-4-[(2-propenyloxy)imino]-6-
H-pyrazolo[3,4-c]pyridine-6-carboxylate having the empirical
formula C.sub.22H.sub.28N.sub.4O.sub.4 are obtained (M=412.49 g).
The corresponding yield is quantitative.
[0504] Stage D
[0505] The procedure is carried out as in Stage F of Example 12
with 300 mg of the product obtained in the preceding stage, 735 mg
of NaBH.sub.3CN, 920 .mu.l of Et.sub.2OBF.sub.3 and 15 ml of
methanol. 55 mg of the compound 1,1-dimethylethyl
1,4,5,7-tetrahydro-1-[(4-methoxyphenyl)methyl]-4-[(2-propenyloxy)amino]-6-
H-pyrazolo[3,4-c]pyridine-6-carboxylate having the empirical
formula C.sub.22H.sub.30N.sub.4O.sub.4 are obtained (M=414.51 g).
The yield is 58%.
[0506] Stage E
[0507] The procedure is carried out as in Stage G of Example 12
with 3.28 g of the product obtained in the preceding stage, 10 ml
of ethyl acetate, 14.2 ml of an ethyl acetate/hydrochloric acid
mixture, and 11.8 ml of 2 N sodium hydroxide. 2.34 g of the
compound
4,5,6,7-tetrahydro-1-[(4-methoxyphenyl)methyl]-4-[(2-propenyloxy)amino]-1-
H-pyrazolo[3,4-c]pyridine having the empirical formula
C.sub.17H.sub.22N.sub.4O.sub.2 are obtained (M=314.39 g). The
corresponding yield is 94%.
[0508] Stage F
[0509] The procedure is carried out as in Stage H of Example 12
with 2.29 g of the product obtained in the preceding stage, 800 ml
of acetonitrile, 439 .mu.l of diphosgene and 2.1 ml of
triethylamine. 1.79 g of compound
1,4,5,8-tetrahydro-1-[(4-methoxyphenyl)methyl]-5-(2-propenyloxy)-6H-4,7-m-
ethanopyrazolo[3,4-e][1,3]diazepin-6-one having the empirical
formula C.sub.18H.sub.20N.sub.4O.sub.3 are obtained (M=340.39 g).
The corresponding yield is 72%.
[0510] Stage G
[0511] 1.5 g of the product obtained in the preceding stage are
dissolved in 30 ml of dichloromethane, in a round-bottomed flask
placed under an argon atmosphere. 504 .mu.l of acetic acid and 2.6
g of Pd(PPh.sub.3).sub.4 are then successively introduced therein.
The medium is stirred for 45 minutes at room temperature and then
30 ml of anhydrous pyridine are added, followed by 2.8 g of the
pyridine-SO.sub.3 complex. The medium is stirred for 2 hours at
room temperature. The reaction medium is evaporated to dryness and
it is taken up several times in toluene in order to carry away the
para-azeotropic pyridine. The residue is taken up in methylene
chloride, washed with water, dried over magnesium sulfate and then
evaporated to dryness. The residue is purified by chromatography on
silica, eluting with pure methylene chloride and then a methylene
chloride/acetone, 98/2, mixture, and then eluting methylene
chloride/acetone, 92/8, and finally eluting methylene
chloride/acetone/triethylamine, 0.6%. After evaporation of the
fractions, 2.22 g of the expected phosphonium salt are
obtained.
[0512] Stage H
[0513] The procedure is carried out as in Stage R of Example 12
with the phosphonium salt obtained in preceding stage and 500 g of
Dowex resin. 1.29 g of sodium salt of
1,4,5,8-tetrahydro-1-[(4-methoxyphenyl)methyl]-5-(sulfoxy)-6H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.15H.sub.15N.sub.4O.sub.6S,Na are obtained (M=402.36 g). The
corresponding yield is 77%.
[0514] LC/MS (negative electrospray): m/z
[0515] M.sup.-=379.1; (2M+Na).sup.-=781.2
[0516] proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 3.09 (d), 3.45 (dd): N--CH.sub.2--CH; 4.67 (d):
N--CH.sub.2--CH; 3.73 (s): CH.sub.3--O-Ph; 4.19 and 4.29 (AB):
N--CH.sub.2--CN.dbd.C, 5.07 and 5.14 (AB): N--CH.sub.2-Ph; 6.88 and
7.13 (AA'BB') the 4 aromatic H; 7.39(s) N.dbd.CH.
Example 19
Sodium salt of methyl
trans-2-(4-fluorophenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate
[0517] Stage A
[0518] 48.14 g (0.281 mol) of methyl alpha-amino-2-thiopheneacetate
having the empirical formula C.sub.7H.sub.19NO.sub.2S (prepared
from commercially available alpha-aminothiophene acetic acid
according to a technique similar to that described in J. Med.
Chem., 26, 1267-1277 (1983)) are dissolved in 930 ml of
acetonitrile.
[0519] 38.8 g of potassium carbonate (0.281 mol) are added,
followed by 55.5 ml of BrCH.sub.2CO.sub.2tBu (0.337 mol).
[0520] The medium is heated at 70.degree. C. for 6 and a half
hours, and then the temperature is allowed to return to 20.degree.
C. and the insolubles are removed by filtration. The medium is
partially concentrated under reduced pressure, taken up in 550 ml
of AcOEt, washed with water and then with a saturated sodium
chloride solution. The organic phase is dried over sodium sulfate,
filtered and the solvent is evaporated off under reduced
pressure.
[0521] 90 g of methyl
alpha-[[[(1,1-dimethylethoxy)carbonyl]methyl]amino]-2-thiopheneacetate
having the empirical formula C.sub.13H.sub.19NO.sub.4S are thus
obtained (M=285.36 g).
[0522] Stage B
[0523] 90 g of the product obtained in Stage A, 620 ml of anhydrous
THF and 61.7 ml of diisopropylethylamine are introduced into a
round-bottomed flask placed under an argon atmosphere.
[0524] The medium is cooled to around 0-5.degree. C., and then 25.2
ml of methyl chloroformate are added. The medium is left in contact
for 1 hour 30 minutes at 20.degree. C. The medium is next diluted
with AcOEt, and then washed with an aqueous tartaric acid solution
at 10% and with demineralized water.
[0525] The organic phase is next dried over magnesium sulfate,
filtered and the solvent is evaporated off under reduced pressure.
70.9 g of methyl alpha-[[[(1,1-dimethylethoxy)carbonyl]methyl]
(methoxycarbonyl)amino]-2-thiopheneacetate having the empirical
formula C.sub.15H.sub.21NO.sub.6S are recovered (M=343.40 g). The
corresponding yield in stages A and B is 73.4%.
[0526] Stage C
[0527] 70 g of the product obtained in Stage B are introduced into
a round-bottomed flask and the medium is cooled to around
0-5.degree. C. and 900 ml of trifluoroacetic acid/dichloromethane
1/1 mixture are added. The medium is left in contact at 20.degree.
C. for 1 hour.
[0528] 75 g of a crude product are obtained, which product is
purified in the following manner. 75 g of product are introduced
into 300 ml of ether, and then 33 ml of cyclohexylamine (0.29 mol)
are added dropwise at 20.degree. C.
[0529] The salt which precipitated is filtered off and washed twice
with 50 ml of ether.
[0530] The product obtained is redissolved in 200 ml of water, then
36 ml of 6 N hydrochloric acid are added dropwise at 20.degree. C.
and then the medium is separated by decantation, and the aqueous
phase extracted twice with 300 ml of AcOEt.
[0531] The aqueous phases are combined and they are washed with
water, and then with a saturated sodium chloride solution.
[0532] The organic phase is filtered and dried over magnesium
sulfate.
[0533] The solvent is evaporated off under reduced pressure.
[0534] 59.95 g of methyl
alpha-[(carboxymethyl)methoxycarbonyl)amino]-2-thiopheneacetate
having the empirical formula C.sub.11H.sub.13NO.sub.6S are thus
obtained (M=287.29 g). The corresponding yield is quantitative.
[0535] Stage D
[0536] 49.76 g of the acid obtained in Stage C and then 57 ml of
SOCl.sub.2 are introduced into a round-bottomed flask equipped with
magnetic stirring, a condenser and a sodium chloride tube.
[0537] The medium is heated to 70.degree. C. and kept at this
temperature for 4 hours.
[0538] The medium is evaporated to dryness under reduced
pressure.
[0539] 44.5 g of methyl
2,5-dioxo-alpha-(2-thienyl)-3-oxazolidineacetate having the
empirical formula C.sub.10H.sub.9NO.sub.5S are thus obtained
(M=255.25 g). The yield is quantitative.
[0540] Stage E
[0541] 44.5 g of the product obtained in Stage D and 500 ml of
dichloromethane are introduced into a round-bottomed flask placed
under a nitrogen atmosphere.
[0542] 92.3 g of aluminum chloride are then added.
[0543] The medium is kept stirred overnight at 20.degree. C., and
then diluted with dichloromethane and brought to pH 8-9 by addition
of a tartaric acid and aqueous ammonia solution while cooling. The
medium is next diluted with 1 l of water and 1 l of
dichloromethane.
[0544] The medium is separated by decantation, extracted several
times with dichloromethane, and the organic phases are combined and
they are dried over sodium sulfate.
[0545] The solvent is then evaporated off under reduced
pressure.
[0546] 32.5 g of methyl
4-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-7-carboxylate having
the empirical formula C.sub.9H.sub.9NO.sub.3S are thus obtained
(M=211.24 g). The corresponding yield is 88%.
[0547] Stage F
[0548] 30 g of the product obtained in Stage E and 360 ml of THF
are introduced into a round-bottomed flask.
[0549] The medium is cooled to 0.degree. C., and then 93 g of
(BOC).sub.2O are added and the reaction is allowed to proceed for 2
hours 30 minutes at 20.degree. C.
[0550] The medium is then diluted with AcOEt, washed with an
aqueous tartaric acid solution at 10%, and then with demineralized
water.
[0551] The organic phase is then dried over magnesium sulfate.
[0552] The solvent is evaporated off under reduced pressure and the
medium is then purified by chromatography on silica.
[0553] 27.91 g of 6-(1,1-dimethylethyl) and 7-methyl
4,5-dihydro-4-oxothieno[2,3-c]pyridine-6(7H), 7-dicarboxylate
having the empirical formula C.sub.14H.sub.17NO.sub.5S are thus
obtained (M=311.36 g). The corresponding yield is 63%.
[0554] Stage G
[0555] 50 g of the product obtained in Stage F (67.1 mmol) and 1500
ml of methanol are introduced into a round-bottomed flask placed
under a nitrogen atmosphere and cooled by an ice bath. 1.6 g of
NaBH.sub.4 are next added. The medium is stirred while allowing the
temperature to return to 20.degree. C. over 30 minutes. The medium
is next diluted with 225 ml of dichloromethane, washed with an
aqueous tartaric acid solution at 10%, and then with demineralized
water, and the organic phase is dried over sodium sulfate. The
solvent is evaporated off under reduced pressure. 51.4 g of
6-(1,1-dimethylethyl) and
7-methyl-4,7-dihydro-4-hydroxythieno[2,3-c]pyridine-6,7(5H)-dicarboxylate
having the empirical formula C.sub.14H.sub.15NO.sub.5S are obtained
(M=313.38 g).
[0556] Stage H
[0557] 59.7 g of the product obtained in Stage G and 583 ml of
dichloromethane are introduced into a round-bottomed flask placed
under an argon atmosphere.
[0558] The medium is cooled to around 0-5.degree. C., and then 39.3
ml of TEA and 48.7 g of (CH.sub.3SO.sub.2).sub.2O are successively
added. The temperature is allowed to return to 20.degree. C. and
the medium is kept stirred for 1 h 20 min at 20.degree. C.
[0559] The medium is diluted with dichloromethane, and then washed
with an aqueous tartaric acid solution at 10% and with
demineralized water. The organic phase is dried over sodium
sulfate.
[0560] The solvent is next evaporated under reduced pressure. 68.9
g of benzyl-O--NH.sub.2 are then added, and the medium is left in
contact at 0-5.degree. C. for 72 hours.
[0561] The medium is next diluted with dichloromethane and washed
with an aqueous tartaric acid solution at 10% and then with
demineralized water.
[0562] The organic phase is dried over sodium sulfate and the
solvent is evaporated off under reduced pressure.
[0563] The dry extract obtained is purified by chromatography on
silica, eluting with a dichloromethane/AcOEt 98/2 mixture.
[0564] 47.0 g of 6-(1,1-dimethylethyl) and 7-methyl
4,7-dihydro-4-[(phenylmethoxy)amino]thieno[2,3-c]pyridine-6,7(5H)-dicarbo-
xylate having the empirical formula C.sub.21H.sub.26O.sub.5N.sub.2S
are obtained (M=418.515 g). The corresponding yield is 60.2%.
[0565] Stage I
[0566] 47 g of the product obtained in Stage H are dissolved in 79
ml of AcOEt and the medium is cooled to 0.degree. C.
[0567] 261 ml of a saturated solution of gaseous HCl in acetate are
added. The medium is left in contact for 1 hour at 20.degree.
C.
[0568] The solvent is evaporated off under reduced pressure and
then the product is crystallized from ethyl ether.
[0569] 44.12 g of methyl
4,5,6,7-tetrahydro-4-[phenylmethoxy)amino]thieno[2,3-c]pyridine-7-carboxy-
late hydrochloride having the empirical formula
C.sub.16H.sub.20N.sub.2O.sub.3S.sub.2Cl.sub.2 are obtained
(M=391.318 g).
[0570] Stage J
[0571] 44.1 g of the product obtained in Stage I are suspended in
1000 ml of dichloromethane. 35 ml of a concentrated solution of
aqueous ammonia are added. The medium is separated by decantation,
washed with demineralized water and the organic phase is dried over
sodium sulfate. The solvent is then separated off under reduced
pressure.
[0572] 34.6 g of methyl
4,5,6,7-tetrahydro-4-[(phenylmethoxy)amino]thieno[2,3-c]pyridine-7-carbox-
ylate having the empirical formula C.sub.16H.sub.18N.sub.2O.sub.3S
are obtained (M=318.4 g). The corresponding yield is 96.7%.
[0573] Stage K
[0574] 34.1 g of the product obtained in Stage J, 8.8 l of
acetonitrile and 30.8 ml of TEA are introduced into a
round-bottomed flask placed under an argon atmosphere and cooled by
an ice bath.
[0575] The medium is stirred for 2 minutes and 6.5 ml of diphosgene
are then introduced therein.
[0576] The solution is stirred at 20.degree. C. for 1 hour.
[0577] The medium is diluted with AcOEt and washed with a tartaric
acid solution at 10% and then with water.
[0578] The organic phase is dried over magnesium sulfate and the
solvent is evaporated off under reduced pressure.
[0579] The crude product is dissolved in 1000 ml of dichloromethane
with 1.2 ml of DBU. After 10 minutes of contact, the reaction
mixture is washed with a tartaric acid solution at 10% and then
with water. After evaporation of the solvent under reduced
pressure, a crude product is obtained which is purified by
chromatography to give 37.2 g of methyl trans
4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-methano-7H-thieno[2,-
3-e][1,3]diazepine-8-carboxylate having the empirical formula
C.sub.17H.sub.16N.sub.2O.sub.4S (M=344.39 g). The corresponding
yield is 80%.
[0580] Stage L
[0581] 211 mg of the product obtained in the preceding stage are
dissolved in 2.2 ml of acetic acid, in a round-bottomed flask
placed under an argon atmosphere, and 1.7 ml of water are then
slowly added. The medium is cooled to 3.degree. C. and then 31.5
.mu.l of bromine in solution in 0.85 ml of acetic acid are slowly
added. The medium is stirred for 45 minutes until a large amount of
cream-colored precipitate appears. The suspension is next
introduced into 20 ml of a 0.5 N aqueous sodium thiosulfate
solution. The medium is extracted with ethyl acetate and the
organic phase is washed several times with a saturated aqueous
sodium bicarbonate solution and then with a saturated aqueous
sodium chloride solution. The organic phase is dried over
MgSO.sub.4, filtered and the solvent is evaporated under reduced
pressure. 293 mg of crude product are obtained, which are purified
by chromatography on a silica column, eluting with a methylene
chloride/ethyl acetate/triethylamine 95/5/0.5 mixture. After
evaporation of the solvent, 222 mg of compound methyl
trans-2-bromo-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-methano-7H-t-
hieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.17H.sub.15BrN.sub.2O.sub.4S are obtained (M=423.29
g). The corresponding yield is 85.6%.
[0582] Stage M
[0583] 226 mg of the product obtained in the preceding stage are
dissolved in 11.5 ml of toluene degassed beforehand by bubbling
argon through, in a round-bottomed flask placed under an argon
atmosphere. 112 mg of 4-fluorophenylboronic acid are next added,
followed by 54 mg of Pd(PPh.sub.3).sub.4. 2.17 ml of a 2 N aqueous
Na.sub.2CO.sub.3 solution are next added. The solution is next
heated under reflux for 4 h 30 min. The reaction medium is cooled
and it is poured into water and then extracted with ethyl acetate.
The organic phase is washed with a saturated aqueous sodium
chloride solution and dried over magnesium sulfate. The solvent is
evaporated under reduced pressure and 126.1 mg of crude product are
obtained, which product is purified by chromatography on silica,
eluting with a methylene chloride/ethyl acetate/triethylamine,
96/4/0.1%, mixture. After evaporation of the solvent, 211 mg of
compound methyl
trans-2-(4-fluorophenyl)-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy-
)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate having
the empirical formula C.sub.23H.sub.19FN.sub.2O.sub.4S are obtained
(M=438.48 g). The corresponding yield is 90%.
[0584] Stage N
[0585] 221.5 mg of the product obtained in the preceding stage are
dissolved in 26.6 ml of ethanol, in a round-bottomed flask. 221.5
mg of 10% palladium on carbon are added and the medium is purged
under vacuum and saturated with hydrogen. After stirring for 1 h 45
min, the catalyst is filtered off and then the solvent is
evaporated off under reduced pressure. After evaporation of the
solvent, 163.5 mg are obtained in the form of cream-colored
crystals of the compound methyl
trans-2-(4-fluorophenyl)-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-4,7-methano-7-
H-thieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.16H.sub.13FN.sub.2O.sub.4S (M=348.35 g). The
corresponding yield is 93%.
[0586] Stage O
[0587] 176.4 mg of the product obtained in the preceding stage are
dissolved in 2 ml of pyridine, in a round-bottomed flask. 241 mg of
the pyridine-SO.sub.3 complex are then introduced therein and the
medium is stirred at room temperature for 16 h 30 min. The yellow
solution obtained is purified by chromatography on silica, eluting
with a methylene chloride/methanol 90/10 mixture. After evaporation
of the fractions, 554.5 mg of compound pyridinium salt of methyl
trans-2-(4-fluorophenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.21H.sub.18FN.sub.3O.sub.7N.sub.2 are obtained
(M=507.51 g). The crude product is purified after converting to the
sodium salt.
[0588] Stage P
[0589] The salt exchange is carried out by passing 554.5 mg of the
pyridinium salt obtained in the preceding stage over 58 g of Dowex
resin prepared beforehand with a 2 N aqueous sodium hydroxide
solution. The product deposited on the Dowex resin column is eluted
with water containing 10% THF. After combining the fractions and
evaporating the solvent under reduced pressure, lyophilization is
carried out and 332.8 mg are obtained, which product is purified by
impasting in methanol and then in ethyl ether. 175.2 mg of compound
sodium salt of methyl
trans-2-(4-fluorophenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.16H.sub.12FO.sub.7N.sub.2S.sub.2,Na are finally
obtained (M=450.40 g). The corresponding yield is 79%.
[0590] NMR spectrum, D.sub.2O to 300 MHz, chemical shift and
multiplicity: 3.89 (s): CH.sub.3--O--CO; 5.49 (s):
CH.sub.3--O--CO--CHN; 3.52 (t) and 3.79 (broad d):
N--CH.sub.2--CH--N; 4.89 (broad s): N--CH.sub.2--CH--N, 7.11 and
7.51: aromatic H; 7.23 (s): CH.dbd.C.dbd.S.
[0591] LC/MS (negative electrospray), m/z: M.sup.-=427 and
(2M+Na).sup.-=877.
Example 20
Sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-2-(3-pyridinyl)-5-(sulfoxy)-4,7-methano-7H-
-thieno[2,3-e][1,3]diazepine-8-carboxamide
[0592] Stage A
[0593] The procedure is carried out as in Stage A of Example 7 with
2.5 g of the product obtained in Stage L of Example 19, 11.2 ml of
dioxane, 11.2 ml of water, 5.95 ml of 1 N aqueous sodium hydroxide.
1.82 g of compound
trans-2-bromo-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-met-
hano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylic acid having the
empirical formula C.sub.16H.sub.13BrO.sub.4N.sub.2S are obtained
(M=409.27 g). The corresponding yield is 75.7%.
[0594] Stage B
[0595] The procedure is carried out as in Stage B of Example 7 with
1.82 g of the product obtained in the preceding stage, 21 ml of
DMF, 2.95 g of BOP, 0.9 g of HOBT, 476.5 mg of NH.sub.4Cl, 3.1 ml
of DIPEA. 870 mg of the compound
trans-2-bromo-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-methano-7H-t-
hieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.16H.sub.14BrN.sub.3O.sub.3S are obtained (M=408.28
g). The corresponding yield is 48%.
[0596] Stage C
[0597] 305.5 mg of product obtained in the preceding stage are
dissolved in 24 ml of 1,4-dioxane, in a round-bottomed flask placed
under an argon atmosphere, and then 413 mg of
3-tri-N-butylstanylpyridine and 86.4 mg of Pd(PPh.sub.3).sub.4 are
added to the solution. The solution is heated at 100.degree. C. for
6 hours and then 86.4 mg of Pd(PPh.sub.3).sub.4 are again added.
The medium is again stirred at 100.degree. C. for 17 hours, the
solvent is evaporated off under reduced pressure. The dry extract
is taken up in 50 ml of ethyl acetate to which 50 ml of an aqueous
KF solution are added. The aqueous phase is again extracted with
ethyl acetate and washed with a saturated aqueous sodium chloride
solution, the organic phases are combined, dried over magnesium
sulfate and the solvent is evaporated off under reduced pressure.
590 mg of crude product are obtained, which product is purified by
chromatography on a silica column, eluting with a methylene
chloride/methanol/triethylamine, 95/5/0.1%, mixture. 92.4 mg of
compound
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-(3-pyridinyl)-4,7-meth-
ano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the
empirical formula C.sub.21H.sub.18O.sub.3N.sub.4S are obtained
(M=406.47 g). The corresponding yield is 30%.
[0598] Stage D
[0599] The procedure is carried out as in Stage M of Example 1 with
55 mg of the product obtained in the preceding stage, 15 ml of
ethanol and 55 mg of palladium on carbon in the presence of
hydrogen. 26 mg of compound
trans-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-2-(3-pyridinyl)-4,7-methano-7H-t-
hieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.14H.sub.12O.sub.3N.sub.4S are obtained (M=316.34 g).
The corresponding yield is 62%.
[0600] Stage E
[0601] The procedure is carried out as in Stage N of Example 1 with
26.6 mg of the product obtained in the preceding stage, 0.34 ml of
pyridine and 40.1 mg of the pyridine-SO.sub.3 complex. 71.5 mg are
obtained in the form of a yellow oil of the compound pyridinium
salt of
trans-4,5,6,8-tetrahydro-6-oxo-2-(3-pyridinyl)-5-(sulfoxy)-4,7-methano-7H-
-thieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.19H.sub.17O.sub.6N.sub.5S.sub.2 (M=475.05 g).
[0602] Stage F
[0603] The procedure is carried out as in Stage R of Example 12
with 10 g of Dowex resin, 71.5 mg of the product obtained in the
preceding stage and 0.5 ml of water at 10% in THF. 26.4 g are
obtained in the form of a cream-colored powder of the compound
sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-2-(3-pyridinyl)-5-(sulfoxy)-4,7-methano-7H-
-thieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.14H.sub.11O.sub.6N.sub.4S.sub.2,Na (M=418.38 g). The
corresponding yield is 75%.
Example 21
Sodium salt of methyl
trans-2-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxylate
[0604] Stage A
[0605] 1 g of the product in Stage L of Example 19 is dissolved in
80 ml of toluene degassed beforehand by bubbling argon through, in
a round-bottomed flask placed under an argon atmosphere. 1.12 g of
vinyltributylstanone are next added, followed by 272 mg of
Pd(PPh.sub.3).sub.4. The suspension is heated to 100.degree. C. and
stirred for one hour. After stirring for 40 minutes, the reaction
medium is cooled to room temperature and the solvent is evaporated
off under reduced pressure. The residue is taken up in 120 ml of
ethyl acetate and 120 ml of an aqueous KF solution. After
extraction, the organic phase is washed with a saturated aqueous
sodium chloride solution, and then dried over magnesium sulfate and
the solvent is evaporated off under reduced pressure. 1.67 g of
crude product are obtained, which product is purified by
chromatography on silica, eluting with a methylene chloride/ethyl
acetate/triethylamine 95/5/0.1% mixture. 405.7 mg of compound
methyl
trans-2-ethenyl-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-methano-7H-
-thieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.19H.sub.18N.sub.2O.sub.4S are obtained (M=370.43 g).
The corresponding yield is 46%.
[0606] Stage B
[0607] 513 mg of the product obtained in the preceding stage, 8.2
ml of THF, 4.1 ml of water and 8.2 ml of tert-butanol are dissolved
in a round-bottomed flask. 220 .mu.l of O.sub.SO.sub.4 in solution
at 5% in water and 888 mg of NaIO.sub.4 are added to the solution
obtained above. A suspension is obtained which is stirred at room
temperature for 1 hour. The reaction medium is then poured into
water and extracted with ethyl acetate. The organic phase is washed
with water and then with a saturated aqueous sodium chloride
solution and dried over magnesium sulfate. After evaporation of the
solvents under reduced pressure, 534.6 mg of crude product are
obtained, which product is purified by chromatography on a silica
column, eluting with a methylene chloride/ethyl
acetate/triethylamine, 90/10/0.1%, mixture. 286.6 mg of compound
methyl
trans-2-formyl-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-methano-7H--
thieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.18H.sub.16N.sub.2O.sub.5S are obtained (M=372.40 g).
The corresponding yield is 55.5%
[0608] Stage C
[0609] 297 mg of the product obtained in the preceding stage are
dissolved in 30 ml of acetone. 189 mg of powdered KMnO.sub.4 are
next added followed by 30 ml of water. The suspension is stirred at
room temperature for 1 h 30 min, and then 30 ml of acetone are
added and the suspension is again stirred for 30 minutes. After
evaporation of the acetone under reduced pressure, the reaction
medium is diluted with water and acidified with 2 ml of a 1 N
aqueous HCl solution. The medium is extracted with ethyl acetate
and the organic phase is washed with a saturated aqueous sodium
chloride solution. The organic phase is dried over magnesium
sulfate and the solvent is evaporated off under reduced pressure.
311.8 mg of compound 8-methyl
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-methano-7H-thieno[2,-
3-e][1,3]diazepine-2,8-dicarboxylate having the empirical formula
C.sub.18H.sub.16N.sub.2O.sub.6S are obtained (M=388.40 g). The
yield is quantitative.
[0610] Stage D
[0611] The procedure is carried out as in Stage B of Example 7 with
69 mg of the product obtained in the preceding stage, 0.84 ml of
DMF, 117.8 mg of BOP, 36 mg of HOBT, 19 mg of NH.sub.4Cl and 0.124
ml of DIPEA. 44.6 mg of a compound methyl
trans-2-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-me-
thano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.18H.sub.17N.sub.5O.sub.3S are obtained
(M=387.41 g). The corresponding yield is 64.8%.
[0612] Stage E
[0613] The procedure is carried out as in Stage M of Example 1 with
44.6 mg of the product obtained in the preceding stage, 4.5 ml of
ethanol and 44.6 mg of 10% palladium on carbon catalyst. 24.3 mg of
compound methyl
trans-2-(aminocarbonyl)-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-4,7-methano-7H-
-thieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.11H.sub.11O.sub.5N.sub.3S are obtained (M=297.29 g).
The corresponding yield is 71%.
[0614] Stage F
[0615] The procedure is carried out as in Stage M of Example 1 with
24.3 mg of the product obtained in the preceding stage, 0.32 ml of
pyridine and 39 mg of the pyridine-SO.sub.3 complex. 74.6 mg of the
compound pyridinium salt of methyl
trans-2-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.16H.sub.16O.sub.8N.sub.4S.sub.2 are obtained
(M=456.45 g).
[0616] The crude product is next converted to a sodium salt.
[0617] Stage G
[0618] The procedure is carried out as in Stage R of Example 12
with 74.6 mg of the product obtained in the preceding stage, 10 g
of Dowex resin. 19.9 mg of compound sodium salt of methyl
trans-2-(aminocarbonyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.11H.sub.10O.sub.8N.sub.3S.sub.2,Na are obtained
(M=399.34 g). The corresponding yield is 61%.
[0619] LC/MS (negative electrospray), m/z: M.sup.-=376.
[0620] Proton NMR, D.sub.2O at 300 MHz, chemical shift and
multiplicity:
[0621] 3.63 (d) and 3.82 (dd) and 3.66 (d) and 3.98 (dd):
N--CH.sub.2--CH; 4.95 (d) and 5.01 (d): N--CH.sub.2--CH; 5.64 (s):
CH.dbd.C--O--OCH.sub.3; 7.67 (s) and 7.70 (s): H of the furan; 3.91
(s), 3.93 (s): CH.sub.3--O--CO.
Example 22
Sodium salt of methyl
trans-4,5,6,8-tetrahydro-6-oxo-2-[[[2-(4-pyridinyl)ethyl]amino]carbonyl]--
5-(sulfoxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate
[0622] Stage A
[0623] The procedure is carried out as in Stage B of Example 7 with
196 mg of the product obtained in Stage C of Example 21, 2.24 ml of
DMF, 335 mg of BOP, 102 mg of HOBT, 123 g of 4,2-aminoethylpyridine
and 176 .mu.l of DIPEA. 203 mg of product methyl
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-[[[2-(4-pyridinyl)ethy-
l]amino]carbonyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate
having the empirical formula C.sub.25H.sub.24O.sub.5N.sub.4S are
obtained (M=492.56 g). The corresponding yield is 70.7%.
[0624] Stage B
[0625] The procedure is carried out as in Stage M of Example 1 with
50 mg of product obtained in the preceding stage, 4.5 ml of
ethanol, 50 mg of 10% palladium on carbon. 36.8 mg of compound
methyl
trans-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-2-[[[2-(4-pyridinyl)ethyl]amino]-
carbonyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate
having the empirical formula C.sub.18H.sub.18O.sub.5N.sub.4S are
obtained (M=402.43 g). The corresponding yield is 98%.
[0626] Stage C
[0627] The procedure is carried out as in Stage M of Example 1 with
36.8 mg of the product obtained in the preceding stage, 0.36 ml of
pyridine and 43.7 mg of pyridine-SO.sub.3 complex. 93.7 mg of
compound pyridinium salt of methyl
trans-4,5,6,8-tetrahydro-6-oxo-2-[[[2-(4-pyridinyl)ethyl]amino]carbonyl]--
5-(sulfoxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate
having the empirical formula C.sub.25H.sub.23O.sub.8N.sub.5S.sub.2
are obtained (M=561.59 g). The crude product is next converted to a
sodium salt.
[0628] Stage D
[0629] The procedure is carried out as in Stage R of Example 12
with 93.7 mg of the product obtained in the preceding stage, 11 g
of Dowex resin. The lyophilizate is obtained after passing over a
Dowex resin and dissolved in 1 ml of water and then attached to a
column of 54 ml of DIAION HP20 resin. The product is successively
eluted with a water/acetone 95/5 mixture, and then with an
acetone/water 10/90, and acetone/water 20/80 mixture. After
evaporation of the fractions obtained in the acetone/water 20/80
elution, 12.2 mg of compound sodium salt of methyl
trans-4,5,6,8-tetrahydro-6-oxo-2-[[[2-(4-pyridinyl)ethyl]amino]car-
bonyl]-5-(sulfoxy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylat-
e having the empirical formula
C.sub.18H.sub.17O.sub.8N.sub.4S.sub.2,Na are obtained (M=504.48 g).
The corresponding yield is 23%.
[0630] LC/MS (negative electrospray) m/z: M-=481
Example 23
Sodium salt of
4,5,6,8-tetrahydro-6-oxo-N.sup.2-[2-(4-pyridinyl)ethyl]-5-(sulfoxy)-4,7-m-
ethano-7H-thieno[2,3-e][1,3]diazepine-2,8-dicarboxamide
[0631] Stage A
[0632] The procedure is carried out as in Stage A of Example 7 with
126 mg of the product obtained in Stage A of Example 22, 1.74 ml of
dioxane, 0.64 ml of water and 281 .mu.l of 1 N aqueous sodium
hydroxide. 124 mg of compound
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-[[[2-(4-pyrid-
inyl)ethyl]amino]carbonyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-ca-
rboxylic acid having the empirical formula
C.sub.24H.sub.22O.sub.5N.sub.4S are obtained (M=478.53 g). The
corresponding yield is quantitative.
[0633] Stage B
[0634] The procedure is carried out as in Stage B of Example 7 with
124 mg of the product obtained in the preceding stage, 162 mg of
BOP, 51.8 mg of HOBT, 27.4 mg of NH.sub.4Cl, 178 .mu.l of DIPEA.
35.8 mg of compound
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-N.sup.2-[2-(4-pyridinyl)-
ethyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-2,8-dicarboxamide
having the empirical formula C.sub.24H.sub.23O.sub.4N.sub.5S are
obtained (M=477.55 g). The corresponding yield is 29.3%.
[0635] Stage C
[0636] The procedure is carried out as in Stage M of Example 1 with
36.4 mg of the product obtained in the preceding stage, 4 ml of
absolute ethanol, 72.8 mg of palladium on carbon. 19.6 mg of
compound
trans-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-N.sup.2-[2-(4-pyridinyl)ethyl]-4-
,7-methano-7H-thieno[2,3-e][1,3]diazepine-2,8-dicarboxamide having
the empirical formula C.sub.17H.sub.17O.sub.4N.sub.5S are obtained
(M=396.42 g).
[0637] The crude product is used without purification in the next
stage.
[0638] Stage D
[0639] The procedure is carried out as in Stage M of Example 1 with
19.6 mg of the product obtained in the preceding stage, 0.20 ml of
pyridine and 24 g of pyridine-SO.sub.3 complex. 53.6 mg of the
compound pyridinium salt of
4,5,6,8-tetrahydro-6-oxo-N.sup.2-[2-(4-pyridinyl)ethyl]-5-(sulfox-
y)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-2,8-dicarboxamide
having the empirical formula C.sub.22H.sub.22O.sub.7N.sub.6S.sub.2
are obtained (M=546.58 g).
[0640] The crude product is converted to a sodium salt.
[0641] Stage E
[0642] The procedure is carried out as in Stage R of Example 4 with
53.8 mg of the product obtained in the preceding stage, and 6.02 g
of Dowex resin. The lyophilizate obtained is purified on DIAION
HP20 resin and 3.3 mg of the compound sodium salt of
4,5,6,8-tetrahydro-6-oxo-N.sup.2-[2-(4-pyridinyl)ethyl]-5-(sulfoxy)-4,7-m-
ethano-7H-thieno[2,3-e][1,3]diazepine-2,8-dicarboxamide having the
empirical formula C.sub.17H.sub.16O.sub.7N.sub.5S.sub.2 are
obtained (M=489.46 g). The corresponding yield is 13.3%.
[0643] LC/MS (negative electrospray): m/z: M.sup.-=466
Example 24
Sodium salt of
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide
[0644] Stage A
[0645] 5.09 g of methyl
4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-methano-7H-thieno[2,3-e][1-
,3]diazepine-8-carboxylate prepared in Stage K of Example 19 are
dissolved under argon in 100 ml of CCl.sub.4, in a 60 ml
round-bottomed flask provided with magnetic stirring, the medium is
cooled on an ice bath, and then 1.87 g (7.4 mmol) of iodine and
3.813 g of PhI(OCOCF.sub.3).sub.2 are added. The temperature is
allowed to return to 20.degree. C. After stirring for 2 to 3 h at
20.degree. C., the solution is poured into a 0.5 N aqueous sodium
thiosulfate solution, the medium is extracted with ethyl acetate,
and then washed again with a 0.5 N aqueous sodium thiosulfate
solution, washed with a saturated aqueous sodium chloride solution,
and then with a phosphate buffer solution, pH=7.0, and finally with
a saturated aqueous sodium chloride solution. After drying over
MgSO.sub.4 and evaporation of the solvent under reduced pressure,
the crude product is obtained which is purified by chromatography
on silica, eluting with a CH.sub.2Cl.sub.2/ethyl acetate (95/5)
mixture, TEA=0.1%.
[0646] 4.88 g of methyl
4,5,6,8-tetrahydro-2-iodo-6-oxo-5-(phenylmethoxy)-4,7-methano-7H-thieno[2-
,3-e][1,3]diazepine-8-carboxylate having the empirical formula
C.sub.17H.sub.15N.sub.2IO.sub.4S are obtained (M=470.29 g). The
yield is 70%.
[0647] Stage B
[0648] The procedure is carried out as in Stage M of Example 19
with 250 mg of the product obtained in the preceding stage, 11.5 ml
of toluene, 108.4 mg of 2-methylphenylboronic acid, 61.43 mg of
Pd(PPh.sub.3).sub.4 and 2.15 ml of a 2 N aqueous Na.sub.2CO.sub.3
solution. 229 mg of the compound methyl
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(phenylmethoxy)-4,7-m-
ethano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.24H.sub.22N.sub.2O.sub.4S are obtained
(M=434.52 g). The corresponding yield is 99%.
[0649] Stage C
[0650] The procedure is carried out as in Stage A of Example 7 with
265.4 mg of product obtained in the preceding stage, 3.5 ml of
dioxane, 1.45 ml of water and 0.64 ml of 1 N aqueous sodium
hydroxide. 235.5 mg of compound
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(phenylmetho-
xy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylic acid
having the empirical formula C.sub.23H.sub.20N.sub.2O.sub.4S are
obtained (M=420.49 g). The corresponding yield is 92%.
[0651] Stage D
[0652] The procedure is carried out as in Stage B of Example 7 with
232 mg of product obtained in the preceding stage, 3 ml of DMS, 365
mg of BOP, 111.6 mg of HOBT, 59 mg of NH.sub.4Cl, 383 .mu.l of
DIPEA. 196.1 mg of compound
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(phenylmetho-
xy)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having
the empirical formula C.sub.23H.sub.21N.sub.3O.sub.3S are obtained
(M=420.49 g). The corresponding yield is 85%.
[0653] Stage E
[0654] The procedure is carried out as in Stage M of Example 1 with
177 mg of the product obtained in the preceding stage, 35 ml of
ethanol, 17 ml of THF and 177 mg of 30% palladium on carbon. 123 mg
of the compound
trans-4,5,6,8-tetrahydro-5-hydroxy-2-(2-methylphenyl)-6-oxo-4,7-methano-7-
H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.16H.sub.15N.sub.3O.sub.3S are obtained (M=329.38 g).
The corresponding yield is 83%.
[0655] Stage F
[0656] The procedure is carried out as in Stage N of Example 1 with
123 mg of product obtained in the preceding stage, 2 ml of
pyridine, 174 mg of SO.sub.3-pyridine complex. 100 mg of compound
triethylammonium salt of
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.22H.sub.30O.sub.6N.sub.4S.sub.2 are obtained
(M=510.63 g). The corresponding yield is 52.4%.
[0657] Stage G
[0658] The procedure is carried out as in Stage R of Example 12
with 100 mg of the product obtained in the preceding stage and 30 g
of Dowex resin. 76.8 mg of compound sodium salt of
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.16H.sub.14O.sub.6N.sub.3S.sub.2,Na are obtained
(M=431.42 g). The corresponding yield is 90%.
[0659] LC/MS (negative electrospray) M.sup.-=408.2 g;
(2M+Na).sup.-=839.
[0660] Proton NMR, D.sub.2O, 300 MHz, chemical shift and
multiplicity: 2.41 (s): CH.sub.3-.phi.; 3.50 (d), 3.83 (dd):
N--CH.sub.2--CH; 4.95 (d): N--CH.sub.2--CH; 5.38 (s): CH--CO--N
7.15 (s): SC.dbd.CH; 7.26 to 7.50 (m): aromatic H.
Example 25
Sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-2-[2-(trifluoromethyl)phenyl]--
4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide
[0661] Stage A
[0662] The procedure is carried out as in Stage M of Example 19
with 250 mg of the product obtained in Stage A of Example 24, 11 ml
of toluene, 151 mg of 2-(trifluoromethyl)phenylboronic acid, 61 mg
of Pd(PPh.sub.3).sub.4, and 2.15 ml of a 2 M aqueous
Na.sub.2CO.sub.3 solution. 199 mg of compound methyl
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-[2-(trifluoromethyl)ph-
enyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate
having the empirical formula C.sub.24H.sub.19N.sub.2O.sub.4SF.sub.3
are obtained (M=488.49 g). The corresponding yield is 76.5%.
[0663] Stage B
[0664] The procedure is carried out as in Stage A of Example 7 with
230 mg of the product obtained in the preceding stage, 5 ml of
dioxane, 1.45 ml of water, and 0.5 ml of 1 N aqueous sodium
hydroxide. 199 mg of compound
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-[2-(trifluoromethyl)ph-
enyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylic acid
having the empirical formula C.sub.23H.sub.17N.sub.2O.sub.4SF.sub.3
are obtained (M=474.46 g). The corresponding yield is 89.2%.
[0665] Stage C
[0666] The procedure is carried out as in Stage B of Example 7 with
196.2 mg of the product obtained in the preceding stage, 2.5 ml of
DMF, 274.3 mg of BOP, 83.8 mg of HOBT, 44.2 mg of NH.sub.4Cl, and
288 .mu.l of DIPEA. 99.1 mg of compound
trans-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-2-[2-(trifluoromethyl)ph-
enyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide
having the empirical formula C.sub.23H.sub.18N.sub.3O.sub.3SF.sub.3
are obtained (M=473.48 g). The corresponding yield is 50.6%.
[0667] Stage D
[0668] The procedure is carried out as in Stage M of Example 1 with
84.3 mg of the product obtained in the preceding stage, 16.8 ml of
methanol, 8.4 ml of THF, and 84.3 mg of 30% palladium on carbon.
74.7 mg of the compound
trans-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-2-[2-(trifluoromethyl)p-
henyl]-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide
having the empirical formula C.sub.16H.sub.22N.sub.3O.sub.3SF.sub.3
are obtained (M=383.35 g). The corresponding yield is 98%.
[0669] Stage E
[0670] The procedure is carried out as in Stage M of Example 1 with
74.7 mg of product obtained in the preceding stage, 1 ml of
pyridine and 92.8 mg of pyridine-SO.sub.3 complex. Purification on
silica of the crude product is carried out as in Stage M of Example
1, eluting with a methylene chloride/ethanol/triethylamine
60/40/0.5 mixture. 73.5 mg of compound triethylammonium salt of
trans-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-2-[2-(trifluoromethyl)phenyl]--
4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the
empirical formula C.sub.22H.sub.27O.sub.6N.sub.4S.sub.2F.sub.3 are
obtained (M=564.61 g). The corresponding yield is 66.8%.
[0671] Stage F
[0672] The procedure is carried out as in Stage R of Example 12
with 73.5 mg of the product obtained in the preceding stage, and 20
g of Dowex resin. Elution is carried out with water containing 20%
of THF and 35.2 mg of the compound sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-2-[2-(trifluoromethyl)phenyl]--
4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the
empirical formula C.sub.16H.sub.11O.sub.6N.sub.3S.sub.2F.sub.3Na
are obtained (M=485.99 g). The corresponding yield is 55.6%.
[0673] LC/MS (negative electrospray), M.sup.-=462;
(2M+Na).sup.-=947.
[0674] Proton NMR, D.sub.2O, 300 MHz, chemical shift and
multiplicity: 3.52 (broad d) and 3.85 (dd): N--CH.sub.2--CH; 4.44
(d): N--CH.sub.2--CH; 5.39 (s): CH--CO--N 7.18 (s): S--C.dbd.CH;
7.54 to 7.72 (m) and 7.87 (broad d): aromatic H.
Example 26
Sodium salt of
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxamide
[0675] Stage A
[0676] The procedure is carried out as in Stage M of Example 19
with 315 mg of the product obtained in Stage A of Example 24, 14.5
ml of toluene, 150.63 mg of 2-ethylbenzene or 2-ethylphenylboronic
acid, 77.4 mg of Pd(PPh.sub.3).sub.4 and 2.7 ml of a 2 M aqueous
Na.sub.2CO.sub.3 solution. 274.2 mg of the compound methyl
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-me-
thano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.25H.sub.24N.sub.2O.sub.4S are obtained
(M=448.54 g). The corresponding yield is 91.2%.
[0677] Stage B
[0678] The procedure is carried out as in Stage A of Example 7 with
270.8 mg of the product obtained in the preceding stage, 5 ml of
dioxane, 1.45 ml of water, 0.63 ml of 1 N aqueous sodium hydroxide.
237.5 mg of compound
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethox-
y)-4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxylic acid
having the empirical formula C.sub.24H.sub.22N.sub.2O.sub.4S are
obtained (M=434.52 g). The corresponding yield is 90.5%.
[0679] Stage C
[0680] The procedure is carried out as in Stage B of Example 7 with
234.2 mg of product obtained in the preceding stage, 3.3 ml of DMF,
357.58 mg of BOP, 109.2 mg of HOBT, 57.7 mg of NH.sub.4Cl and 375.5
.mu.l of DIPEA. 210 mg of compound
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(phenylmethoxy)-4,7-me-
thano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the
empirical formula C.sub.24H.sub.23N.sub.3O.sub.3S are obtained
(M=433.53 g). The corresponding yield is 90%.
[0681] Stage D
[0682] The procedure is carried out as in Stage M of Example 1 with
191.1 mg of product obtained in the preceding stage, 38.2 ml of
methanol, 19.1 ml of THF and 191.1 mg of 30% palladium on carbon.
107.2 mg of the compound
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-4,7-m-
ethano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the
empirical formula C.sub.17H.sub.17N.sub.3O.sub.3S are obtained
(M=343.41 g). The corresponding yield is 70.8%.
[0683] Stage E
[0684] The procedure is carried out as in Stage N of Example 1,
with 107.2 mg of the product obtained in the preceding stage, 149
mg of the pyridine-SO.sub.3 complex.
[0685] The crude product obtained is purified by chromatography on
silica, eluting with a methylene chloride/ethanol/triethylamine
60/40/0.5 mixture. 106.3 mg of the compound triethylammonium salt
of
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.23H.sub.32O.sub.6N.sub.4S.sub.2 are obtained
(M=524.66 g). The corresponding yield is 76.6%.
[0686] Stage F
[0687] The procedure is carried out as in Stage R of Example 12
with 106.3 mg of the product obtained in the preceding stage and 31
g of Dowex resin. The elution is carried out with water containing
20% of THF. 81.1 mg of compound sodium salt of
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.17H.sub.16O.sub.6N.sub.3S.sub.2Na are obtained
(M=445.45 g). The corresponding yield is 89.8%.
[0688] LC/MS (negative electrospray) M.sup.-=422.3;
(2M+Na).sup.-=867.
[0689] Proton NMR, D.sub.20, 300 MHz, chemical shift and
multiplicity: 1.13 (t): CH.sub.3--CH.sub.2-.phi.; 2.74 (q):
CH.sub.3--CH.sub.2-.phi.; 3.62 (broad d) and 3.84 (dd):
N--CH.sub.2--CH; 4.94 (d): N--CH.sub.2--CH; 5.39 (s): CH--CO--N;
7.11 (s): S--C.dbd.CH; 7.33 (m) and 7.42 (m): aromatic H.
Example 27
Ethyl
trans-1,2,3,5-tetrahydro-9-hydroxy-3-oxo-2-(phenylmethoxy)-1,4-metha-
no-4H-2,4-benzodiazepine-5-carboxylate
[0690] Stage A
[0691] 50 g of 3-methoxybenzaldehyde are dissolved in 245 ml of
acetic acid. 22 ml of bromine are added dropwise at 0.degree. C.,
the medium is stirred at room temperature for 4 hours, and then
left overnight at room temperature. 300 ml of water are added to
the solution and the expected product crystallizes. After
filtration and washing with water and drying, 68 g of
2-bromo-5-methoxybenzaldehyde having the empirical formula
C.sub.8H.sub.7Br.O.sub.2 are obtained (M=114 g). The corresponding
yield is 87%.
[0692] Stage B
[0693] 30 g of the product obtained in the preceding step B are
dissolved in 200 ml of dichloromethane. 0.4 g of Znl.sub.2 is added
at 0.degree. C., followed dropwise by 20.86 ml of TMSCN. The medium
is stirred for 1 h 30 min, and then the mixture is poured into a
saturated aqueous sodium bicarbonate solution. After decantation,
the organic phase is dried over magnesium sulfate and the solvent
is evaporated off under reduced pressure. The crude product is
solubilized in 9 ml of ethanol and 6 ml of concentrated
hydrochloric acid. After heating under reflux for 1 h, the reaction
medium is poured into a saturated NaHCO.sub.3 solution, and then
extracted with ethyl acetate. After evaporation of the solvent
under reduced pressure, 41 g of ethyl
2-bromo-.alpha.-hydroxy-5-methoxybenzeneacetate having the
empirical formula C.sub.11H.sub.13BrO.sub.4 are obtained (M=288 g).
The corresponding yield is 63%.
[0694] Stage C
[0695] 23.5 g of the product obtained in the preceding step are
introduced into 250 ml of dichloromethane, in a round-bottomed
flask placed under a nitrogen atmosphere. 100 ml of TEA, and 1.05 g
of DMAP are added. The medium is cooled to 0.degree. C. and then
6.31 ml of mesyl chloride are introduced therein. The medium is
stirred for 1 hour at 0.degree. C.
[0696] The reaction medium is next poured over a mixture of water
and dichloromethane. The medium is extracted twice with
dichloromethane, washed twice with water, the organic phases are
combined and they are dried over sodium sulfate, and then the
solvent is evaporated off under reduced pressure.
[0697] 32 g of the expected compound having the empirical formula
C.sub.17H.sub.24N.BrO.sub.5 are obtained in the form of an oil
(M=401 g).
[0698] Stage D
[0699] The procedure is carried at as indicated in Stage C of
Example 21 with 130 ml of DMF, 16 g of tert-butyl glycinate and
9.66 ml of lutidine.
[0700] 30 g of the product obtained in the preceding Stage C and
130 ml of DMF are introduced into a round-bottomed flask placed
under a nitrogen atmosphere. 9.66 ml of 2,6-lutidine and 16 g of
tert-butyl glycinate are added. The medium is heated at 80.degree.
C. for 6 hours. The temperature is allowed to return to room
temperature and the medium is poured into a mixture of ice and
sulphuric ether. The medium is extracted once with ether. The ether
phase is washed four times with water. The organic phase is dried
over sodium sulfate, and then it is filtered and the solvent is
evaporated off under reduced pressure. The toluene is carried away.
The crude product is taken up in AcOEt, the medium is washed with
an aqueous tartaric acid solution at 10% and then twice with water
and next with a saturated aqueous sodium hydrogen carbonate
solution.
[0701] The organic phase is dried over sodium sulfate, filtered and
the solvent is evaporated off under reduced pressure. 15.3 g of
ethyl
2-bromo-.alpha.-[[2-(1,1-dimethylethoxy)-2-oxoethyl]amino]-5-methoxybenze-
neacetate having the empirical formula C.sub.17H.sub.24BrNO.sub.5
are obtained in the form of an oil (M=402.29 g). The corresponding
yield is 47%.
[0702] Stage E
[0703] 6 g of the product obtained in Stage D, 2.2 ml of
triethylamine and 60 ml of dichloromethane are introduced into a
round-bottomed flask cooled by an ice bath.
[0704] The medium is cooled to 0.degree. C. and 2.4 ml of
trifluoroacetic anhydride and are added.
[0705] The medium is left in contact for 2 hours 30 minutes.
[0706] The reaction medium is next poured over an ice/aqueous
ammonia/dichloromethane mixture. The medium is washed with water,
and extracted with dichloromethane. The organic phases are dried
over sodium sulfate. The medium is filtered and the solvent is
evaporated off under reduced pressure.
[0707] 6.05 g of ethyl
2-bromo-.alpha.-[[2-(1,1-dimethylethoxy)-2-oxoethyl](trifluoroacetyl)amin-
o]-5-methoxybenzeneacetate having the empirical formula
C.sub.19H.sub.23BrF.sub.3NO.sub.6 are obtained (M=498.30 g). The
corresponding yield is 81%.
[0708] Stage F
[0709] 6.05 g of the product obtained in Stage E and 30 ml of
dichloromethane are introduced into a round-bottomed flask placed
under a nitrogen atmosphere.
[0710] The medium is cooled to 0.degree. C. and 30 ml of
trifluoroacetic acid are rapidly introduced.
[0711] The temperature is allowed to rise to room temperature and
then the medium is kept stirred for 4 hours.
[0712] The solvent is evaporated off under reduced pressure.
[0713] The product is dissolved in AcOEt, successively washed with
a dilute solution of aqueous ammonia and then with a saturated
aqueous NaH.sub.2PO.sub.4 solution.
[0714] The organic phases are next dried over sodium sulfate,
filtered and the solvent is evaporated off under reduced
pressure.
[0715] 5.2 g of ethyl
2-bromo-.alpha.-[[(carboxymethyl)(trifluoroacetyl)amino]-5-methoxybenzene-
acetate having the empirical formula
C.sub.15H.sub.15BrF.sub.3NO.sub.6 are obtained in the form of white
crystals (M=442.19 g). The corresponding yield is 97%.
[0716] Stage G
[0717] Step 1--Preparation of the Acid Chloride
[0718] 61 g of the product obtained in Stage F is solubilized in
120 ml of SOCl.sub.2. The medium is heated at 80.degree. C. for 2 h
and then evaporated to dryness.
[0719] Step 2
[0720] The acid chloride is solubilized in 300 ml of
CH.sub.3NO.sub.2. 76 g of aluminum chloride are then added in
fractions, and the medium is stirred overnight at room temperature.
The reaction medium is then poured into a hepthane/ethyl acetate
mixture and the organic phase is washed with 1 M NaH.sub.2PO.sub.4.
After drying the organic phase over MgSO.sub.4 and evaporation of
the solvent under reduced pressure, the residue obtained is
purified by chromatography on silica, eluting with a heptane/ethyl
acetate 4:1 mixture. A residue is obtained which is crystallized
from a pentane/ether mixture.
[0721] 31 g of ethyl
8-bromo-1,2,3,4-tetrahydro-5-hydroxy-4-oxo-2-(trifluoroacetyl)-1-isoquino-
linecarboxylate having the empirical formula
C.sub.14H.sub.11BrF.sub.3NO.sub.5 are obtained (M=409.15 g). The
corresponding yield is 55%.
[0722] Stage H
[0723] 30 g of the product obtained in the preceding Stage G are
dissolved in 250 ml of ethanol. 3 g of 10% by weight of palladium
on carbon and 21.1 ml of triethylamine are then added. The medium
is placed under hydrogen pressure. After 1 h 30 min, the catalyst
is filtered off and then the filtrate is poured into a
heptane/ethyl acetate mixture, the organic phase is washed with a 1
M aqueous NaH.sub.2PO.sub.4 solution, and then dried over magnesium
sulfate and the solvent is evaporated off under reduced pressure.
The crude product obtained is purified on silica, eluting with a
heptane/ethyl acetate 4/1 mixture.
[0724] 22.2 g of ethyl
1,2,3,4-tetrahydro-5-hydroxy-4-[(phenylmethoxy)imino]-2-(trifluoroacetyl)-
-1-isoquinolinecarboxylate having the empirical formula
C.sub.14H.sub.12F.sub.2NO.sub.5 are obtained (M=331.25 g). The
corresponding yield is 92%.
[0725] Stage I
[0726] The procedure is carried out as in Stage E of Example 12
with 24.4 g of the product obtained in the preceding stage, 250 ml
of pyridine and 15.5 g of O-benzylhydroxylamine hydrochloride. 25.6
g of compound ethyl
1,2,3,4-tetrahydro-5-hydroxy-4-[(phenylmethoxy)imino]-2-(trifluoroacetyl)-
-1-isoquinolinecarboxylate having the empirical formula
C.sub.21H.sub.19F.sub.3N.sub.2O.sub.5 are obtained (M=436.39). The
corresponding yield is 80%.
[0727] Stage J
[0728] 25.7 g of the product obtained in the preceding stage are
dissolved in 300 ml of acetone. 90 g of K.sub.2CO.sub.3 and 17.3 ml
of allyl bromide are added to the solution. The medium is heated
overnight under reflux and then the solution is poured into a
heptane/ethyl acetate 1/2 mixture, and the medium is washed with
water. The organic phase is then washed with an NaH.sub.2PO.sub.4
solution, and then dried over magnesium sulfate. After evaporation
of the solvent under reduced pressure, 30 g of crude product are
obtained, which product is purified by chromatography on a silica
column, eluting with a heptane/ethyl acetate 4/1 mixture. After a
second purification by chromatography on silica, eluting with a
heptane/ethyl acetate 8/1 mixture, 24.8 g of the compound ethyl
1,2,3,4-tetrahydro-4-[(phenylmethoxy)imino]-5-(2-propenyloxy)-2-(trifluor-
oacetyl)-1-isoquinolinecarboxylate having the empirical formula
C.sub.24H.sub.23F.sub.3N.sub.2O.sub.5 are obtained in the form of a
yellow oil (M=476.47). The corresponding yield is 87%.
[0729] Stage K
[0730] 25.2 g of the product obtained in the preceding stage are
dissolved in 300 ml of ethanol. Gaseous NH.sub.3 is bubbled through
at 0.degree. C. for 5 minutes and then the solution is stirred at
room temperature for 3 hours. The solution is treated by adding
ethyl acetate and the organic phase is washed with an aqueous
NaH.sub.2PO.sub.4 solution and then dried over magnesium sulfate.
After evaporation of the solvents under reduced pressure and
carrying away with toluene, 21.2 g of the compound ethyl
1,2,3,4-tetrahydro-4-[(phenylmethoxy)imino]-5-(2-propenyloxy)-1-isoquinol-
inecarboxylate having the empirical formula
C.sub.22H.sub.24N.sub.2O.sub.4 are obtained in the form of a yellow
oil (M=300.45 g). The yield is quantitative.
[0731] Stage L
[0732] 22.5 g of the product obtained in the preceding stage are
dissolved in 300 ml of THF. 1.1 equivalent of Boc.sub.2-O reagent
are added. The medium is stirred for 2 hours at room temperature
and then the reaction medium is poured into a heptane/ethyl acetate
1/2 mixture and the mixture is washed with a tartaric acid solution
at 10%. The organic phase is next dried over magnesium sulfate and
the solvent is evaporated under reduced pressure. A residue is
obtained which is purified by chromatography on a silica column,
eluting with a heptane/ethyl acetate 5/1 mixture. After evaporation
of the solvent, 19.3 g of the compound 2-(1,1-dimethylethyl) and
1-ethyl
3,4-dihydro-4-[(phenylmethoxy)imino]-5-(2-propenyloxy)-1,2(1H)-isoquinoli-
nedicarboxylate having the empirical formula
C.sub.27H.sub.32N.sub.2O.sub.6 are obtained in the form of white
crystals (M=480.57).
[0733] Stage M
[0734] The procedure is carried out as in Stage F of Example 12
with 19.3 g of the product obtained in the preceding stage, 250 ml
of methanol, 40.5 g of NaBH.sub.3CN, 59 ml of boron trifluoride
etherate. 21 g of compound 2-(1,1-dimethylethyl) and 1-ethyl
3,4-dihydro-4-[(phenylmethoxy)amino]-5-(2-propenyloxy)-1,2(1H)-isoquinoli-
nedicarboxylate having the empirical formula
C.sub.27H.sub.34N.sub.2O.sub.6 are obtained (M=482.58 g). The
corresponding yield is 79%.
[0735] Stage N
[0736] The procedure is carried out as in Stages I and J of Example
1 with 15.3 g of the product obtained in the preceding stage, 10 ml
of ethyl acetate, 83 ml of an HCl solution in ethyl acetate. Then
130 ml of methylene chloride and 35 ml of 2 N aqueous sodium
hydroxide [lacuna]. 12.1 g of the compound ethyl
1,2,3,4-tetrahydro-4-[(phenylmethoxy)amino]-5-(2-propenyloxy)-1-isoquinol-
inecarboxylate having the empirical formula
C.sub.22H.sub.26N.sub.2O.sub.4 are obtained in the form of a
colorless oil (M=382.46 g). The yield is quantitative.
[0737] Stage O
[0738] The procedure is carried out as in Stage K of Example 1 with
12.1 g of the product obtained in the preceding stage, 9 ml of
triethylamine and 2 ml of diphosgene and 31 [lacuna] of
acetonitrile. 7 g of the compound ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(phenylmethoxy)-9-(2-propenyloxy)--
1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.23H.sub.24N.sub.2O.sub.5 are obtained
(M=408.48 g). The yield is 55%.
[0739] Stage P
[0740] 4.1 g of the compound obtained in the preceding stage are
dissolved in 50 ml of toluene, in a round-bottomed flask placed
under an argon atmosphere. 231 mg of Pd(PPh.sub.3).sub.4 and 630
.mu.l of acteic acid are added. 3.49 ml of Bu.sub.3SnH are then
added dropwise at 0.degree. C. over 10 minutes. The reaction medium
is stirred at room temperature for two hours. 200 ml of CH.sub.3CN
are next added to the reaction medium and the medium is extracted
three times with 60 ml of pentane. The acetonitrile solution is
next evaporated and the residue is purified by chromatography on
silica, eluting with a heptane/ethyl acetate 2/1 then 1/1 mixture.
3.45 g of the compound ethyl
1,2,3,4-tetrahydro-5-hydroxy-4-[(phenylmethoxy)imino]-2-(trifluoroacetyl)-
-1-isoquinolinecarboxylate having the empirical formula
C.sub.20H.sub.20N.sub.2O.sub.5 are obtained (M=368.39 g). The
corresponding yield is 94%.
[0741] LC/MS (positive electrospray), m/z: M.sup.+=369.
[0742] LC/MS (negative electrospray), m/z:
(M.sup.-H).sup.-=367.
[0743] Proton NMR, CDCl.sub.3 to 300 MHz, chemical shift and
multiplicity: 1.32 (t): CH.sub.3--CH.sub.2O--CO; 4.27 (qd):
CH.sub.3--CH.sub.2--O--CO; 3.52 (dd) and 3.67 (d): N--CH.sub.2--CH;
4.60 (d): N--CH.sub.2--CH; 4.93 and 4.99 (ab): O--CH.sub.2-.phi.;
5.01 (s): .phi.-OH; 5.10 (s): CH.sub.2--CO--O--CH.sub.2--CH.sub.3;
6.68 (d), 6.93 (d) and 7.13 (t): aromatic H, 7.37 (m) and 7.46 (m):
CH.sub.2-.phi..
Example 28
Sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-9-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate
[0744] Stage A
[0745] 0.1 g of the product obtained in Stage P of Example 27 is
dissolved in 2 ml of dichloromethane, in a round-bottomed flask
placed under an argon atmosphere. 0.019 ml of triethylamine is
added and then PhNCO is added dropwise at 0.degree. C. The medium
is stirred for 30 minutes and then the solution is poured into
dichloromethane and the organic phase is washed with an aqueous
NaH.sub.2PO.sub.4 solution. The organic phase is dried over
magnesium sulfate and the solvent is evaporated off under reduced
pressure. 0.130 g of crude product is obtained which is purified by
chromatography on silica, eluting with an ethane/ethyl acetate 1/1
mixture. 0.119 g of compound ethyl
trans-1,2,3,5-tetrahydro-3-oxo-9-[[(phenylamino)carbonyl]oxy]-2-(phenylme-
thoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.27H.sub.25N.sub.3O.sub.6 are obtained
(M=487.52 g). The corresponding yield is 90%.
[0746] Stage B
[0747] The procedure is carried out as in Stage M of Example 1 with
0.115 g of the product obtained in the preceding stage, 10 ml of
THF and 0.027 g of 10% palladium on carbon. The product obtained is
treated as in Stage N of Example 1 with 2 ml of pyridine, 114 mg of
the pyridine-SO.sub.3 complex. The product obtained is treated as
in Stage R of Example 12 in the presence of 25 g of Dowex resin. At
the end of these three steps, 0.107 g of the compound sodium salt
of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-9-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.20h.sub.18N.sub.3O.sub.9S,Na is obtained in
the form of pale yellow crystals (M=476.45 g+22.99 g). The
corresponding yield is 90%.
[0748] LC/MS (positive electrospray) m/z: M+Na.sup.+=522.
[0749] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 1.28 (t): CH.sub.3--CH.sub.2--O; 4.24 (q):
CH.sub.3--CH.sub.2--O; 3.52 (d), 3.60 (dd): CH.sub.2--CH; 4.98 (d):
CH.sub.2--CH; 5.05 (s): CH--CO.sub.2Et; 7.04, 7.33, 7.50, 7.42,
7.22: aromatic H, 10.08 (1H) active.
Example 29
Disodium salt of 5-ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2,9-bis(sulfoxy)-1,4-methano-4H-2,4-benzod-
iazepine-5-carboxylate
[0750] Stage A
[0751] The procedure is carried out as in Stage M of Example 1 with
0.130 g of the product obtained in Stage P of Example 27, 13 ml of
THF and 10% palladium on carbon. The compound ethyl
trans-1,2,3,5-tetrahydro-2,9-dihydroxy-3-oxo-1,4-methano-4H-2,4-benzodiaz-
epine-5-carboxylate having the empirical formula
C.sub.13H.sub.14N.sub.2O.sub.5 is obtained with a quantitative
yield (M=278.27 g).
[0752] Stage B
[0753] The procedure is carried out as in Stage N of Example 1 with
0.1 g of the product obtained in the preceding stage, 0.33 g of
pyridine-SO.sub.3 complex and 2 ml of pyridine. The product is then
obtained and treated in the same manner as in Stage R of Example 12
in the presence of 25 g of Dowex resin. 0.170 g of the compound
disodium salt of 5-ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2,9-bis(sulfoxy)-1,4-methano-4H-2,4-benzod-
iazepine-5-carboxylate having the empirical formula
C.sub.13H.sub.12N.sub.2Na.sub.2O.sub.11S.sub.2 is obtained
(M=482.35 g). The corresponding yield is quantitative.
[0754] LC/MS (positive electrospray) m/z: M+Na.sup.+=505.
[0755] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 3.44 (d): CH.sub.2--CH; 3.53 (dd): CH.sub.2--CH; 1.26
(t): CH.sub.3--CH.sub.2--O--CO; 4.21 (q):
CH.sub.3--CH.sub.2--O--CO; 4.94 (s): CH--CH.sub.2Et; 5.20 (d):
CH--CH.sub.2; 7.06 (d), 7.18 (d), 7.27 (d): the three aromatic
H.
Example 30
Sodium salt of 5-ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-9-[[(trifluoromethyl)sulfonyl]-
oxy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate
[0756] Stage A
[0757] 1 g of the product obtained in Stage P of Example 27 is
dissolved in 15 ml of dichloromethane, in a round-bottomed flask
placed under argon at -15.degree. C. 1.17 ml of triethylamine are
added, followed by 0.67 ml of (CF.sub.3SO.sub.2).sub.2O. The medium
is stirred for 30 minutes at -15.degree. C. and then, once the
reaction medium has returned to room temperature, it is treated
with an NaHCO.sub.3 solution and extracted with methylene chloride.
The organic phase is then dried over magnesium sulfate and the
solvent is evaporated off under reduced pressure. 1.5 g of a gum
are obtained, which gum is purified by chromatography on silica,
eluting with a heptane/ethyl acetate 4/1 mixture. 0.8 g of the
compound ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(phenylmethoxy)-9-[[(trifluorometh-
yl)sulfonyl]oxy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate
having the empirical formula C.sub.21H.sub.19F.sub.3N.sub.2O.sub.7F
is obtained in the form of white crystals (M=500.4 g). The
corresponding yield is 60%.
[0758] Stage B
[0759] The procedure is carried out as indicated in Stage M of
Example 1 with 0.130 mg of the product obtained in the preceding
stage, 13 ml of THF and 25 mg of 10% palladium on carbon. 91 mg of
the compound ethyl
trans-1,2,3,5-tetrahydro-2-hydroxy-3-oxo-9-[[(trifluoromethyl)sulfonyl]ox-
y]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.14H.sub.13N.sub.2O.sub.7S are obtained
(M=410.33 g). The corresponding yield is 90%.
[0760] Stage C
[0761] The procedure is carried out as indicated in Stage N of
Example 1 with 91 mg of the product obtained in the preceding
stage, 2 ml of pyridine and 105 mg of the pyridine-SO.sub.3
complex. The product obtained is then treated as indicated in Stage
R of Example 12 with 25 g of Dowex resin. 0.110 g of the compound
sodium salt of 5-ethyl trans-1,2,3,5-tetrahydro-3-oxo-2-(su
foxy)-9-[[(trifluoromethyl)sulfonyl]oxy]-1,4-methano-4H-2,4-benzodiazepin-
e-5-carboxylate having the empirical formula
C.sub.14H.sub.12F.sub.3N.sub.2O.sub.10S.sub.2Na is obtained in the
form of white crystals (M=489.38+22.99 g). The corresponding yield
is 97%.
[0762] LC/MS (positive electrospray), m/z: M+Na.sup.+=535.
[0763] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 1.26 (t): CH.sub.3--CH.sub.2--O--CO; 4.24 (q):
CH.sub.3--CH.sub.2--O--CO; 3.50 (d) and 3.67 (dd): CH.sub.2--CH
5.02 (d): CH.sub.2--CH; 5.17 (s): CH--CO.sub.2Et; 7.45 (d), 7.50
(d), 7.59 (t): the 3 aromatic H.
Example 31
Sodium salt of 5-ethyl
trans-9-(4-fluorophenyl)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano-
-4H-2,4-benzodiazepine-5-carboxylate
[0764] Stage A
[0765] The procedure is carried out as in Stage M of Example 19
with 0.35 g of the product obtained in Stage A of Example 30, 15 ml
of toluene, 0.146 g of 4-fluorophenylboronic acid, 70 mg of
Pd(P.phi..sub.3).sub.4, 2.8 ml of a 2 M Na.sub.2CO.sub.3 solution.
0.280 g of compound ethyl
trans-9-(4-fluorophenyl)-1,2,3,5-tetrahydro-3-oxo-2-(phenylmethoxy)-1,4-m-
ethano-4H-2,4-benzodiazepine-5-carboxylate having the empirical
formula C.sub.26H.sub.23FN.sub.2O.sub.4 is obtained (M=446.48 g).
The corresponding yield is 90%.
[0766] Stage B
[0767] The procedure is carried out as indicated in Stage M of
Example 1 with 0.270 g of the product obtained in the preceding
stage, 5 ml of THF, and 10% palladium on carbon. The product
obtained is treated as indicated in Stage N of Example 1 with 3 ml
of pyridine and 257 mg of pyridine-SO.sub.3 complex. The product
obtained is treated as indicated in Stage R of Example 12 with 25 g
of Dowex resin. 0.28 g of the compound sodium salt of 5-ethyl
trans-9-(4-fluorophenyl)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano-
-4H-2,4-benzodiazepine-5-carboxylate having the empirical formula
C.sub.19H.sub.16FN.sub.2NaO.sub.7S is obtained in the form of white
crystals (M=458.40 g). The corresponding yield is quantitative.
[0768] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 1.28 (t): CH.sub.3--CH.sub.2--O; 4.23 (q):
CH.sub.3--CH.sub.2--O; 3.46 (dd) and 3.53 (d): CH.sub.2--CH; 4.59
(d): CH.sub.2--CH; 5.05 (s): CH--CO.sub.2; 7.14 (m) and 7.52 (m):
the 4 aromatic H of the fluorinated nucleus; 7.19 (d), 7.34 (d) and
7.43 (t): the 3 aromatic H.
Example 32
Ethyl
1,2,3,5-tetrahydro-3-oxo-8-hydroxy-2-(phenylmethoxy)-1,4-methano-4H--
2,4-benzodiazepine-5-carboxylate
[0769] Stage A
[0770] Step 1
[0771] 51.72 g of an ethyl glyoxalate solution at 50% in toluene
are introduced, in the hot state, into a solution of 48 g (0.253
mol) of D,L-norphenylephrine hydrochloride in 94 ml of methanol
heated under reflux.
[0772] After refluxing for 30 minutes, the hydrochloride of the
expected product precipitates. The suspension is again left for 30
minutes under reflux before being cooled by an ice bath in order to
cause the expected hydrochloride to crystallize.
[0773] After adding 50 ml of ether, the filtered precipitate,
washed with ether, gives 46 g of ethyl
1,2,3,4-tetrahydro-4,6-dihydro-1-isoquinolinecarboxylate.
[0774] Step 2
[0775] 25 ml of TEA are added to a suspension, cooled to 0.degree.
C., of 44 g (0.160 mol) of the compound obtained in the preceding
step in 500 ml of THF. Then, after a change in the appearance of
the suspension, 38.7 g (0.177 mol) of (BOC).sub.2O are added. The
medium is next stirred for 2 hours at 20.degree. C. before pouring
the reaction medium over a 10% aqueous sodium hydrogen sulfate
solution.
[0776] After extraction with THF and with ethyl acetate, the
organic phase is again washed with a first sodium hydrogen sulfate
solution and then a second sodium dihydrogen phosphate solution at
1 molar. The organic phase is dried over magnesium sulfate and then
filtered and the solvent is evaporated off under reduced pressure
to give 60.2 g of 2-(1,1-dimethylethyl) and 1-ethyl
3,4-dihydro-4,6-dihydroxy-1,2(1H)-isoquinolinedicarboxylate having
the empirical formula C.sub.17H.sub.23NO.sub.6 (M=337.38 g)
[0777] Stage B
[0778] 60 g (1.177 mol) of the compound obtained in Stage A2 are
introduced into 600 ml of acetone. 49.4 g of potassium carbonate
are then added, followed dropwise by 29 ml of allyl bromide. The
medium is heated under reflux for 2 hours 30 minutes and then the
salts are filtered, and the acetone is evaporated off.
[0779] The residue is dissolved in a heptane/ACOEt mixture. The
organic phase is next washed with a saturated sodium bicarbonate
solution, dried over magnesium sulfate, and the solvent is then
evaporated off under reduced pressure.
[0780] 66 g of 2-(1,1-dimethylethyl) and 1-ethyl
3,4-dihydro-4-hydroxy-6-(2-propenyloxy)-1,2(1H)-isoquinolinedicarboxylate
having the empirical formula C.sub.20H.sub.27NO.sub.6 are obtained
(M=377.44 g). The corresponding yield is 98%.
[0781] Stage C
[0782] 57.5 g of pyridinium chlorochromate and 120 g of molecular
sieve are introduced into 1 liter of dichloromethane. A solution of
65.5 g (0.178 mol) of the compound obtained in Stage B is then
introduced at 0.degree. C. into 300 ml of dichloromethane. The
solution is stirred for 1 hour 30 minutes, while allowing the
temperature to return to room temperature, and then the medium is
filtered on 1 kg of Florisil, eluting with dichloromethane.
[0783] After evaporation of the solvent under reduced pressure,
49.92 g of 2-(1,1-dimethylethyl) and 1-ethyl
3,4-dihydro-4-oxo-6-(2-propenyloxy)-1,2(1H)-isoquinolinedicarboxylate
having the empirical formula C.sub.20H.sub.25NO.sub.6 are obtained
(M=375.40 g). The corresponding yield is 78%.
[0784] Stage D
[0785] 49.9 g of the compound obtained in Stage C are introduced
into 500 ml of pyridine and then 23.3 g of PhCH.sub.2ONH.sub.2,HCl
are added and the reaction medium is stirred for 1 hour.
[0786] The solvent is evaporated off under reduced pressure and
then the residue is dissolved in a mixture of heptane/ACOEt 1/2
solvent
[0787] The organic phase is washed 3 times with a sodium hydrogen
sulfate solution at 10% and then dried over magnesium sulfate.
[0788] 57 g of 2-(1,1-dimethylethyl) and 1-ethyl
3,4-dihydro-4-[(phenylmethoxy)imino]-6-(2-propenyloxy)-1,2(1H)-isoquinoli-
nedicarboxylate having the empirical formula
C.sub.27H.sub.32N.sub.2O.sub.6 are obtained in the form of an oil
(M=480.57 g). The corresponding yield is 89%.
[0789] Stage E
[0790] The procedure is carried out as indicated in H of Example 31
with 56 g of the product obtained in Stage D, 44 g of sodium
cyanoborohydride and 500 ml of glacial acetic acid.
[0791] 56 g of the product obtained in Stage D and 500 ml of
glacial acetic acid are introduced into a round-bottomed flask
placed under a nitrogen atmosphere. The medium is cooled to
10.degree. C. and about 44 g of sodium cyanoborohydride are added.
The temperature is allowed to return to room temperature and the
reaction is allowed to proceed for 5 hours. The medium is taken up
in 400 ml of AcOEt, poured into 600 ml of 1 N sodium hydroxide, the
medium is separated by decantation, extracted several times with
AcOEt, washed again with 1 N sodium hydroxide, and then with water
and then with a sodium chloride solution. The aqueous phase is
dried over magnesium sulfate, filtered and the solvent is
evaporated off under reduced pressure. The residue is purified by
chromatography on silica, eluting with a dichloromethane/AcOEt 97/3
mixture.
[0792] 22 g of 2-(1,1-dimethylethyl) and 1-ethyl
(1S)-3,4-dihydro-4-[(phenylmethoxy)amino]-6-(2-propenyloxy)-1,2(1H)-isoqu-
inolinedicarboxylate having the empirical formula
C.sub.27H.sub.34N.sub.2O.sub.6 are obtained (M=482.58 g). The
corresponding yield is 40%.
[0793] Stage F
[0794] The procedure is carried out as in Stages I and J of Example
1 with 22 g of the product obtained in Stage E, 22 ml of ethyl
acetate, 95 ml of a 4.6 M hydrochloric acid solution in ACOEt.
[0795] 16.5 g of ethyl
(1S)-1,2,3,4-tetrahydro-4-[(phenylmethoxy)amino]-6-(2-propenyloxy)-1-isoq-
uinolinecarboxylate having the empirical formula
C.sub.22H.sub.26N.sub.2O.sub.4 are obtained (M=382.46 g). The
corresponding yield is quantitative.
[0796] Stage G
[0797] The procedure is carried out as in Stage K of Example 1 with
16.4 g of the product obtained in Stage F, 3.5 liters of ethyl
acetate, 14.2 ml of TEA, and 4.2 g of diphosgene.
[0798] 3.5 g of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(phenylmethoxy)-8-(2-propenyloxy)-1,4-me-
thano-4H-2,4-benzodiazepine-5-carboxylate having the empirical
formula C.sub.23H.sub.24N.sub.2O.sub.5 are obtained (M=408 g). The
corresponding yield is 20%.
[0799] Stage H
[0800] 3.5 g of the product obtained in the preceding Stage G are
dissolved in 35 ml of toluene. 0.191 g of Pd(PPh.sub.3).sub.4 is
introduced therein under argon at 0.degree. C., followed by 0.52 g
of acetic acid, and finally, dropwise, 2.89 g of Bu.sub.3SnH.
[0801] The medium is stirred for 45 minutes at 0.degree. C. and
then the solvent is evaporated off under reduced pressure and the
residue is purified by chromatography on silica with a
heptane/AcOEt 1/1 mixture.
[0802] 2.92 g of ethyl
1,2,3,5-tetrahydro-3-oxo-8-hydroxy-2-(phenylmethoxy)-1,4-methano-4H-2,4-b-
enzodiazepine-5-carboxylate having the empirical formula
C.sub.20H.sub.20N.sub.2O.sub.5 are obtained in the form of white
crystals (M=368 g). The corresponding yield is 96%.
Example 33
Sodium salt of
trans-1,2,3,5-tetrahydro-N-methoxy-8-[(2-methoxyethoxy)methoxy]-3-oxo-2-(-
sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide
[0803] Stage A
[0804] 3.68 g of the product obtained in Stage H of Example 32 are
dissolved in 40 ml of dichloromethane. 1.24 ml of MEMCl and 2 ml of
DIEA are added to the reaction medium cooled to 0.degree. C. The
medium is stirred for 30 minutes at 0.degree. C. and then 1.24 ml
of MEMCl and 2 ml of DIEA are again added. The reaction is next
poured into water containing NaH.sub.2PO.sub.4. The organic phase
is extracted and dried over magnesium sulfate and the solvent is
evaporated off under reduced pressure. The residue obtained is
purified by chromatography on silica, eluting with a
dichloromethane mixture containing 5% acetone. 2.8 g of compound
ethyl
trans-1,2,3,5-tetrahydro-8-[(2-methoxyethoxy)methoxy]-3-oxo-2-(phenylmeth-
oxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.24H.sub.28N.sub.2O.sub.7 are obtained
(M=456.50 g). The corresponding yield is 63%.
[0805] Stage B
[0806] The procedure is carried out as in Stage A of Example 7 with
2.8 g of the product obtained in the preceding stage, 40 ml of
dioxane and 3 ml of water, 6.13 ml of 1 N aqueous sodium hydroxide.
2.18 g of the compound
trans-1,2,3,5-tetrahydro-8-[(2-methoxyethoxy)methoxy]-3-oxo-2-(phenylmeth-
oxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylic acid having the
empirical formula C.sub.22H.sub.24N.sub.2O.sub.7 are obtained
(M=428.35 g). The corresponding yield is 86%.
[0807] Stage C
[0808] The procedure is carried out as indicated in Stage B of
Example 7 with 0.31 g of the product obtained in the preceding
stage, 5 ml of DMF, 0.46 g of BOP, 0.15 g of HOBT, 0.13 g of
NH.sub.2OMe,HCl, 0.5 ml of DIEA. 0.215 g of compound
trans-1,2,3,5-tetrahydro-N-methoxy-8-[(2-methoxyethoxy)methoxy]-3-oxo-2-(-
phenylmethoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide
having the empirical formula C.sub.23H.sub.27N.sub.3O.sub.7 is
obtained (M=457.49 g). The corresponding yield is 64%.
[0809] Stage D
[0810] The procedure is carried out as indicated in Stage M of
Example 1 with 0.2 g of the product obtained in the preceding
stage, 3 ml of ethanol, and 25 mg of 10% palladium on carbon. The
compound
trans-1,2,3,5-tetrahydro-2-hydroxy-N-methoxy-8-[(2-methoxyethoxy)methoxy]-
-3-oxo-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide having the
empirical formula C.sub.16H.sub.21N.sub.3O.sub.7 is obtained with a
quantitative yield (M=367.36 g).
[0811] Stage E
[0812] The procedure is carried out as indicated in Stage N of
Example 1 with 0.16 g of the product in the preceding stage, 2 ml
of pyridine, 240 mg of the pyridine-SO.sub.3 complex. 0.138 g of
the compound sodium salt of
trans-1,2,3,5-tetrahydro-N-methoxy-8-[(2-methoxyethoxy)methoxy]-3-oxo--
2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide having
the empirical formula C.sub.16H.sub.20N.sub.3O.sub.10S,Na is
obtained (M=446.42+22.99 g). The corresponding yield is 68%.
[0813] LC/MS (negative electrospray), m/z: M.sup.-=446.1.
[0814] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity:
[0815] 3.23 (s): CH.sub.3--O--(CH.sub.2).sub.2--O--CH.sub.2--O;
3.46 (m), 3.72 (m): CH.sub.3--O--(CH.sub.2).sub.2--O--CH.sub.2--O;
5.24 (broad s): CH.sub.3--O--(CH.sub.2).sub.2--O--CH.sub.2--O; 3.41
(m), 3.88 (broad d): N--CH.sub.2--CH; 4.61 (masked):
N--CH.sub.2--CH; 4.61 (s): CH--CO--N--O--CH.sub.3; 3.65 (broad s):
CH--CO--N--O--CH.sub.3; 6.78 (d), 7.03 (dd), 7.09 (dd): the 3
aromatic H and 11.78 (s): 0=C--NH--O.
Example 34
Sodium salt of
trans-1,2,3,5-tetrahydro-8-hydroxy-N-methoxy-3-oxo-2-(sulfoxy)-1,4-methan-
o-4H-2,4-benzodiazepine-5-carboxamide
[0816] Stage A
[0817] 0.06 g of the product obtained in Stage E of Example 33 is
dissolved in a solution containing 1 ml of trifluoroacetic acid, 1
ml of dichloromethane and 0.4 ml of anisole. The medium is stirred
for 30 minutes and then the reaction medium is evaporated to
dryness under reduced pressure. Toluene is added and then the
medium is again dried under reduced pressure. The residue is taken
up in ether and 30 mg of the compound sodium salt of
trans-1,2,3,5-tetrahydro-8-hydroxy-N-methoxy-3-oxo-2-(sulfoxy)-1,4-methan-
o-4H-2,4-benzodiazepine-5-carboxamide are obtained in the form of
yellow crystals. The corresponding yield is 44%.
[0818] LC/MS (negative electrospray), m/z: M.sup.-=358 g.
Example 35
Sodium salt of ethyl
trans-8-(2-aminoethoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano--
4H-2,4-benzodiazepine-5-carboxylate
[0819] Stage A
[0820] 0.5 g of the product obtained in Stage H of Example 32 is
dissolved in 5 ml of dichloromethane. 0.239 g of Boc-NH--CH.sub.2OH
and 0.39 g of P.phi..sub.3 are then added. The reaction medium is
cooled to 0.degree. C. and 258 .mu.l of DEAD are added dropwise.
After stirring for one hour at room temperature, the medium is
poured over water, the organic phase is extracted and dried over
sodium sulfate. The solvent is evaporated under reduced pressure
and the residue is purified by chromatography on silica, eluting
with dichloromethane containing 5% acetone. 320 mg of compound
ethyl
trans-8-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-1,2,3,5-tetrahydr-
o-3-oxo-2-(phenylmethoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate
having the empirical formula C.sub.27H.sub.33N.sub.3O.sub.7 are
obtained (M=511.58 g). The corresponding yield is 47%.
[0821] Stage B
[0822] The procedure is carried out as indicated in Stage M of
Example 1 with 60 mg of the product obtained in the preceding
stage, 0.5 ml of ethanol and 7 mg of 10% palladium on carbon. The
product obtained is treated as indicated in Stage M of Example 1
with 0.8 ml of pyridine, and 56 mg of the pyridine-SO.sub.3
complex, and then as indicated in Stage R of Example 12 with 50 g
of Dowex resin. 51 mg of the compound sodium salt of ethyl
trans-8-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-1,2,3,5--
tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxyla-
te having the empirical formula C.sub.20H.sub.26N.sub.3O.sub.10S,Na
are obtained (M=500.51+22.99 g). The corresponding yield is
84%.
[0823] Stage C
[0824] The procedure is carried out as indicated in Stage A of
Example 1 with 0.048 g of the product obtained in the preceding
stage and 0.5 ml of trifluoroacetic acid. 30 mg of the compound
sodium salt of ethyl
trans-8-(2-aminoethoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano--
4H-2,4-benzodiazepine-5-carboxylate having the empirical formula
C.sub.15H.sub.18N.sub.3O.sub.8S,Na are obtained in the form of
white crystals (M=400.39+22.99 g). The corresponding yield is
79%.
[0825] LC/MS (negative electrospray), m/z: (M-H).sup.-=400.
[0826] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 1.25(t): CH.sub.3--CH.sub.2--OCO--CH; 4.21 (q):
CH.sub.3--CH.sub.2--OCO--CH; 4.95 (s); CH.sub.3--CH.sub.2--OCO--CH;
2.23(tl): N--CH.sub.2--CH.sub.2--O; 4.16(m):
N--CH.sub.2--CH.sub.2--O; 3.52(s): N--CH.sub.2--CH--; 4.67(s):
N--CH.sub.2--CH--; 6.81 (d), 7.01 (dd), 7.29(d) the 3 aromatic H;
7.95(broad s) the 2 active H.
Example 36
Sodium salt of
trans-8-(2-aminoethoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano--
4H-2,4-benzodiazepine-5-carboxamide
[0827] Stage A The procedure is carried out as indiciated in Stage
A of Example 7 with 0.327 g of the product obtained in Stage A of
Example 35, 3 ml of dioxane, 3 ml of water and 0.639 ml of 1 N
aqueous sodium hydroxide. 0.285 g of the compound
trans-8-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethoxy]-1,2,3,5-tetrahydr-
o-3-oxo-2-(phenylmethoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylic
acid having the empirical formula C.sub.25H.sub.29N.sub.3O.sub.7 is
obtained (M=483.53 g). The corresponding yield is 95%.
[0828] Stage B
[0829] The procedure is carried out as indicated in Stage B of
Example 7 with 0.28 g of the product obtained in the preceding
stage, 4 ml of DMF, 0.368 g of BOP, 0.117 g of HOBt, 0.062 g of
NH.sub.4Cl and 0.4 ml of DIEA. 0.182 mg of the compound
1,1-dimethylethyl
trans-[2-[[5-(aminocarbonyl)-1,2,3,5-tetrahydro-3-oxo-2-(phenylmethoxy)-1-
,4-methano-4H-2,4-benzodiazepin-8-yl]oxy]ethyl]carbamate having the
empirical formula C.sub.25H.sub.30N.sub.4O.sub.6 is obtained
(M=482.54 g). The corresponding yield is 65%.
[0830] Stage D
[0831] The procedure is carried out as indicated in Stage M of
Example 1 with 0.175 g of the product obtained in the preceding
stage, 2 ml of ethanol, 2 ml of acetic acid and 40 mg of 10%
palladium on carbon. The product obtained is treated as indicated
in Stage N of Example 1 with 3 ml of pyridine and 250 mg of the
pyridine-SO.sub.3 complex. The product obtained is treated as in
Stage R of Example 12 with 40 g of Dowex resin which are prepared
with sodium hydroxide. 0.130 g of compound sodium salt of
1,1-dimethylethyl
trans-[2-[[5-(aminocarbonyl)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-met-
hano-4H-2,4-benzodiazepin-8-yl]oxy]ethyl]carbamate having the
empirical formula C.sub.18H.sub.23N.sub.4O.sub.9S,Na is obtained
(M=471.47+22.99 g). The corresponding yield is 73%
[0832] Stage E
[0833] The procedure is carried out as indicated in Stage A of
Example 13 with the 130 mg of product obtained in the preceding
stage in the presence of 1 ml of trifluoroacetic acid. 80 mg of the
compound sodium salt of
trans-8-(2-aminoethoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4--
methano-4H-2,4-benzodiazepine-5-carboxamide having the empirical
formula C.sub.13H.sub.15N.sub.4O.sub.7S,Na are obtained in the form
of beige crystals (M=371.35+22.99 g). The corresponding yield is
77%.
[0834] LC/MS (negative electrospray), m/z: M.sup.-=371.
Example 37
Sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-8-[[(phenylamino)carbonyl]oxy]-2-(sulfoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate
[0835] Stage A
[0836] The procedure is carried out as indicated in Stage A of
Example 28 with 0.2 g of the product obtained in Stage H of Example
32, 2 ml of dichloromethane, 0.04 ml of triethylamine and 0.06 ml
of phenyl isocyanate. 0.170 g of the compound ethyl
trans-1,2,3,5-tetrahydro-3-oxo-8-[[(phenylamino)carbonyl]oxy]-2-(phenylme-
thoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.27H.sub.25N.sub.3O.sub.6 is obtained
(M=487.52 g). The corresponding yield is 65%.
[0837] Stage B
[0838] The procedure is carried out as indicated in Stage M of
Example 1 with 0.170 g of the product obtained in the preceding
stage, 4 ml of ethanol, 2 ml of THF and 35 mg of 10% palladium on
carbon. 0.153 g of compound ethyl
trans-1,2,3,5-tetrahydro-2-hydroxy-3-oxo-8-[[(phenylamino)carbonyl]oxy]-1-
,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the empirical
formula C.sub.20H.sub.19N.sub.3O.sub.6 is obtained (M=397.39 g).
The corresponding yield is quantitative.
[0839] Stage C
[0840] The procedure is carried out as indicated in Stage N of
Example 1 with 0.153 mg of the product obtained in the preceding
stage, 2 ml of pyridine and 0.177 g of the pyridine-SO.sub.3
complex. The compound obtained is then treated as indicated in
Stage R of Example 12 with 50 g of Dowex resin. The compound sodium
salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-8-[[(phenylamino)arbonyl]oxy]-2-(sulfoxy)--
1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.20H.sub.18N.sub.3O.sub.9Sna is obtained
(M=476.45+22.99).
[0841] LC/MS (negative electrospray), m/z: M.sup.-(476.1 g)
[0842] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 1.27 (t) and 4.24 (q): CO.sub.2-Et; 3.55:
N--CH.sub.2--CH; 4.72 (broad s): N--CH.sub.2--CH; 5.04 (broad s):
N--CH--CO 6.99 (d), 7.26 (dd), 7.39 (d): the 3 aromatic H, 7.51,
7.32 and 7.05: the 5 aromatic H; 10.29: NH.
Example 38
Sodium salt of ethyl
trans-8-[[(ethylamino)carbonyl]oxy]-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)--
1,4-methano-4H-2,4-benzodiazepine-5-carboxylate
[0843] Stage A
[0844] The procedure is carried out as indicated in Stage A of
Example 28 with 0.2 g of the product obtained in Stage H of Example
32, 3 ml of dichloromethane, 0.037 ml of TEA and 0.041 ml of ethyl
isocyanate. 0.170 g of the compound ethyl
trans-8-[[(ethylamino)carbonyl]oxy]-1,2,3,5-tetrahydro-3-oxo-2-(phenylmet-
hoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.23H.sub.25N.sub.3O.sub.6 is obtained (M=439
g). The corresponding yield is 73%.
[0845] Stage B
[0846] The procedure is carried out as indicated in Stage M of
Example 1 with 0.170 g of the compound obtained in the preceding
stage, 3 ml of ethanol and 35 mg of 10% palladium on carbon. 0.14
mg of the compound ethyl
trans-8-[[(ethylamino)carbonyl]oxy]-1,2,3,5-tetrahydro-2-hydroxy-3--
oxo-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.16H.sub.19N.sub.3O.sub.6 is obtained
(M=349.35 g).
[0847] Stage C
[0848] The procedure is carried out as indicated in Stage N of
Example 1 with 0.140 mg of the product obtained in the preceding
stage, 2 ml of pyridine and 0.180 g of the pyridine-SO.sub.3
complex. The product obtained is then treated as indicated in Stage
E of Example 12 with 25 g of Dowex resin. The compound sodium salt
of ethyl
trans-8-[[(ethylamino)carbonyl]oxy]-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)--
1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.16H.sub.18N.sub.3O.sub.9S,Na is obtained
(M=428 g).
[0849] LC/MS (negative electrospray), m/z: M.sup.-=428.1 g.
[0850] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 1.08 (t): CH.sub.3--CH.sub.2--NH; 3.09 (m):
CH.sub.3--CH.sub.2--NH; 7.82 (t): CH.sub.3--CH.sub.2--NH; 1.26 (t):
CH3--CH.sub.2-0-CO; 4.22 (q): CH.sub.3--CH.sub.2--O--CO; 3.52
(broad s): N--CH.sub.2--CH; 4.67 (broad s): N--CH.sub.2--CH; 5.00
(s): N--CH--C.dbd.O; 6.86 (broad s), 7.13 (broad d), 7.33 (d): the
3 aromatic H.
Example 39
Sodium salt of ethyl
trans-8-(4-fluorophenyl)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano-
-4H-2,4-benzodiazepine-5-carboxylate
[0851] Stage A
[0852] The procedure is carried out as indicated in Stage A of
Example 30 with 1 g of the compound obtained in Stage H of Example
32, 1.17 ml of triethylamine and 0.67 ml of triflic anhydride. 0.9
g of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(phenylmethoxy)-8-[[(trifluoromethyl)sul-
fonyl]oxy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having
the empirical formula C.sub.21H.sub.19F.sub.3N.sub.2O.sub.7 is
obtained (M=500.45 g).
[0853] Stage B
[0854] The procedure is carried out as indicated in Stage M of
Example 19 with 0.3 g of the product obtained in the preceding
stage, 12 ml of toluene, 60 mg of Pd(P.phi..sub.3).sub.4, 0.125 g
of 4-fluoronylboronic acid, 2.4 ml of a 2 N Na.sub.2CO.sub.3
solution. 0.25 g of the compound ethyl
trans-8-(4-fluorophenyl)-1,2,3,5-tetrahydro-3-oxo-2-(phenylmethoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.26H.sub.23FN.sub.2O.sub.4 is obtained
(M=446.48 g). The corresponding yield is 70%.
[0855] Stage C
[0856] The procedure is carried out as indicated in Stage M of
Example 1 with 0.25 g of the product obtained in the preceding
stage, 6 ml of ethanol, 40 mg of 10% palladium on carbon. 0.20 g of
the compound ethyl
trans-8-(4-fluorophenyl)-1,2,3,5-tetrahydro-2-hydroxy-3-oxo-1,4-methano-4-
H-2,4-benzodiazepine-5-carboxylate having the empirical formula
C.sub.19H.sub.17FN.sub.2O.sub.4 is obtained (M=356.36 g). The
corresponding yield is quantitative.
[0857] Stage D
[0858] The procedure is carried out as indicated in Stage N of
Example 1 with 0.20 g of the product obtained in the preceding
stage, 2 ml of pyridine and 0.20 g of the pyridine-SO.sub.3
complex. The product obtained is treated as indicated in Stage E of
Example 12 with 25 g of Dowex resin. 0.150 g of the compound sodium
salt of ethyl
trans-8-(4-fluorophenyl)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-methano-
-4H-2,4-benzodiazepine-5-carboxylate having the empirical formula
C.sub.19H.sub.16FN.sub.2O.sub.5S,NA is obtained in the form of
yellow crystals (M=458.40 g).
[0859] LC/MS (negative electrospray), m/z: M.sup.-=435.1.
[0860] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 1.27 (t): CH.sub.3--CH.sub.2--O--CO; 4.23 (q):
CH.sub.3--CH.sub.2--O--CO; 3.58 (broad s): N--CH.sub.2--CH; 4.79
(broad s): N--CH.sub.2--CH; 5.06 (s): CH--CO.sub.2-Et; 7.30 (t) and
7.68 (m): the H of the fluorinated aromatic nucleus; 7.38 (d), 7.43
(d), 7.66 (masked): the 3 aromatic H.
Example 40
Sodium salt of ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[[(trifluoromethyl)sulfonyl]-
oxy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate
[0861] Stage A
[0862] The procedure is carried out as indicated in Stage M of
Example 1 with 0.12 g of the product obtained in Stage A of Example
39. 4 ml of ethanol and 30 mg of 10% palladium on carbon. 0.105 g
of the compound ethyl
trans-1,2,3,5-tetrahydro-2-hydroxy-3-oxo-8-[[(trifluoromethyl)sulfo-
nyl]oxy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula C.sub.14H.sub.13F.sub.3N.sub.2O.sub.7S is
obtained (M=410.33 g). The corresponding yield is quantitative.
[0863] Stage B
[0864] The procedure is carried out as indicated in Stage N of
Example 1 with 0.108 g of the product obtained in the preceding
stage, 2 ml of pyridine and 120 mg of the pyridine-SO.sub.3
complex. The product obtained is treated as indicated in Stage R of
Example 12 with 25 g of Dowex resin. The compound sodium salt of
ethyl
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[[(trifluoromethyl)sulfonyl]-
oxy]-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate having the
empirical formula (to be verified by the client)
C.sub.14H.sub.12F.sub.3N.sub.2O.sub.10S.sub.2 is obtained (M=489
g).
[0865] LC/MS (negative electrospray), m/z: M.sup.-=489.
[0866] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 1.26 (t): CH.sub.3--CH.sub.2--O--CO; 4.22 (q):
CH.sub.3--CH.sub.2--O--CO; 3.51 (m): N--CH.sub.2--CH; 4.78:
N--CH.sub.2--CH; 5.15 (broad s): N--CH--CO; 7.23 (broad s) and 7.56
(broad s): the 3 aromatic H.
Example 41
Disodium salt of
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[2-(sulfoxy)ethoxy]-1,4-meth-
ano-4H-2,4-benzodiazepine-5-carboxamide
[0867] Stage A
[0868] The procedure is carried out as indicated in Stage I of
Example 12 with 3 g of the product obtained in Stage G of Example
32, 60 ml of THF, 60 ml of tert-butanol, 30 ml of water, 0.054 g of
osmium tetroxide and 0.99 g of N-methylmorpholine N-oxide. 3.3 g of
crude product are obtained which are used as they are in the next
step.
[0869] Stage B
[0870] 3.3 g of the crude product obtained above are dissolved in
60 ml of dimethoxypropane and 14 ml of acetone in the presence of
para-toluenesulfonic acid at 0.degree. C. After stirring for 30
minutes, the solution is evaporated to dryness and the residue is
purified by chromatography on silica, eluting with a heptane/ethyl
acetate 1/1 mixture. 3.075 g of compound ethyl
trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-3-ox-
o-2-(phenylmethoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylate
having the empirical formula C.sub.26H.sub.30N.sub.2O.sub.7 are
obtained (M=482.54 g). The corresponding yield is 90%.
[0871] Stage C
[0872] The procedure is carried out as indicated in Stage A of
Example 7 with 3 g of the product obtained in the preceding stage,
0.261 g of LiOH.H.sub.2O, 15 ml of THF and 15 ml of water. 2 g of
the compound
trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-3-ox-
o-2-(phenylmethoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxylic
acid having the empirical formula C.sub.24H.sub.26N.sub.2O.sub.7
are obtained (M=454.48 g). The corresponding yield is 72%.
[0873] Stage D
[0874] The procedure is carried out as indicated in Stage B of
Example 7 with 2 g of the product obtained in the preceding stage,
32 ml of DMF, 2.79 g of BOP, 10.89 g of HOBt, 0.47 g of NH.sub.4Cl,
3.06 ml of diisopropylethylamine. 1.6 g of the compound
trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-3-ox-
o-2-(phenylmethoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide
having the empirical formula C.sub.24H.sub.27N.sub.3O.sub.6 are
obtained in the form of white crystals (M=453.50 g). The
corresponding yield is 80%.
[0875] Stage E
[0876] 1 g of the product obtained in the preceding stage is
dissolved in 10 ml of a trifluoroacetic acid/water 9/1 mixture. The
medium is stirred for 10 minutes and then the reaction medium is
evaporated to dryness while carrying away with toluene. The residue
is solubilized in 50 ml of methylene chloride to which 40 ml of a
saturated aqueous NaHCO.sub.3 solution are added. 100 ml of THF and
40 ml of a saturated aqueous NaCl solution are added. After
decantation, the organic phase is washed with a saturated NaCl
solution and it is dried over magnesium sulfate. After evaporation
of the solvent under reduced pressure, crystals are obtained which
are taken up in ether. After filtration, 0.82 g of the compound
trans-8-(2,3-dihydroxypropoxy)-1,2,3,5-tetrahydro-3-oxo-2-(phenylmethoxy)-
-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide having the
empirical formula C.sub.21H.sub.23N.sub.3O.sub.6 is obtained
(M=413.43 g). The corresponding yield is 90%.
[0877] Stage F
[0878] 0.6 g of the product obtained in the preceding stage is
dissolved in a mixture containing 13 ml of THF, 4 ml of water and 4
ml of methanol. 0.62 g of NalO.sub.4 is added to the solution
cooled to 0.degree. C. The medium is stirred at 0.degree. C. and
the product crystallizes. The suspension is poured into ethyl
acetate, washed with water and the organic phase is dried over
magnesium sulfate. After evaporation under reduced pressure, 53 g
of the compound
trans-1,2,3,5-tetrahydro-3-oxo-8-(2-oxoethoxy)-2-(phenylmethoxy)-1,4-meth-
ano-4H-2,4-benzodiazepine-5-carboxamide having the empirical
formula C.sub.20H.sub.19N.sub.3O.sub.5 are obtained. The
corresponding yield is 90%.
[0879] Stage G
[0880] 0.52 g of the product obtained in the preceding stage is
dissolved in ethanol. The solution is cooled to 0.degree. C. and
four equivalents of NaBH.sub.4 are added. The medium is stirred for
two hours and then a heptane/ethyl acetate 1/4 mixture is added to
the reaction medium. The organic phase is washed with water and
then with an aqueous NaH.sub.2PO.sub.4 solution and then dried over
magnesium sulfate. After evaporation of the solvent, 0.43 g of
crude product is obtained which is purified by chromatography on
silica, eluting with a methylene chloride mixture containing 10%
methanol. After evaporation of the fractions, 0.187 g of white
crystals of the compound
trans-1,2,3,5-tetrahydro-8-(2-hydroxyethoxy)-3-oxo-2-(phenylmethoxy)-1,4--
methano-4H-2,4-benzodiazepine-5-carboxamide having the empirical
formula C.sub.20H.sub.21N.sub.3O.sub.5 is obtained (M=383.41 g).
The corresponding yield is 38%.
[0881] Stage H
[0882] The procedure is carried out as indicated in Stage M of
Example 1 with 0.18 g of the product obtained in the preceding
stage, 2 ml of ethanol, 2 ml of THF and 0.043 g of 10% palladium on
carbon. 0.12 g of the compound
trans-1,2,3,5-tetrahydro-2-hydroxy-8-(2-hydroxyethoxy)-3-oxo-1,4-methano--
4H-2,4-benzodiazepine-5-carboxamide having the empirical formula
C.sub.13H.sub.15N.sub.3O.sub.5 is obtained. The corresponding yield
is 90%.
[0883] Stage I
[0884] The procedure is carried out as indicated in Stage N of
Example 1 with 0.12 g of the product obtained in the preceding
stage, 3 ml of pyridine and 159 mg of the pyridine-SO.sub.3
complex. The product obtained is treated as in Stage R of Example
12 with 25 g of Dowex resin. 0.15 g of the compound disodium salt
of
trans-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-8-[2-(sulfoxy)ethoxy]-1,4-meth-
ano-4H-2,4-benzodiazepine-5-carboxamide having the empirical
formula C.sub.13H.sub.13N.sub.3O.sub.11S.sub.2,2Na is obtained
(M=451.39+2.times.22.99 g).
[0885] LC/MS (negative electrospray), m/z:
(M.sup.2-+H).sup.-=451.9. (M.sup.2-+H).sup.-=451.9.
[0886] Proton NMR, DMSO-d.sub.6, 300 MHz, chemical shift and
multiplicity: 3.41 (dd) and 3.77 (d): N--CH.sub.2--CH; 4.60 (d):
N--CH.sub.2--CH; 4.02 (m) and 4.10 (m): 0-CH.sub.2--CH.sub.2; 4.72
(s): CH--CO--NH.sub.2; 7.40 (broad s) and 7.86 (broad s):
CH--CO--NH.sub.2; 6.66 (d), 6.93 (dd), 7.16 (d): the 3 aromatic
H.
Example 42
Sodium salt of
trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-3-ox-
o-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide
[0887] Stage A
[0888] The procedure is carried out as in Stage M of Example 1 with
0.6 g of the product obtained in Stage D of Example 41, 60 mg of
10% palladium on carbon and 20 ml of ethanol and 3 ml of THF. 0.46
g of the compound
trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-2-hy-
droxy-3-oxo-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide having
the empirical formula C.sub.17H.sub.21N.sub.3O.sub.6 is obtained
(M=363.37 g). The corresponding yield is 86%.
[0889] Stage B
[0890] The procedure is carried out as in Stage N of Example 1 with
0.46 g of the product obtained in the preceding stage, 3 ml of
pyridine and 159 mg of the pyridine-SO.sub.3 complex. A compound is
obtained which is treated as indicated in Stage R of Example 12
with 25 g of Dowex resin. 0.136 g of the compound sodium salt of
trans-8-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1,2,3,5-tetrahydro-3-ox-
o-2-(sulfoxy)-1,4-methano-4H-2,4-benzodiazepine-5-carboxamide
having the empirical formula C.sub.17H.sub.20N.sub.3O.sub.9S.Na is
obtained (M=442.43+22.99 g). The corresponding yield is 93%.
[0891] LC/MS (negative electrospray), m/z: M.sup.-=442.
[0892] Proton NMR, DMSO-d.sub.6 to 300 MHz, chemical shift and
multiplicity: 1.30 (s), 1.36 (s): (CH.sub.3).sub.2--C--C; 3.42
(broad d), 3.74 (m): N--CH.sub.2--CH; 4.60 (broad d)
N--CH.sub.2--CH; 3.76 (m), 4.09 (dd), 3.95 (m), 4.01 (m):
O--CH.sub.2--CH--CH.sub.2--O; 4.40 (m):
O--CH.sub.2--CH--CH.sub.2--O; 4.73 (broad s): CH--CO--NH.sub.2;
7.41 (broad s), 7.87 (broad s): CH--CO--NH.sub.2; 6.68 (d), 6.94
(dd), 7.16 (d): the 3 aromatic H.
Example 43
Sodium salt of
trans-8-(2,3-dihydroxypropoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-m-
ethano-4H-2,4-benzodiazepine-5-carboxamide
[0893] 0.136 g of the product obtained in Stage B of Example 42 is
dissolved in 1.3 ml of a trifluoroacetic acid/water 9/1 mixture at
0.degree. C. The medium is stirred for 15 minutes, and then the
reaction medium is evaporated to dryness. The residue is taken up
in ether and then filtered. 0.106 g of the compound sodium salt of
trans-8-(2,3-dihydroxypropoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-m-
ethano-4H-2,4-benzodiazepine-5-carboxamide having the empirical
formula C.sub.14H.sub.16N.sub.3O.sub.9S.Na is obtained (M=401.37
g+23 g). The corresponding yield is 85%.
[0894] LC/MS (negative electrospray), m/z: M.sup.-=402.
[0895] Proton NMR, DMSO-d.sub.6, 300 MHz, (chemical shift and
multiplicity) 3.43 (m): CH.sub.2--OH; 4.67: CH.sub.2--OH; 3.99 (m):
0-CH.sub.2--CH--OH; 3.82 (m): O--CH.sub.2--CH--OH; 4.97 (broad d):
O--CH.sub.2--CH--OH; 3.46 and 3.72: N--CH.sub.2--CH--N; 4.60 (d):
N--CH.sub.2--CH--N; 4.73 (s): .phi.-CH--N--CO; 6.67 (d), 6.91 (dd),
7.16 (d): the 3 aromatic H; 7.41 (broad s) and 7.87 (broad s):
CO--NH.sub.2.
Example 44
Sodium salt of ethyl
trans-3-(4-fluorophenyl)-4,6,7,8-tetrahydro-6-oxo-7-(sulfoxy)-5,8-methano-
-5H-thieno[2,3-e][1,3]diazepine-4-carboxylate
[0896] Stage A
[0897] 100 mg of the compound 3,4-dibromothiophene are introduced
into 300 ml of ether, in a round-bottomed flask placed under an
argon atmosphere. The medium is stirred and the reaction medium is
cooled to -70.degree. C. and then 271 ml of a 1.6 M butyllithium
solution in ether is introduced therein with the aid of a
canula-like tube. The medium is stirred for 45 minutes at
-70.degree. C. This solution is introduced via a canula-like tube
into a solution cooled beforehand to -70.degree. C. under an argon
atmosphere of 172 mg of diethyl oxalate in 250 ml of ether
containing a small amount of THF. The medium is stirred for 1 hour
at -70.degree. C. Then a solution having returned to room
temperature, a 1 M aqueous NaH.sub.2PO.sub.4 solution is added, the
medium is separated by decantation and the aqueous phase is
extracted several times with ether. The organic phases are combined
and then dried over magnesium sulfate and filtered. After
evaporation of the solvent under reduced pressure, 108 g of the
expected brominated compound are obtained. The corresponding yield
is quantitative.
[0898] Stage B
[0899] 108.6 g of the product obtained in the preceding stage are
dissolved in 570 ml of ethanol and 230 ml of THF. The solution is
cooled to -35.degree. C. and 15.7 g of NaBH.sub.4 are very slowly
added. A gaseous emission is observed and, once the addition is
complete, the reaction medium is treated by adding a heptane/ethyl
acetate 4/1 mixture. The solution is then poured over an ice-cold 1
M NaH.sub.2PO.sub.4 solution and the aqueous phase is extracted
with a heptane/ethyl acetate 1/4 mixture. After decantation, the
aqueous phase is saturated with NaCl and the aqueous phase is again
extracted with a heptane/ethyl acetate 1/42 mixture. The organic
phases are combined and dried over magnesium sulfate and then
concentrated under reduced pressure. The residue obtained after
evaporation is treated with 150 ml of a heptane/ethyl acetate 6/1
mixture and 150 ml of ether. The solution is cooled to -10.degree.
C. by a methanol/ice bath in order to cause the boron salts to
precipitate. After filtration, the filtrate is purified on silica,
eluting with a heptane/ethyl acetate 4/1 mixture. After evaporation
of the fractions, 74.5 g of the compound ethyl
4-bromo-.alpha.-hydroxy-3-thiopheneacetate having the empirical
formula C.sub.8H.sub.9BrO.sub.3S are obtained (M=265.13 g). The
corresponding yield is 68%.
[0900] Stage C
[0901] The procedure is carried out as in Stage C of Example 27
with 74.5 g of the product obtained in the preceding stage, 97.5 g
of (CH.sub.3SO.sub.2).sub.2O and 80.8 ml of triethylamine and 395
ml of methylene chloride. The compound ethyl
4-bromo-.alpha.-[(methylsulfonyl)oxy]-3-thiopheneacetate having the
empirical formula C.sub.9H.sub.11BrO.sub.5S.sub.2 is obtained with
a quantitative yield (M=343.22 g).
[0902] Stage D
[0903] The procedure is carried out as in Stage D of Example 27
with the product obtained in the preceding stage, 57.8 ml of
tert-butyl glycinate, 50 ml of 2,6-lutidine. 82.3 g of the compound
ethyl
4-bromo-.alpha.-[[2-(1,1-dimethylethoxy)-2-oxoethyl]amino]-3-thiopheneace-
tate having the empirical formula C.sub.14H.sub.20BrN.sub.4S are
obtained (M=378.29 g). The corresponding yield is 77%.
[0904] Stage E
[0905] The procedure is carried out as in Stage E of Example 27
with 48 g of the product obtained in the preceding stage, 24 ml of
trifluoroacetic anhydride and 22 ml of triethylamine and 250 ml of
dichloromethane. 32.75 g of the compound ethyl
4-bromo-.alpha.-[[2-(1,1-dimethylethoxy)-2-oxoethyl](trifluoroacetyl)amin-
o]-3-thiopheneacetate having the empirical formula
C.sub.16H.sub.19BrF.sub.3NO.sub.5S are obtained (M=474.30). The
corresponding yield is 53%.
[0906] Stage F
[0907] The procedure is carried out as in Stage F of Example 27
with 40 g of the product obtained in the preceding stage, 234 ml of
trifluoroacetic acid and 230 ml of dichloromethane. 37 g of the
compound ethyl
4-bromo-.alpha.-[(carboxymethyl)(tri-fluoroacetyl)amino]-3-thiopheneaceta-
te having the empirical formula C.sub.12H.sub.11BrF.sub.3NO.sub.5S
are obtained (M=418.19 g). The corresponding yield is
quantitative.
[0908] Stage G
[0909] The procedure is carried out as in Stage G of Example 27
with 37 g of the product obtained in the preceding stage and 66 ml
of SOCl.sub.2. The medium is heated under reflux and the solution
is stirred for one hour. After evaporation to dryness, the product
is still treated as in Stage G of Example 27 with 30 g of
AlCl.sub.3 in solution in 230 ml of nitromethane. 9.94 g of ethyl
3-bromo-4,5,6,7-tetrahydro-7-oxo-5-(trifluoroacetyl)thieno[3,2-c]pyridine-
-4-carboxylate having the empirical formula
C.sub.12H.sub.9BrF.sub.3NO.sub.4S are obtained (M=400.17 g). The
corresponding yield is 28%.
[0910] Stage H
[0911] 9.3 g of the product obtained in the preceding stage are
dissolved in 100 ml of dichloromethane and 88 ml of methanol and
0.44 g of NaBH.sub.4 is added. The medium is stirred for 30
minutes, and then the reaction medium is poured into a 1 M aqueous
solution of NaH.sub.2PO.sub.4 and ethyl acetate at 0.degree. C. The
organic phase is dried over magnesium sulfate and the solvent is
evaporated off under reduced pressure. 8.73 g of the compound ethyl
3-bromo-4,5,6,7-tetrahydro-7-hydroxy-5-(trifluoroacetyl)thieno[3,2-c]pyri-
dine-4-carboxylate having the empirical formula
C.sub.12H.sub.11BrF.sub.3NO.sub.3S are obtained (M=402.19 g). The
corresponding yield is 94%.
[0912] Stage I
[0913] The procedure is carried out as in Stage H of Example 1 with
8.73 g of the product obtained in the preceding stage, 5.67 g of
methanesulfonic anhydride, 3.4 ml of triethylamine, 17 ml of
benzylhydroxylamine and 80 ml of dichloromethane. 5.9 g of the
compound ethyl
trans-3-bromo-4,5,6,7-tetrahydro-7-[(phenylmethoxy)amino]-5-(trifluoroace-
tyl)thieno[3,2-c]pyridine-4-carboxylate having the empirical
formula C.sub.19H.sub.18BrF.sub.3N.sub.2O.sub.4S are obtained
(M=507.33 g). The corresponding yield is 50%.
[0914] Stage J
[0915] 0.05 g of the compound obtained in the preceding stage is
dissolved in 1.25 ml of methanol and 0.5 ml of THF in a
round-bottomed flask. The solution is cooled to 0.degree. C. and
placed under argon. The medium is stirred and 0.007 g of NaBH.sub.4
and 0.013 g of CaCl.sub.2 powder are added. Once the gaseous
emission ceases, the reaction medium is poured over a 1 M
NaH.sub.2PO.sub.4 solution; the aqueous phase is extracted with a
heptane/ethyl acetate 1/2 mixture at 0.degree. C. several times.
The organic phases are combined, dried over magnesium sulfate, and
then concentrated under reduced pressure. 44 mg of crude product
are obtained which are purified by chromatography on silica,
eluting with a heptane/ethyl acetate 1/2 mixture. After evaporation
of the solvents, 14.6 mg of the compound ethyl
trans-3-bromo-4,5,6,7-tetrahydro-7-[(phenylmethoxy)amino]thieno[3,2-c]pyr-
idine-4-carboxylate having the empirical formula
C.sub.17H.sub.19BrN.sub.2O.sub.3S are obtained (M=411.32 g). The
corresponding yield is 36%.
[0916] Stage K
[0917] The procedure is carried out as in Stage K of Example 1 with
4.5 g of the product obtained in the preceding stage, 2.84 ml of
triethylamine and 0.6 ml of diphosgene and 1215 ml of acetonitrile.
328 mg of the compound ethyl
trans-3-bromo-4,6,7,8-tetrahydro-6-oxo-7-(phenylmethoxy)-5,8-methano-5H-t-
hieno[2,3-e][1,3]diazepine-4-carboxylate having the empirical
formula C.sub.18H.sub.17BrN.sub.2O.sub.4S are obtained (M=437.32
g). The corresponding yield is 7.6%.
[0918] Stage L
[0919] The procedure is carried out as in Stage M of Example 19
with 308 mg of the compound obtained in the preceding stage, 2.86
ml of a 2 M Na.sub.2CO.sub.3 solution, 71.8 mg of
Pd(P.phi..sub.3).sub.4 and 148.2 mg of 4-fluorophenylboronic acid
and 15.24 ml of toluene. 109 mg of the compound ethyl
trans-3-(4-fluorophenyl)-4,6,7,8-tetrahydro-6-oxo-7-(phenylmethoxy)-5,8-m-
ethano-5H-thieno[2,3-e][1,3]diazepine-4-carboxylate having the
empirical formula C.sub.24H.sub.23FN.sub.2O.sub.4S are obtained
(M=452.52 g). The corresponding yield is 34%.
[0920] Stage M
[0921] The procedure is carried out as indicated in Stage M of
Example 1 with 50 mg of the product obtained in the preceding
stage, 50 mg of 30% palladium on carbon and 0.8 ml of methanol and
2 ml of THF. The compound ethyl
trans-3-(4-fluorophenyl)-4,6,7,8-tetrahydro-7-hydroxy-6-oxo-5,8-met-
hano-5H-thieno[2,3-e][1,3]diazepine-4-carboxylate having the
empirical formula C.sub.17H.sub.15FN.sub.2O.sub.4S is obtained with
a quantitative yield (M=362.38 g).
[0922] Stage N
[0923] The procedure is carried out as in Stage M of Example 1 with
the compound obtained in the preceding stage and 53 mg of the
pyridine-SO.sub.3 complex and 0.8 ml of pyridine. The product
obtained is treated as in Stage R of Example 12 with 15 g of Dowex
resin. 15.4 mg of the compound sodium salt of ethyl
trans-3-(4-fluorophenyl)-4,6,7,8-tetrahydro-6-oxo-7-(sulfoxy)-5,8-methano-
-5H-thieno[2,3-e][1,3]diazepine-4-carboxylate having the empirical
formula C.sub.17H.sub.14FN.sub.2O.sub.7S.sub.2,Na are obtained
(M=464.43 g). The corresponding yield is 30%.
[0924] LC/MS (negative electrospray), m/z: M.sup.-=441.
[0925] Proton NMR, D.sub.2O, 300 MHz, chemical shift and
multiplicity: 0.95 (t): CO--O--CH.sub.2--CH.sub.3; 3.97 (m):
CO--O--CH.sub.2--CH.sub.3; 3.58 (broad d), 3.79 (broad d):
N--CH.sub.2--CH--C.dbd.; 5.07 (broad s): N--CH.sub.2--CH--C.dbd.;
5.45 (s): N--CH--C.dbd.; 7.17 (m) and 7.31 (m): the 4 aromatic H of
the fluorinated nucleus; 7.35 (s): S--CH.dbd..
Example 45
Sodium salt of
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide
[0926] Stage A
[0927] 54.2 mg of the product obtained in Stage K of Example 1 are
dissolved in 2 ml of dichloromethane in the presence of 40.6 mg of
phenylboronic acid, in a round-bottomed flask. A suspension is
obtained to which 45 mg of Cu(OAc).sub.2 and 2 .mu.l of pyridine
and 125 mg of 4 .ANG. sieve are added. The medium is stirred at
20.degree. C. for 3 h 30 min and then the reaction medium is
concentrated under reduced pressure. The residue obtained is
purified by chromatography on silica, eluting with a methylene
chloride/acetone/triethylamine 95/5/0.1% mixture. 33 mg of the
compound methyl
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(phenylmethoxy)-4H-4,7-methanop-
yrazolo[3,4-e][1,3]diazepine-8-carboxylate having the empirical
formula C.sub.22H.sub.20N.sub.4O.sub.4 are obtained (M=404.43 g).
The corresponding yield is 50%.
[0928] Stage B
[0929] The procedure is carried out as in Stage A of Example 7 with
81 mg of the product obtained in the preceding stage, 1.7 ml of
dioxane, 1.7 ml of water and 0.22 ml of 1 N sodium hydroxide. 70 mg
of the compound
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(phenylmethoxy)-4H-4,7-methanop-
yrazolo[3,4-e][1,3]diazepine-8-carboxylic acid having the empirical
formula C.sub.21H.sub.18N.sub.4O.sub.4 are obtained (M=390.4 g).
The corresponding yield is 89.5%.
[0930] Stage C
[0931] The procedure is carried out as in Stage B of Example 7 with
70 mg of the product obtained in the preceding stage, 2.8 ml of
DMF, 114 mg of BOP, 37 mg of HOBt, 20 mg of NH.sub.4Cl and 125
.mu.l of DIPEA. 67.5 mg of the compound
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(phenylmethoxy)-4H-4,7-methanop-
yrazolo[3,4-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.21H.sub.19N.sub.5O.sub.3 are obtained (M=389.42 g).
The corresponding yield is 95%.
[0932] Stage D
[0933] The procedure is carried out as in Stage M of Example 1 with
67.5 mg of the product obtained in the preceding stage, 5 ml of
methanol, 4 ml of THF, and 60 mg of 30% palladium on carbon. 48 mg
of the compound
trans-2,5,6,8-tetrahydro-5-hydroxy-6-oxo-2-phenyl-4H-4,7-methanopyrazolo[-
3,4-e][1,3]diazepine-8-carboxamide having the empirical formula
C.sub.14H.sub.13N.sub.5O.sub.3 are obtained (M=299.29 g). The
corresponding yield is 92%.
[0934] Stage E
[0935] The procedure is carried out as in Stage N of Example 1 with
48 mg of the product obtained in the preceding stage, 5 ml of
pyridine, 77 mg of the pyridine-SO.sub.3 complex. The product
obtained is purified by chromatography on silica, eluting with a
dichloromethane/ethanol/triethylamine 6/4/0.1% mixture. 50 mg of
the compound triethylammonium salt of
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide having the empirical formula
C.sub.20H.sub.28N.sub.6O.sub.6S,C.sub.6H.sub.15N are obtained
(M=480.55 g). The corresponding yield is 64%.
[0936] Stage F
[0937] The procedure is carried out as in Stage R of Example 12
with 50 mg of the product obtained in the preceding stage and 35 g
of Dowex resin. 34 mg of the compound sodium salt of
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide having the empirical formula
C.sub.14H.sub.12N.sub.5O.sub.6S,Na are obtained (M=401.34 g). The
corresponding yield is 81%.
[0938] LC/MS (negative electrospray), m/z: M.sup.-=378.
[0939] Proton NMR, D.sub.20 to 300 MHz, chemical shift and
multiplicity:
[0940] 3.45 (d), 3.83 (dd): N--CH.sub.2--CH--C.dbd.; 5.07 (d):
N--CH.sub.2--CH--C.dbd.; 5.35 (s): N--CH--C.dbd.--C.dbd.; 7.43
(broad t), 7.54 (broad t), 7.65 (broad d), 8.28 (s): the 5H of the
aromatic nucleus.
Example 46
Sodium salt of
1,4,5,8-tetrahydro-1-phenyl-5-(sulfoxy)-6H-4,7-methanopyrazolo[3,4-e][1,3-
]diazepin-6-one
[0941] Stage A
[0942] 5.51 g of the product obtained in Stage A1 of Example 2 are
dissolved in 100 ml of ethanol, in a round-bottomed flask. 2.23 ml
of phenylhydrazine are added and then the solution is stirred for
one hour at room temperature. The reaction medium is next
concentrated under vacuum. 6.71 g of the compound 1,1-dimethylethyl
3,5-dioxo-4-[(2-phenylhydrazino)methylene]-1-piperidinecarboxylate
are obtained with a quantitative yield.
[0943] Stage B
[0944] 6.71 g of the product obtained in the preceding stage are
dissolved in 145 ml of acetic acid. This solution is heated under
reflux for one hour and then the acetic acid is evaporated off.
Toluene is added to the residue and the medium is again evaporated
off. 7.3 g of crude product are obtained, which product is purified
by chromatography on silica, eluting with a methylene
chloride/acetone 95/5 mixture. 1.82 g of the compound
1,1-dimethylethyl
1,4,5,7-tetrahydro-4-oxo-1-phenyl-6H-pyrazolo[3,4-c]pyridine-6-carboxylat-
e having the empirical formula C.sub.17H.sub.19N.sub.3O.sub.3 are
obtained (M=313.36 g). The corresponding yield is 28%.
[0945] Stage C
[0946] 300 mg of the product obtained in the preceding stage are
mixed with 10 ml of ethanol. 3 ml of dichloromethane are added
followed by 115 mg of NH.sub.2O--CH.sub.2--CH--CH.sub.2--HCl and
0.23 ml of pyridine. The medium is stirred at 20.degree. C. for 3
hours and then the reaction medium is diluted with dichloromethane.
The solution is washed with water and the organic phase is dried
over magnesium sulfate and then concentrated under reduced
pressure. 355 mg of the compound 1,1-dimethylethyl
1,4,5,7-tetrahydro-1-phenyl-4-[(2-propenyloxy)imino]-6H-pyrazolo[3,4-c]py-
ridine-6-carboxylate having the empirical formula
C.sub.20H.sub.24N.sub.4O.sub.3 are obtained (M=368.44 g). The
corresponding yield is quantitative.
[0947] Stage D
[0948] 0.355 g of the product obtained in the preceding stage is
dissolved in 5 ml of acetic acid. The solution is cooled to
10.degree. C. and 500 mg of NaBH.sub.3CN are added in several
portions. The medium is stirred for 5 hours at room temperature and
then the reaction medium is diluted with 150 ml of ethyl acetate.
The medium is cooled to 0.degree. C. before being neutralized with
35 ml of a 2 N sodium hydroxide solution. The medium is further
stirred for 15 minutes at 0.degree. C. and extracted with ethyl
acetate. The organic phases are washed with 1 N aqueous sodium
hydroxide solutions and then dried over magnesium sulfate. After
evaporation of the solvent under reduced pressure, 360 mg of crude
product are obtained which are purified by chromatography on
silica, eluting with a methylene chloride/acetone 95/5 mixture.
After evaporation of the solvents, 310 mg of the compound
1,1-dimethylethyl
1,4,5,7-tetrahydro-1-phenyl-4-[(2-propenyloxy)amino]-6H-pyrazolo[3,4-c]py-
ridine-6-carboxylate having the empirical formula
C.sub.20H.sub.26N.sub.4O.sub.3 are obtained (M=370.46 g). The
corresponding yield is 86%.
[0949] Stage E
[0950] The procedure is carried out as in Stage I of Example 1 with
305 mg of the product obtained in the preceding stage, 3 ml of
ethyl acetate, 3 ml of a 5.5 M HCl solution in ethyl acetate. 256
mg of the compound
4,4,6,7-tetrahydro-1-phenyl-4-[(2-propenyloxy)amino]-1H-pyrazolo[3,4-c]py-
ridine dichloride having the empirical formula
C.sub.15H.sub.18N.sub.40.3HCl are obtained (M=379.72 g). The
corresponding yield is 90%.
[0951] Stage F
[0952] The procedure is carried out as in Stage K of Example 1 with
197 mg of the product obtained in the preceding stage, 32 ml of
acetonitrile, 0.44 ml of triethylamine, and 40 .mu.l of diphosgene.
76 mg of the compound
1,4,5,8-tetrahydro-1-phenyl-5-(2-propenyloxy)-6H-4,7-methanopyra-
zolo[3,4-e][1,3]diazepin-6-one having the empirical formula
C.sub.16H.sub.16N.sub.4O.sub.2 are obtained (M=296.33 g). The
corresponding yield is 49%.
[0953] Stage G
[0954] The procedure is carried out as in Stage G of Example 18
with 71 mg of the derivative obtained in the preceding stage, 7 ml
of dichloromethane, 35 .mu.l of acetic acid and 139 mg of
Pd(P.phi..sub.3).sub.4. The product obtained is then treated with 8
ml of pyridine and 153 mg of the pyridine-SO.sub.3 complex. 136 mg
of the compound 1-propenyltriphenylphosphonium salt of
1,4,5,8-tetrahydro-1-phenyl-5-(sulfoxy)-6H-4,7-methanopyrazolo[3,4-e][1,3-
]diazepin-6-one having the empirical formula C.sub.21H.sub.20P,
C.sub.13H.sub.11N.sub.4O.sub.5S are obtained (M=638.69 g). The
corresponding yield is 71.8%.
[0955] Stage H
[0956] The procedure is carried out as in Stage R of Example 12
with 136 mg of the product obtained in the preceding stage and 45 g
of Dowex resin. 67 mg of the compound sodium salt of
1,4,5,8-tetrahydro-1-phenyl-5-(sulfoxy)-6H-4,7-methano-pyrazolo[3,4-e][1,-
3]diazepin-6-one having the empirical formula
C.sub.13H.sub.11N.sub.4NaO.sub.5S are obtained (M=358.31 g). The
corresponding yield is 88%.
[0957] LC/MS (negative electrospray), m/z: M.sup.-=335 and
(2M+H).sup.-=671. [0958] Proton NMR, D.sub.2O, 300 MHz, chemical
shift and multiplicity: 5.04 (d): N--CH.sub.2--CH--C.dbd.; 3.48 (d)
and 3.84 (dd): N--CH.sub.2--CH--C.dbd.; 4.48 and 4.74:
N--CH.sub.2--C.dbd.; 7.50 (m), 7.57 (m), 7.45 (m): the 5H of the
aromatic nucleus; 7.85 (s): N.dbd.CH--C.dbd..
Example 47
Sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5-(sulfoxy)-1H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide
[0959] Stage A
[0960] The procedure is carried out as in Stage C of Example 1 with
312 mg of the product obtained in Stage B of Example 46, 20 ml of
methanol and 38 mg of NaBH.sub.4. 312 mg of the compound
1,1-dimethylethyl
1,4,5,7-tetrahydro-4-hydroxy-1-phenyl-6H-pyrazolo[3,4-c]pyridine-6-carbox-
ylate having the empirical formula C.sub.16H.sub.21N.sub.3O.sub.3
are obtained (M=315.38 g). The corresponding yield is 99%.
[0961] Stage B
[0962] The procedure is carried out as in Stage G of Example 1 with
160 mg of the product obtained in the preceding stage, 4 ml of
anhydrous THF and 0.89 ml of a 1.7 M solution of tert-butyllithium
in pentane and in the presence of a gaseous stream of CO.sub.2. The
product obtained is next acidified with 2 N HCl and then treated
with diazomethane and 115 mg of the compound 6-(1,1-dimethylethyl)
and 7-methyl
1,4,5,7-tetrahydro-4-hydroxy-1-phenyl-6H-pyrazolo[3,4-c]pyridine-6,7-dica-
rboxylate having the empirical formula
C.sub.19H.sub.23N.sub.3O.sub.5 are obtained (M=373.41 g). The
corresponding yield is 60%.
[0963] Stage C
[0964] The procedure is carried out as in Stage H of Example 1 with
157 mg of the product obtained in the preceding stage, 5 ml of
dichloromethane, 90 .mu.l of triethylamine, 110 mg of MS.sub.2O and
156 mg of benzylhydroxylamine. 102 mg of the compound
6-(1,1-dimethylethyl) and 7-methyl
1,4,5,7-tetrahydro-1-phenyl-4-[(phenylmethoxy)amino]-6H-pyrazolo-
[3,4-c]pyridine-6,7-dicarboxylate having the empirical formula
C.sub.26H.sub.30N.sub.4O.sub.5 are obtained (M=478.55 g). The
corresponding yield is 50.6%.
[0965] Stage D
[0966] The procedure is carried out as in Stage I of Example 1 with
102 mg of the product obtained in the preceding stage, 1 ml of
ethyl acetate, 1 ml of methanol and 1 ml of a 5.5 M HCl solution in
ethyl acetate. 91 mg of the compound methyl
4,5,6,7-tetrahydro-1-phenyl-4-[(phenylmethoxy)amino]-1H-pyrazolo[3,4-c]py-
ridine-7-carboxylate dihydrochloride having the empirical formula
C.sub.21H.sub.22N.sub.4O.sub.3.3HCl are obtained (M=487.82 g).
[0967] Stage E
[0968] The procedure is carried out as in Stage K of Example 1 with
90 mg of the compound obtained in the preceding stage, 10 ml of
acetonitrile, 150 ml of triethylamine, 14 .mu.l of diphosgene. 72
mg of the compound methyl
trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5-(phenylmethoxy)-1H-4,7-m-
ethanopyrazolo[3,4-e][1,3]diazepine-8-carboxylate having the
empirical formula C.sub.22H.sub.20N.sub.4O.sub.4 are obtained
(M=404.43 g). The corresponding yield on both stages D and E is
84%.
[0969] Stage F
[0970] The procedure is carried out as in Stage A of Example 7 with
72 mg of the product obtained in the preceding stage, 1.5 ml of
dioxane, 1.5 ml of water and 0.2 ml of a 1 N sodium hydroxide
solution. 69 mg of the compound
trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5-(phenylmethoxy)-1H-4,7-
-methanopyrazolo[3,4-e][1,3]diazepine-8-carboxylic acid having the
empirical formula C.sub.21H.sub.18N.sub.4O.sub.4 are obtained
(M=390.4 g). The corresponding yield is 99%.
[0971] Stage G
[0972] The procedure is carried out as in Stage D of Example 7 with
68 mg of the product obtained in the preceding stage, 2 ml of DMF,
112 mg of BOP, 36 mg of HOBt, 20 mg of NH.sub.4Cl and 123 .mu.l of
DIPEA. 50 mg of the compound
trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5-(phenylmethoxy)-1H-4,7-methanop-
yrazolo[3,4-e][1,3]diazepine-8-carboxamide having the empirical
formula C.sub.21H.sub.19N.sub.5O.sub.3 are obtained (M=389.42 g).
The corresponding yield is 72%.
[0973] Stage H
[0974] The procedure is carried out as in Stage M of Example 1 with
50 mg of the compound obtained in the preceding stage, 5 ml of
methanol, 95 mg of 10% palladium on carbon and 4 ml of THF. 36.8 mg
of the compound
trans-4,5,6,8-tetrahydro-5-hydroxy-6-oxo-1-phenyl-1H-4,7-methanopyrazolo[-
3,4-e][1,3]diazepine-8-carboxamide having the empirical formula
C.sub.14H.sub.13N.sub.5O.sub.3 are obtained (M=299.29 g). The
corresponding yield is 95%.
[0975] Stage I
[0976] The procedure is carried out as in Stage N of Example 1 with
36.8 mg of the product obtained in the preceding stage, 5 ml of
pyridine, 60 mg of the pyridine-SO.sub.3 complex. The product
obtained is treated as indicated in Stage R of Example 12 with 25 g
of Dowex resin. 24 mg of the compound sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5-(sulfoxy)-1H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide having the empirical formula
C.sub.14H.sub.12N.sub.5O.sub.6S,Na are obtained (M=401.34 g). The
corresponding yield is 48%.
[0977] LC/MS (negative electrospray), m/z: M.sup.-=378.
(2M+Na).sup.-=779.
[0978] Proton NMR, D.sub.2O, 300 MHz, chemical shift and
multiplicity: 3.40 (d), 3.76 (dd): N--CH.sub.2--CH.dbd.C.dbd.; 5.07
(d): N--CH.sub.2--CH.dbd.C.dbd.; 5.62 (s): N--CH--C.dbd.; 7.50 (m),
7.55 (m), 7.44 (m): the 5H of the aromatic nucleus.
[0979] Pharmacological Study of the Products of the Invention
[0980] Activity in vitro, method of dilutions in liquid medium
[0981] A series of tubes is prepared into which the same quantity
of sterile nutrient medium is distributed. Increasing quantities of
the product to be studied are distributed into each tube, and then
each tube is inoculated with a bacterial strain. After incubating
for twenty-four hours in an oven at 37.degree. C., the inhibition
of growth is assessed by transillumination, which makes it possible
to determine the minimum inhibitory concentrations (MIC) expressed
in .mu.g/ml.
[0982] Tests are thus carried out with the following products of
the invention:
[0983] the triethylammonium salt of
5,6-dihydro-6-oxo-N.sup.2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazolo[3,4-e-
][1,3]diazepine-2,8(8H)-dicarboxamide (A),
[0984] the sodium salt of
4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-1H-4,7-methanopyrazolo[3,4-e][1,3]di-
azepine-1-carboxamide (B),
[0985] the sodium salt of
1,4,5,8-tetrahydro-1-[(4-methoxyphenyl)methyl]-5-(sulfoxy)-6H-4,7-methano-
pyrazolo[3,4-e][1,3]diazepin-6-one (C),
[0986] the sodium salt of
trans-4,5,6,8-tetrahydro-2-(2-methylphenyl)-6-oxo-5-(sulfoxy)-4,7-methano-
-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide (D),
[0987] the sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-2-[2-(trifluoromethyl)phenyl]--
4,7-methano-7H-thieno[2,3-e][1,3]diazepine-8-carboxamide (E),
[0988] the sodium salt of
trans-2-(2-ethylphenyl)-4,5,6,8-tetrahydro-6-oxo-5-(sulfoxy)-4,7-methano--
7H-thieno[2,3-e][1,3]diazepine-8-carboxamide (F),
[0989] the sodium salt of
trans-8-(2,3-dihydroxypropoxy)-1,2,3,5-tetrahydro-3-oxo-2-(sulfoxy)-1,4-m-
ethano-4H-2,4-benzodiazepine-5-carboxamide (G),
[0990] the sodium salt of ethyl
trans-3-(4-fluorophenyl)-4,6,7,8-tetrahydro-6-oxo-7-(sulfoxy)-5,8-methano-
-5H-thieno[2,3-e][1,3]diazepine-4-carboxylate (H),
[0991] the sodium salt of
trans-2,5,6,8-tetrahydro-6-oxo-2-phenyl-5-(sulfoxy)-4H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide (I),
[0992] the sodium salt of
1,4,5,8-tetrahydro-1-phenyl-5-(sulfoxy)-6H-4,7-methanopyrazolo[3,4-e][1,3-
]diazepin-6-one (J),
[0993] the sodium salt of
trans-4,5,6,8-tetrahydro-6-oxo-1-phenyl-5-(sulfoxy)-1H-4,7-methanopyrazol-
o[3,4-e][1,3]diazepine-8-carboxamide (K).
[0994] These compounds have the activities grouped together in the
following table:
TABLE-US-00002 Compounds Gram-dositive MIC .mu.g/ml at 24 hours S.
aureus SG511 0.3-40 A to K E. faecium M 78 L 2.5-80 A and C to K S.
pyogenes A561 <0.15-2.5 A to K Gram-negative MIC .mu.g/ml at 24
hours E. coli UC1894 <0.15-2.5 B to G E. coli 250HT7 0.3-80 B,
C, F, G E. cloacae 1321E <0.15-10 B and D to G E. coli K 12
1.2-10 A and H to K E. coli DB 10 <0.15-2.5 A and H to K
[0995] The compounds according to the invention therefore show an
antibacterial activity.
II/.beta.-Lactamase Inhibiting Activity
[0996] The compounds of formula (I) and their pharmaceutically
acceptable salts exhibit marked inhibitory activities against
.beta.-lactamases of various bacterial strains and these
therapeutically advantageous properties may be determined in vitro
on isolated .beta.-lactamases:
[0997] A. Preparation of the .beta.-Lactamases Tem-1 and P99
[0998] The .beta.-lactamases are isolated from bacterial strains
resistant to penicillins and to cephalosporins (Tem1 and P99 are
produced by E. coli 250HT21 and E. Cloacae 293HT6,
respectively).
[0999] The bacteria are cultured in heart-brain broth at 37 g/l
(DIFCO), at 37.degree. C. They are harvested at the end of the
exponential phase, cooled and centrifuged. The bacterial pellets
are taken up in 50 mM sodium phosphate buffer pH 7.0 and again
centrifuged. The bacteria are taken up in two volumes of this same
buffer and lyzed by means of a French-Press kept at 4.degree. C.
After centrifugation for 1 h 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.
[1000] B. Determination of the .beta.-Lactamase Activity
[1001] The method uses, as substrate, Nitrocefin (OXOID), a
chromogenic cephalosporin, whose product of hydrolysis by
Beta-lactamases is red and absorbs at 485 nm. The .beta.-lactamase
activity is kinetically determined by measuring the variation in
absorbance at 485 nm resulting from the hydrolysis of the substrate
on a plate spectrophotometer (Spectra Max Plus from Molecular
Devices). The experiments are performed at 37.degree. C. The
quantity of enzyme was normalized and the measurements are
performed at the initial speed.
[1002] C. Determination of the .beta.-Lactamase Inhibiting
Activity
[1003] Two measurements are carried out, without preincubation and
with preincubation of the enzyme and of the inhibitor (5 min), 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
pH 7.0.
[1004] D. Calculations of the IC.sub.50 Values
[1005] The rates of hydrolysis are measured with and without
inhibitor. The concentration of inhibitor which inhibits by 50% the
reaction of hydrolysis of Nitrocefin by the enzyme (IC50) is
determined. The data processing is carried out with the aid of the
GraFit software (Erathycus Software).
TABLE-US-00003 EXAMPLE No. IC.sub.50 nM/TEM1 IC.sub.50nM/P99 28 33
25 38 59 19 37 41 21 40 11 12 42 15 44 18 5 13 41 9 29 19 5 16 21 7
69 33 56 17 24 2 10 25 2 6 26 1 6 46 5 80 7 1 14 44 34 2 11 11 39
10 12 18 47 12 3 5 13 17 4 34 7 45 1 12 2 16 20 3 2 11 1 3 5 9 60
50 IC.sub.50 after 5 min of preincubation with the enzyme.
[1006] Examples of pharmaceutical compositions:
[1007] 1) A pharmaceutical composition for injection was prepared
in which the ingredients are the following:
TABLE-US-00004 compound of the example 500 mg sterile aqueous
excipient qs 10 ml
[1008] 2) A pharmaceutical composition (lyophilisate) for injection
was prepared, containing:
TABLE-US-00005 on the one hand: compound of the example 500 mg on
the other hand: Cefotaxime 1 g sterile aqueous excipient qs 5
ml
[1009] The two active ingredients may, if desired, be introduced
separately into two separate ampoules or vials.
* * * * *