U.S. patent application number 11/734608 was filed with the patent office on 2007-08-16 for novel heterocyclic compounds, preparation process and intermediates, and use as medicaments, in particular as beta-lactamase inhibitors and antibacterials.
Invention is credited to Branislav Musicki.
Application Number | 20070191312 11/734608 |
Document ID | / |
Family ID | 31725838 |
Filed Date | 2007-08-16 |
United States Patent
Application |
20070191312 |
Kind Code |
A1 |
Musicki; Branislav |
August 16, 2007 |
NOVEL HETEROCYCLIC COMPOUNDS, PREPARATION PROCESS AND
INTERMEDIATES, AND USE AS MEDICAMENTS, IN PARTICULAR AS
BETA-LACTAMASE INHIBITORS AND ANTIBACTERIALS
Abstract
The invention relates to novel heterocyclic compounds of general
formula (I) and to their salts with a base or an acid: ##STR1## The
invention also relates to processes and to intermediates for the
preparation of these compounds, and to their use as medicaments, in
particular as antibacterials and .beta.-lactamase inhibitors.
Inventors: |
Musicki; Branislav; (Paris,
FR) |
Correspondence
Address: |
HARNESS, DICKEY & PIERCE, P.L.C.
P.O. BOX 828
BLOOMFIELD HILLS
MI
48303
US
|
Family ID: |
31725838 |
Appl. No.: |
11/734608 |
Filed: |
April 12, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10655364 |
Sep 4, 2003 |
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11734608 |
Apr 12, 2007 |
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Current U.S.
Class: |
514/80 ;
540/487 |
Current CPC
Class: |
C07D 243/02 20130101;
A61P 43/00 20180101; A61P 31/00 20180101; C07D 487/08 20130101;
A61P 31/04 20180101; C07D 237/28 20130101 |
Class at
Publication: |
514/080 ;
540/487 |
International
Class: |
A61K 31/675 20060101
A61K031/675 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 5, 2002 |
FR |
02 10957 |
Claims
1. A compound of formula (I), or a pharmaceutically acceptable salt
thereof with a base or acid: ##STR36## in which: n is 2; R.sub.1 is
selected from the group consisting of hydrogen, alkyl having up to
8 carbon atoms and (CH.sub.2).sub.n'R.sup.o.sub.1 in which n' is 0
or 1 and R.sup.o.sub.1 is selected from the group consisting of
aryl having up to 12 carbon atoms; heteroaryl having up to 15
carbon atoms and at least one heteroatom selected from N, S, and O;
COR'; CONR'R''; CSNR'R''; COCOOR'; SO.sub.2NR'R''; SO.sub.2R';
CO.sub.2R' and CN; R' is selected from the group consisting of
hydrogen, alkyl having up to 8 carbon atoms, alkenyl having up to 8
carbon atoms, aralkyl having up to 12 carbon atoms and aryl having
up to 12 carbon atoms; R'' is selected from the group consisting of
hydrogen; alkyl having up to 8 carbon atoms; aryl having up to 12
carbon atoms; aralkyl having up to 12 carbon atoms; SO.sub.2--R'
and COR'; in each case R' being independently selected from the
group consisting of hydrogen, alkyl having up to 8 carbon atoms,
alkenyl having up to 8 carbon atoms, aralkyl having up to 12 carbon
atoms and aryl having up to 12 carbon atoms; R2 is selected from
the group consisting of hydrogen, halo, alkyl, OH, Oalkyl,
NO.sub.2, NH.sub.2, NHalkyl, N(alkyl).sub.2, NHCOalkyl,
NHSO.sub.2alkyl, CONHalkyl, SO.sub.2NHalkyl, COOH, COOalkyl, CN,
OSO.sub.2alkyl, NHCONHalkyl and COalkyl; said alkyl having up to 8
carbon atoms; X is a divalent group --C(O)--N(OR.sub.3)-- connected
to the ring nitrogen atom via its carbonyl carbon atom and to the
ring carbon atom via its nitrogen atom, in which R.sub.3 is
selected from the group consisting of hydrogen and the R, Y,
Y.sub.1, Y.sub.2 and Y.sub.3 moieties defined below; R is selected
from the group consisting of alkyl having up to 6 carbon atoms,
optionally substituted by pyridyl or carbamoyl; alkenyl having up
to 8 carbon atoms; aryl having up to 12 carbon atoms; and aralkyl
having up to 12 carbon atoms; each said aryl group optionally being
substituted by an --OH, --NH.sub.2, --NO.sub.2, alkyl having up to
8 carbon atoms, an alkoxy having up to 8 carbon atoms or by one or
more halogens; Y is selected from the group consisting of COR,
COOH, COOR, CONHR, CONHOH, CONHSO.sub.2R, CH.sub.2COOH,
CH.sub.2COOR, CH.sub.2CONHOH, CH.sub.2CONHCN, CH.sub.2tetrazole,
CH.sub.2 (protected 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, wherein R is as defined
hereinabove; Y.sub.1 is selected from the group consisting of
SO.sub.2R, SO.sub.2NHCOR, SO.sub.2NHCOOR, SO.sub.2NHCONHR and
SO.sub.3H, wherein R is as defined hereinabove; Y.sub.2 is selected
from the group consisting of PO(OH).sub.2, PO(OR).sub.2, PO(OH)(OR)
and PO(OH)(R), wherein R is as defined hereinabove; Y.sub.3 is
selected from the group consisting of tetrazole, tetrazole
substituted by R, squarate, NRtetrazole, NRtetrazole substituted by
R, and NRSO.sub.2R, wherein R is as defined above, including the
pure enantiomers thereof, in the R, S or RS configuration, as well
as any racemic mixture of said enantiomers.
2. A compound as claimed in claim 1, wherein R.sup.2 is
hydrogen.
3. A compound as claimed in claim 1, wherein R.sup.1 is hydrogen,
alkyl having up to 8 carbon atoms or (CH.sub.2).sub.n,
R.sup.o.sub.1 wherein n' is 0 or 1 and R.sup.o.sub.1 is aryl having
up to 12 carbon atoms; heteroaryl having up to 15 carbon atoms and
at least one heteroatom selected from N, S, and O; CONR'R'';
CSNR'R''; COCOOR'; SO.sub.2NR'R''; SO.sub.2R' or CO.sub.2R'; R' and
R'' being as defined in claim 1.
4. A compound as claimed in claim 1, wherein X is a divalent group
--C(O)--N(OR.sub.3)-- in which R.sub.3 is selected from the group
consisting of hydrogen and the R, Y and Y.sub.1 radicals, R, Y and
Y.sub.1 being as defined in claim 1.
5. A compound of formula (I) as defined in claim 1, selected from
the group consisting of:
[[1,5-dihydro-1-(methylsulfonyl)-3-oxo-2,5-methano-2-H-1,2,4-benzotriazep-
in-4(3H)-yl]oxy]acetic acid,
[[1-[(benzoylamino)carbonyl]-1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzo-
triazepin-4(3H)-yl]oxy]acetic acid,
[[1,5-dihydro-3-oxo-1-[(phenylsulfonyl)aminocarbonyl]-2,5-methano-2H-1,2,-
4-benzotriazepin-4(3H)-yl]oxy]acetic acid,
[(1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzotriazepin-4(3H)-yl)oxy]acet-
ic acid,
4,5-dihydro-1-methyl-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzotriaz-
epin-3(1H)-one,
4,5-dihydro-4-(2-propenyloxy)-1-(3-pyridinylmethyl)-2,5-methano-2H-1,2,4--
benzotriazepin-3(1H)one,
4,5-dihydro-3-oxo-N-(phenylsulfonyl)-4-(2-propenyloxy)-2,5-methano-2H-1,2-
,4-benzotriazepine-1(3H)-carboxamide,
N-benzoyl-4,5-dihydro-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzot-
riazepine-1(3H)-carboxamide, ethyl
4,5-dihydro-.alpha.,3-dioxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzot-
riazepine-1(3H)-acetate, ethyl
4,5-dihydro-3-oxo-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzo-triazepine-1(3H)-
-acetate, and their salts and enantiomers as defined in claim
1.
6. A process for the preparation of a compound as claimed in claim
1, which process comprises: a) a first stage during which a
compound of formula (II): ##STR37## in which: R'.sub.1 is R.sub.1
or a precursor thereof, R.sub.2 is R.sub.2, and R.sub.2 and n are
as defined in claim 1 and R'.sub.3 is selected from the group
consisting of a protective group for hydroxyl, Rp, Yp, Y.sub.1p,
Y.sub.2p and Y.sub.3p, which, respectively, correspond to R, Y,
Y.sub.1, Y.sub.2 and Y.sub.3 as defined in claim 1, in which the
possible reactive functional groups present are, if appropriate,
protected, is reacted with a carbonylating agent, if appropriate in
the presence of a base, for the purpose of obtaining an
intermediate compound of formula (III): ##STR38## in which:
R'.sub.1 and R.sub.2 are as defined above, and R2 and n are as
defined in claim 1 and either (1) X.sub.1 is hydrogen and X.sub.2
represents an --N(OR'.sub.3)--CO--X.sub.3 group, wherein R'.sub.3
is as defined above and X.sub.3 is the residue of the carbonylating
agent, or (2) X.sub.2 is --NH--OR'.sub.3 and X.sub.1 is CO--X.sub.3
group, X.sub.3 being as defined above; and b) a second stage during
which the intermediate of formula III obtained above is cyclized,
in the presence of a base.
7. The process of claim 6 further comprising, either before stage
a) or after stage b), as appropriate: c) one or more of the
following reactions, in an appropriate order: protection of the
reactive functional groups, deprotection of the reactive functional
groups, esterification, saponification, sulfonation, phosphatation,
amidation, acylation, sulfonylation, alkylation, formation of a
urea group, introduction of a tetrazole group, reduction of
carboxylic acids, dehydration of amide to nitrile, salification,
exchange of ions, separation of enantiomers, nitration, reduction
of a nitro to an amino, halogenation, carbamoylation, introduction
of a cyano group.
8. The process as claimed in claim 6, wherein the carbonylating
agent is selected from the group consisting of phosgene,
diphosgene, triphosgene, aryl, aralkyl, alkyl and alkenyl
chloroformates, alkyl dicarbonates, carbonyldiimidazole and their
mixtures.
9. The process as claimed in claim 6, wherein the carbonylation
reaction takes place in the presence of a base.
10. The process as claimed in claim 6, wherein, in stage b), the
base is selected from the group consisting of amines, alkali metal
hydrides, alkoxides, amides and carbonates and alkaline earth metal
hydrides, alkoxides, amides and carbonates.
11. The process as claimed in claim 10, wherein the base is an
amine.
12. The process as claimed in claim 6, wherein the compound of
formula (II) is obtained by a process wherein a compound of formula
(IV): ##STR39## in which R'.sub.1, R.sub.2 and n are as defined in
claim 6, R.sub.2 is selected from the group consisting of hydrogen,
halo, alkyl, OH, Oalkyl, NO.sub.2, NH.sub.2, NHalkyl,
N(alkyl).sub.2, NHCOalkyl, NHSO.sub.2alkyl, CONHalkyl,
SO.sub.2NHalkyl, COOH, COOalkyl, CN, OSO.sub.2alkyl, NHCONHalkyl
and Coalkyl, said alkyl having up to 8 carbon atoms, n is 2, and A
is hydrogen or a protective group for the nitrogen, is treated with
a reducing agent, to obtain a compound of formula (V): ##STR40## in
which A is defined above in claim 6, R'.sub.1 and R.sub.2 are as
defined in claim 6, and R.sub.2 and n are as defined above, and in
which process, if appropriate, the OH group is replaced by a
leaving group, to obtain a compound of formula (VI): ##STR41## in
which A is defined above, R'.sub.1 and R.sub.2 are as defined in
claim 6, and R.sub.2 and n are as defined above and B represents a
leaving group, which compound of formula VI is then treated with a
compound of formula NH.sub.2--OR'.sub.3, R'.sub.3 being as defined
in claim 6, and then, if appropriate, with an appropriate
deprotecting agent for the nitrogen atom.
13. The process as claimed in claim 12, wherein the compound of
formula (II) is obtained by a process wherein a compound of formula
(IV) as defined in claim 12 is treated with a compound of formula
H.sub.2N--OR'.sub.3, to obtain a compound of formula (VI):
##STR42## in which A is as defined in claim 12, and R'.sub.1,
R.sub.2, n and R'.sub.3 are as defined in claim 12, which compound
of formula VII is then reacted with a reducing agent, to obtain a
compound of formula (VIII): ##STR43## in which A, R'.sub.1,
R.sub.2, n and R'.sub.3 are as defined in claim 12, which compound
of formula VIII is then treated, if appropriate, with an
appropriate deprotecting agent for the nitrogen atom.
14. A pharmaceutical composition comprising the compound as defined
in claim 1 in combination with a pharmaceutically acceptable
carrier.
15. A pharmaceutical composition comprising the compound as defined
in claim 6 in combination with a pharmaceutically acceptable
carrier.
16. A compound of general formula (III) or one of its salts with an
acid, in particular its hydrochloride and its trifluoroacetate:
##STR44## in which: R'.sub.1, R.sub.2, X.sub.1, X.sub.2 and n are
as defined in claim 6.
17. A compound of general formula (II) or one of its salts with an
acid, in particular its hydrochloride and its trifluoroacetate: in
which R'.sub.1, R.sub.2, R'.sub.3 and n are as defined in claim 6.
##STR45##
18. A compound selected from the compounds of formulas (IV) and (V)
or a salt thereof with an acid: ##STR46## in which A, R.sub.2 and n
have the same meanings as in claim 12 and R'.sub.1 is
(CH.sub.2).sub.n'R.sup.o.sub.1 in which n' is 0 or 1 and
R.sup.o.sub.1 is selected from the group consisting of heteroaryl
containing up to 15 carbon atoms and one or more heteroatoms
selected from nitrogen, sulfur and oxygen, COR', CONR'R'',
CSNR'R'', COCOOR', SO.sub.2NR'R'', SO.sub.2R', CO.sub.2R' and CN,
R' is hydrogen, alkyl or alkenyl containing up to 8 carbon atoms,
aralkyl containing up to 12 carbon atoms or aryl containing up to
12 carbon atoms, and R'' is hydrogen, alkyl containing up to 8
carbon atoms, aryl containing up to 12 carbon atoms, aralkyl
containing up to 12 carbon atoms, SO.sub.2--R' or COR', R' being as
defined above.
19. A compound of formula (VI) or one of its salts with an acid:
##STR47## in which A, R'.sub.1, R.sub.2, B and n are as defined in
claim 12.
20. A compound of formula (VII) or (VIII) or one of its salts with
an acid: ##STR48## ##STR49## in which A, R'.sub.1, R.sub.2, n and
R'.sub.3 are as defined in claim 13.
21. A method of treating a bacterial infection in a mammal
comprising administering to a mammal in need thereof an
antibacterially effective amount of a compound of claim 1.
22. A method of treating an infection or infection-causing
condition in a mammal that is due to the presence of bacteria that
generate beta-lactamases, which comprises administering to a mammal
in need thereof an amount of a compound of claim 1 that is
effective to inhibit beta-lactamase in said mammal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/655,364, filed on Sep. 4, 2003, which claims the
benefit of priority from French Patent Application 02 10957, filed
Sep. 5, 2002. The disclosures of the above applications are
incorporated herein by reference.
SUMMARY OF THE INVENTION
[0002] The present disclosure relates to novel heterocyclic
compounds, to their preparation and their use as medicaments, in
particular as .beta.-lactamase inhibitors and antibacterials.
BACKGROUND OF THE INVENTION
[0003] The statements in this section merely provide background
information related to the present disclosure and may not
constitute prior art.
[0004] The preparation of a bicyclic derivative of empirical
formula C.sub.10H.sub.18N.sub.2O is disclosed in J. Org. Chem.,
Vol. 37, No. 5, 1972, pages 697 to 699.
[0005] The preparation of bicyclic derivatives of empirical
formulae C.sub.6H.sub.9NO.sub.2 and C.sub.7H.sub.11NO.sub.2 is
disclosed in J. Org. Chem., Vol. 45, No. 26, 1980, pages
5325-5326.
[0006] The preparation of bicyclic derivatives of empirical
formulae C.sub.10H.sub.18N.sub.2O and C.sub.7H.sub.12N.sub.2O is
disclosed in Chemical Reviews, 1983, Vol. 83, No. 5, pages 549 to
555.
[0007] The preparation of a compound of empirical formula
C.sub.12H.sub.12N.sub.2O is disclosed in Angew. Chem. Int. Ed.,
2000, 39, No. 3, pages 625 to 628.
[0008] No specific therapeutic use of these compounds was disclosed
in these documents.
[0009] French patent application No. 2 812 635 discloses that
variously substituted heterocyclic compounds, in particular of the
7-oxo-1-aza- or 1,6-diazabicyclo[3.2.1]octane type, exhibit
antibacterial properties.
DETAILED DESCRIPTION
[0010] The following description is merely exemplary in nature and
is not intended to limit the present disclosure, application, or
uses.
[0011] The present invention relates to compounds of formula (I):
##STR2##
[0012] in which:
[0013] n is 1 or 2;
[0014] R.sub.1 is selected from the group consisting of hydrogen,
alkyl having up to 8 carbon atoms and (CH.sub.2).sub.n,
R.sup.o.sub.1 in which n' is 0 or 1 and R.sup.o.sub.1 is selected
from the group consisting of aryl having up to 12 carbon atoms;
heteroaryl having up to 15 carbon atoms and at least one heteroatom
selected from N, S, and O; COR'; CONR'R''; CSNR'R''; COCOOR';
SO.sub.2NR'R''; SO.sub.2R'; CO.sub.2R' and CN;
[0015] R' is selected from the group consisting of hydrogen, alkyl
having up to 8 carbon atoms, alkenyl having up to 8 carbon atoms,
aralkyl having up to 12 carbon atoms and aryl having up to 12
carbon atoms;
[0016] R'' is selected from the group consisting of hydrogen; alkyl
having up to 8 carbon atoms; aryl having up to 12 carbon atoms;
aralkyl having up to 12 carbon atoms; SO.sub.2--R' and COR'; in
each case R' being independently selected from the group consisting
of hydrogen, alkyl having up to 8 carbon atoms, alkenyl having up
to 8 carbon atoms, aralkyl having up to 12 carbon atoms and aryl
having up to 12 carbon atoms;
[0017] R.sub.2 is selected from the group consisting of hydrogen,
halo, alkyl, OH, Oalkyl, NO.sub.2, NH.sub.2, NHalkyl,
N(alkyl).sub.2, NHCOalkyl, NHSO.sub.2alkyl, CONHalkyl,
SO.sub.2NHalkyl, COOH, COOalkyl, CN, OSO.sub.2alkyl, NHCONHalkyl
and COalkyl; said alkyl having up to 8 carbon atoms;
[0018] X is a divalent group --C(O)--N(OR.sub.3)-- connected to the
ring nitrogen atom via its carbonyl carbon atom and to the ring
carbon atom via its nitrogen atom, in which R.sub.3 is selected
from the group consisting of hydrogen and the R, Y, Y.sub.1,
Y.sub.2 and Y.sub.3 moieties defined below,
[0019] R is selected from the group consisting of alkyl having up
to 6 carbon atoms, optionally substituted by pyridyl or carbamoyl;
alkenyl having up to 8 carbon atoms; aryl having up to 12 carbon
atoms; and aralkyl having up to 12 carbon atoms; each said aryl
group optionally being substituted by an --OH, --NH.sub.2,
--NO.sub.2, alkyl having up to 8 carbon atoms, an alkoxy having up
to 8 carbon atoms or by one or more halogens;
[0020] Y is selected from the group consisting of COR, COOH, COOR,
CONHR, CONHOH, CONHSO.sub.2R, CH.sub.2COOH, CH.sub.2COOR,
CH.sub.2CONHOH, CH.sub.2CONHCN, CH.sub.2tetrazole, CH.sub.2
(protected 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, wherein R is as defined hereinabove;
[0021] Y.sub.1 is selected from the group consisting of SO.sub.2R,
SO.sub.2NHCOR, SO.sub.2NHCOOR, SO.sub.2NHCONHR and SO.sub.3H,
wherein R is as defined hereinabove;
[0022] Y.sub.2 is selected from the group consisting of
PO(OH).sub.2, PO(OR).sub.2, PO(OH)(OR) and PO(OH)(R), wherein R is
as defined hereinabove;
[0023] Y.sub.3 is selected from the group consisting of tetrazole,
tetrazole substituted by R, squarate, NRtetrazole, NRtetrazole
substituted by R, and NRSO.sub.2R, wherein R is as defined
above.
[0024] The invention includes the pharmaceutically acceptable salts
of these compounds, which can be obtained with inorganic or organic
bases or acids.
[0025] The asymmetric carbon atom present in the compounds of
formula (I) can exist in the R, S or R configuration. The invention
therefore also includes the compounds of formula (I) which exist in
the form of pure enantiomers or in the form of a mixture of
enantiomers, in particular, of racemates.
[0026] The term "alkyl having up to 8 carbon atoms" is understood
to include, in particular, methyl, ethyl, propyl, isopropyl, linear
or branched butyl, linear or branched pentyl and linear or branched
hexyl.
[0027] The term "alkenyl having up to 8 carbon atoms" is understood
to include, for example, allyl, butenyl, pentenyl and hexenyl.
[0028] The term "aryl having up to 12 carbon atoms" is understood
to include phenyl and naphthyl.
[0029] The term "aralkyl having up to 12 carbon atoms" is
understood to include benzyl, phenethyl and methylnaphthyl.
[0030] The term "alkoxy having up to 8 carbon atoms" is understood
to include, in particular, methoxy, ethoxy, propoxy, isopropoxy,
butoxy, isobutoxy, sec-butoxy and tert-butoxy.
[0031] The term "halo" or "halogen" is understood to include
fluorine, chlorine, bromine and iodine.
[0032] The term "squarate" is understood to mean the radical of
formula: ##STR3##
[0033] The term "heteroaryl" is understood to include, in
particular, the following: ##STR4## wherein X.dbd.S, O or NR.sub.4
(R.sub.4.dbd.H or alkyl).
[0034] The acid salts of the products of formula (I) include, inter
alia, those formed with inorganic acids, such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric
acid, or with organic acids, such as formic acid, acetic acid,
trifluoroacetic acid, propionic acid, benzoic acid, maleic acid,
fumaric acid, succinic acid, tartaric acid, citric acid, oxalic
acid, glyoxylic acid and aspartic acid, alkanesulfonic acids, such
as methanesulfonic acid and ethanesulfonic acid, and arylsulfonic
acids, such as benzenesulfonic acid and para-toluenesulfonic
acid.
[0035] The base salts of the products of formula (I) include, inter
alia, those formed with inorganic bases, such as, for example,
sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium
hydroxide, magnesium hydroxide and 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 and
N-methylglucamine, or, alternatively, phosphonium salts, such as
alkylphosphoniums, arylphosphoniums, alkylarylphosphoniums and
alkenylarylphosphoniums, or quaternary ammonium salts, such as
tetra(n-butyl)ammonium salt.
[0036] Particularly preferred compounds of formula (I), are those
in which n is equal to 1, those in which R.sub.2 is hydrogen, those
in which R.sub.1 is selected from hydrogen, alkyl radical having up
to 8 carbon atoms and (CH.sub.2).sub.n, R.sup.o.sub.1 in which n'
is 0 or 1 and R.sup.o.sub.1 is aryl, heteroaryl, CONR'R'',
CSNR'R'', COCOOR', SO.sub.2NR'R'', SO.sub.2R' or CO.sub.2R', the
aryl radical having up to 12 carbon atoms, the heteroaryl radical
having up to 15 carbon atoms and one or more heteroatoms selected
from nitrogen, sulfur and oxygen, and R' and R'' are as defined
above, as well as those in which X is a divalent group
--C(O)--N(OR.sub.3)-- in which R.sub.3 is selected from the group
consisting of hydrogen, R, Y and Y.sub.1, R, Y and Y.sub.1 being as
defined above.
[0037] More particularly preferred compounds of formula (I), are
the compounds selected from: [0038]
[[1,5-dihydro-1-(methylsulfonyl)-3-oxo-2,5-methano-2H-1,2,4-benzotriazepi-
n-4(3H)-yl]oxyl]acetic acid, [0039]
[[1-[(benzoylamino)carbonyl]-1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzo-
triazepin-4(3H)-yl]oxyl]acetic acid, [0040]
[[1,5-dihydro-3-oxo-1-[(phenylsulfonyl)aminocarbonyl]-2,5-methano-2H-1,2,-
4-benzotriazepin-4(3H)-yl]oxy]acetic acid, [0041]
[[1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzotriazepin-4(3H)-yl)oxy]acet-
ic acid, [0042]
4,5-dihydro-1-methyl-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzotriazepin-3(1H-
)-one, [0043]
4,5-dihydro-4-(2-propenyloxy)-1-(3-pyridinylmethyl)-2,5-methano-2H-1,2,4--
benzotriazepin-3(1H)one, [0044]
4,5-dihydro-3-oxo-N-(phenylsulfonyl)-4-(2-propenyloxy)-2,5-methano-2H-1,2-
,4-benzotriazepine-1(3H)-carboxamide, [0045]
N-benzoyl-4,5-dihydro-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzot-
riazepine-1(3H)-carboxamide, [0046] ethyl
4,5-dihydro-.alpha.,3-dioxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzot-
riazepine-1(3H)-acetate, [0047] ethyl
4,5-dihydro-3-oxo-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzotriazepine-1(3H)--
acetate,
[0048] and their salts as defined above.
[0049] The invention also includes a process for the preparation of
the compounds of formula (I), this process comprising:
[0050] a) a first stage during which a compound of formula (II):
##STR5##
[0051] in which:
[0052] R'.sub.1 is R.sub.1 or a precursor thereof, R.sub.2 and n
are as defined in claim 1 and R'.sub.3 is selected from the group
consisting of a protective group for hydroxyl, Rp, Yp, Y.sub.1p,
Y.sub.2p and Y.sub.3p, which, respectively, correspond to R, Y,
Y.sub.1, Y.sub.2 and Y.sub.3 as defined above, in which the
possible reactive functional groups present are, if appropriate,
protected, is reacted with a carbonylating agent, if appropriate in
the presence of a base, for the purpose of obtaining an
intermediate compound of formula (III): ##STR6## in which: [0053]
R'.sub.1, R.sub.2 and n are as defined above and either (1) X.sub.1
is hydrogen and X.sub.2 represents an --N(OR'.sub.3)--CO--X.sub.3
group, wherein R'.sub.3 is as defined above and X.sub.3 is the
residue of the carbonylating agent, or (2) X.sub.2 is
--NH--OR'.sub.3 and X.sub.1 IS CO--X.sub.3 group, X.sub.3 being as
defined above; and
[0054] b) a second stage during which the intermediate of formula
III obtained above is cyclized, in the presence of a base.
[0055] This process may further comprise, either before stage a) or
after stage b), as appropriate:
[0056] c) one or more of the following reactions, in an appropriate
order:
[0057] protection of the reactive functional groups,
[0058] deprotection of the reactive functional groups,
[0059] esterification,
[0060] saponification,
[0061] sulfonation,
[0062] phosphatation,
[0063] amidation,
[0064] acylation,
[0065] sulfonylation,
[0066] alkylation,
[0067] formation of a urea group,
[0068] introduction of a tetrazole group,
[0069] reduction of carboxylic acids, dehydration of amide to
nitrile,
[0070] salification,
[0071] exchange of ions,
[0072] separation of enantiomers,
[0073] nitration,
[0074] reduction of a nitro to an amino,
[0075] halogenation,
[0076] carbamoylation,
[0077] introduction of a cyano group.
[0078] Suitable carbonylating agents include phosgene, diphosgene,
triphosgene, an aryl chloroformate, such as phenyl chloroformate or
p-nitrophenyl chloroformate, an aralkyl chloroformate, such as
benzyl chloroformate, an alkyl or alkenyl chloroformate, such as
methyl chloroformate or allyl chloroformate, an alkyl dicarbonate,
such as di(tert-butyl)carbonate, carbonyldimidazole and their
mixtures.
[0079] The reaction preferably takes place in the presence of a
base or of a mixture of bases that neutralizes the acid formed. The
base can be, in particular, an amine, such as triethylamine,
diisopropylethylamine, pyridine or dimethylaminopyridine. However,
the reaction can also be carried out using the starting material of
formula II as the base. An excess thereof is then used.
[0080] If appropriate, the product of formula II is employed in the
form of an acid salt, for example a hydrochloride or a
trifluoroacetate.
[0081] The base in stage b) may be selected from amines, alkali
metal hydrides, alkoxides, amides or carbonates or alkaline earth
metal hydrides, alkoxides, amides or carbonates.
[0082] The amines can be selected, for example, from the above
list.
[0083] Sodium hydride or potassium hydride can, in particular, be
used as the hydride.
[0084] Potassium t-butoxide is preferably used as the alkali metal
alkoxide.
[0085] Lithium bis(trimethylsilyl)amide can, in particular, be used
as the alkali metal amide.
[0086] Sodium carbonate, sodium bicarbonate, potassium carbonate or
potassium bicarbonate can, in particular, be used as the
carbonate.
[0087] If appropriate, the intermediate of formula III can be
obtained in the form of an acid salt generated during the
carbonylation reaction and, in particular, in the form of a
hydrochloride. It is subsequently employed in the cyclization
reaction in this form.
[0088] If appropriate, the cyclization can be carried out without
isolation of the intermediate of formula III.
[0089] The reactions mentioned in stage c) are generally
conventional reactions well known to a person skilled in the art.
Illustrations are provided hereinafter in the experimental
part.
[0090] The reactive functional groups that it is advisable, if
appropriate, to protect are the carboxylic acid, amine, amide,
hydroxyl and hydroxylamine functional groups.
[0091] The protection of the acid functional group is carried out,
in particular, by forming alkyl esters, allyl esters or benzyl,
benzhydryl or p-nitrobenzyl esters.
[0092] The deprotection is carried out by saponification, acid
hydrolysis, hydrogenolysis or, alternatively, cleavage using
soluble palladium(0) complexes.
[0093] The protection of the amines, heterocyclic nitrogens and
amides is carried out, in particular, according to the
circumstances, by forming benzyl or trityl derivatives, carbamates,
in particular allyl, benzyl, phenyl or tert-butyl carbamates, or,
alternatively, silyl derivatives, such as
(tert-butyl)dimethylsilyl, trimethylsilyl, triphenylsilyl or
diphenyl(tert-butyl)silyl derivatives, or phenylsulfonylalkyl or
cyanoalkyl derivatives.
[0094] The deprotection is carried out, depending on the nature of
the protective group, by sodium or lithium in liquid ammonia, by
hydrogenolysis or using soluble palladium(0) complexes, 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.
[0095] The protection of the hydroxylamines is carried out, in
particular, by forming benzyl or allyl ethers.
[0096] The cleavage of the ethers is carried out by hydrogenolysis
or by using soluble palladium(0) complexes.
[0097] The protection of the alcohols and phenols is carried out
conventionally by forming ethers, esters or carbonates. The ethers
can be alkyl or alkoxyalkyl ethers, preferably methyl or
methoxyethoxymethyl ethers, aryl or, preferably, aralkyl ethers,
for example, benzyl ethers, or silyl ethers, for example, the silyl
derivatives mentioned above. The esters can be any cleavable ester
known to a person skilled in the art, preferably, the acetate, the
propionate or the benzoate or p-nitrobenzoate. The carbonates can
be, for example, methyl, tert-butyl, allyl, benzyl or p-nitrobenzyl
carbonates.
[0098] The deprotection is carried out by means known to a person
skilled in the art, in particular, by saponification,
hydrogenolysis, cleavage by soluble palladium(0) complexes,
hydrolysis in an acidic medium or, alternatively, for silyl
derivatives, treatment with tetrabutylammonium fluoride.
[0099] The sulfatation 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 operation being carried out in
pyridine, it being possible for the salt formed, for example, the
pyridine salt, subsequently to be exchanged, for example, with a
salt of another amine, of a quaternary ammonium or of an alkali
metal.
[0100] The phosphatation reaction is carried out, for example, by
the action of a chlorophosphate, such as dimethyl, dibenzyl or
diphenyl chlorophosphate.
[0101] The amidation reaction is carried out starting from the
carboxylic acid using an activating agent, such as an alkyl
chloroformate, EDCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride) or BOP
(benzotriazol-1-yloxytripyrrolidinophosphonium
hexafluorophosphate), by the action of ammonia or an appropriate
amine or an acid salt thereof.
[0102] The acylation and sulfonylation reactions are carried out on
the hydroxyureas, the alcohols, the amines or the heterocyclic
nitrogens by the action, according to the circumstances, of an
appropriate carboxylic acid or sulfonic acid halide or anhydride,
if appropriate, in the presence of a base.
[0103] The alkylation reaction is carried out by the action, on the
hydroxylated derivatives, the enolates of esters or of ketones, the
amines or the heterocyclic nitrogens, according to the
circumstances, of an alkyl sulfate or an alkyl or substituted alkyl
halide, preferably, by a free or esterified carboxyl radical.
[0104] The reduction of acids to alcohols can be carried out by the
action of a borane or, via an intermediate mixed anhydride, by the
action of an alkaline borohydride. The mixed anhydride is prepared,
for example, using an alkyl chloroformate. The reduction of
aldehydes to alcohols is preferably carried out by the action of
sodium borohydride.
[0105] The dehydration of amides to nitriles can take place under
the conditions of the carbonylation and cyclization reactions.
[0106] The salification by acids is, if appropriate, carried out by
addition of an acid in the soluble phase to the compound. The
salification by bases can relate to the compounds comprising an
acid functional group and, in particular, the compounds comprising
a carboxyl functional group, those comprising a sulfoxy functional
group or a functional group derived from phosphoric acid, or those
comprising a heterocycle possessing an acidic nature.
[0107] In the case of a carboxyl functional group, the salification
is carried out by addition of an appropriate base, such as those
mentioned above. In the case of a sulfoxy functional group or
functional group derived from phosphoric acid, the pyridinium salt
is obtained directly during the action of the SO.sub.3-pyridine
complex and the other salts are obtained from this pyridinium salt.
In either case, it is alternatively possible to operate by exchange
of ions on a resin.
[0108] The nitration can be carried out by nitric acid or one of
its metal salts in an acidic medium.
[0109] The reduction of a nitro group can be carried out by sodium
dithionite or alternatively by zinc in acetic acid.
[0110] The term "halogenation" is understood to mean the
introduction of a halogen substitutent by the direct halogenation
of the aromatic ring or by transformation of an aromatic hydroxy
group to a halogen. According to the circumstances, the reaction
can, 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 alternatively of iodine in the presence of
C.sub.6H.sub.5I(OCOCF.sub.3).sub.2, or, alternatively, by reaction
of an electrophilic halogenated reagent, such as
N-fluorosulfonylimide, in the presence of a strong base. Such
reagents are known to a person skilled in the art.
[0111] The carbamoylation reaction can be carried out by the use of
a chloroformate and then of an amine or, if appropriate, of
ammonia.
[0112] The introduction of cyano is carried out by nucleophilic
substitution using an alkaline cyanide or cyanogen bromide.
[0113] The separation of the enantiomers can be carried out
according to techniques known to a person skilled in the art, in
particular, by chromatography.
[0114] In addition to the processes described above, compounds of
formula (I) can, of course, be obtained by methods that use, at the
start, a compound of formula (II) in which R'.sub.1, R.sub.2 and
R'.sub.3 have the values which result directly (without conversion)
in those of the compounds which it is desired to prepare. If
appropriate, those of these values which would include reactive
functional groups such as mentioned above are then protected, the
deprotection taking place on conclusion of the cyclization stage b)
or at any other opportune moment in the synthesis. The protection
and deprotection are carried out as described above.
[0115] The invention also provides a process according to the
above, but wherein the compound of formula (II) is obtained by a
process according to which a compound of formula (IV): ##STR7## in
which R'.sub.1, R.sub.2 and n are as defined above and A is
hydrogen or a protective group for the nitrogen, is treated with a
reducing agent, to obtain a compound of formula (V): ##STR8## in
which A, R'.sub.1, R.sub.2 and n are as defined above, and in which
process, if appropriate, the OH group is replaced by a leaving
group, to obtain a compound of formula (VI): ##STR9## in which A,
R'.sub.1, R.sub.2 and n are as defined above mentioned meaning and
B represents a leaving group, which compound of formula VI is then
treated with a compound of formula NH.sub.2--OR'.sub.3, R'.sub.3
being as defined above, and then, if appropriate, with an
appropriate deprotecting agent for the nitrogen atom.
[0116] The invention further provides a process according to the
above, but wherein the compound of formula (II) is obtained by a
process according to which a compound of formula (IV) as defined
above is treated with a compound of formula H.sub.2N--OR'.sub.3, to
obtain a compound of formula (VII): ##STR10## in which A, R'.sub.1,
R.sub.2, n and R'.sub.3 are as defined above, which compound of
formula VII is then reacted with a reducing agent, to obtain a
compound of formula (VIII): ##STR11## in which A, R'.sub.1,
R.sub.2, n and R'.sub.3 are as defined above, which compound of
formula VIII is then treated, if appropriate, with an appropriate
deprotecting agent for the nitrogen atom.
[0117] The protective group for the nitrogen is preferably one of
those which are mentioned above.
[0118] The reducing agent is preferably an alkaline
borohydride.
[0119] The leaving group is preferably a sulfonate, for example, a
mesylate or a tosylate, obtained by the action of the corresponding
sulfonyl chloride in the presence of a base, or a halide, more
particularly, a chloride, a bromide or an iodide, obtained, for
example, by the action of thionyl chloride or of
P(C.sub.6H.sub.5).sub.3/CBr.sub.4 or PBr.sub.3 or, in the case of
an iodide, by the action of an alkaline iodide on a sulfonate.
[0120] The deprotecting agent is preferably one of those mentioned
above.
[0121] The reducing agent which acts on the compound of formula
(VII) is preferably sodium cyanoborohydride or sodium
acetoxyborohydride.
[0122] The compounds of general formula (I) have good antibiotic
activity with regard to gram (+) bacteria, such as staphylococci.
Their effectiveness with regard to gram (-) bacteria, in particular
with regard to enterobacteria, is particularly significant.
[0123] These properties render said products, and their
pharmaceutically acceptable acid and base salts, capable of being
used as medicaments in the treatment of conditions involving
sensitive microorganisms and in particular in that of
staphylococcal infections, such as staphylococcal septicemia,
malignant staphylococcal infections of the face or skin,
pyodermatitis, septic or suppurating wounds, anthrax, abscesses,
erysipelas, primary or post-influenza acute staphylococcal
infections, bronchopneumonia or pulmonary suppurations.
[0124] These products can also be used as medicaments in the
treatment of colibacillosis and associated infections, in proteus,
klebsiella and salmonella infections and in other conditions
brought about by gram (-) bacteria.
[0125] The compounds of general formula (I) furthermore possess
inhibitory properties for .beta.-lactamases and consequently are of
advantage in combating infectious diseases or preventing the
latter, in the form of a combination with various antibiotic
compounds of .beta.-lactam type, in order to strengthen their
effectiveness in combating pathogenic bacteria producing
.beta.-lactamases.
[0126] It is well known that the enzymatic inactivation of
antibiotics of .beta.-lactam type, whether compounds of penicillin
or cephalosporin type, in the treatment of bacterial infections, is
an obstacle for compounds of this type. This inactivation consists
of a process of decomposition of the .beta.-lactams and constitutes
one of the mechanisms by which bacteria can become resistant to
treatments. It is therefore desirable to succeed in countering this
enzymatic process by combining, with the antibacterial agent of
.beta.-lactam type, an agent capable of inhibiting the enzyme. When
a .beta.-lactamase inhibitor is used in combination with an
antibiotic of .beta.-lactam type, it can therefore strengthen its
effectiveness against certain microorganisms.
[0127] Another subject matter of the present invention is therefore
the use of compounds of formula (I) as defined above, and their
salts with pharmaceutically acceptable acids and bases, and in
particular the preferred compounds mentioned above, as medicaments
and, in particular, medicaments intended for the treatment of
bacterial infections in man or animals and medicaments intended to
inhibit the production of .beta.-lactamases by pathogenic
bacteria.
[0128] Accordingly, the present invention provides a method of
treating an infection or infection-causing condition in a mammal
that is due to the presence of bacteria that generate
.beta.-lactamases, which comprises administering to a mammal in
need thereof an amount of a compound of claim 1 that is effective
to inhibit .beta.-lactamase in said mammal.
[0129] The antibiotics of .beta.-lactam type with which the
compounds of formula (I) can be combined can be selected from the
group consisting of penams, penems, carbapenems, cephems,
carbacephems, oxacephems, cephamycins and monobactams.
[0130] The term ".beta.-lactams" is understood to mean, for
example, penicillins, such as amoxicillin, ampicillin, aziocillin,
meziocillin, apalcillin, hetacillin, bacampicillin, carbenicillin,
sulbenicillin, ticarcillin, piperacillin, mecillinam,
pivmecillinam, methicillin, ciclacillin, talampicillin,
aspoxicillin, oxacillin, cloxacillin, dicloxacillin,
flucloxacillin, nafcillin or pivampicillin, cephalosporins, such as
cephalothin, cephaloridine, cefaclor, cefadroxil, cefamandole,
cefazolin, cephalexin, cephradine, ceftizoxime, cefoxitin,
cephacetrile, cefotiam, cefotaxime, cefsulodin, cefoperazone,
ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin, cefonicid,
cefodizime, cefpirome, ceftazidime, ceftriaxone, cefpiramide,
cefbuperazone, cefozopran, cefepime, cefoselis, cefluprenam,
cefuzonam, cefpimizole, cefclidin, cefixime, ceftibuten, cefdinir,
cefpodoxime axetil, cefpodoxime proxetil, cefteram pivoxil,
cefetamet pivoxil, cefcapene pivoxil or cefditorenpivoxil,
cefuroxime, cefuroxime axetil, loracarbacef or latamoxef,
carbapenems, such as imipenem, meropenem, biapenem or panipenem,
and monobactams, such as aztreonam and carumonam, and their
salts.
[0131] The compounds of formula (I) or their pharmaceutically
acceptable salts can be administered at the same time as
antibiotics of .beta.-lactam type are taken, or separately,
preferably after antibiotics of .beta.-lactam type have been taken.
This can be carried out in the form of a mixture of the two active
principles or in the form of a pharmaceutical combination of the
two separate active principles.
[0132] The dosage of the compounds of formula (I) and of their
pharmaceutically acceptable salts can, of course, vary within wide
limits and should naturally be adapted, in each specific case, to
the individual conditions and to the pathogenic agent to be
combated. Generally, for use in the treatment of bacterial
infections, the daily dose can be between 0.250 g and 10 g per day,
orally in man, with the product described in Example 11, or between
0.25 g and 10 g per day, intramuscularly or intravenously. For use
as .beta.-lactamase inhibitor, a daily dose in man which can range
from 0.1 to approximately 10 g may be suitable.
[0133] Furthermore, the ratio of the .beta.-lactamase inhibitor of
formula (I) or of the pharmaceutically acceptable salt of the
latter to the antibiotic of .beta.-lactam type can also vary within
wide limits and should be adapted, in each specific case, to the
individual conditions. Generally, a ratio ranging from
approximately 1:20 to approximately 1:1 should be employed.
[0134] The antibiotic medicaments or .beta.-lactamase inhibitor
medicaments as defined above are employed in the form of
pharmaceutical compositions as a mixture with an organic or
inorganic, inert pharmaceutical excipient adapted to the desired
method of administration, and the present invention also includes
pharmaceutical compositions comprising, as active principle, at
least one of the compounds of the invention as defined above.
[0135] These compositions can be administered buccally, rectally,
parenterally, in particular, intramuscularly, or locally by topical
application to the skin and mucous membranes.
[0136] These compositions can be solid or liquid and are provided
in the pharmaceutical forms commonly used in human medicine, such
as, for example, simple or sugar-coated tablets, hard gelatin
capsules, granules, suppositories, injectable preparations,
ointments, creams or gels; they are prepared according to
conventional methods. The active principle or principles can be
incorporated therein with excipients commonly employed in such
pharmaceutical compositions, such as talc, gum arabic, lactose,
starch, magnesium stearate, cocoa butter, aqueous or nonaqueous
vehicles, fatty substances of animal or vegetable origin, paraffin
derivatives, glycols, various wetting, dispersing or emulsifying
agents, and preservatives.
[0137] These compositions can also be provided in the form of a
lyophilisate that is intended to be dissolved at the time of use in
an appropriate vehicle, for example sterile apyrogenic water.
[0138] The products of formula (I) can also be used as disinfecting
agents for surgical instruments.
[0139] The invention also provides, as novel intermediate
compounds: the products of formula (III) as defined above and their
salts with acids and, in particular, their hydrochlorides and
trifluoroacetates,
[0140] the products of formula (II) as defined above and their
salts with acids and, in particular, their hydrochlorides and
trifluoroacetates,
[0141] and the products of formulae (IV), (V), (VI), (VII) and
(VIII) as defined above and their salts with an acid and, in
particular, their hydrochlorides and trifluoroacetates.
[0142] These novel industrial products are intermediates especially
useful for the preparation of the products of formula (I).
[0143] The products of formula (IV) can be prepared, for example,
according to methods provided hereinafter in the experimental
part.
[0144] The following examples illustrate the invention without,
however, limiting the scope thereof.
EXAMPLE 1
4-(2-Propenyloxy)-2,3,4,5-tetrahydro-2,5-methano-1H-1,2,4-benzotriazepin-3-
-one
Stage A: 4-Cinnolinol hydrochloride
[0145] 560 ml of concentrated hydrochloric acid are introduced into
a reactor. 111.6 g of 2-acetylaniline are added at ambient
temperature. 62.8 g of sodium nitrite, in solution in 170 ml of
water, are added to this orange-colored solution at -5.degree. C.
over 1 hour. The temperature is kept below 0.degree. C. throughout
the introduction. The reaction medium is heated at 65.degree. C.
for 3 hours. The mixture is subsequently cooled over 20 minutes and
the product is then filtered off and washed with ether. The
compound is dried over P.sub.2O.sub.5 at 45.degree. C. overnight.
118.6 grams (77%) of the expected product are obtained.
##STR12##
[0146] NMR spectrum: (d.sub.6-DMSO) 1H, 7.43 ppm (bt, J=7.5) 1H,
7.80 ppm (td, J=7.5 and 1.5) Hb and Hc; 1H, 7.68 ppm (bd, J=7.5).
1H, 8.04 ppm (bd, J=7.5) Ha and Hd; 1H, 7.76 ppm (s) He; 1H, 13.8
ppm (s) OH.
[0147] Mass spectrum: 146+M+.
[0148] 36+/38+Characteristic doublet
H.sup.35Cl.sup.+/H.sup.37Cl.sup.+.
[0149] IR spectrum: 1625/1564 cm.sup.-1 aromatic+conjugated
system.
[0150] UV spectrum: 242 nm .epsilon.=8700; 340 nm
.epsilon.=6700.
Stage B: 2,3-Dihydro-4(1H)-cinnolinone hydrochloride
[0151] 69.41 g of the product obtained in stage A are dissolved in
2.5 l of ethanol. 62.79 g of zinc powder are subsequently added,
followed, slowly, by a mixture of 300 ml of ethanol and 150 ml of
acetic acid at ambient temperature. The mixture is heated at reflux
for 30 min. The reaction medium is subsequently separated by
settling, and the zinc residue is washed several times with
ethanol. After being allowed to cool for 20 minutes in an
ice/methanol mixture (-15.degree. C.), a solution of hydrogen
chloride gas in ethyl acetate is then added (350 ml; 4M). The
precipitate formed is filtered off, washed with ether and then with
pentane, and finally dried (under reduced pressure). 42.12 grams
(60%) of the expected product are obtained. ##STR13##
[0152] NMR spectrum: (d.sub.6-DMSO) 2H, 4.04 ppm (s) He; 1H, 7.00
ppm (td, J=8 and 1.5) 1H, 7.55 ppm (td, J=8 and 1.5) Hb and Hc; 1H,
7.06 ppm (bd, J=8) 1H, 7.73 ppm (dd, J=8 and 1.5) Ha and Hd; 1H,
9.77 ppm (s) mobile proton.
[0153] Mass spectrum: 148+M+; 119+M+; 92+M+; 36+/38+ salification
of the product.
[0154] IR spectrum: 1686 cm.sup.-1 v(C.dbd.O); 1606, 1550, 1520
cm.sup.-1 aromatic+conjugated system.
Stage C: 1,1-Dimethylethyl 3,4-dihydro-4-oxo-2(1H)-cinnoline
carboxylate
[0155] 82.16 g of the product obtained in stage B are dissolved in
THF (1.7 l). 106.72 g of di(t-butyl) dicarbonate are subsequently
added, followed, dropwise over 15 min, by 94.4 g of triethylamine.
The mixture is left stirring for 20 hours and is then filtered to
remove the triethylamine salts, which are rinsed with THF. The
solvent is evaporated and the residue is taken up in a
heptane/AcOEt (1:2) mixture and NaH.sub.2PO.sub.4 (1M aqueous
solution). Extraction is carried out with ethyl acetate and washing
is carried out with water. The organic phase is dried over
MgSO.sub.4 and then evaporated to dryness. 65.42 grams (59%) of the
expected product are obtained. ##STR14##
[0156] NMR spectrum: (CDCl.sub.3) 9H, 1.46 ppm (s) Hf; 2H, 4.38 ppm
(s) He; 1H, 6.91 ppm (bd, J=8) Hd or Ha; 1H, 6.96 ppm (td, J=8 and
1.5) Hc; 1H, 7.43 ppm (td, J=8 and 1.5) Hb; 1H, 7.91 ppm (dd, J=8
and 1.5) Ha or Hd; 1H, 7.1 ppm (s) mobile proton.
[0157] Mass spectrum: 248+M+; 233+M+--CH.sub.3; 192+M+-tBu;
148+M+-boc; 119+M+--[--(NH--Nboc)-]; 57+ tBu+;
[0158] IR spectrum: 1712, 1670 cm.sup.-1 v(C.dbd.O); 1610, 1578
cm.sup.-1 v(C.dbd.C) aromatic.
Stage D: 1,1-Dimethylethyl
3,4-dihydro-4-[(2-propenyl-oxy)imino]-2(1-H)-cinnoline
carboxylate
[0159] 30.8 g of the product obtained in stage C are dissolved in
200 ml of pyridine. 14.95 g of alkylhydroxylamine are added with
stirring under argon. After one hour, the pyridine is evaporated.
The residue is taken up in a heptane/AcOEt (1:2) mixture and
NaHSO.sub.4 (10% aqueous solution). Extraction is carried out with
ethyl acetate and washing is carried out with water. The organic
phase is dried over MgSO.sub.4 and evaporated to dryness. 36.08 g
of the expected product (96%) are isolated. ##STR15##
[0160] NMR spectrum: (CDCl.sub.3) 9H, 1.44 ppm (s) Hf; 2H, 4.73 ppm
(s) He; 2H, 4.69 ppm (td, J=5.5 and 1) Hg; 1H, 5.22 ppm (dq, J=10
and 1); Hi1; 1H, 5.32 ppm (dq, J=17.5 and 1) Hi2; 1H, 6.05 ppm (m)
Hh; 1H, 6.91 ppm (td, J=8 and 1.5); 1H, 7.22 ppm (td, J=8 and 1.5)
Hb and Hc; 1H, 6.81 ppm (bd, J=8) 1H, 7.86 ppm (dd, J=8 and 1.5) Ha
and Hd.
[0161] Mass spectrum: 304+MH+;
247+M+--(O--CH.sub.2--CH.dbd.CH.sub.2).
[0162] IR spectrum: 1708 cm.sup.-1 v(C.dbd.O); 1638, 1610, 1589,
1494 cm.sup.-1 aromatic+conjugated system.
Stage E: 1,1-Dimethylethyl
3,4-dihydro-4-[(2-propenyl-oxy)amino]-2(1-H)-cinnoline
carboxylate
[0163] 19 g of the product obtained in stage D are dissolved in 2 l
of methanol and then 63.18 g of sodium cyanoborohydride are added.
107.03 g (95.5 ml) of boron trifluoride etherate are introduced
dropwise at 0.degree. C. After evaporating the methanol, the
residue is treated with NaH.sub.2PO.sub.4 (1M aqueous solution) and
then extraction is carried out with a heptane/AcOEt (1:2) mixture.
Washing is subsequently carried out with water, and the organic
phase is dried with MgSO.sub.4 and evaporated to dryness. The
compound is taken up in an ether/pentane mixture at 0.degree. C.
The compound crystallizes. 13.95 g of the expected product (73%)
are isolated. ##STR16##
[0164] NMR spectrum: (CDCl.sub.3): 9H, 1.49 ppm (s) Hf; 1H, 3.35
ppm (d) He1; 1H, 4.60 ppm (dd) He2; 1H, 4.15 ppm (t) Hj; 1H, 4.30
ppm (m) Hg; 1H, 5.20 ppm (m) Hi1; 1H, 5.30 ppm (m) Hi2; 1H, 5.96
ppm (m) Hb; 1H, 6.75 ppm Hh; 1H, 6.86 ppm Hd; 1H, 7.16 ppm Hc; 1H,
7.28 ppm Ha.
[0165] Mass spectrum: 305+M+; 205+M+--CO.sub.2tBu+H; 57+tBu+.
[0166] IR spectrum: 3344 cm.sup.-1 v(NH); 1708 cm.sup.-1
v(C.dbd.O); 1638, 1610, 1589, 1494 cm.sup.-1
v(C.dbd.C)+aromatic.
[0167] UV spectrum: 244 nm .epsilon.=8500; 290 nm
.epsilon.=2000.
[0168] Microanalysis: TABLE-US-00001 Calculated: Obtained: % C:
62.9% % C: 63% % H: 7.5% % H: 7.6% % N: 13.8% % N: 13.7%
Stage F: 1,2,3,4-Tetrahydro-4-[(2-propenyloxy)amino]cinnoline
dihydrochloride
[0169] 11.28 g of the product obtained in stage E are dissolved in
43 ml of ethyl acetate and then 70 ml of a 5.3M solution of
hydrogen chloride gas in ethyl acetate are added at 0.degree. C.,
with stirring and under argon. After 30 min, the precipitate is
filtered off, washed with ether and then dried. 8.93 g of the
expected compound (100%) are isolated. ##STR17##
[0170] NMR spectrum: (d.sub.6-DMSO): 1H, 3.37 ppm (dd, J=4 and 13)
He.sub.1; 1H, 3.68 ppm (dd, J)=3 and 13) He.sub.2; 2H: 4.23 ppm
(td, J=5.5 and 1) Hg; 1H: 4.28 (dd, J=3 and 4) Hj; 1H, 5.18 ppm
(dq, J=10.5 and 1.5) Hi1; 1H, 5.29 ppm (dq, J=17.5 and 1.5) Hi2;
1H, 5.95 ppm (m) Hh; 1H, 6.83 ppm (dd, J=7.5 and 1), 1H, 7.39 ppm
(dd, J=7.5 and 1) Ha and Hd; 1H, 6.93 (td, J=7.5 and 1); 1H, 7.21
ppm (td, J=7.5 and 1) Hb and Hc; 1H, 7.32 (bs) mobile proton; 1H:
8.96 (bs) mobile proton; 1H, 11.00 (bs) mobile proton; 1H, 11.78
(bs) mobile proton.
[0171] Mass spectrum: 205+M+; 36+/38+H.sup.35Cl+/H.sup.37Cl+.
[0172] IR spectrum: >3000 cm.sup.-1 v(NH); 1642 cm.sup.-1
v(C.dbd.C); 1612, 1590, 1530, 1497 cm.sup.-1
v(C.dbd.C)+aromatic;
[0173] Microanalysis: TABLE-US-00002 Calculated (with two
hydrochlorides): Obtained: % C: 47.5% % C: 47.8% % H: 6.2% % H:
6.1% % N: 15.1% % N: 15.2% % Cl: 25.5% % Cl: 24.7%
Stage G:
4,5-Dihydro-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotr-iazepi-
n-3(1H)-one
[0174] 8.93 g of the product obtained in stage F are dissolved in
3.7 l of acetonitrile. 14.92 g (20.6 ml) of triethylamine are added
dropwise. 3.66 g (2.25 ml) of diphosgene are subsequently
introduced over 5 min at 0.degree. C., followed by 4.96 g of
dimethylaminopyridine. The mixture is subsequently allowed to
return to ambient temperature. After one hour, the acetonitrile is
evaporated and the residue is treated with NaH.sub.2PO.sub.4 (1M
aqueous solution). Extraction is carried out with a heptane/AcOEt
(1:2) mixture and washing is carried out with water. The organic
phase is dried over MgSO.sub.4. It is filtered and evaporated and
the compound is taken up in ether at 0.degree. C. It crystallizes.
3.94 g of the expected compound (46%) are obtained. ##STR18##
[0175] NMR spectrum: (CDCl.sub.3): 1H, 3.29 ppm (d, J=11.5) Hf1,
1H, 3.70 ppm (dd, J=11.5 and 3) Hf2; 1H, 4.38 ppm (d, J=3) He; 2H,
4.42 ppm (bd, J=6) Hg; 1H, 6.02 ppm (m) Hh; 1H, 5.33 ppm (bd,
J=10.5) Hi1; 1H, 5.38 ppm (bd, J=17) Hi2; 1H, 6.63 ppm (dd, J=8 and
1); 1H, 7.10 ppm (dd, J=8 and 1.5) Ha and Hd; 1H, 6.82 ppm (td, J=8
and 1), 1H, 7.21 ppm (td, J=8 and 1.5) Hc and Hb.
[0176] Mass spectrum: 231+M+;
174+M+--(O--CH.sub.2--CH.dbd.CH.sub.2); 131+ opening of the
carbamate ring.
[0177] IR spectrum: 3312 cm.sup.-1 v(NH); 1744 cm.sup.-1
v(C.dbd.O); 1648 v(C.dbd.C); 1608, 1582, 1492 cm.sup.-1
aromatic.
[0178] UV spectrum: 246 nm .epsilon.=7400; 291 nm
.epsilon.=1800.
[0179] Microanalysis: TABLE-US-00003 Calculated: Obtained: % C:
62.3% % C: 62.1% % H: 5.7% % H: 5.5%% N: 18.2% % N: 18.1%
EXAMPLE 2
4-Benzyloxy-2,3,4,5-tetrahydro-2,5-methano-1H-1,2,4-benzotriazepin-3-one
Stage A: 1,1-Dimethylethyl 3,4-dihydro-4-(phenylmethoxy)
imino-2(1H)-cinnoline carboxylate
[0180] 3 g of the compound obtained in stage C of Example 1 are
dissolved in 25 ml of pyridine and then 2.12 g of
benzylhydroxylamine hydrochloride are added with stirring and under
argon. After one hour, the pyridine is evaporated. The residue is
taken up in a heptane/AcOEt 1:2 mixture and NaHSO.sub.4 (10%
solution in H.sub.2O). Extraction is carried out with ethyl acetate
and washing is carried out with water. The organic phase is dried
over MgSO.sub.4. It is filtered, the solvent is evaporated and 4.3
g of the expected compound (100%) are isolated.
Stage B: 1,1-Dimethylethyl
3,4-dihydro-4-[(phenylmethoxy)amino]-2(1-H)-cinnoline
carboxylate
[0181] 4.27 g of the compound obtained in stage A are dissolved in
450 ml of methanol. 12.14 g of sodium cyanoborohydride are
subsequently added, followed, dropwise at 0.degree. C., by 20.57 g
(18.36 ml) of boron trifluoride etherate. After evaporating the
methanol, the residue is treated with NaH.sub.2PO.sub.4 (1M aqueous
solution) and then extraction is carried out with a heptane/AcOEt
1:2 mixture. Washing is subsequently carried out with an acidic
aqueous solution and then the organic phase is dried with
MgSO.sub.4 and the solvent is evaporated. The compound is taken up
in an ether/pentane mixture at 0.degree. C. The compound
crystallizes. 3.81 g of the expected compound (89%) are isolated.
##STR19##
[0182] NMR spectrum: (CDCl.sub.3) 9H, 1.51 ppm (s) Hh; 1H, 3.35 ppm
(bd, J=13.5) He1; 1H, 4.63 ppm (bd, J=13.5) He2; 1H, 4.10 ppm (t,
J=2) Hf; 2H, 4.81 ppm system of AB type Hg; 1H, 6.75 ppm (d, J=8),
1H, 6.83 ppm (td, J=8 and 1.5), 2H, 7.16 ppm (m): Ha, b, c, d; 5H,
7.26 to 7.42 ppm Hi.
[0183] Mass spectrum: 356+MH+; 378+MNa+; 733+[2M+Na]+;
300+MH.sup.+-tBu; 233+MH+--(--NH--O--CH.sub.2-Ph);
177+233+-tBu;
[0184] 133+233+--CO.sub.2tBu; 106+(Ph-CH.sub.2--O)+.
Stage C: 1,2,3,4-Tetrahydro-4-[(phenylmethoxy)amino]-cinnoline
dihydrochloride
[0185] 3.81 g of the compound obtained in stage B are dissolved in
15 ml of ethyl acetate, and then 25 ml of a 4.3M solution of
hydrogen chloride gas in ethyl acetate are added at 0.degree. C.
with stirring and under argon. After 30 min, the reaction medium is
filtered and the filter residue is washed with ether. The compound
is dried and 3.13 g of the expected compound (89%) are
isolated.
Stage D:
4,5-Dihydro-4-(phenylmethoxy)-2,5-methano-2H-1,2,4-benzotriazepin-
-3(1H)-one
[0186] 3.13 g of the compound obtained in stage C are dissolved in
1.9 l of acetonitrile. 4.81 g (6.6 ml) of triethylamine are added
dropwise over 10 minutes. 0.943 g (575 .mu.l) of diphosgene is
subsequently added slowly at 0.degree. C., followed by 1.27 g of
dimethylaminopyridine. The temperature is subsequently allowed to
return to ambient temperature. After one hour, the acetonitrile is
evaporated and the residue is treated with NaH.sub.2PO.sub.4 (1M
aqueous solution). Extraction is carried out with a heptane/AcOEt
1:2 mixture and washing is carried out with water. The organic
phase is dried over MgSO.sub.4 and evaporated to dryness. This
residue is crystallized from ether at 0.degree. C. 1.82 g of the
expected compound (68%) are obtained. ##STR20##
[0187] NMR spectrum: (CDCl.sub.3): 1H, 3.16 ppm (d, J=11) Hf1, 1H,
3.55 ppm (dd, J=11 and 2.5) Hf2; 1H, 3.80 ppm (d, J=2.5) He; 1H,
4.86 ppm, 1H, 4.98 ppm system of AB type Hg; 1H, 6.60 ppm (bd,
J=8), 1H, 6.93 ppm (dd, J=8 and 1.5) Ha and Hd; 1H, 6.80 ppm (td,
J=8 and 1.5), 1H, 7.19 ppm (td, J=8 and 1.5) Hb and Hc; 5H, 7.43
ppm (m) Hh.
[0188] Mass spectrum: 281+M+; 174+M+--(O--CH.sub.2-Ph); 131+opening
of the carbamate ring; 91+PhCH.sub.2.sup.+.
[0189] IR spectrum: 3320 cm.sup.-1 v(NH); 1746 cm.sup.-1v(C.dbd.O);
1607, 1580, 1490 cm.sup.-1 aromatic.
[0190] UV spectrum: 247 nm .epsilon.=7000; 290 nm
.epsilon.=1800.
[0191] Microanalysis: TABLE-US-00004 Calculated: Obtained: % C:
68.3% % C: 67.7% % H: 5.4% % H: 5.4% % N: 14.9% % N: 14.7%
EXAMPLE 3
2-Propenyl
[(3-oxo-2,3,4,5-tetrahydro-2,5-methano-1H-1,2,4-benzotriazepin--
4-yl)oxy]acetate
Stage A: 1,1-Dimethylethyl
4-[(carboxymethoxy)imino]-3,4-dihydro-2(1H)-cinnoline
carboxylate
[0192] 3 g of the compound obtained in stage C of example 1 are
dissolved in 25 ml of pyridine, and then 3.9 g of
carboxymethylhydroxylamine are added with stirring and under argon.
After one hour, the pyridine is evaporated and the residue is taken
up in a heptane/AcOEt (1:2) mixture and NaHSO.sub.4 (10% aqueous
solution). Extraction is carried out once with ethyl acetate, and
washing is carried out with water. The organic phase is
subsequently dried over MgSO.sub.4. It is filtered, the solvent is
evaporated and 3.56 g of the expected compound (92%) are isolated.
##STR21##
[0193] NMR spectrum: (d.sub.6-DMSO): 9H, 1.35 ppm (s) Hf; 2H, 4.63
ppm (s), 2H, 4.67 ppm (s) He and Hg; 1H, 6.81 ppm (td, J=8 and
1.5), 1H, 7.24 ppm (td, J=8 and 1.5) Hb and Hc; 1H, 6.96 ppm (bd,
J=8), 1H, 7.62 ppm (bd, J=8) Ha and Hd; 1H, 8.49 ppm (bs) NH; 1H,
12.82 ppm (s) Hh.
[0194] Mass spectrum: 322+MH+; 344+MNa+; 643+(2M+H)+; 266+MH+-tBu;
146+MH+-boc-(O--CH.sub.2--COOH).
[0195] IR spectrum: 3344 cm.sup.-1 v(NH); 1708 cm.sup.-1
v(C.dbd.O); 1638, 1610, 1589, 1494 cm.sup.-1
v(C.dbd.C)+aromatic.
[0196] UV spectrum: 236 nm .epsilon.=14800; 259 nm .epsilon.=12600;
330 nm .epsilon.=4000.
[0197] Microanalysis: TABLE-US-00005 Calculated: Obtained: % C:
56.1% % C: 55.7% % H: 6% % H: 5.8% % N: 13.1% % N: 13.3%
Stage B: 1,1-Dimethylethyl
3,4-dihydro-4-[[2-oxo-2-(2-propenyloxy)ethoxy]imino]-2(1H)-cinnoline
carboxylate
[0198] 15.5 g of the product obtained as described in stage A are
dissolved in 200 ml of DMF. 12.17 g of sodium bicarbonate and 17.53
g (12.5 ml) of allyl bromide are added to the solution. After 48
hours at ambient temperature with stirring under argon, the
reaction medium is treated with a heptane/AcOEt (1:2) mixture and
NaH.sub.2PO.sub.4 (1M aqueous solution). After extracting with
heptane/AcOEt (1:2) and washing the organic phase with water and
then with a saturated aqueous sodium bicarbonate solution, the
organic phase is dried over MgSO.sub.4 and the solvent is
evaporated. The product is crystallized from pentane. 12.68 g of
the expected product (81%) are isolated. ##STR22##
[0199] NMR spectrum: (CDCl.sub.3) 9H, 1.45 ppm (s) He; 2H, 4.69 ppm
(d) Hh; 1H, 5.93 ppm (m) Hi; 1H, 5.25 ppm (qd) Hj1, 1H, 5.35 ppm
(qd) Hj2; 2H, 4.76 ppm (s) Hg; 2H, 4.80 ppm (s) Hf; 1H, 6.81 ppm
(d) Hd; 1H, 6.89 ppm (td) Ha; 1H, 7.23 ppm (td) Hb; 1H, 7.81 ppm
(dd) Hc.
[0200] Mass spectrum: 362+MH+; 384+MNa+; 328+MNa+-tBu;
369+MNa+-tBu+CH.sub.3CN; Presence of diallyl structure: 424+MNa+;
402+MH+; 346+MH+-tBu.
[0201] IR spectrum: 3475 cm.sup.-1 v(NH); 3365, 3340 cm.sup.-1
v(C.dbd.O); 1757, 1698 cm.sup.-1 v(C.dbd.C); 1645 cm.sup.-1
aromatic; 1622, 1608, 1578 cm.sup.-1.
[0202] UV spectrum: 237 nm .epsilon.=14500; 259 nm .epsilon.=12000;
330 nm .epsilon.=3800.
Stage C: 1,1-Dimethylethyl
3,4-dihydro-4-[[2-oxo-2-(2-propenyloxy)ethoxy]amino]-2(1H)-cinnoline
carboxylate
[0203] 12.68 g of the product obtained in stage B are dissolved in
1.4 l of methanol. 35.3 g of sodium cyanoborohydride are added at
0.degree. C., followed, dropwise, by 59.75 g of boron trifluoride
etherate. After evaporating the methanol, the residue is treated
with NaH.sub.2PO.sub.4 (1M aqueous solution) and then extraction is
carried out with a heptane/AcOEt (1:2) mixture. The organic phase
is washed with water and dried with MgSO.sub.4, and the solvent is
evaporated. The compound is subsequently passed through silica
(eluent: heptane/t-BuOMe (4:1)). 6.16 g of the expected product
(48%) are isolated.
Stage D: 2-Propenyl
[[(1,2,3,4-tetrahydro-4-cinnolinyl)amino]oxy]acetate
dihydrochloride
[0204] The 6.16 g of the product obtained in stage C are dissolved
in 22 ml of ethyl acetate, and then 38 ml of a 4.3M solution of
hydrogen chloride gas in ethyl acetate are added at 0.degree. C.
with stirring and under argon. The mixture is brought back to
ambient temperature. After 30 min, the precipitate is filtered off,
washed with ether and dried under reduced pressure. 5.63 g of the
expected product (99%) are isolated.
Stage E: 2-Propenyl
[(1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzotriazepin-4(3H)-yl)oxy]acet-
ate
[0205] 5.63 g of the product obtained in stage D are dissolved in 2
l of acetonitrile. 8.45 g of triethylamine are slowly added,
followed, at 0.degree. C., by 1.658 g of diphosgene and 2.25 g of
dimethylaminopyridine. The temperature is allowed to return to
ambient temperature. After one hour, the acetonitrile is evaporated
and the residue is treated with NaH.sub.2PO.sub.4 (1M aqueous
solution). Extraction is carried out with AcOEt, and the organic
phase is washed with water. It is dried over MgSO.sub.4 and the
solvent is evaporated. The residue is chromatographed on silica
(eluent: heptane/AcOEt (4:1)). The compound obtained is
crystallized from ether at 0.degree. C. and 1.96 g of the expected
product (41%) are isolated. ##STR23##
[0206] NMR spectrum: (CDCl.sub.3) 1H, 3.32 ppm (d) Hf1; 1H, 3.69
ppm (dd) Hf2; 1H, 4.83 ppm (d) He; 2H, 4.55 ppm (s) Hg; 2H, 4.71
ppm (d) Hh; 1H, 5.96 ppm (m) Hi; 1H, 5.32 ppm (qd) Hj1; 1H, 5.38
ppm (qd) Hj2; 1H, 6.64 ppm (d) Hd; 1H, 7.28 ppm (dd) Ha; 1H, 6.85
ppm (td) Hb; 1H, 7.22 ppm (td) Hc.
[0207] Mass spectrum: 290+MH+; 312+(M+Na).sup.+; 601+(2M+Na)+;
[0208] IR spectrum: 3320 cm.sup.-1 v(NH); 1746 cm.sup.-1
v(C.dbd.O); 1678, 1580, 1490 cm.sup.-1 aromatic.
EXAMPLE 4
2-Propenyl
[[1,5-dihydro-1-(methylsulfonyl)-3-oxo-2,5-methano-2H-1,2,4-ben-
zotriazepin-4(3H)-yl]oxy]acetate
[0209] 100 mg of the product obtained in example 3 are dissolved in
2 ml of anhydrous CH.sub.2Cl.sub.2. 43.53 mg of methanesulfonic
chloride are subsequently added at 0.degree. C., followed by 38.4
mg of triethylamine and then 46.4 mg of dimethylaminopyridine.
After 10 minutes, the solvent is evaporated. The residue is treated
with a heptane/AcOEt (1:2) mixture and NaH.sub.2PO.sub.4 (1M
aqueous solution). After extracting with AcOEt, then washing the
organic phase with water and drying over MgSO.sub.4, the solvent is
evaporated. 114.5 mg of the expected product (90%) are
isolated.
EXAMPLE 5
N-(1-Methylethyl)-2-propanaminium salt of
[[1,5-dihydro-1-(methylsulfonyl)-3-oxo-2,5-methano-2H-1,2,4-benzotriazepi-
n-4(3H)-yl]oxy]acetic acid
[0210] 112 mg of the product obtained in example 4 are dissolved in
0.8 ml of THF. 35.3 mg of tetrakis (triphenylphosphine)palladium
and then 154.2 mg of diisopropylamine are added to the solution.
The reaction mixture is left at 0.degree. C. with stirring and
under argon for 20 minutes. 0.1 ml of ether is added and then the
solid is filtered off and washed with 1 ml of a THF/ether (4:1)
mixture. 99.5 mg of the expected product (76%) are isolated.
##STR24##
[0211] NMR spectrum: (d.sub.6-DMSO) 12H, 1.19 ppm (d, J=6.5) Hh;
2H, 3.27 ppm (sept, J=6.5) Hi; 1H, 3.44 ppm (d, J=9) Hf1; 1H, 3.65
ppm (dd, J=2.5) Hf2; 1H, 5.22 ppm (d, J=2.5) He; 3H, 3.39 ppm (s)
Hk; 1H, 7.45 ppm (dd, J=8 and 1.5) Ha; 1H, 7.10 ppm (td, J=8 and
1.5) Hb; 1H, 7.35 ppm (td, J=8 and 1.5) Hc; 1H, 7.61 ppm (dd, J=8
and 1.5) Hd.
[0212] Mass spectrum: 102+M+; 279+Ph.sub.3P.dbd.O+; 326-M-.
[0213] UV spectrum: 278 nm .epsilon.=1400; 322 nm .epsilon.=1200;
inflection at 260, 275, 286 nm.
EXAMPLE 6
2-Propenyl
[[1-[(benzoylamino)carbonyl]-1,5-dihydro-3-oxo-2,5-methano-2H-1-
,2,4-benzotriazepin-4(3H)-yl]oxy]acetate
[0214] 100 mg of the product obtained in example 3 are dissolved in
5 ml of toluene. 50.85 mg of benzoyl isocyanate are added at
0.degree. C. The mixture is allowed to return to ambient
temperature. After stirring for one hour under argon, the product
is filtered off and washed with 1 ml of toluene. It is dried, and
80 mg of the expected product (53%) are isolated.
EXAMPLE 7
N-(1-Methylethyl)-2-propanaminium salt of
[[1-[(benzoylamino)carbonyl]-1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzo-
triazepin-4(3H)-yl]oxy]acetic acid
[0215] 80 mg of the product obtained in example 6 are dissolved in
0.8 ml of THF. 21.2 mg of tetrakis(triphenylphosphine)palladium and
then 92.6 mg of diisopropylamine are added to the solution. The
reaction mixture is left at 0.degree. C. with stirring and under
argon for 20 minutes. 0.1 ml of ether is added and then the product
is filtered off. The solid is washed with 1 ml of a THF/ether (4:1)
mixture. 50.9 mg of the expected product (56%) are isolated.
##STR25##
[0216] NMR spectrum: (d.sub.6-DMSO): 12H, 1.18 ppm (d, J=6.5) Hh;
2H, 3.26 ppm (sept, J=6.5) Hi; 1H, 3.55 ppm (d, J=11.5) Hf1; 1H,
3.78 ppm (dd, J=11.5 and 2.5) Hf2; 1H, 5.30 ppm (d, J=2.5) He; 2H,
4.07 ppm system of AB type Hg; 9H, 7.12-8.35 ppm (m); Ha, Hb, Hc,
Hd, Hj; <1H, 8.84 ppm (bs) mobile H.
[0217] Mass spectrum: 397+MH+; 395-(M-H)-.
[0218] IR spectrum: Absorptions region v(NH); 1776, 1758 cm.sup.-1
v(C.dbd.O); 1678, 1630 cm.sup.-1 v(C.dbd.O)+v(COO); 1586, 1501
cm.sup.-1 amide II+aromatics.
[0219] Microanalysis: TABLE-US-00006 Calculated: Obtained: % C:
60.3% % C: 60% % H: 6.3% % H: 6.5% % N: 14.08% % N: 12.9%
EXAMPLE 8
2-Propenyl
[[1,5-Dihydro-3-oxo-1-[[(phenylsulfonyl)amino]carbonyl]-2,5-met-
hano-2H-1,2,4-benzotriazepin-4(3H)-yl]oxy]acetate
[0220] 100 mg of the product obtained in example 3 are dissolved in
1 ml of toluene. 63.3 mg of benzenesulfonyl isocyanate are added at
0.degree. C. and the reaction mixture is left stirring under argon
at ambient temperature for 45 min. The resulting compound is
purified by preparative thin layer chromatography operations
(eluent: heptane/AcOEt (2:1)) and 150 mg of the expected product
(92%) are isolated.
EXAMPLE 9
Bis[N-(1-methylethyl)-2-propanaminium] salt of
[[1,5-dihydro-3-oxo-1-[[(phenylsulfonyl)amino]carbonyl]-2,5-methano-2H-1,-
2,4-benzotriazepin-4(3H)-yl]-oxy]acetic acid
[0221] 148 mg of the product obtained in example 8 are dissolved in
1.5 ml of THF 36 mg of tetrakis(triphenylphosphine)palladium and
then 158.4 mg of diisopropylamine are added to the solution. The
reaction mixture is left stirring under argon at 0.degree. C. for
20 minutes. 0.1 ml of ether is added and then the precipitate is
filtered off. It is washed with 1 ml of a THF/ether (4:1) mixture.
66 mg of the expected product (35%) are isolated. ##STR26##
[0222] NMR spectrum: (d.sub.6-DMSO) 24H, 1.18 ppm (d, J=6.5) Hh;
4H, 3.28 ppm (sept, J=6.5); Hi; 1H, 2.98 ppm (d, J=11.5) Hf1; 1H,
3.44 ppm (dd, J=11.5 and 2.5) Hf2; 1H, 4.94 ppm (d, J=2.5) He; 2H,
4.06 ppm; system of AB type Hg; 1H, 6.84 ppm (td, J=8 and 1.5) Hb;
1H, 7.13 ppm (td, J=8 and 1.5) Hb and Hd; 1H, 7.23 ppm (dd, J=8 and
1.5) Ha, 1H, 8.06 ppm (dd, J=8 and 1.5) Hd; 3H, 7.37 ppm (m) Hj;
2H, 7.78 ppm (m) Hj; <4H, 8.49 ppm (bs) mobile H.
[0223] Mass spectrum: 433+MH+; 431+MH.sup.+.
[0224] IR spectrum: Absorptions region v(NH); 1748 c.sup.-1
v(C.dbd.O)+v(COO--); 1500 cm.sup.-1 aromatics.
EXAMPLE 10
Ethyl
4,5-dihydro-.alpha.,3-dioxo-4-[2-oxo-2-(2-propenyloxy)ethoxy]-2,5-me-
thano-2H-1,2,4-benzotriazepin-1(3H)-acetate
[0225] 100 mg of the product obtained in example 3 are dissolved in
4 ml of anhydrous CH.sub.2Cl.sub.2. 45.4 mg of triethylamine are
subsequently added, followed, at 0.degree. C., by 61.37 mg of ethyl
chloroglyoxylate and then by 54.8 mg of dimethylaminopyridine. The
temperature is allowed to return to ambient temperature. After 15
min, the CH.sub.2Cl.sub.2 is evaporated and the residue is treated
with a heptane:AcOEt 1:1 mixture and NaH.sub.2PO.sub.4 (1M aqueous
solution). After extracting with AcOEt and then washing the organic
phase with water and drying over MgSO.sub.4, the solvent is
evaporated and 124.6 mg of the expected product (93%) are
isolated.
EXAMPLE 11
N-(1-Methylethyl)-2-propanaminium salt of
[(1,5-dihydro-3-oxo-2,5-methano-2H-1,2,4-benzotriazepin-4(3H)-yl)oxy]acet-
ate acid
[0226] 80.7 mg of the product obtained in example 10 are dissolved
in 0.8 ml of THF. 32.2 mg of tetrakis(triphenylphosphine)palladium
and then 141.6 mg of diisopropylamine are added to the solution.
The reaction mixture is left stirring under argon at 0.degree. C.
for 20 minutes. 0.1 ml of ether is added and then the precipitate
is filtered off and washed with 1 ml of a THF/ether (4:1) mixture.
87 mg of the expected product (89%) are isolated. ##STR27##
[0227] NMR spectrum: (d.sub.6-DMSO): 12H, 1.18 ppm (d, J=6.5) Hh;
2H, 3.24 ppm (sept, J=6.5) Hi; 1H, 3.00 ppm (d, J=11) Hf1; 1H, 3.48
ppm (dd, J=11 and 2.5) Hf2; 1H, 4.98 ppm (d, J=2.5) He; 1H, 4.02
ppm (s) Hg; 1H, 6.54 ppm (dd, J=8 and 1) Ha or Hd; 1H, 6.65 ppm
(tt) Hd; 1H, 7.11 ppm (td, J=8 and 1.5) Hb and Hc; 1H, 7.15 ppm
(dd, J=8 and 1) Ha or Hd; 1H, 8.54 mobile H.
[0228] Mass spectrum: 351+MH+.
[0229] IR spectrum: Absorptions region v(NH) v(C.dbd.O); 1750
cm.sup.-1 v(COO--)+aromatics+def. NH--NH.sub.2.sup.+; 1641, 1607,
1572, 1505 cm.sup.-1.
[0230] UV spectrum: 245 nm .epsilon.=7200; 288 nm
.epsilon.=1800.
[0231] Microanalysis: TABLE-US-00007 Calculated: Obtained: % C:
58.3% % C: 58.4% % H: 7.5% % H: 7.5% % N: 16% % N: 15.5% %
H.sub.2O: 0.4%
EXAMPLE 12
Ethyl
4,5-dihydro-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotriaze-
pine-1(3H)-acetate
[0232] 500 mg of the product obtained in example 1 are dissolved in
4 ml of DMF. 397.2 mg of ethyl bromoacetate are subsequently added,
followed, at 0.degree. C., by 114.1 mg of sodium hydride (50% in
oil). After stirring for 20 minutes under argon, the reaction
medium is treated with a heptane/AcOEt (1:2) mixture and
NaH.sub.2PO.sub.4 (1M aqueous solution). After extracting with
AcOEt and then washing the organic phase with water, the organic
phase is dried over MgSO.sub.4 and the solvent is evaporated. The
residue is chromatographed on silica (eluent: heptane/AcOEt 2:1).
418.4 mg of the expected product (61%) are isolated. ##STR28##
[0233] NMR spectrum: (CDCl.sub.3): 3H, 1.27 (t, J=7) CH.sub.3 of
the ethyl; 2H, 4.20 ppm (q, J=7) CH.sub.2 of the ethyl; 1H, 4.40
ppm, 1H, 4.47 ppm system of AB type Hj; 1H, 3.52 ppm (d, J=11.5)
Hf1; 1H, 3.60 ppm (dd, J=11.5 and 3) Hf2; 1H, 4.40 ppm (d, J=3) He;
2H, 4.42 ppm (masked) Hg; 1H, 6.01 ppm (m) Hh; 1H, 5.31 ppm (bd,
J=10.5) Hi1, 1H: 5.35 ppm (dq, J=17 and 1.5) Hi2; 1H, 6.46 ppm (bd,
J=8) Hd or Ha; 1H, 7.11 ppm (dd, J=8 and 1.5) Ha or Hd; 1H, 6.76
ppm (bt, J=8), 1H, 7.22 ppm (td, J=8 and 1.5) Hc and Hb.
[0234] Mass spectrum: 340+MNa+; 318+MH+;
260+M+--(O.dbd.C--NH--O--CH.sub.2--CH.dbd.CH.sub.2); 217+little or
no .dbd.C--NH.
[0235] IR spectrum: 1767 cm.sup.-1 v(C.dbd.O) (complex); 1646
cm.sup.-1 v(C.dbd.C); 1608, 1578 cm.sup.-1 aromatics
[0236] UV spectrum: 250 nm .epsilon.=10000; 295 nm
.epsilon.=2300.
[0237] Microanalysis: TABLE-US-00008 Calculated: Obtained: % C:
62.9% % C: 63% % H: 7.5% % H: 7.6% % N: 13.8% % N: 13.7%
EXAMPLE 13
4,5-Dihydro-1-methyl-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotriazepin-
-3(1H)-one
[0238] 462.5 mg of the product obtained in Example 1 are dissolved
in 5 ml of DMF. 567.6 mg of methyl iodide are subsequently added,
followed, at 0.degree. C., by 96 mg of sodium hydride (50% in oil).
After stirring for 30 minutes under argon, the reaction medium is
treated with a heptane/AcOEt (1:2) mixture and NaH.sub.2PO.sub.4
(1M aqueous solution). After extracting with AcOEt and then washing
the organic phase with water, the organic phase is dried over
MgSO.sub.4 and the solvent is evaporated. The residue is
chromatographed on silica (eluent:heptane:AcOEt 2:1). 392 mg of the
expected product (80%) are isolated. ##STR29##
[0239] NMR spectrum: (CDCl.sub.3): 3H, 3.29 (s) Hj; 1H, 3.23 ppm
(d, J=11.5) Hf1; 1H, 3.59 ppm (dd, J=11.5 and 3) Hf2; 1H, 4.37 ppm
(d, J=3) He; 2H, 4.41 ppm (bd, J=7) Hg; 1H, 6.01 ppm (m) Hh; 1H,
5.31 ppm (bd, J=10.5) Hi1; 1H, 5.35 ppm (dq, J=11.5 and 1.5) Hi2;
1H, 6.64 ppm (dd, J=8 and 1.5), 1H, 7.07 ppm (dd, J=8 and 1.5) Ha
and Hd; 1H, 6.77 ppm (td, J=8 and 1.5), 1H, 7.25 ppm (td, J=8 and
1.5) Hc and Hb.
[0240] Mass spectrum: 245+M+;
188+M+--(O--CH.sub.2--CH.dbd.CH.sub.2); 145+M+--(NCO--O-All).
[0241] IR spectrum: 1764 cm.sup.-1 v(C.dbd.O); 1644 cm.sup.-1
v(C.dbd.C); 1608, 1576 cm.sup.-1 aromatics.
[0242] UV spectrum: 253 nm .epsilon.=8900; 293 nm
.epsilon.=2100.
EXAMPLE 14
4,5-Dihydro-4-(2-propenyloxy)-1-(3-pyridinylmethyl)-2,5-methano-2H-1,2,4-b-
enzotriazepin-3(1H)-one
[0243] 462.5 mg of the product obtained in example 1 are dissolved
in 10 ml of DMF. 426.5 mg of 3-chloromethylpyridine hydrochloride
are subsequently added, followed, at 0.degree. C., by 113.5 mg of
sodium hydride (50% in oil). After stirring for 1 hour under argon,
the reaction medium is treated with a heptane/AcOEt (1:1) mixture
and NaH.sub.2PO.sub.4 (1M aqueous solution). After extracting with
AcOEt and then washing the organic phase with water, the organic
phase is dried over MgSO.sub.4, the solvent is evaporated and the
residue is chromatographed on silica (eluent:heptane:AcOEt 3:1).
180 mg of the expected product (28%) are isolated.
EXAMPLE 15
4,5-Dihydro-3-oxo-N-(phenylsulfonyl)-4-(2-propenyloxy)-2,5-methano-2H-1,2,-
-4-benzotriazepin-1(3H)-carboxamide
[0244] 300 mg of the product obtained in Example 1 are dissolved in
3 ml of toluene. 237.6 mg of benzenesulfonyl isocyanate are added
at 0.degree. C. The temperature is allowed to return to ambient
temperature. After stirring for 15 min under argon, the crystals
are filtered off and washed with toluene. 480 mg of the expected
product (89%) are isolated.
EXAMPLE 16
N-Benzoyl-4,5-dihydro-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotr-
-iazepine-1(3H)-carboxamide
[0245] 400 mg of the product obtained in Example 1 are dissolved in
5 ml of toluene. 279.55 mg of benzoyl isocyanate are added at
0.degree. C. The temperature is allowed to return to ambient
temperature. After stirring for 30 min under argon, the crystals
are filtered off and washed with toluene. 429.4 mg of the expected
product (66%) are isolated.
EXAMPLE 17
Ethyl
4,5-dihydro-.alpha.,3-dioxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-b-
enzotriazepine-(3H)-carboxamide
[0246] 400 mg of the product obtained in Example 1 are dissolved in
4 ml of anhydrous CH.sub.2Cl.sub.2. 192.1 mg (265 .mu.l) of
triethylamine are subsequently added, followed, at 0.degree. C., by
259.8 mg of ethyl chloroglyoxylate and then 232 mg of
dimethylaminopyridine. The temperature is allowed to return to
ambient temperature. After stirring for 15 min under argon, the
CH.sub.2Cl.sub.2 is evaporated. The residue is treated with a
heptane:AcOEt 1:1 mixture and NaH.sub.2PO.sub.4 (1M aqueous
solution). After extracting with AcOEt and then washing the organic
phase with water and drying over MgSO.sub.4, the solvent is
evaporated. 556 mg of the expected product (97%) are isolated.
##STR30##
[0247] NMR spectrum: (CDCl.sub.3): 3H, 1.40 (t, J=7) CH.sub.3 of
the ethyl; 2H, 4.40 ppm (q, J=7) CH.sub.2 of the ethyl; 1H, 3.50
ppm (d, J=12) Hf1; 1H, 3.75 ppm (dd, J=12 and 3) Hf2; 1H, 4.40 ppm
(d, J=3) He; 1H, 4.41 ppm (masked) Hg; 1H, 6.01 ppm (m) Hh; 1H,
5.34 ppm (bd, J=10) Hi1; 1H, 5.37 ppm (dq, J=17.5 and 1.5) Hi2; 1H,
7.16 ppm (td, J=8 and 1), 1H, 7.42 ppm (td, J=8 and 1) Hb and Hc;
1H, 7.23 ppm (dd, J=8 and 1) Ha; 1H, 8.40 ppm (dd, J=8 and 1)
Hd.
[0248] Mass spectrum: 332+MH+; 354+MNa+; 395+MNa++CH.sub.3CN;
685+(2M+Na)+; 259+MH+--(COOEt);
131+MH+--(COCOOEt)-(CO--N--OAll).
[0249] IR spectrum: 1794, 1743, 1699 cm.sup.-1 v(C.dbd.O); 1602,
1582 cm.sup.-1 aromatics;
[0250] UV spectrum: 237 nm .epsilon.=7700; 260 nm .epsilon.=8800;
inflection at 276 nm.
EXAMPLE 18
4,5-Dihydro-N-methyl-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotri-
azepine-1(3H)-sulfonamide
[0251] 400 mg of the product obtained in Example 1 are dissolved in
5 ml of anhydrous CH.sub.2Cl.sub.2. 576 mg of triethylamine are
subsequently added at 0.degree. C., followed by 740 mg of
methylsulfamoyl chloride. The medium is kept stirred for 20 min.
The CH.sub.2Cl.sub.2 is evaporated. The residue is treated with a
heptane/AcOEt (1:1) mixture and NaH.sub.2PO.sub.4 (1M aqueous
solution). After extracting with AcOEt and then washing the organic
phase with water and drying over MgSO.sub.4, the solvent is
evaporated. The reaction is repeated with 1.5 eq. of the two above
reactants. The compound is subsequently chromatographed on silica
(eluent: heptane/AcOEt (2:1)). 226 mg of the expected product (40%)
are isolated. ##STR31##
[0252] Mass spectrum: 325+MH+; 347+MNa+; 388+MNa++CH.sub.3CN;
267+MH+--(--O--CH.sub.2--CH.dbd.CH.sub.2);
232+MH+--(--SO.sub.2--NH--CH.sub.3);
131+MH+--(CO--N--O--CH.sub.2--CH.dbd.CH.sub.2)--(--SO.sub.2--NH--CH.sub.3-
).
[0253] IR spectrum: 3380 cm.sup.-1 v(NH); 1781 cm.sup.-1
v(C.dbd.O); 1646 cm.sup.-1 v(C.dbd.C); 1602 cm.sup.-1 aromatics;
1355, 1175 cm.sup.-1 v(SO.sub.2).
[0254] UV spectrum: inflection at 226, 272, 287 nm.
EXAMPLE 19
4,5-Dihydro-3-oxo-N-phenyl-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotri-
azepine-1(3H)-carbothioamide
[0255] 40 mg of the product obtained in Example 1 are dissolved in
2 ml of DMF. 25.71 mg of phenyl isothiocyanate are subsequently
added at 0.degree. C., followed by 9.129 mg of sodium hydride (50%
in oil). The temperature is allowed to return to ambient
temperature. After 20 minutes, the medium is treated with a
heptane/AcOEt (1:2) mixture and NaH.sub.2PO.sub.4 (1M aqueous
solution). After extracting with AcOEt and then washing the organic
phase with water and drying over MgSO.sub.4, the solvent is
evaporated. The compound is triturated in ether. 41.5 mg of the
expected product (66%) are isolated. ##STR32##
[0256] NMR spectrum: (CDCl.sub.3): 1H, 3.68 (dd, J=13 and 2) Hf1;
1H, 4.86 ppm (dd, J=13 and 2) Hf2; 1H, 4.43 ppm (t, J=2) He; 2H,
4.22 ppm (m) Hg; 1H, 5.91 ppm (m) Hh; 1H: .delta. 5.21 ppm (bd,
J=10) Hi1; 1H, 5.27 ppm (dq, J=17 and 1.5) Hi2; 1H, 5.52 ppm (bs)
mobile H; 1H, 7.31 ppm (td, J=8 and 1), 1H, 7.50 ppm (masked) Hb
and Hc; 1H, 7.41 ppm (dd, J=8 and 1) Ha; 1H, 9.28 ppm (dd, J=8 and
1) Hd; 5H, 7.43 and 7.60 ppm (m) Hj.
[0257] Mass spectrum: 367+MH+;
294+MH+--(--N--O--CH.sub.2--CH.dbd.CH.sub.2);
189+MH+--(O.dbd.C--N--O--CH.sub.2--CH.dbd.CH.sub.2)-(Ph);
175+MH+--(CO--N--O--CH.sub.2--CH.dbd.CH.sub.2)--(--NH-Ph).
[0258] IR spectrum: 3468-3265 cm.sup.-1 v(NH); 1745 cm.sup.-1
v(C.dbd.O); 1646 cm.sup.-1 v(C.dbd.C); 1605, 1596, 1585, 1494
cm.sup.-1 aromatics; 1355, 1175 cm.sup.-1.
[0259] UV spectrum: 240 nm .epsilon.=17400; 311 nm
.epsilon.=15600.
EXAMPLE 20
4,5-Dihydro-1-(methylsulfonyl)-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benz-
otriazepin-3(1H)-one
[0260] 500 mg of the product obtained in Example 1 are dissolved in
5 ml of anhydrous CH.sub.2Cl.sub.2. 545.2 mg of methanesulfonyl
chloride are subsequently added at 0.degree. C., followed by 480.8
mg of triethylamine and then 581 mg of dimethylaminopyridine. After
30 min, the CH.sub.2Cl.sub.2 is evaporated and the residue is
treated with a heptane/AcOEt (1:2) mixture and NaH.sub.2PO.sub.4
(1M aqueous solution). After extracting with AcOEt and then washing
the organic phase with water and drying over MgSO.sub.4, the
solvent is evaporated. 393.8 mg of the expected product (59%) are
isolated. ##STR33##
[0261] NMR spectrum: (CDCl.sub.3): 3H, 3.41 (s) Hj; 1H, 3.63 ppm
(d) Hf1; 1H, 3.71 ppm (dd) Hf2; 1H, 4.38 ppm (d) He; 2H, 4.43 ppm
(d) Hg; 1H, 6.01 ppm (m) Hh; 1H, 5.35 ppm (d) Hi1; 1H, 5.37 ppm
(dq) Hi2; 1H, 7.03 ppm (td) Hb; 1H, 7.34 ppm (td) Hd; 1H, 7.17 ppm
(d) Ha; 1H, 7.75 ppm (d) Hd.
[0262] Mass spectrum: 309+M+;
252+M+--(--O--CH.sub.2--CH.dbd.CH.sub.2); 230+M+--SO.sub.2CH.sub.3;
210+252+--(N.dbd.C.dbd.O);
174++M+--(--O--CH.sub.2--CH.dbd.CH.sub.2)--(SO.sub.2--CH.sub.3);
131 174+--(N.dbd.C.dbd.O); 103+131+--N.sub.2.
[0263] IR spectrum: Little or no .dbd.C--NH; 1790 cm.sup.-1
v(C.dbd.O); 1645 cm.sup.-1 v(C.dbd.C); 1603, 1578 cm.sup.-1
aromatics; probable SO.sub.2.
[0264] Microanalysis: TABLE-US-00009 Calculated: Obtained: % C:
50.5% % C: 62.9% % H: 4.9% % H: 7.5% % N: 13.6% % N: 13.8% % S:
10.4% % S: 10.4%
EXAMPLE 21
4,5-Dihydro-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotriazepine-1-
-(3H)-carboxamide
[0265] 500 mg of the product obtained in Example 1 are dissolved in
35 ml of CH.sub.2Cl.sub.2. 642 mg of triethylamine are subsequently
added, followed, at 0.degree. C., by 982.63 mg of diphosgene and,
finally, 290 mg of dimethylaminopyridine. The temperature is
allowed to return to ambient temperature. After stirring for 20
minutes under argon, a few drops of CH.sub.2Cl.sub.2 saturated with
ammonia are added, the solvent is then evaporated and the residue
is then treated with a heptane/AcOEt (1:2) mixture and
NaH.sub.2PO.sub.4 (1M aqueous solution). After extracting with
AcOEt and then washing the organic phase with water and drying over
MgSO.sub.4, the solvent is evaporated. The product, taken up in
ether, crystallizes. 286 mg of the expected product (48%) are
isolated. ##STR34##
[0266] NMR spectrum: (CDCl.sub.3): 1H, 3.36 ppm (d, J=11.5) Hf1;
1H, 3.73 ppm (dd, J=11.5 and 3) Hf2; 1H, 4.40 ppm (d, J=3) He; 2H,
4.44 ppm (bd, J=6.5) Hg; 1H, 6.02 ppm (m) Hh; 1H, 5.35 ppm (bd,
J=10) Hi1; 1H, 5.37 ppm (dq, J=17 and 1.5) Hi2; 1H, 7.01 ppm (td,
J=8 and 1), 1H, 7.35 ppm (td, J=8 and 1) Hb and Hc; 1H, 7.15 ppm
(dd, J=8 and 1) Ha; 1H, 8.40 ppm (dd, J=8 and 1) Hd; 1H, 6.52 ppm
(st) mobile H; 1H, 4.96 ppm (bs) and 6.96 (bs) mobile NH.sub.2.
[0267] UV spectrum: 241 nm .epsilon.=10000; inflection at 277.3
nm.
[0268] IR spectrum: 3475 cm.sup.-1 v(NH); 1774, 1700 cm.sup.-1
v(C.dbd.O); 1569 cm.sup.-1 aromatics.
[0269] Microanalysis: TABLE-US-00010 Calculated: Obtained: % C:
56.9% % C: 56.6% % H: 5.1% % H: 5.1% % N: 20.4% % N: 20.4%
EXAMPLE 22
4,5-Dihydro-3-oxo-N-(phenylmethyl)-4-(2-propenyloxy)-2,5-methano-2H-1,2,4
benzotriazepine-1(3H)-carboxamide
[0270] 500 mg of the product obtained in Example 1 are dissolved in
220 ml of anhydrous CH.sub.2Cl.sub.2. 428 mg of triethylamine are
subsequently added at 0.degree. C., followed by 436.7 mg of
diphosgene and then 290 mg of dimethylaminopyridine. 20 minutes
later, 254 mg of benzylamine are added. The temperature is allowed
to return to ambient temperature. The CH.sub.2Cl.sub.2 is
evaporated and the residue is treated with a heptane/AcOEt (1:2)
mixture and NaH.sub.2PO.sub.4 (1M aqueous solution). After
extracting with AcOEt and then washing the organic phase with
water, the organic phase is dried over MgSO.sub.4 and the solvent
is evaporated. 132 mg of the expected product (17%) are isolated.
##STR35##
[0271] NMR spectrum: (CDCl.sub.3): 1H, 3.31 ppm (d, J=11.5) Hf1;
1H, 3.68 ppm (dd, J=1.5 and 3) Hf2; 1H, 4.39 ppm (d, J=3) He; 2H,
4.43 ppm (dd, J=6) Hg; 1H, 6.01 ppm (m) Hh; 1H, 5.33 ppm (d, J=10)
Hi1; 1H, 5.36 ppm (dq, J=17 and 1.5) Hi2; 2H, 4.51 ppm (m) Hj; 1H,
7.08 ppm (broad t, J=5.5) mobile NH; 1H, 6.99 ppm (td, J=8.1) Hb;
1H, 7.14 ppm (dd, J=8 and 1) Ha; 6H, 7.27 and 7.40 ppm (m) Hk+Hc;
1H, 8.45 ppm (bd, J=8) Hd.
[0272] Mass spectrum: 365+MH+; 387+MNa+; 428+MNa+--CH.sub.3CN;
751+(2M+Na).sup.+; 322+MH+--(--O--CH.sub.2--CH.dbd.CH.sub.2);
292+MH+--(--N--O--CH.sub.2--CH.dbd.CH.sub.2);
265+MH+--(CO--N--O--CH.sub.2--CH.dbd.CH.sub.2).
[0273] IR spectrum: 3428 cm.sup.-1 v(NH); 1783, 1689 cm.sup.-1
v(C.dbd.O); 1645 cm.sup.-1 v(C.dbd.C); 1605, 1585, 1575, 1505
cm.sup.-1 aromatics.
[0274] UV spectrum: max. 244 nm .epsilon.=12800; infl. 279, 288
nm.
EXAMPLE 23
4,5-Dihydro-1-(phenylmethyl)-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzot-
riazepin-3(1H)-one
[0275] 300 mg of the product obtained in Example 1 are dissolved in
3 ml of DMF. 180.6 mg of benzyl chloride are added at 0.degree. C.,
followed by 68.5 mg of sodium hydride (50% in oil). After stirring
for 5 minutes at 0.degree. C. under argon, a further 3 ml of DMF
are added. After 20 minutes at 0.degree. C., benzyl chloride and
sodium hydride are again added (same amounts). After 10 minutes,
the reaction medium is treated with a heptane/AcOEt (1:2) mixture
and NaH.sub.2PO.sub.4 (1M aqueous solution). After extracting with
AcOEt and then washing the organic phase with water and drying over
MgSO.sub.4, the solvent is evaporated. The product is crystallized
from ether 95.8 mg of the expected product (23%) are isolated.
EXAMPLE 24
1,1-Dimethylethyl
4,5-dihydro-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotriazepine--
1(3H)-acetate
[0276] 1.2 g of the product obtained in Example 1 are dissolved in
15 ml of anhydrous DMF 1.21 g of tert-butyl bromoacetate are
subsequently added at 0.degree. C., followed by 271 mg of sodium
hydride (50% in oil). The mixture is left at 0.degree. C. for 15
minutes. The reaction medium is treated with a heptane/AcOEt (1:2)
mixture and NaH.sub.2PO.sub.4 (1M aqueous solution). After
extracting with AcOEt and then washing the organic phase with water
and drying over MgSO.sub.4, the solvent is evaporated. The residue
is chromatographed on silica (eluent: heptane/AcOEt 1:2) and 1.52 g
of the expected ester (85%) are isolated.
EXAMPLE 25
4,5-Dihydro-3-oxo-4-(2-propenyloxy)-2,5-methano-2H-1,2,4-benzotriazepine-1-
-(3H)-acetic acid
[0277] The ester obtained in Example 24 is dissolved in 2.5
cm.sup.3 of CH.sub.2Cl.sub.2 and 7.5 cm.sup.3 of trifluoroacetic
acid. After 15 min, the solvent is evaporated by entraining it with
toluene, and then the compound is crystallized from ether. 519 mg
of the expected acid (41%) are obtained.
EXAMPLE 26
4,5-Dihydro-3-oxo-4-(2-propenyloxy)-N-propyl-2,5-methano-2H-1,2,4-benzotri-
azepine-1(3H)-acetamide
[0278] 480 mg of the acid obtained in Example 25 are dissolved in 5
ml of DMF. 336.5 mg of 1-hydroxybenzotriazole hydrate and then 350
mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
are added at 0.degree. C. After 20 min at 0.degree. C., 107.9 g of
propylamine are added and then the mixture is left at 0.degree. C.
for 20 min. The reaction medium is treated with a heptane/AcOEt
(1:2) mixture and NaH.sub.2SO.sub.4 (1M aqueous solution). After
extracting with AcOEt and then washing the organic phase with
water, the organic phase is dried over MgSO.sub.4 and the solvent
is evaporated. The residue is chromatographed on silica (eluent:
CH.sub.2Cl.sub.2; 6% acetone). 207 mg of the expected product (38%)
are isolated.
EXAMPLE 27
Sodium Salt of Ethyl
4,5-dihydro-3-oxo-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzotriazepine-1(3H)--
acetate
[0279] 410 mg of the product obtained in Example 12 are dissolved
in 4 ml of CH.sub.2Cl.sub.2. 155.6 mg of acetic acid and then 746
mg of tetrakis(triphenylphosphine)palladium are added to the
solution. After stirring for 30 minutes under argon, the solvent is
evaporated and the residue is chromatographed on silica (eluent:
CH.sub.2Cl.sub.2; acetone/CH.sub.2Cl.sub.2;
acetone/CH.sub.2Cl.sub.2+0.1% NEt.sub.3 (100 ml)). After
evaporating the fractions, 4 cm.sup.3 of pyridine and then 764 mg
of SO.sub.3-pyridine complex are added to the residue, which is
left stirring under argon for 2 hours. The
1-propenyltriphenylphosphonium salt of ethyl
4,5-dihydro-3-oxo-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzo-triazepine-1(3H)-
-acetate, in solution in the reaction medium, is obtained. The
product is subsequently passed through a Dowex 50*8 resin in the
Na.sup.+ form, elution being carried out with H.sub.2O: 10% THF.
The THF is evaporated, the corresponding fractions are lyophilized
and, to end, the product is taken up in acetone to remove
Na.sub.2SO.sub.4 formed. 182 mg of the expected product (37%) are
isolated.
EXAMPLE 28
Sodium salt of
4,5-dihydro-1-methyl-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzotriazepin-3(1H-
)-one
[0280] 392 mg of the product obtained in Example 13 are dissolved
in 4 cm.sup.3 of CH.sub.2Cl.sub.2. 192 mg of acetic acid and then
924.47 mg of tetrakis(triphenylphosphine)palladium are added to the
solution. After stirring for 30 min under argon, 4 cm.sup.3 of
pyridine and then 764 mg of SO.sub.3-pyridine complex are added and
the mixture is left stirring under argon for 2 hours. The solvent
is evaporated. The expected triphenylphosphonium salt is isolated
by chromatography on a silica plate (20% acetone+0.1%
triethylamine). The silica comprising the expected product is
isolated and the latter is extracted with 25 ml of
CH.sub.2Cl.sub.2/15% MeOH. The product is subsequently passed
through a Dowex 50*8 resin in the Na.sup.+ form, elution being
carried out with H.sub.2O: 10% THF. The THF is evaporated, the
corresponding fractions are lyophilized and, to finish, the product
is taken up in acetone to remove Na.sub.2SO.sub.4 formed. 220 mg of
the expected product (45%) are isolated.
[0281] NMR spectrum: (d.sub.6-DMSO): 3H, 3.16 ppm (s) Hg; 1H, 3.19
ppm (d, J=11.5) Hf1; 1H, 3.54 ppm (dd, J=11.5 and 3) Hf2; 1H, 4.73
ppm (d, J=3) He; 1H, 6.74 ppm (bd, J=8), 1H, 7.05 ppm (dd, J=8 and
1) Ha and Hd; 1H, 6.76 ppm (td, J=8 and 1), 1H, 7.24 ppm (td, J=8
and 1) Hc and Hb.
[0282] Mass spectrum: 279+Ph.sub.3P.dbd.O+; 284+MH+;
[0283] IR spectrum: 3475 cm.sup.-1 aromatics.
[0284] UV spectrum (EtOH/HCl): 242 nm .epsilon.=7300; 296 nm
.epsilon.=1700.
EXAMPLE 29
Sodium salt of
4,5-dihydro-1-(3-pyridinylmethyl)-4-(sulfoxy)-2,5-methano-2H-1,2,4-benzot-
riazepin-3(1H)-one
[0285] 170 mg of the product obtained in Example 14 are dissolved
in 2 ml of CH.sub.2Cl.sub.2. 63.3 mg of acetic acid and then 304.7
mg of tetrakis(triphenylphosphine)palladium are added to the
solution. After stirring for 30 min under argon, 2 cm.sup.3 of
pyridine are added directly to the CH.sub.2Cl.sub.2, followed by
246 mg of SO.sub.3-pyridine complex, and the mixture is left
stirring under argon for 2 hours. The solvent is evaporated and the
residue is chromatographed on a silica plate (3% acetone+0.1%
triethylamine). The silica comprising the expected product is
isolated and the latter is extracted with 25 cm.sup.3 of
CH.sub.2Cl.sub.2/15% MeOH. The product is subsequently passed
through Dowex 50 W*8 resin in the Na.sup.+ form, elution being
carried out with H.sub.2O: 10% THF. The THF is evaporated, the
corresponding fractions are lyophilized and, to finish, the product
is taken up in acetone to remove Na.sub.2SO.sub.4 formed. 54 mg of
the expected product (27%) are isolated.
[0286] NMR spectrum: (d.sub.6-DMSO): 1H, 3.15 ppm (d, J=11.5) Hf1;
1H, 3.52 ppm (dd, J=11.5 and 2.5) Hf2; 1H, 4.76 ppm (d, J=2.5) He;
1H, 4.64 ppm (d, J.sub.AB=16) Hg1; 1H, 4.89 ppm (d, J.sub.AB=16)
Hg2; 1H, 6.85 ppm (bd, J=8), 1H, 7.09 ppm (dd, J=8 and 1) Ha and
Hd; 1H, 6.78 ppm (td, J=8 and 1), 1H, 7.23 ppm (td, J=8 and 1) Hb
and Hc; 7.38 and 8.63 ppm (m) Hh.
[0287] Mass spectrum: 363+(M'+2H)+; 385+(M'+H+Na);
747+(2M'+2H+Na).sup.+; 361+M+; 723+(2M'+H); 745+(2M'+Na).
[0288] IR spectrum: Absorption in the region v(NH); 1762 cm.sup.-1
v(C.dbd.O); 1604, 1575 cm.sup.-1 heterocycle+aromatics.
[0289] Pharmacological Study on the Products of the Invention
[0290] I) In Vitro Antibacterial Activity, Method of Dilutions in
Liquid Medium
[0291] A series of tubes is prepared, the same amount of sterile
nutrient medium being distributed in the tubes. Increasing amounts
of the test product are distributed in 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., inhibition of growth
is assessed by transillumination, which makes it possible to
determine the minimum inhibitory concentrations (M.I.C.), expressed
in .mu.g/ml.
[0292] Tests are thus carried out with the products of Examples 11,
14 and 28.
[0293] These compounds have the activities combined in the
following table: TABLE-US-00011 MIC, .mu.g/ml, at 24 hours
Gram-positive S. aureus SG511 80-160 S. pyogenes A561 40-160
Gram-negative E. coli UC1894 20-80 E. coli 1507E 20-160 E. coli DC2
20-80 E. cloacae 1321E 40-80
[0294] The compounds according to the invention thus show an
antibacterial activity.
[0295] II) Inhibitory Activity for .beta.-Lactamases
[0296] 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 can be determined in vitro
with regard to isolated .beta.-lactamases:
[0297] A. Preparation of the .beta.-Lactamases Tem-1 and P99
[0298] The .beta.-lactamases are isolated from bacterial strains
resistant to penicillins and to cephalosporins (Tem1 and P99 are
produced respectively by E. coli 250HT21 and E. cloacae
293HT6).
[0299] The bacteria are cultured in 37 g/l brain-heart broth
(DIFCO) at 37.degree. C. They are harvested in the exponential
phase, cooled and centrifuged. The bacterial pellets are taken up
in 50 mM sodium phosphate buffer, pH 7.0, and are again
centrifuged. The bacteria are taken up in two volumes of the same
buffer and lyzed using a French press maintained at 4.degree. C.
After centrifuging for 1 h at 100 000 g at 4.degree. C., the
supernatants comprising the soluble fraction of the bacterial
extracts are recovered and frozen at -80.degree. C.
[0300] B. Determination of the .beta.-Lactamase Activity
[0301] The method uses nitrocefin (Oxoid), a chromogenic
cephalosporin, the product of hydrolysis by .beta.-lactamases of
which is red and absorbed at 485 nm, as substrate. The
.beta.-lactamase activity is determined kinetically by the
measurement, on a plate spectrophotometer (Spectra Max Plus from
Molecular Devices), of the variation in absorbance at 485 nm
resulting from the hydrolysis of the substrate. The experiments are
carried out at 37.degree. C. The amount of enzyme was standardized
and the measurements are carried out at the initial rate.
[0302] C. Determination of the Inhibitory Activity for
.beta.-Lactamases
[0303] 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
comprises 100 .mu.M nitrocefin and 50 mM sodium phosphate buffer,
pH 7.0.
[0304] D. Calculations of the IC.sub.50 Values
[0305] The rates of hydrolysis are measured with and without
inhibitor. The concentration of inhibitor which inhibits by 50% the
reaction for the hydrolysis of nitrocefin by the enzyme is
determined (IC.sub.50). The processing of the data is carried out
using GraFit software (Erathycus Software). TABLE-US-00012 EXAMPLE
No. IC.sub.50 nM/TEM1 IC.sub.50 nM/P99 5 5.7 .times. 10.sup.-4 M
4.6 .times. 10.sup.-4 M 7 1.1 .times. 10.sup.-4 M 6.3 .times.
10.sup.-5 M 9 1.6 .times. 10.sup.-4 M 1.8 .times. 10.sup.-4 M 11
1.4 .times. 10.sup.-5 M 1.5 .times. 10.sup.-5 M 14 2.6 .times.
10.sup.-5 M 1.7 .times. 10.sup.-5 M 15 4.5 .times. 10.sup.-4 M 1.1
.times. 10.sup.-4 M 27 7.5 .times. 10.sup.-6 M 5.3 .times.
10.sup.-7 M 28 1.2 .times. 10.sup.-5 M 3.7 .times. 10.sup.-5 M
IC.sub.50 after 5 min of preincubation with the enzyme.
[0306] Pharmaceutical Composition Examples:
[0307] 1) A pharmaceutical composition for injection was prepared,
the ingredients of which are as follows: TABLE-US-00013 compound of
example 11 500 mg sterile aqueous excipient q.s. for 10 ml
[0308] 2) A pharmaceutical composition (lyophilisate) for injection
was prepared, including: TABLE-US-00014 on the one hand: compound
of example 9 500 mg on the other hand: cefotaxime 1 g sterile
aqueous excipient q.s. for 5 ml
[0309] The two active principles can, if desired, be introduced
separately in two separate vials or bottles.
* * * * *